Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[C:4]=2[CH:3]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: Cc1ccc(Br)nc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-n2c(-c3cnn(C)c3)cc3cnc(Br)cc32)nc1
Temperature: 210 °C
Yield: 46.6 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 84 mg 0.303 mmole) and 2-bromo-5-methylpyridine (78 mg, 0.45 mmole) were dissolved in DMA (2.1 ml) and potassium carbonate (60 mg, 0.42 mmole) and copper(I) iodide (12 mg, 0.066 mmole) were added. The reaction was placed under argon and heated by microwave at 210° C. for 60 minutes. Further 2-bromo-5-methylpyridine (49 mg) and potassium carbonate (40 mg) were added and the reaction again heated at 210° C. under microwave irradiation for 60 minutes. The reaction was taken up in ethyl acetate (30 mL) and the solution washed with water (3×10 mL) and brine. The aqueous was filtered through Celite and backwashed with ethyl acetate (10 mL). The combined organic layers were dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with ethyl acetate to afford the title compound 52 mg (46%). 1H-NMR (CDCl3, 500 MHz): 2.48 (s, 3H), 3.88 (s, 3H), 6.70 (d, J=0.95 Hz, 1H), 7.09 (d, J=7.88 Hz, 1H), 7.24 (m, 1H), 7.25 (s, 1H), 7.44 (t, J=0.95 Hz, 1H), 7.66 (m, 1H), 8.53 (m, 1H), 8.65 (d, J=0.95 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:7][C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])=[CH:5][C:4]=2[N:3]=1.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:16]1([NH:15][S:12]([C:8]2[C:9]3[CH:10]=[CH:11][C:2]([CH:28]4[CH2:30][CH2:29]4)=[N:3][C:4]=3[CH:5]=[C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:7]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OB(O)C1CC1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(C3CC3)nc2c1
Temperature: 110 °C

Procedure:
A mixture of 2-chloro-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide (23 mg, 0.057 mmol), cyclopropaneboronic acid (50 mg, 10 equiv) dppf PdCl2 (8 mg, 20 mol %), potassium carbonate (60 mg) and dioxane (1 mL) was purged with nitrogen and heated at 110° C. for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC to give the desired product, N-cyclopentyl-2-cyclopropyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:12]([N:14]([CH2:15][CH3:16])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[OH:11])[CH3:13]
Reactant: CCNCC
Reactant: O=C(O)c1cccc(Cl)c1O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccc(Cl)c1O
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a stirring solution of 3-chloro-2-hydroxybenzoic acid (7.2 g, 42 mmol) and diethyl amine (15.2 g, 209 mmol) in dry CH2Cl2 (200 mL) was added benzotriazol-1-yloxy tripyrrolidinophosphonium hexafluorophosphate (22.8 g, 44 mmol) in dry CH2Cl2 (200 mL). The reaction was stirred overnight and then quenched with 6M HCl. The layers were separated and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was purified by flash chromatography (silica gel, 0-50% EtOAc in hexanes) to yield 7.6 g of the desired product as a reddish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][CH2:12][C:13]1[N:17]([C:18]2[S:19][C:20]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:21][C:22]=2[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:16]([CH3:37])=[N:15][N:14]=1>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]([C:22]1[CH:21]=[C:20]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[S:19][C:18]=1[N:17]1[C:16]([CH3:37])=[N:15][N:14]=[C:13]1[CH2:12][NH:11][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])=[O:31]
Reactant: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C=Nc1ccccc1Cl
Product: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2ccccc2Cl)s1

Procedure:
2-Chlorophenyl isocyanate and methyl (2-(3-aminomethyl-5-methyl[1,2,4]triazol-4-yl)-3-(2-chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methyl (3-(2-chlorobenzoyl)-2-(3-(3-(2-chlorophenyl)ureidomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.O>ClC1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(CBr)cc1F
Yield: 109.4 %

