Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[Br:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][O:15][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])=[CH:5][C:4]=1[Cl:14]
Reactant: BrCCCBr
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
First, 10.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 14.0 g of 1,3-dibromopropane, and 50 ml of N,N-dimethylformamide were placed in a reaction vessel, to which 5.3 g of potassium carbonate was added. After stirring at room temperature for 12 hours, the reaction mixture was filtered. The filtrate was poured into diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed twice with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 6.1 g (yield, 43%) of 1-(3-bromopropyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]#[N:5].C[O:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15]>C1COCC1>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8](=[O:7])[CH2:3][C:4]#[N:5]
Reactant: CC#N
Reactant: COC(=O)c1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccccc1Br
Temperature: 0 °C
Yield: 59 %

Procedure:
To a suspension of NaH (60% dispersion, 1.14 g, 28.4 mmol) in dry THF (50 mL) under N2 was added CH3CN followed by 2-bromo-benzoic acid methyl ester (2 mL, 14.2 mmol). The reaction mixture was refluxed for 1.5 hour, then cooled to 0° C., quenched with water (1 mL), and concentrated in vacuo. The residue was diluted with water and the aqueous layer was extracted with hexane (2×), then acidified to pH 3-4 with 1N aqueous HCl. The milky aqueous layer was extracted with CHCl3 (3×), the combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification on silica gel with 0-35% EtOAc in hexane as eluent provided 1.89 g (59 % yield) of 3-(2-bromo-phenyl)-3-oxo-propionitrile as a yellow oil. 1H-NMR (d6-DMSO) δ: 11.8 (broad m, 1H, tautomers), 7.73 (broad s, 1H), 7.42 (m, 3H), 4.99 (s, 0.3H, tautomer), 4.64 (s, 0.6H, tautomer); HPLC/MS m/z: 223.9, 225.9 [MH]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:8]=3[N:7]=2)[CH2:2]1.Br[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1>N1C=CC=CC=1>[Cl:24][C:23]1[C:18]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]3[NH:10][C:9]4[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:8]=4[N:7]=3)[CH2:2]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#Cc1ccc2[nH]c(C3CCNC3)nc2c1
Reactant: Clc1cccnc1Br
Solvent: c1ccncc1
Product: N#Cc1ccc2[nH]c(C3CCN(c4ncccc4Cl)C3)nc2c1
Temperature: 130 °C
Yield: 13.5 %

Procedure:
The mixture of 2-pyrrolidin-3-yl-1H-benzoimidazole-5-carbonitrile (120 mg, 0.57 mmol), 2-bromo-3-chloro-pyridine (109 mg, 0.57 mmol) in pyridine was heated at 130° C. by microwave for 45 mins. Then it was concentrated to give the crude product and purified by column chromatography and followed by preparative HPLC to afford pure product (25 mg, 18%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[C:9]([F:16])[CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:31][C:32]1[C:40]([NH2:41])=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH2:36])=[O:35]>N1C=CC=CC=1.CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]2[NH:41][C:40]3[CH:39]=[CH:38][CH:37]=[C:33]([C:34]([NH2:36])=[O:35])[C:32]=3[N:31]=2)=[C:9]([F:16])[CH:8]=1
Reactant: O=C(O)c1ccc(C2OCCCO2)cc1F
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4OCCCO4)cc3F)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A solution of EXAMPLE 22B (770 mg, 3.4 mmol) in pyridine (5 mL) and N,N′-dimethylformamide (10 mL) was treated with 1,1′-carbonyldiimidazole (763 mg, 3.4 mmol) at 40° C. for 30 minutes. 2,3-Diaminobenzamide dihydrochloride (826 mg, 5.1 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the residue refluxed overnight in 20 mL of xylene and 2 mL of acetic acid. After cooling and concentration, the residue was purified by flash chromatography on silica gel using ethyl acetate to give the title compound (550 mg, 50%). MS (DCI/NH3) m/z 342 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])([OH:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([N:21]([CH2:26][CH3:27])[C:22](=[O:25])[CH2:23]Cl)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)CC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])([OH:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)CCl
Reactant: CCC(O)(c1cccc(Cl)c1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Product: CCN(CC)C(=O)COc1ccccc1C(O)(CC)c1cccc(Cl)c1

