Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:22])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (9.3 mg, 36 μmol) in 10 mL of dichloromethane was cooled to −5° C. and a solution of phenyl chloroformate (7 mg, 45 μmol) in 1.5 mL of dichloromethane was added, with argon bubbling to facilitate mixing. The mixture was then allowed to warm to room temp while being vortexed for 10 min. Aminomethylpolystyrene (ca. 80 mg, 1 meq/g, 100-200 mesh, Bachem) was added to quench excess chloroformate, and the mixture was refluxed and vortexed for several hours. The mixture was chromatographed through a short plug of silica gel with 10:1 dichloromethane-methanol as eluant to isolate the product as a solid.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cnc3ccccc32)nc1
Reaction time: 9 h
Yield: 65.2 %

Procedure:
To a mixture of ethyl 6-chloronicotinate (2.43 g), 1H-benzimidazole (1.7 g) and potassium carbonate (5.43 g) was added N,N-dimethylformamide (20 mL), and the mixture was stirred at 50° C.-60° C. for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (2.28 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][C:27]([CH3:30])([CH3:29])[O:26][C:25](=[O:31])[C:24]=2[CH:32]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:28][C:27]([CH3:29])([CH3:30])[O:26][C:25](=[O:31])[C:24]=4[CH:32]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Reactant: COc1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: COc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Yield: 53.8 %

Procedure:
The title compound was prepared following procedure described in Example 1, step c) from 4-[(4-methoxyphenyl)ethynyl]benzaldehyde (1.31 g; 5.53 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) and 6-amino-2,2-dimethyl-benzo[1,3]dioxin-4-one (1.07 g; 5.53 mmol). The crude (1.7 g) was purified by recrystallisation from MeOH/EtOAc to give 1.23 g (54%) of the title compound as a yellow powder. HPLC, Rt: 4.77 min (purity: 77%). 1H NMR (CDCl3) δ: 7.46 (m, 4H), 7.31 (d, J=7.9 Hz, 2H), 7.15 (d, J=2.6 Hz, 1H), 6.85 (d, J=8.5 Hz, 2H), 6.78 (m, 2H), 4.30 (s, 2H), 3.81 (s, 3H), 1.68 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([NH:19][NH2:20])=O.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][C:5]2[N:4]([C:17]([C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=3[F:14])=[N:19][N:20]=2)[N:3]=1
Reactant: Clc1cc(-c2cccs2)c(Cl)nn1
Reactant: NNC(=O)c1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C)cc1
Product: Fc1ccccc1-c1nnc2cc(-c3cccs3)c(Cl)nn12
Yield: 26 %

Procedure:
A mixture of 3,6-dichloro-4-(thien-2-yl)pyridazine from above (0.5 g, 2.1 mmol), 2-fluorobenzhydrazide (0.66 g, 4.3 mmol) and triethylamine hydrochloride (0.59 g, 4.3 mmol) in p-xylene (10 ml) was stirred and heated at reflux under nitrogen for 30 hours. Upon cooling the volatiles were removed in vacuo. The residue was partly purified by chromatography on silica gel eluting with 50%→66%→100% ethyl acetate-hexane to give the title compound as a yellow solid (0.19 g, 26%). MS (ES+) m/e 33 1 [MH]+, 333 [MH]+. This material was used without further purification.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9][C:8]=2[CH:19]=1)=[O:3].[NH3:20]>O1CCCC1>[O:14]=[C:13]1[CH2:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[S:9][C:8]2[CH:19]=[C:4]([C:2]([NH2:20])=[O:3])[CH:5]=[CH:6][C:7]1=2
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1CC2=O
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1CC2=O

