Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([S:8][C:9]([Cl:12])([Cl:11])[F:10])[CH:5]=[N:4]1.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:11][C:9]([Cl:12])([F:10])[S:8][C:6]1[CH:5]=[N:4][N:3]([CH2:2][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])[CH:7]=1
Reactant: FC(Cl)(Cl)Sc1cnn(CCl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(SC(F)(Cl)Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
0.21 g of 1-(chloromethyl)-4-[(dichlorofluoromethyl)thio]-1H-pyrazole and 0.14 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 2 ml of N,N-dimethylformamide. 0.12 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure to obtain 0.06 g of [(4-{(dichlorofluoromethyl)thio}-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl)malononitrile (referred as the compound of the present invention (43), hereinafter) shown by below formula.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([C:16]1[C:20]([CH3:21])=[CH:19][NH:18][C:17]=1[CH3:22])=[O:15])[CH3:12].Cl>ClCCl>[CH2:11]([O:13][C:14]([C:16]1[C:20]([CH3:21])=[C:19]([CH:3]=[O:4])[NH:18][C:17]=1[CH3:22])=[O:15])[CH3:12]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(C)c[nH]c1C
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring. Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes. The maximum temperature reached was 18° C. The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring. The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring. The temperature increased to 22° C. The mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40° C. The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition. After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour. The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100% yield) as a yellow solid. 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2×s, 2×3H, 2×CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1].
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]([CH:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](OCC)=[NH:24])=[CH:17][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])[CH3:5].[CH2:28](N)[CH2:29][NH2:30].Cl>O>[CH2:13]([O:12][C:10]([CH:9]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[NH:24][CH2:28][CH2:29][N:30]=2)=[CH:19][CH:20]=1)[C:7]([O:6][CH2:4][CH3:5])=[O:8])=[O:11])[CH3:14]
Reactant: NCCN
Reactant: CCOC(=N)COc1ccc(C(C(=O)OCC)C(=O)OCC)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OCC2=NCCN2)cc1
Yield: 54.8 %

Procedure:
With ice cooling and stirring, 40 ml of ethanol solution containing 3.6 g of ethyl 2-ethoxycarbonyl-2-[4-(2-ethoxy-2-iminoethoxy]phenyl]acetate obtained in the above step b) was added dropwise to a 10 ml ethanol solution containing 0.6 g of ethylenediamine, and the resulting mixture was stirred at room temperature for 1.5 hours, followed by refluxing under heating for 0.5 hours. After cooling, the resulting reaction solution was adjusted to an acidic pH with ethanol containing 13% (w/v) of hydrochloric acid, and then concentrated to dryness. The residue thus obtained was dissolved in water and washed with diethyl ether. Thereafter, the resulting water layer was adjusted to pH 9-10 with dilute sodium hydroxide aqueous solution, and crystals thus precipitated were collected by filtration. In this way, 1.83 g of the title compound was obtained in the form of colorless crystals.
Reaction SMILES: [CH2:1]([N:3]([CH:7]1[CH2:12][CH2:11][S:10](=[O:14])(=[O:13])[C:9]2[S:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:8]1=2)[C:4](=O)[CH3:5])[CH3:2].CSC.B>C1COCC1>[CH2:1]([N:3]([CH:7]1[CH2:12][CH2:11][S:10](=[O:13])(=[O:14])[C:9]2[S:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:8]1=2)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(C(C)=O)C1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCN(CC)C1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reaction time: 1 h
Yield: 65 %