Procedure:
5.3 g. of 1-(3-chlorophenyl)-1-(2-hydroxyphenyl)-propan-1-ol and 3.3 g. of monochloroacetic acid diethyl amide are dissolved in 36 ml. of n-propanol, and the reaction mixture is boiled for 4 hours, with stirring in the presence of 3 g. of anhydrous potassium carbonate. After cooling the solvent is distilled off under reduced pressure. To the residue water is added and it is extracted with ether. The ethereal solution is washed with water, a 5% aqueous sodium hydroxide solution and again with water until neutral. After drying over anhydrous magnesium sulfate, the solvent is distilled off in vacuo. The residue is crystallized from a mixture of n-hexane and ethyl acetate to yield 5.8 g. of the named compound, melting at 93°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:23])[C:17]=1[F:24].[CH2:25]([N:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[C:30](=[O:36])[N:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:28]1=[O:44])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:33]([C:31]2[C:30](=[O:36])[N:29]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28](=[O:44])[N:27]([CH2:25][CH3:26])[CH:32]=2)=[O:34])=[C:18]([F:23])[C:17]=1[F:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3F)c2cc1OC
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2F)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxyquinolin-4-yloxy)-2,3-difluoro-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=270-272° C.; LCMS m/z=593 (M+1); 1H NMR (CDCl3) δ: 11.08 (s, 1H), 8.63 (s, 1H), 5.51 (d, 1H, J=6 Hz), 8.28-8.22 (m, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.25-7.23 (m, 4H), 7.09-7.03 (m, 1H), 6.46 (d, 1H, J=5 Hz), 4.05 (d, 6H), 4.04-3.99 (m, 2H), 1.47 (t, 3H, J=8 Hz).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:40](Br)[CH3:41].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][N:30]5[CH2:35][CH2:34][N:33]([CH2:40][CH3:41])[CH2:32][CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:38][CH3:39])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)NN2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1
Temperature: 40 °C
Yield: 67.1 %

Procedure:
4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperazin-1-yl)benzamide (108 mg, 0.2 mmols), ethyl bromide (33 mg, 0.3 mmols) and N,N-diisopropyl ethylamine (106 μL, 0.3 mmols) were mixed in a screw cap vial (5 mL) in DMF (2 mL) heated at 40° C. for 5-8 hrs, then purified to provide the title compound (76.9 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (t, J=7.1 Hz, 3H) 1.14-1.89 (m, 10H) 2.33 (q, J=6.99 Hz, 2H) 2.48 (m, 4H) 2.93 (t, J=4.55 Hz, 4H) 3.31 (s, 3H) 3.93 (s, 3H) 4.06 (t, J=13.22 Hz, 2H) 4.45 (m, 1H). 7.41 (d, J=8.0 Hz, 1H) 7.43 (s, 1H) 7.90 (s, 1H) 8.20 (s, 1H) 8.26 (d, J=8.08 Hz, 1H) 9.38 (s, 1H) [M+H] calculated for C28H38F2N8O3, 572. found 572.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2)=[CH2:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[O:13]=[C:9]1[C:10]2[C:5](=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C=Cc1ccc2c(=O)[nH]ncc2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(=O)n(CC(=O)OCC)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a stirred solution of 6-vinylphthalazine-1(2H)-one (0.5 g, 2.90 mmol) in DMF (5.0 mL) was added Cs2CO3 (0.94 g, 2.90 mmol) and the reaction was stirred for 10 min Ethyl bromoacetate (0.48 g, 2.90 mmol) was added to the reaction mixture at ambient temperature and the reaction was stirred for 8 h at ambient temperature. The reaction mixture was diluted and extracted with ethyl acetate, and the ethyl acetate layer was washed with water and brine solution (2×). The separated ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 25% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.34 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 8.45 (m, 1H), 8.24 (m, 1H), 8.04 (m, 2H), 7.01 (m, 1H), 6.17 (d, J=2.1 Hz, 1H), 5.56 (d, J=10.8 Hz, 1H), 4.92 (s, 2H), 4.19 (m, 2H), 1.23 (m, 3H). ESIMS m/z 259.10 ([M+H]+); IR (thin film) 1750, 1660 cm−1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CC(N(C)C)=O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(I)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Ic1ccc(N2CCNCC2)nc1
Temperature: 120 °C
Yield: 82 %