Procedure:
Dissolve the acid chloride from Step 1 in 20 ml. of dry tetrahydrofuran and add this solution dropwise with stirring to a cooled (ice-bath) saturated solution of ammonia in 60 ml. of tetrahydrofuran. Pass ammonia through the reaction for 15 minutes. Stir at room temperature for an additional 15 minutes and evaporate the reaction mixture to dryness. Add a mixture of 12 ml. of ethanol and 60 ml. of water to the residue and stir at room temperature for an additional 30 minutes. Separate the solid by filtration and wash with water, then with ethanol and then with ether. Dry in vacuo to obtain the title product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CCO>[N+:13]([C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:6]=[CH:7][C:2]=1[NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)([O-:15])=[O:14]
Reactant: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Solvent: CCO
Product: COC(=O)Nc1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28 g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75° C. for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1/hexanes:EtOAc as eluent. Yield: 2.53 g (88%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.42 (ddd, J=25.24, 12.06, 4.49 Hz, 2H), 1.73 (d, J=1.76 Hz, 1H), 1.76 (d, J=1.95 Hz, 1H), 1.88-2.01 (m, 1H), 3.22 (dd, J=6.74, 5.57 Hz, 2H), 3.42 (td, J=11.86, 2.05 Hz, 2H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1H), 4.04 (d, J=3.51 Hz, 1H), 6.48 (br.s, 1H), 6.85 (d, J=9.37 Hz, 1H), 7.65 (br.s, 1H), 8.03-8.09 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][CH2:11][CH3:12])=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN1CCOCC1>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH:10][CH2:11][CH3:12])=[C:4]([NH:9][C:28](=[O:29])[CH2:27][C:25]#[N:26])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: CCNc1c(Br)cnc(Cl)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCNc1c(Br)cnc(Cl)c1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 5-bromo-2-chloro-N4-ethyl-pyridine-3,4-diamine (II, 550 g, 2.21 mol) in CH2Cl2 (5.5 L) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (634.5 g, 3.31 mol), cyanoacetic acid (282 g, 3.31 mol) and N-methylmorpholine (897 g, 8.84 mol). A significant exotherm (˜20° C.) was observed upon the addition of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and cyanoacetic acid. After stirring at ambient temperature for 2 h, the solvent was removed under reduced pressure. The resulting reside was extracted with warm EtOAc (40° C., 20 L) and water (40° C., 8 L). The aqueous layer was washed with addition EtOAc (10 L) and the combined organic extracts were washed with water (10 L). The organic extract was concentrated under reduced pressure to a slurry and filtered. The solid was washed with EtOAc and dried to give 534 g (76% yield) of the desired compound (III) as a white crystalline solid. This was used in the next step without further purification. MS (ES+) m/z 317 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[C:9]1[CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.[C:32]([NH:35][CH2:36][CH2:37][NH2:38])(=[O:34])[CH3:33]>CS(C)=O>[O:25]([CH2:24][C:9]1[NH:8][C:12]2[N:13]=[C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:15]=[C:16]([NH:38][CH2:37][CH2:36][NH:35][C:32](=[O:34])[CH3:33])[C:11]=2[CH:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)n1c(COc2ccccc2)cc2c(Cl)nc(-c3ccccc3)nc21
Reactant: CC(=O)NCCN
Solvent: CS(C)=O
Product: CC(=O)NCCNc1nc(-c2ccccc2)nc2[nH]c(COc3ccccc3)cc12
Temperature: 100 °C
Yield: 90.9 %

Procedure:
A solution containing (8.1) (85 mg, 0.20 mmol), N-acetylethylene-diamine (201 mg, 1.95 mmol) and DMSO (3 mL) was heated to 100° C. After 1 h the temperature was raised to 130° C. After 3 h the reaction was cooled to room temperature and partitioned between EtOAc and water. The water layer was extracted with EtOAc (2×). The combined EtOAc layers are washed with water, dried over MgSO4, filtered and concentrated. Flash chromatography (SiO2; 1/10 EtOH/CHCl3, Rf 0.25) yielded 73 mg (93%) of a white foamy solid, mp. 196-197° C. 1H NMR (200 MHz, DMSO-d6): δ 1.79 (s, 3H), 3.36 (m, 2H), 3.61 (m, 2H), 5.12 (s, 2H), 6.59 (s, 1H), 6.89-7.09 (m, 3H), 7.20-7.50 (m, 5H), 7.57 (brt, 1H), 8.03 (brt, 1H), 8.39 (m, 2H), 11.81 (br s, 1H); MS (ES): 402.6 (MH+). tR (method A)=3.6 min.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.[Al].Cl.[N+](C1C=CC(OC(=O)[NH:53][C:54]2[CH:59]=[CH:58][C:57]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[CH:56][CH:55]=2)=CC=1)([O-])=O>>[N:60]1([C:57]2[CH:56]=[CH:55][C:54]([NH:53][C:6]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)=[O:7])=[CH:59][CH:58]=2)[CH2:61][CH2:62][O:63][CH2:64][CH2:65]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCNS(C)(=O)=O)ccc23)CC1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCCCOc1ccc2c(C3CCN(C(=O)Nc4ccc(N5CCOCC5)cc4)CC3)ncnc2c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 38.5 %