Procedure:
To a suspension of product from Step A (1.8 g, 0.005 mol) in THF (40 ml) heated at reflux under N2 was added dropwise borane dimethylsulfide (10M, 1.5 ml, 0.015 mol) with the continuous removal of dimethylsulfide by way of a short path distillation apparatus. After 1 hour, the mixture was concentrated to dryness and the residue treated carefully with 6N HCl (12 ml). After heating at reflux for 0.5 hour, the mixture was concentrated to dryness. The residue was treated with NaHCO3 and the suspension extracted with ethyl acetate (4x). The organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with 5% CH3OH--CHCl3 saturated with NH3 gas. The product was crystallized as the hydrochloride salt from ethanol to yield 1.1 g of product (56%), m.p. 236°-238° C.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[NH:12][CH:13]=[N:14]2.CO>CC(N(C)C)=O>[CH3:3][NH:4][CH2:5][CH2:6][O:7][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[NH:12][CH:13]=[N:14]2
Reactant: O=c1[nH]cnc2cccc(F)c12
Reactant: CNCCO
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CNCCOc1cccc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 732 mg, 18.3 mmol) was suspended in DMA (50 ml) and N-methylethanolamine (734 μl, 9.15 mmol) was added under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at ambient temperature, and 5-fluoroquinazolin-4(3H)-one (1.0 g, 6.10 mmol) was added. The mixture was heated under an atmosphere of nitrogen at 85° C. for 90 minutes. The mixture was cooled to ambient temperature, and the resulting slurry poured into methanol (100 ml). Dowex resin (50WX4-400, 25 g) was added, and the mixture stirred for 1 hour at ambient temperature. The resin was collected by filtration, and washed with methanol (100 ml). The resin was suspended in a solution of ammonia in methanol (2.3 N, 150 ml), and the mixture stirred for 30 minutes. The mixture was filtered and the residue washed with ammonia in methanol (2.3 N, 100 ml). The combined filtrates were concentrated in vacuo, and dried in vacuo (1 mbar, 60° C.) for 16 hours to give 5-[2-(methylamino)ethoxy]quinazolin-4(3H)-one as an off white solid (1.09 g, 82%); NMR Spectrum (DMSO-d6, 400) 2.36 (s, 3H), 2.85 (t, 2H), 5.11 (t, 2H), 6.97 (d, 1H), 7.14 (d, 1H), 7.61 (dd, 1H), 7.97 (s, 1H); Mass spectrum MH+ 220.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=2[CH:21]=1.[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=3[CH:21]=2)=[CH:28][CH:27]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(NC(C)=O)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-diethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[CH3:21][C:22]([CH3:26])=[CH:23][CH2:24][NH2:25]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:24][CH:23]=[C:22]([CH3:26])[CH3:21])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CC(C)=CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)=CCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To 10 ml of a solution of 438 mg (2.0 mmol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 243 mg (2.0 mmol) of 3-methyl-2-butenylamine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 396 mg (yield: 74.0%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C=Nc1ccccc1
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2ccccc2)[C@@H]1O
Yield: 58 %

Procedure:
A suspension of (trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (prepared according to Evans et al., J. Med. Chem., 1983, 26, p. 1582 and J. Med. Chem., 1986, 29, p. 2194) (1.0 g, 4.6 mmol) in ethanol (4 ml) under argon was treated with phenylisocyanate (0.55 g, 4.6 mmol) and the reaction was heated at reflux temperature for 4 hours. The product precipitate out of the reaction. The reaction was then concentrated in vacuo and the residue was triturated with isopropylether to give the title compound as a colorless solid (0.9 g, 63%), m.p. 240°-241° C.: 1H NMR (CDCl3 /DMSO) δ8.3 (s, 1H), 7.7 (s, 1H), 7.4 (d, J=8.0 Hz, 3H), 7.26 (t, J=8.0 Hz, 2H), 7.0 (t, J=9.0 & 7.0 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 6.4 (d, J=8.0 Hz, 1H), 5.3 (d, J=5.0 Hz, 1H), 4.9 (t, J=9.0 & 8.0 Hz, 1H), 3.6 (dd, J=4.0 & 6.0 Hz, 1H), 1.5 (s, 3H), 1.3 (s, 3H); 13C NMR (CDCl3 /DMSO) 157.0, 156.5, 139.1, 132.2, 132.1, 128.4, 123.9, 121.8, 118.2, 117.8, 80.0, 74.3, 49.9, 26.1, 18.4; IR (KBr) 1132, 1267, 1491, 1550, 1612, 1645, 2226, 2932, 2978, 3433 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20]#[N:21])=[CH:13][CH:14]=2)[C:9]1([CH2:24][CH3:25])[CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].C([OH:29])C.CN(C=O)C>O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:29])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:22][CH3:23])[CH2:24][CH3:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCO
Reactant: CCC1(CC)c2cc(C#N)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a mixture of trans-(7-cyano-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (33.0 g, 92 mmol), ethanol (45 mL), DMF (25 mL) and water (7.5 mL) was added hydrido(dimethylphosphoniousacid-kP) [hydrogen bis(dimethylphosphinito-kP)]platinum(II) (0.25 g, 0.58 mmol) and the reaction mixture was heated at 80° C. for 24 h. The reaction was cooled to room temperature and concentrated to dryness under vacuum to give the title compound (36.3 g) which was used without further purification. (m/z): [M+H]+ calcd for C21H32N2O4 377.24; found 377.8. 1H NMR (d6-DMSO, 400 mHz) δ (ppm): 7.92 (s, 1H), 7.64 (m, 2H), 7.26 (s, 1H), 7.14 (d, J=7.9 Hz, 1H), 6.64 (d, J=9.4 Hz) 3.81 (t, J=10.0 Hz), 3.58 (m, 1H), 3.30 (s, 3H), 2.58 (dd, J=16.9 Hz, 9.4 Hz, 1H), 1.82 (m, 1H), 1.56-1.45 (m, 4H), 1.41 (s, 9H), 0.58 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>>[F:17][C:15]1[CH:14]=[CH:13][C:12]2[N:11]([N:10]=[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:32])[CH2:26][C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=[CH:22][CH:23]=3)[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[C:34]([F:33])[CH:35]=3)[N:7]=2)[CH:16]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Cl)n2)c1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3cc(F)ccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1