Procedure:
To a stirred solution of 2-chloro-5-iodo-pyridine (CAS number 69045-79-0, 10.52 g, 43.9 mmol) and diisopropylethylamine (11.5 mL, 65.9 mmol) in DMA (200 mL) was added piperazine (15.14 g, 0.176 mol). The mixture was then heated to 120° C. for 20 hours. The solid precipitate was then filtered off, and the filtrate evaporated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was then extracted with EtOAc (2×100 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo, to give 1-(5-iodopyridin-2-yl)piperazine as a yellow solid (10.42 g, 36 mmol, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[C:11]#[CH:12]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COc1ccccc1N
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C=CNc1ccccc1OC
Yield: 49.7 %

Procedure:
o-Anisidine (57 ml, 0.5 mol) and ethyl propiolate (51 ml, 0.5 mol) were heated together under reflux in ethanol (200 ml) for 3 hours. The solvent was evaporated to afford ethyl 3-(2-methoxyphenylamino)acrylate as a yellow oil (55 g, 100%).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1)=O.[CH:16]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)C.[BH4-].[Na+]>O>[CH:16]1([NH:23][CH2:1][C:3]2[CH:15]=[CH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6][C:5]=3[CH:4]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: NC1CCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)Cc1cc(CNC3CCCCCC3)ccc1-2
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
2-Formylfluorene (2.27 g, 11.7 mmol) and cycloheptylamine (1.39 g, 12.3 mmol) were heated together at 120° C. for 14 hrs. After cooling, the reaction mixture was distilled under reduced pressure. Then, ethanol (30 ml) and sodium borohydride (0.44 g, 11.7 mmol) were added to the residue and the mixture was stirred for 0.5 hr. The mixture was then diluted with water (100 ml) and extracted with chloroform (80 ml×2 times). The organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to give 3.15 g of a pale yellow solid residue.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1.[CH3:20][NH:21][CH3:22]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:21]([CH3:22])[CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1F
Reactant: CNC
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(F)c(F)c1
Yield: 31.8 %

Procedure:
A solution of 2,4-dichloro-7-(3,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (446 mg, 1.481 mmol) and excess dimethylamine (2.222 mL, 4.44 mmol) in MeOH (6 mL) was stirred at rt for 30 min. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-7-(3,4-difluorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (146 mg, 0.471 mmol, 31.8% yield). LC-MS (M+H)+=310.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+]([O-])=O)[CH:10]=[C:6](C(O)=O)[C:5]=1[OH:16])([O-:3])=[O:2].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:6][C:5]=1[OH:16])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: O=[N+]([O-])c1ccccc1O

Procedure:
This material was prepared from 3,5-dinitrosalicylic acid (1d) (1 g, 4.4 mmol), HOBt (1 g, 7.4 mmol), DIC (1,3-diisopropylcarodiimide, 1 mL, 6.4 mmol), and an amino tantagel resin (1 g, 0.45 mmol) using a procedure similar to polystyrene resin (PS-2a).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:14]=2[CH3:29])[CH:7]=1)[CH3:2].I[CH2:32][CH3:33]>>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:14]=2[CH3:29])[CH:7]=1)[CH2:32][CH3:33])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1
Product: CCOC(=O)C(CC)c1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 108, step 1, using the following starting materials: [3-(6-Chloro-2-methyl-1-pyridin-3-yl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and iodoethane.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:31]=2[N:32]=1.Cl.C(OCC)(=O)C>C(O)=O>[ClH:27].[Cl:37][C:35]1[CH:34]=[CH:33][C:31]2[N:32]=[C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=3)[S:29][C:30]=2[CH:36]=1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1nc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2,6-dichloro-1,3-benzothiazole as starting materials and by an operation similar to that of Example 303-3 was treated with formic acid and 4 mol/L hydrochloric acid-ethyl acetate, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure to give the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCCCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (47 mg, 0111 mmol), 5-aminovaleric acid (4.46 g, 38.1 mmol) and NaOMe solution (57 mL, 28.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1M HCl was added with vigorous stirring until pH was about 1. The organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 50 mg of the title compound as a brown oil. MS: (+) m/z 497.17 (M+1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30]Cl)=[CH:27][C:21]=3[CH2:20][S:19](=[O:34])(=[O:33])[C:18]=2[CH:35]=1)=[O:13]>CN(C=O)C>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[C:16]([CH3:36])[C:17]2[O:23][C:22]3[C:24]([Cl:32])=[CH:25][C:26]([NH:28][CH2:29][CH2:30][N:4]4[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]4)=[CH:27][C:21]=3[CH2:20][S:19](=[O:33])(=[O:34])[C:18]=2[CH:35]=1)=[O:13]
Reactant: OCCN1CCNCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCN(CCO)CC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 6 h

