Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH:6]1[CH2:10][CH:9]=[CH:8][CH:7]=1.[CH3:11][Si:12]([CH3:35])([C:14]1[C:26]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=3)[C:18]=2[CH:17]=[CH:16][C:15]=1[C:31]([CH3:34])([CH3:33])[CH3:32])Cl>CCCCCC.O=O.O>[CH3:11][Si:12]([CH3:35])([C:14]1[C:26]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=3)[C:18]=2[CH:17]=[CH:16][C:15]=1[C:31]([CH3:34])([CH3:33])[CH3:32])[CH:7]1[CH:6]=[CH:10][CH:9]=[CH:8]1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1[Si](C)(C)Cl
Reactant: C1=CCC=C1
Agent: O=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1[Si](C)(C)C1C=CC=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
8.5 ml (21 mmol) of a 2.5M solution of butyllithium in hexane were added dropwise to 1.4 g (21 mmol) of cyclopentadiene in 45 ml of O2 -free and H2O-free THF at 0° C. under argon and the mixture was stirred for a further 2 hours at room temperature. This solution was subsequently added at room temperature to a solution of 7.9 g (21 mmol) of 2 in 100 ml of O2 -free and H2O-free THF over a period of 2 hours and the mixture was stirred for a further 1 hour at room temperature. 50 ml of H2O were added, the phases were separated and the aqueous phase was further extracted twice with 30 ml of Et2O each time. The combined organic phases were dried (MgSO4) and the solvent was removed in vacuo. After chromatography on 200 g of silica gel (hexane/methylene chloride 20:1), 4.4 g (51%) of 3 were obtained as a colorless oil.
Reaction SMILES: [S:1]1(=[O:10])(=[O:9])[CH2:5][CH2:4][CH:3]([C:6](O)=[O:7])[CH2:2]1.CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[S:1]1(=[O:10])(=[O:9])[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1
Reactant: O=C(O)C1CCS(=O)(=O)C1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: O=S1(=O)CCC(CO)C1
Reaction time: 0.02 h
Yield: 24 %

Procedure:
To a solution of tetrahydrothiophene-3-carboxylic acid 1,1-dioxide (Enamine, 1 g, 6.1 mmol) in THF (20 mL) at −10° C. was added 4-methylmorpholine (0.67 mL, 6.1 mmol). The mixture was stirred for 1 min then ethyl chloroformate (0.58 mL, 6.1 mmol) was added dropwise. This mixture was stirred at −10° C. for 15 min then was filtered through Celite and the filtrated was added dropwise via syringe to a mixture of NaBH4 (0.52 g, 13.7 mmol) in water (10 mL) at 5° C. The ice-bath was removed after the addition was complete and the mixture was stirred at ambient temperature for 2 h. The mixture was quenched with saturated, aqueous NH4Cl (10 mL) and diluted with EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.22 g) which was used without further purification. MS (DCI/NH3) m/z 168 (M+NH4)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1)[CH2:12][C:13]#[CH:14]>>[N:16]1[N:15]([CH2:11][CH2:12][C:13]#[C:14][C:2]2[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=2)[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CC(=O)c1cccc(Br)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: CC(=O)c1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 51.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(6-bromo-pyridin-2-yl)-ethanone (500 mg, 2.66 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (455 mg, 2.66 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 380 mg (1.36 mmol, 51%) of 1-[6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl]-ethanone as a white solid.
Reaction SMILES: [O:1]=[C:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[BH4-].[Na+]>CCO>[OH:1][CH:2]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1
Reactant: O=C(CCC1CCC(=O)N1)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCC(CCC(O)Cc2ccccc2)N1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 72.2 %

Procedure:
To a solution of 5-(3-oxo-4-phenyl-butyl)-pyrrolidin-2-one (5.902 g, 25.52 mmol) in EtOH (30 mL) at 0° C. was added NaBH4 (485 mg, 12.76 mmol) and the reaction mixture was stirred at 0° C. for 2.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride. Water and CH2Cl2 were added. The aqueous layer was washed with CH2Cl2 (2×) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography with a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2) to yield 4.3 g of 5-(3-hydroxy-4-phenyl-butyl)-pyrrolidin-2-one. 1H NMR (CDCl3) δ7.35-7.16 (m, 5H), 6.02 (m, 1H), 3.80 (m, 1H), 3.63 (m, 1H), 2.79 (m, 1H), 2.64 (m, 1H), 2.26 (m, 3H), 1.72-1.22 (m, 6H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:10]([O:39][CH3:40])=[N:11][CH:12]=[C:13]([C:15]2[N:20]=[C:19]([N:21]3[CH2:29][C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[C:18]3=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:31]=[CH:32][N:17]3[N:16]=2)[CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C([O-])(O)=O.[Na+]>[CH3:40][O:39][C:10]1[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][C:13]([C:15]2[N:20]=[C:19]([N:21]3[CH2:29][C:28]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[C:18]3=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:31]=[CH:32][N:17]3[N:16]=2)=[CH:12][N:11]=1
Reactant: COc1ncc(-c2nc(N3Cc4cccnc4C3)c3c(-c4ccccc4)ccn3n2)cc1S(=O)(=O)NC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-c2nc(N3Cc4cccnc4C3)c3c(-c4ccccc4)ccn3n2)cc1S(N)(=O)=O
Temperature: 70 °C
Yield: 19.8 %