Procedure:
1-Chloro-4-fluoro-2-methyl-5-nitrobenzene (1 g) was dissolved in chlorobenzene (6 mL) and N-bromosuccinimide (1.408 g) was added followed by benzoyl peroxide (0.183 mg). The reaction mixture was stirred at reflux for 4 hours. The reaction mixture was cooled and water was added. The mixture was extracted with dichloromethane (3×) and concentrated under reduced pressure. The crude oil obtained was triturated with diethyl ether, filtered and the filtrate concentrated under reduced pressure (3×) to yield the title compound (1.55 g).
Reaction SMILES: ClN1C(=O)CCC1=O.Cl[CH2:10][CH2:11][Cl:12].[CH:13]1([CH2:16][NH:17][C:18]2[N:26]=[CH:25]C=C[C:19]=2[C:20]([OH:22])=[O:21])[CH2:15][CH2:14]1>CN(C=O)C>[Cl:12][C:11]1[CH:25]=[N:26][C:18]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15]2)=[C:19]([CH:10]=1)[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1cccnc1NCC1CC1
Reactant: ClCCCl
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cnc1NCC1CC1
Reaction time: 24 h

Procedure:
1-Chloro-2,5-pyrrolidinedione was added at room temperature to a 1,2-dichloroethane and DMF solution of 2-[(cyclopropylmethyl)amino]nicotinic acid, followed by stirring for 1 day. By post-treating the reaction liquid, 5-chloro-2-[(cyclopropylmethyl)amino]nicotinic acid was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: OCCN1CCCCC1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCCN2CCCCC2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, hydroxyethylpiperidine and DBU in DME. ES-MS m/e (%:314 (M+H+, 100).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:9][N:8]=[C:7]([CH2:10][S:11]([OH:14])(=[O:13])=N)[C:5]=2[CH:6]=1.BrCC1C2C=CC=CC=2[O:19]N=1.S([O-])([O-])=O.[Na+:30].[Na+]>>[Na+:30].[O:9]1[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[C:7]([CH2:10][S:11]([O-:14])(=[O:19])=[O:13])=[N:8]1
Reactant: BrCc1noc2ccccc12
Reactant: N=S(=O)(O)Cc1noc2ccccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=S(=O)([O-])Cc1noc2ccccc12

Procedure:
A process for the preparation of zonisamide, disclosed in U.S. Pat. No. 4,172,896, comprises the sulfonation of 3-bromomethyl-benzo[d]isoxazole (1) with sodium sulfite to obtain benzo[d]isoxazol-3-yl-methanesulfonic acid sodium salt (2) which is then transformed into the corresponding sulfonyl chloride (3) by treatment with phosphorous oxychloride. The reaction of the latter with gas ammonia yields zonisamide (4), as reported hereinbelow.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[N:34]([Si](C)(C)C)=[N+:35]=[N-:36]>C1(C)C=CC=CC=1>[CH2:32]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:36][N:35]=[N:34][N:31]=4)[CH:25]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:33]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCC(C)CN1CCC(c2cccc(C#N)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Solvent: Cc1ccccc1
Product: CCCC(C)CN1CCC(c2cccc(-c3nnn[nH]3)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Temperature: 100 °C
Yield: 46.3 %

Procedure:
To a stirring solution of 2-[4-(3-cyano-phenyl)-1-(2-methyl-pentyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid diethylamide (45 mg, 0.11 mmol) in 4 mL toluene at room temperature was added Bu2SnO (12 mg, 0.05 mmol) and azidotrimethylsilane (0.09 mL, 0.66 mmol). The reaction mixture was heated to 100° C. for 28 hours and cooled to room temperature. The reaction was quenched with water, neutralized with NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried and concentrated. The resulting crude material was purified by flash chromatography with 5% MeOH/CH2Cl2 to afford 25 mg (51%) of the desired tetrazole. 1HNMR (400 MHz, CDCl3) δ 8.70 (s, 2H), 8.15 (s, 1H), 7.94 (d, 1H), 7.25-7.13 (comp, 2H), 3.53-3.51 (comp, 4H), 3.25-3.22 (comp, 4H), 2.70 (br s, 6H), 1.93 (br s, 1H), 1.40-1.12 (comp, 10H), 1.01 (d, 3H), 0.81 (t, 3H); MS (M+1) 491.4.
Reaction SMILES: CO[C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[CH3:30][O-:31].[Na+]>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:21]1[C:7]2[N:8]=[C:9]([O:31][CH3:30])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]1=[O:29]
Reactant: COC(=O)/C=C/c1c(Nc2ccccc2Cl)nc(SC)nc1-c1ccccc1F
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc(-c2ccccc2F)c2ccc(=O)n(-c3ccccc3Cl)c2n1