Procedure:
2-Piperazin-1-yl-ethanol (0.227 g, 1.74 mmol) was added with stirring to a solution of Example 56k (0.5 g, 1.16 mmol) in DMF (10 mL) in an atmosphere of nitrogen. The reaction mixture was stirred at 110° C. for 6 h, concentrated, treated with chilled water and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as an off-white solid. Yield: 0.521 g, (85.69%); 1H NMR (DMSO-d6): δ 2.50 (s, 3H, CH3), 3.10 (t, 4H, 2CH2), 3.70 (t, 10H, 5CH2), 3.90 (s, 3H, OCH3), 4.40 (s, 2H, CH2), 5.20 (s, 2H, CH2), 6.10 (s, 1H, Ar), 6.80-6.85 (m, 2H, Ar), 8.10 (m, 2H, Ar); MS: m/e (ES+) 551 (M+).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.Cl[CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C[Si]([C:26]#[N:27])(C)C>C(Cl)Cl.O>[C:26]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2)#[N:27]
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: N#CC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 88.9 %

Procedure:
6.0 g (23.0 mmol) of tin tetrachloride are slowly added to a solution of 21.1 g (92.3 mmol) of 5-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene [V. Mychajlyszyn et al, Coll. Czech. Chem. Comm. 24, 3955 (1959)] and 11.3 g (114 mmol) of trimethylsilylcyanide in 150 ml of methylene chloride. The reaction mixture is stirred at room temperature for 10 hours and then diluted with 150 ml of methylene chloride, and 200 ml of water are added. The organic phase is separated off, washed with dilute sodium bicarbonate solution, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallization of the residue from toluene gives 18.0 g (88.9%) of 5-cyano-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene, melting point 89°-90° C. (compound (104), Table 1).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.ClCCCl>[C:19]([N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:3][C@@H:2]1[CH3:1])(=[O:21])[CH3:20]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2ccccc2N1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(=O)N1c2ccccc2N(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 50 °C
Yield: 99.6 %

Procedure:
A 40 mL reaction vial was charged with (S)-tert-butyl 3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.3 g, 1.21 mmol) and 1,2-dichloroethane (10 mL). 4-Dimethylaminopyridine (DMAP) (0.030 g, 0.242 mmol) was added as a solid followed by the addition of acetic anhydride (0.456 ml, 4.83 mmol). The reaction mixture was heated to 50° C. for 16 h on a heater shaker. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The organic layer was removed and set aside. The aqueous layer was washed with another portion of ethyl acetate (20 mL) and the organic layers were combined and concentrated under reduced pressure to yield (S)-tert-butyl 4-acetyl-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.35 g) which was used without further purification. MS (ESI, Na+ ion) m/z 313 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39]>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:35]=[CH:34][C:33]([F:32])=[C:38]([F:39])[CH:37]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1F
Yield: 29.4 %

Procedure:
The title compound (42.7 mg) was prepared as in Example 177, Steps C and D, using 205.2 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 224.9 mg of 3,4-difluorophenylboronic acid. MS (ESI): exact mass calculated for C19H23F2N3, 331.40; found, m/z 332.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.44 (m, 1H), 7.34-7.28 (m, 1H), 7.17-7.13 (m, 1H), 3.91-3.84 (m, 1H), 3.42-3.38 (m, 2H), 3.18-3.14 (m, 2H), 2.78-2.74 (m, 2H), 1.96-1.78 (m, 6H), 1.70-1.64 (m, 1H), 1.32-1.19 (m, 3H).