Procedure:
N-(tert-Butyl)-2-methoxy-5-(5-phenyl-4-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.180 g, 0.324 mmol) was dissolved in TFA (2.00 mL, 26.0 mmol) and heated at 70° C. for 2 h. The volatile components were removed under reduced pressure and resulting residue was diluted with saturated NaHCO3 (30 mL). The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition B-98 as described in general methods) to afford 2-methoxy-5-(5-phenyl-4-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (32.0 mg, 19.8%) as off-white solid. LCMS Condition B-22: retention time 1.93 min, [M+1]=500.2. HPLC Condition B-31: retention time 9.01 min, purity 97.4%. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 3H), 4.57 (br s, 2H), 4.89 (br s, 2H), 6.83 (d, J=2.7 Hz, 1H), 7.09 (br s, 2H), 7.26 (dd, J=7.8 Hz, J=4.9 Hz, 1H), 7.37-7.43 (m, 1H), 7.44-7.55 (m, 4H), 7.61 (d, J=6.0 Hz, 1H), 7.99 (d, J=2.8 Hz, 1H), 8.38 (d, J=5.1 Hz, 1H), 8.80 (d, J=2.6 Hz, 1H), 8.96 (d, J=2.5 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@H:14]([CH3:15])[CH2:13][N:12]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)=[O:17])[C@@H:11]([CH3:28])[CH2:10]2)=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].O.[Cl-].[NH4+]>CO.[Fe]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16]([N:12]2[CH2:13][C@@H:14]([CH3:15])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:5]=3)[CH2:10][C@@H:11]2[CH3:28])=[O:17])=[CH:24][CH:23]=1
Reactant: C[C@@H]1CN(C(=O)Nc2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(C(=O)Nc2ccc(N)cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
A 450 mg portion of trans-4-(4-cyano-3-trifluoromethylphenyl)-2,5-dimethyl-4′-nitropiperazine-1-carboxanilide synthesized in Example 1-4 was dissolved in 8 ml of methanol, and the solution was mixed with 4 ml of water, 280 mg of iron powder and 30 mg of ammonium chloride and heated under reflux for 5 hours. The reaction solution was again mixed with 280 mg of iron powder and 30 mg of ammonium chloride and further heated under reflux for 2 hours. The reaction solution was filtered through celite, and the solvent in the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine in that order and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by a silica gel column chromatography (methanol-chloroform) to obtain 260 mg of the title compound as colorless crystals.
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH:10]=[C:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]1([CH3:30])[CH3:29].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:31]([O:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH:10]=[C:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]1([CH3:30])[CH3:29])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.5 h

Procedure:
To a solution of 3βhydroxy-4,4-dimethylcholesta-5,16-diene (220 mg, 0.5 mmol) in pyridine (1.5 mL) at ice bath temperature was added benzoyl chloride (0.1 mL) and the whole stirred for 1.5 hours. Concentration under reduced pressure and purification of the residue by flash chromatography gave 3β-benzoyloxy-4,4-dimethylcholesta-5,16-diene (300 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[S:17]1[C:21]2[CH:22]=[CH:23][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:20]=2[CH:19]=[CH:18]1.N.[C:36]([C:40]([OH:42])=[O:41])([F:39])([F:38])[F:37]>>[F:37][C:36]([F:39])([F:38])[C:40]([OH:42])=[O:41].[S:17]1[CH:18]=[CH:19][C:20]2[CH:25]=[C:24]([C:2]3[N:7]=[N:6][C:5]([O:8][C@@H:9]4[CH:14]5[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]5)[CH2:10]4)=[CH:4][CH:3]=3)[CH:23]=[CH:22][C:21]1=2
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Reactant: CC1(C)OB(c2ccc3sccc3c2)OC1(C)C
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: c1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2s1