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(2-chloro-phenylamino)-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and sodium methoxide to afford the title compound 8-(2-chloro-phenyl)-4-(2-fluoro-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.70 (s, 3H), 6.59 (d, 1H, J=9.7 Hz), 7.01-7.20 (m, 3H), 7.40 (m, 2H), 7.56 (m, 4H); LC MS (m/e)=382 (MH+). Rt=2.24 min.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH2:11])=[O:10].CO[C:17](OC)([N:19](C)C)[CH3:18]>>[CH3:18][C:17]1[N:11]=[C:9]([C:8]2[CH:7]=[C:6]([CH:14]=[CH:13][CH:12]=2)[CH:2]=[O:3])[O:10][N:19]=1
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=O)c1cccc(C2OCCO2)c1
Product: Cc1noc(-c2cccc(C=O)c2)n1
Temperature: 90 °C
Yield: 102.7 %

Procedure:
A mixture of 3-[1,3]dioxolan-2-yl-benzamide (2.3 g) and dimethylacetamide dimethylacetal (4 g) was heated under reflux for 1 hour and then evaporated to dryness. The oily residue was dissolved in dioxane (20 mL) and hydroxylamine hydrochloride (1.18 g), acetic acid (20 mL) and a 2N aqueous sodium hydroxide solution (9 mL) were added and the mixture was heated at 90° C. for 2 hours. After evaporation, the residue was dissolved in toluene (100 mL) and a 1N hydrochloric acid solution (50 mL) was added and the mixture was stirred at reflux for 2 hours. After cooling at room temperature the organic phase was decanted, washed with water, dried over Na2SO4, filtered and evaporated to give the title compound (2.3 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Na+].CN(C)C=O.[Cl:27][CH2:28]/[CH:29]=[CH:30]/[CH2:31]Cl>O1CCCC1>[CH3:1][N:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:31]/[CH:30]=[CH:29]/[CH2:28][Cl:27])[CH:14]=1)[CH2:3]/[CH:4]=[CH:5]/[C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: ClC/C=C/CCl
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(OC/C=C/CCl)c1
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
245 mg of (E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxybenzylamine was dissolved in 5 ml of tetrahydrofuran, and under ice cooling, 40 mg of oily sodium hydride was added. After the mixture was stirred for 15 minutes, a dimethylformamide solution (3ml) of 125 mg of (E)-1,4-dichloro-2-butene was added. The mixture was stirred at room temperature for 12 hours, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 216 mg of the captioned compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]([CH3:20])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[O:7])=[CH:4][N:3]=1.Cl.[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:20][C:11]1[S:10][C:9]([NH:8][C:6]([C:5]2[CH:21]=[CH:22][C:2]([N:35]3[CH2:36][CH2:37][CH:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:38])[F:39])[CH:27]=4)[CH2:33][CH2:34]3)=[N:3][CH:4]=2)=[O:7])=[N:13][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Reactant: Cc1sc(NC(=O)c2ccc(Cl)nc2)nc1-c1ccccc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(NC(=O)c2ccc(N3CCC(c4cccc(C(F)(F)F)c4)CC3)nc2)nc1-c1ccccc1
Temperature: 70 °C

Procedure:
To a mixture of 6-chloro-N-(5-methyl-4-phenyl-thiazol-2-yl)-nicotinamide (50 mg, 0.152 mmol) and anhydrous N-methylpyrrolidinone (10 mL) in a sealed tube was added 4-(3-trifluoromethyl-phenyl)-piperidine hydrochloride (80 mg, 0.30 mmol) followed by diisopropylethylamine (0.11 mL, 0.63 mmol). The mixture was heated in an oil bath at 70° C. overnight. After concentration, the crude was purified by RP-HPLC to give 4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (5-methyl-4-phenyl-thiazol-2-yl)-amide as an off-white powder. LCMS calcd for C28H25F3N4OS (m/e) 522, obsd 523 (M+H).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4](=[O:16])[C:3]=1[S:17][C:18]#[N:19].O>CN(C)C=O>[NH2:19][C:18]1[S:17][C:3]2[C:4](=[O:16])[N:5]=[C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:7][C:2]=2[N:1]=1
Reactant: N#CSc1c(N)[nH]c(SCc2ccccc2)nc1=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2[nH]c(SCc3ccccc3)nc(=O)c2s1