Procedure:
The title compound was synthesized from N-{3-[3-(2-chloro-4-pyrimidinyl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (0.070 g) and 3-fluoroaniline (0.033 g) using the procedure described in Example 30, step E. The title compound was isolated as a white solid (0.048 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 2H), 6.54 (d, 1H, J=5.52 Hz), 6.70 (m, 1H), 6.94 (m, 2H), 7.24 (m, 2H), 7.34-7.45 (m, 3H), 7.60 (m, 1H), 7.68-7.77 (m, 2H), 7.87 (s, 1H), 8.29 (d, 1H, J=5.52 Hz), 8.51 (m, 1H), 9.16 (m, 1H), 9.81 (s, 1H), 10.32 (s, 1H). ES-LC/MS m/z=539 [M+H]+.
Reaction SMILES: [OH-].[K+].[I-].[K+].[OH:5][C:6]1[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[CH:9]=[CH:8][C:7]=1[CH3:18].[CH2:19](Br)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.CO>[CH2:19]([O:5][C:6]1[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[CH:9]=[CH:8][C:7]=1[CH3:18])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCC=Cc1ccccc1
Reactant: Cc1cc(=O)n2ccc(C)c(O)c2n1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(=O)n2ccc(C)c(OCC=Cc3ccccc3)c2n1
Reaction time: 1 h

Procedure:
To a solution of 6.6 g of potassium hydroxide (85%) and 0.2 g of potassium iodide in 100 ml of water is added 150 ml of methanol and 19.0 g of 9-hydroxy-2,8-dimethyl-4H-pyrido[ 1,2-a]-pyrimidin-4-one and the whole stirred for about 1 hour. To this is added 20.1 g of cinnamyl bromide dissolved in 20 ml of methanol. The mixture is stirred at room temperature for about 18 hours and then worked up to give 9-[ (cinnamyl)oxy] -2,8-dimethyl-4H-pyrido[ 1,2-a] pyrimidin-4-one.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[NH:14]1[CH2:15][CH2:16][O:17][CH:12]([CH2:11][NH:10][C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN[C@@H]2C[C@H]2c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: c1ccc([C@@H]2C[C@H]2NCC2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroform (5 mL) was added to a 200 mL round-bottomed flask containing 1,1-dimethylethyl 2-({[trans-2-phenylcyclopropyl]amino}methyl)-4-morpholinecarboxylate (330 mg, 0.993 mmol) to give a suspension. HCl/1,4-Dioxane (6.20 mL, 24.82 mmol) was added and the mixture stirred 18 hours at room temperature. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 12 g column). The compound was further purified via reverse phase column chromatography on Gilson ((C18 column: 0.1% Formic acid H2O/CH3CN, 95-5%) affording the title compound as an amber oil LC-MS (ES) m/z=233 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) d 7.22 (t, J=7.58 Hz, 2H), 7.11 (t, J=7.33 Hz, 1H), 7.03 (d, J=8.08 Hz, 2H), 3.63-3.73 (m, 1H), 3.35-3.43 (m, 2H), 2.73-2.81 (m, 1H), 2.52-2.70 (m, 4H), 2.25-2.35 (m, 2H), 2.22 (qd, J=2.40, 4.59 Hz, 1H), 1.76 (ddd, J=2.91, 5.94, 9.09 Hz, 1H), 0.86-1.01 (m, 2H).
Reaction SMILES: [CH3:1][C:2]12[C:13]3[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:12]=3[CH2:11][CH:9]([NH:10]1)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CN([CH:25]=[O:26])C.O>[Cu].CCOCC>[CH3:1][C:2]12[C:13]3[CH:14]=[C:15]([O:26][CH3:25])[CH:16]=[CH:17][C:12]=3[CH2:11][CH:9]([NH:10]1)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC12NC(Cc3ccc(Br)cc31)c1ccccc12
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)C1(C)NC(C2)c2ccccc21