Procedure:
The product of Example 9A (120 mg, 0.5 mmol) was coupled with 2-(1-benzothiophen-5-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Maybridge, 260 mg, 1.0 mmol) according to the procedure of Example 26B. The title product was purified by preparative HPLC (column: Xterra™ RP-18, 5 μm, 30×100 mm. eluting solvent, MeCN/H2O (with 0.1% v. TFA), (v. 90/10 to 10/90 over 20 min.) flow rate, 40 mL/min., uv, 254 nm) to provide a solid (157.3 mg, yield, 70%). 1H NMR (300 MHz, CD3OD) δ 1.92-2.25 (m, 3H) 2.35-2.49 (m, 1H) 2.63-2.71 (m, 1H) 3.35-3.56 (m, 5H) 3.95-4.06 (m, 1H) 5.55-5.62 (m, 1H) 7.37 (d, J=9.16 Hz, 1H) 7.50 (dd, J=5.43, 0.68 Hz, 1H) 7.68 (d, J=5.43 Hz, 1H) 7.96-8.02 (m, 1H) 8.05-8.10 (m, 1H) 8.22 (d, J=9.49 Hz, 1H) 8.45 (d, J=1.70 Hz, 1H) ppm. MS (DCI/NH3) m/z 338 (M+H)+. Anal. Calculated for C19H19N3OS.CF3CO2H: C, 55.87; H, 4.47; N, 9.31. Found: C, 55.51; H, 4.28; N, 9.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]S(C)(=O)=O)[C:8]1=[O:25].[F:33][C:34]1[CH:56]=[CH:55][C:37]([CH2:38][N:39]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[N:41]=[C:40]2[C:48]2([OH:54])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:52][CH2:53][C:48]([C:40]3[N:39]([CH2:38][C:37]4[CH:55]=[CH:56][C:34]([F:33])=[CH:35][CH:36]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)([OH:54])[CH2:49][CH2:50]2)([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]1=[O:25]
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Reactant: COc1cc(CN2CCC(CCS(C)(=O)=O)(Cc3ccccc3)C2=O)cc(OC)c1OC
Product: COc1cc(CN2CCC(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccccc3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzyl)-3-(phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.42 (silica gel, 30% methanol/ethyl acetate)
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([NH2:20])=O)[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH2:22][O:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:30])[CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]#[N:20])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:21][CH2:22][O:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:30])[CH:5]=1
Reactant: NC(=O)COc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCOC(=O)C(F)(F)F)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N#CCOc1cc2c(c(Cl)c1Cl)C1=CC(=O)CCC1(CCOC(=O)C(F)(F)F)C2

Procedure:
{[(5,6-Dichloro-3-oxo-2,3,9,9a-tetrahydro-9a-(2-trifluoroacetoxyethyl)-1H-fluoren-7-yl]oxy}acetamide (3.65 g, 10 mMole) is dissolved in pyridine (25 ml) an N,N'-dicyclohexylcarbodiimide (2.17 g, 10.5 mMole) in pyridine (15 ml) is added portionwise over 30 minutes with stirring at 15°-20° C. The mixture is then stirred at ambient temperature for 3 hours. The precipitated dicyclohexylurea is removed by filtration and the pyridine removed from the filtrate by evaporation in vacuo to provide the [(5,6-dichloro-3-oxo-2,3,9,9a-tetrahydro-9a-(2-trifluoroacetoxyethyl)-1H-fluoren-7-yl)oxy]acetonitrile.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[CH3:18][C:16]1[CH:15]=[CH:14][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=3[CH:2]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:3][C:4]=2[CH:17]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(C)ccc1O2
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)CC(N1CCN(C)CC1)c1cc(C)ccc1O2

Procedure:
0.8 G. of 10-chloro-10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin and 0.58 g. of 1-methyl-piperazine are dissolved in 4 ml. of chloroform and heated at reflux for 21 hours. Then, the chloroform is evaporated in vacuo. The residue is partitioned between benzene and aqueous sodium carbonate solution. The benzene solution is extracted with dilute hydrochloric acid. The hydrochloric acid extract is made alkaline with sodium carbonate and extracted with benzene. Thereafter, the benzene extract is washed several times with water, dried over sodium sulfate, evaporated in vacuo, and there is obtained 1-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine, the dihydrochloride of which melts at 197°-198° C. (with decomposition).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH3:10])[CH3:2].[C:11](=O)([O-:13])[O-:12].[K+].[K+]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[C:6]([OH:9])=[CH:5][C:4]=1[CH3:10])[CH3:2]
Reactant: CCc1ccc(O)cc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc(C(=O)O)c(O)cc1C