Procedure:
4-[7-(3-methanesulfonylamino-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (7.4 mg, 16 μmol), as prepared in Example 65c, and TFA (100 μL, 1.35 mmol) was capped tightly and stirred at 100° C. (aluminum block) for 5 min. The reaction was then concentrated, and pyridine (100 μL) was added to give a homogeneous solution. (4-Morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (7.5 mg, 20 μmol) was then added in one portion at rt, and the solution was stirred at 80° C. for 10 min, then at rt overnight. The reaction was then concentrated and subjected to silica flash chromatography (4:3→3:5 DCM/acetone) to afford the title compound as an off-white semisolid (3.5 mg, 39%). 1H-NMR (400 MHz, 95:5 v/v CDCl3:CD3OD) δ 9.10 (s, 1H), 8.09 (d, 1H), 7.33-7.25 (m, 4H), 6.89 (m, 2H), 4.27 (m, 4H), 3.87 (m, 4H), 3.70 (m, 1H), 3.38 (t, 2H), 3.17-3.07 (m, 6H), 2.96 (s, 3H), 2.20-2.05 (m, 4H), 2.01-1.92 (m, 2H). LC/MS (ESI): calcd mass 568.2, found 569.1 (MH)+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([F:26])=[CH:21][C:20]=3[Cl:27])=[C:16]([C:28](OCC)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([F:26])=[CH:21][C:20]=3[Cl:27])=[C:16]([C:28]([N:43]3[CH2:44][CH2:45][CH:40]([C:37]4[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=4)[CH2:41][CH2:42]3)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(C)c(F)cc1Cl
Product: Cc1cc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(=O)(=O)NC(C)(C)C)cnn23)c(Cl)cc1F
Yield: 24 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-4-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (2.94 g, 6.07 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (1.18 g, 6.58 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.90 g, 33%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]([CH3:16])[C:14]#[N:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.B.CO.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:13]([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C#N)c1nc(-c2ccc(F)cc2)cs1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(CN)c1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a stirred solution of 2-(4-(4-fluorophenyl)thiazol-2-yl)propanenitrile (140 mg, 0.6 mmol) in THF (3 mL) at room temperature was added borane (1M in THF; 3.01 mL, 3.01 mmol) and the reaction mixture was stirred at room temperature for 1 h and then heated at 40° C. for 1 h. The reaction mixture was then cooled to 0° C. and quenched with MeOH (˜5 eq, ˜0.2 mL), and allowed to warm to room temperature where 2N HCl solution was added until the pH ˜2. The reaction mixture was refluxed at 65° C. for 15 min and then cooled to room temperature and concentrated under reduced pressure. The solid obtained was triturated with ether twice and dichloromethane another two times. The remaining solid was dissolved in water (˜50 mL) and basified to pH ˜11 with NaOH pellets. The aqueous mixture was then extracted with ether and dried over sodium sulfate and concentrated under reduced pressure to give 2-(4-(4-fluorophenyl)thiazol-2-yl)propan-1-amine (75 mg, yield 52%), which was carried through without further purification; MS (ESI) m/z: Calculated for C12H13FN2S: 236.08. found: 237.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:6][CH2:5][C:4]1=[O:19].[O:20]=[C:21]1[NH:30][C:29]2[N:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH:35]=O)[CH:26]=[CH:25][C:24]=2[CH:23]=[CH:22]1>>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH2:18][CH2:17][N:16]([CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:27]3[N:28]=[C:29]4[C:24]([CH:23]=[CH:22][C:21](=[O:20])[NH:30]4)=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)[CH2:6][CH2:5][C:4]1=[O:19]
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: CN1C(=O)CCc2cccc(N3CCNCC3)c21
Agent: Cl
Product: CN1C(=O)CCc2cccc(N3CCN(CCCCOc4ccc5ccc(=O)[nH]c5n4)CC3)c21

Procedure:
In a manner similar to that of other examples above, 1-methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 462.2 (Exact Mass: 461.24).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].CON(C)[C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:20]=1>C1COCC1>[CH3:7][N:6]1[C:2]([C:18]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)=[O:29])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 5.300000190734863 °C
Reaction time: 1 h