Procedure:
A mixture of 0.00905 mol of 3-bromo-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, 0.181 mol of sodium methoxide, 5.56 g of electrolytic copper dust, and 87 ml of DMF is stirred and heated on a steam bath for 2.5 hours. After cooling, 150 ml of water and 150 ml of ether is added to the mixture, and, after stirring, the mixture is filtered through a pad of celite. The ether phase is separated, washed with water, dried over magnesium sulfate, filtered, and the ether is removed on a rotary evaporator. The residue is dissolved in warm acetonitrile. On standing, the solution deposits crystals. The supernatant, containing the desired product, is decanted from the crystals. Evaporation of the solvent gives 3-methoxy-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]=2[CH:15]=1.Cl.Cl.[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][NH:28][CH3:29].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][N:28]([CH3:29])[C:12](=[O:14])[CH2:11][N:7]1[C:6]2[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][C:8]1=[O:10]
Reactant: CNCc1nc2ccccc2[nH]1
Reactant: O=C(O)Cn1c(=O)sc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(Cc1nc2ccccc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a mixture of (5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetic acid (731 mg), 1-(1H-benzimidazol-2-yl)-N-methylmethanamine dihydrochloride (736 mg), and dichloromethane (20 mL) were added HOBt (448 mg), WSC.HCl (633 mg), and TEA (1.05 mL), followed by stirring at room temperature overnight. The resulting solid was collected by filtration and then washed with chloroform to obtain N-(1H-benzimidazol-2-ylmethyl)-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (925 mg).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:33][CH2:34][O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O.C(OCC)(=O)C>CN(C=O)C>[C:36]([O:35][CH2:34][CH2:33][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CC(C)(C)OCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 2-tert-butoxyethyl methanesulfonate (0.218 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL) and brine (1× 30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 384.2 (M+H)+, HRMS calcd for C22H30N3O3 384.2287 (M+H)+, found 384.2276, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=10.5 min, 97.7% purity.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[O:27]1[CH2:29][CH:28]1[CH2:30][OH:31]>CCO.C(N(CC)CC)C>[OH:27][CH:28]([CH2:30][OH:31])[CH2:29][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCCCc1ccc(O)c2ccccc12)OCc1ccccc1
Reactant: OCC1CO1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCCCCc1ccc(OCC(O)CO)c2ccccc12)OCc1ccccc1
Yield: 84.4 %

Procedure:
A solution of benzyl 4-(4-hydroxynaphthalen-1-yl)butylcarbamate (20, 287 mg, 0.82 mmole), oxiran-2-ylmethanol (21, 0.07 mL, 1.00 mmole) and triethylamine (0.01 mL, 0.05 mmole) in absolute EtOH (9.28 mL) was subjected to microwave irradiation at 130° C. for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silical gel, 95:5 CH2Cl2/MeOH) to afford butylcarbamate 22 (293 mg, 83%) as a light yellow thick oil: 1H NMR (300 MHz, CDCl3) δ 8.24 (d, J=7.7 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.52-7.45 (m, 2H), 7.37 7.28 (m, 5H), 7.18 (d, J=7.7 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.09 (br s, 2H), 4.71 (br s, 1H), 4.29-4.20 (m, 3H), 3.98-3.81 (m, 2H), 3.23 (q, J=6.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.65 (d, J=4.5 Hz, 1H), 2.06 (t, J=5.8 Hz, 1H), 1.83-1.53 (m, 4H).
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9]([C:11]1[CH:12]=[C:13]([CH:17]([CH3:21])[C:18]([OH:20])=O)[CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C(OCC)C.Cl>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:18](=[O:20])[CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]([C:2]2[S:1][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[CH:3]=2)=[O:10])[CH:12]=1)[CH3:21]
Reactant: CC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Reactant: CN(C)CCN
Agent: Cl
Solvent: CCOCC
Product: CC(C(=O)NCCN(C)C)c1cccc(C(=O)c2cc3ccsc3s2)c1
Reaction time: 20 h
Yield: 37.3 %

Procedure:
N,N'-Carbonyldiimidazole (3.8 g) is added to 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (7.25 g) [prepared as described in a previous Example] in solution in diethyl ether (70 cc). When the evolution of gas has ceased, 2-dimethylaminoethylamine (2.1 g) in solution in diethyl ether (25 cc) is then added. After 20 hours at 25° C., the reaction mixture is evaporated. The residue, dissolved in methylene chloride (100 cc), is washed four times with a 5% (w/v) aqueous sodium chloride solution (total 400 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. The oil obtained (5.4 g) is dissolved in N aqueous hydrochloric acid solution (50 cc). This solution is washed three times with diethyl ether (total 150 cc) and then rendered alkaline to pH 11 by the addition of 1N aqueous sodium hydroxide solution (55 cc). The resulting precipitate is extracted three times with methylene chloride (total 150 cc). The combined methylene chloride solutions are washed three times with distilled water (total 150 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. N-(2-Dimethylaminoethyl) 2-{3-(thieno-[2,3-b]thien-2-yl)carbonyl-phenyl}propionamide (3.3 g), in the form of an oil, is thus obtained.