Procedure:
The product of step (a) (7.35 g) was heated at 120° C. in dimethylformamide (40 mL) and water (10 mL) for 10 hours. After cooling, the resulting solid was filtered off, washed with water, ether and ethyl acetate to give the title compound containing 0.4 moles of dimethylformamide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])[CH3:12].[C:20](OC)(=[O:25])[C:21]([O:23][CH3:24])=[O:22]>O1CCCC1>[CH3:24][O:23][C:21](=[O:22])[C:20](=[O:25])[CH2:12][C:11]([C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1cccnn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(=O)CC(=O)c1cccnn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In an argon atmosphere and while cooling at −78° C., 1.0M lithium bis(trimethylsilyl)amide in tetrahydrofuran (19 mL) was added dropwise to 3-acetylpyridazine (2.097 g) in tetrahydrofuran (50 mL), followed by stirring for 1 hour. To the reaction mixture, dimethyl oxalate (4.055 g) in tetrahydrofuran (35 mL) was added dropwise, and the resultant mixture was stirred at 0° C. for 2 hours. The reaction solvent was removed under reduced pressure. Water was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was slightly acidified with aqueous 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 4-(3-pyridazinyl)-2,4-dioxobutanoic acid methyl ester as a solid (2.63 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)=[CH:34][CH:33]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[S:45][CH:46]=[CH:47][CH:48]=3)=[CH:36][CH:37]=2)[C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccccc2-c2cccs2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3cccs3)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 174 mg (0.465 mmol) of 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step I) in 3.0 mL of dry dimethylformamide was treated with 22.2 mg of 60% sodium hydride oil dispersion (13.3 mg NaH, 0.558 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 30 minutes. To the solution was added 153 mg (0.465 mmol) of a solution of 4-bromomethyl-2'-(2-thienyl)-1,1'-biphenyl dissolved in 3 mL of dry dimethylformamide. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (4×), dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (1:1) to give 160 mg of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:17][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:11][CH2:12][C:13]([OH:16])([CH3:17])[CH2:14][CH2:15]2)=[O:9])=[N:6][CH:7]=1
Reactant: O=C1CCN(C(=O)c2ccc(Br)cn2)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCN(C(=O)c2ccc(Br)cn2)CC1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
1-(5-Bromo-pyridine-2-carbonyl)-piperidin-4-one (Example 37, step 1) (135 mg, 0.48 mmol) was dissolved in THF (3 ml) and the mixture was cooled to 0-5° C. 3M Methylmagnesium bromide (190 μl, 0.57 mmol, 1.2 equiv.) was added drop wise at 0-5° C. and the mixture was stirred for 2 hours at 0-5° C. The reaction mixture was extracted with saturated NH4Cl solution and two times with ethyl acetate. The organic layers were extracted with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0→0:100. The desired (5-bromo-pyridin-2-yl)-(4-hydroxy-4-methyl-piperidin-1-yl)-methanone (35 mg, 25% yield) was obtained as a colorless oil, MS: m/e=299.2/301.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH:10]([C:12]([CH3:14])=O)=[CH2:11]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[N:5]=[CH:11][CH:10]=[C:12]2[CH3:14]
Reactant: C=CC(C)=O
Reactant: COc1ccccc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: COc1cccc2c(C)ccnc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirred solution of 2-methoxyaniline (1 g. 8.1 mmol.) in acetic acid (10 ml), activated silferc (1.3 g. ferric chloride 8.1 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.62 g, 8.9 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.1 g. 8.1 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 60%.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH3:20])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:19][CH3:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCC[C@@H](O)[C@H](CC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 6 (660 mg, 2.47 mmol) and 1-bromotetradecane (1.71 g, 6.17 mmol), alcohol 53 was obtained as a colorless oil (535 mg, 47% yield).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1F)#[N:2].[NH:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.[H-].[Na+]>CN(C)C=O.O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(F)c1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(-n2cccn2)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
Methyl 4-cyano-3-fluorobenzoate (0.30 g) and 1H-pyrazole (0.14 g) were dissolved in N,N-dimethylformamide (10 ml). To the reaction solution, sodium hydride (0.10 g) was added under ice cooling while stirring the mixture, and the mixture was stirred for 30 min. After increasing the temperature to room temperature, the solution was further stirred for 2 hours. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product, which was then purified by column chromatography to give methyl 4-cyano-3-(1H-pyrazol-1-yl)benzoate (0.28 g, yield 73%).