Procedure:
To a 3 L 4-neck flask equipped with an overhead stirrer, nitrogen bubbler, and thermocouple was added 5-bromo-1-methyl-1H-imidazole (47.96 g, 297.9 mmol), followed by THF (537 mL). To this room temperature solution was added isopropylmagnesium chloride/lithium chloride complex (246.8 mL, 320.8 mmol, 1.3 M in THF) (addition temperature maintained between 16.6 and 25° C.) to afford a milky suspension and the reaction was stirred for 60 minutes and then cooled to 5.3° C. in an ice bath. To this mixture was added a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (53.66 g, 229.14 mmol, Intermediate 2, step b) in THF (268.3 mL) (addition temperature between 5.3 and 5.6° C.) to afford an orange mixture. After addition, the reaction was warmed to room temperature over 2 hours. After stirring at room temperature for 18 hours, THF (200 mL) was added and the reaction was stirred for 2 hours. The reaction was then cooled to 4° C. with an ice bath and carefully quenched with 2 N aqueous HCl to pH=7, quenching temperature reached 12° C. The mixture was diluted with ethyl acetate (500 mL), phase separated and the organic layer was washed with brine (2×200 mL) and dried over sodium sulfate, filtered and the solvent was removed. Hot ether was added and then filtered to give the title compound as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].Cl[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN(C)C=O>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][O:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH3:3])[CH:5]=1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: ClCc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2nc3ccccc3s2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
23.0 g of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 80.0 g of 3-methyl-4-nitrophenol in 700 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 20 minutes, at the end of which time a solution of 95.9 g of 2-chloromethylbenzothiazole in 50 ml of dimethylformamide was added to the reaction mixture. The temperature of the resulting mixture was elevated to 80° C. and the mixture was then stirred for 2 hours. At the end of this time, the reaction mixture was poured into ice-water and the precipitated crystalline solid was washed with water. The crude crystalline solid thus obtained was recrystallised from toluene to give 98.8 g (yield 63%) of the title compound as a solid having a melting point of 145° to 147° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.[OH-].[K+]>C(O)C.Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)CCc1ccc(OC)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CCC(=O)O)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 3-(3-fluoro-4-methoxyphenyl)propionate (29.1 g, 129 mmol) in ethanol(50 ml)-water(50 ml) was added potassium hydroxide (9.4 g, 167 mmol) and the mixture was stirred at 80° C. for 1 hour. After cooling, the reaction mixture was poured in diluted hydrochloric acid and the resulting crystals were recovered by filtration and washed with diethyl ether to provide the title compound (yield 24.4 g, 96%).
Reaction SMILES: C([O-])([O-])=[O:2].[Na+].[Na+].OO.O.[CH3:10][O:11][CH:12]([O:22][CH3:23])[CH2:13][C:14]1[S:18][C:17]([CH3:19])=[N:16][C:15]=1[C:20]#[N:21]>CC(C)=O>[CH3:23][O:22][CH:12]([O:11][CH3:10])[CH2:13][C:14]1[S:18][C:17]([CH3:19])=[N:16][C:15]=1[C:20]([NH2:21])=[O:2]
Reactant: COC(Cc1sc(C)nc1C#N)OC
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(Cc1sc(C)nc1C(N)=O)OC
Reaction time: 2 h

Procedure:
2M Na2CO3-solution (64 ml, 127 mmol), H2O2 (30%, 43.3 ml, 424 mmol) and 45 ml water were placed and a solution of 5-(2,2-dimethoxy-ethyl)-2-methyl-thiazole-4-carbonitrile (4.5 g, 21 mmol) in 45 ml acetone was added dropwise at room temperature. The white suspension was stirred for 2 hrs. Acetone was evaporated and the aqueous residue was extracted three times with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (4.8 g, 98%) was used without any further purification for the next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][CH2:12][CH2:11][CH2:10]1.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(C)=O.O>[CH3:7][N:8]([CH3:20])[CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CN(C)C1CCCNc2ccccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Yield: 97.1 %

Procedure:
38.8 g of potassium carbonate was added to a solution of 50 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of acetone and 200 ml of water. To the solution was added 40 g of p-nitrobenzoyl chloride with ice-cooling and stirring. The resulting mixture was stirred overnight at room temperature. The reaction mixture was mixed with an appropriate amount of water. The resulting crystals were collected by filtration and dried to obtain 71 g of 5-dimethylamino-1-(4-nitro-benzoyl)-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[C:53]([C:54](O)=[O:55])=[CH:52][O:51][N:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:53]2[C:49]([CH3:48])=[N:50][O:51][CH:52]=2)=[O:55])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1nocc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nocc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 55 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 3-methylisoxazole-4-carboxylic acid as starting materials in 55% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z=573.2.