Procedure:
A mixture of 4-ethyl-3-methylphenol (31.51 g) and anhydrous potassium carbonate (91.25 g) was heated at 175° for 4 hours under a carbon dioxide pressure of 1,300 p.s.i. The cooled reaction products were dissolved in water (2 l). Acidification with hydrochloric acid, filtration and recrystallisation of the solid from ethanol-water gave 5-ethyl-4-methylsalicylic acid, m.p. 152.5°-154° C. (Found; C, 66.55; H, 6.71; C10H12O3 requires; C, 66.65; H, 6.71.)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1.[CH:25](I)([CH3:27])[CH3:26].O>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]([CH:25]([CH3:27])[CH3:26])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1
Reactant: CC(C)I
Reactant: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2[N+](=O)[O-])C(C)C)cc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in DMF (7.0 ml), 4′-chloro-4-ethyl-2′-nitrobenzenesulfonanilide (1.00 g (2.93 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, isopropyl iodide (0.70 ml (7.01 mmol)) was added dropwise and heated at 130° C. for 2 hours with stirring. After being allowed to cool to room temperature, water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed with 1% aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent to give 0.41 g (37%) of the title compound as pale red crystals.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].CO[C:10](=O)[C@H:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>C1COCC1>[C:16]([O:15][C:13]([NH:12][CH:11]([C:10]1[O:5][N:4]=[C:1]([CH3:2])[N:3]=1)[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(C(Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Yield: 48.7 %

Procedure:
To a solution of acetamide oxime [2.67 g, J. Saunders et al., J. Med. Chem., 33, 1128 (1990)] in THF (125 ml) was added 60% sodium hydride (1.44 g) in oil, and the mixture was refluxed under heating for 1 hour. Then, the reaction mixture was allowed to cool, and a solution of N-tert-butoxycarbonyl-L-phenylalanine methyl ester (8.38 g) in THF (40 ml) was added at room temperature. The mixture was refluxed under heating for 20 minutes. The mixture was allowed to cool, and water (10 ml) was added, which was followed by concentration under reduced pressure. A 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1 v/v) to give 4.43 g of N-tert-butoxycarbonyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenylethylamine. This compound was added to a 4N hydrogen chloride-dioxane solution (50 ml), and the mixture was stirred at room temperature for 2 hours. Toluene was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ether was added to the residue for crystallization to give the title compound (3.25 g, yield 47%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][C:22](Cl)=[CH:23][C:18]3=[N:17][CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:30]4[CH:29]=[N:28][C:27]([F:26])=[CH:32][CH:31]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cnc3cc(-c4ccc(F)nc4)ccn23)cc1
Yield: 23.4 %

Procedure:
Suspend [4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester (1.90 g, 5.30 mmol, 1.0 eq.) in dioxane/water (2:1, 36 mL). Add 2-fluoro-5-pyridine boronic acid (0.75 g, 5.30 mmol, 1.0 eq.), K3PO4 (2.25 g, 10.6 mmol, 2.0 eq.), and S-phos (0.272 g, 0.66 mmol, 0.125 eq.). Deoxygenate the mixture and fill with nitrogen. Add Pd(OAc)2 (0.059 g, 0.265 mmol, 0.05 eq.). Deoxygenate the reaction mixture and fill with nitrogen. Stir the reaction at 80° C. under nitrogen for 16 hours. A white solid is formed after the solution is cooled down. Filter off the white solid, wash with water (3×15 mL), EtOAc (3×15 mL). Collect the solid (1.50 g). Purify the filtrate by silica gel flash chromatography with a 0-5% MeOH/DCM gradient to afford the title compound (0.52 g) as a slightly yellow solid. Combine the chromatography product and the filtered solids to give slightly yellow solid. (2.02 g, 4.83 mmol) MS(ES), m/z 419 (M+1).
Reaction SMILES: Cl.Cl.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@@H:14]([N:16]([CH2:29][CH2:30]C)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[C:27](=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH3:15])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[O:32]1[C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=[N:33]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].O>[CH2:29]([N:16]([CH:14]([CH3:15])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:8][CH:9]=1)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:27](=[O:28])[CH2:26][CH2:25][N:24]([C:37]([C:36]2[O:32][N:33]=[CH:34][CH:35]=2)=[O:38])[CH2:23][CH2:22]1)[CH3:30]
Reactant: CCCN(CCCCN1CCNCCC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CCCCN1CCN(C(=O)c2ccno2)CCC1=O)C(C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-(4-{[(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-propylamino)butyl)-[1,4]diazepan-5-one dihydrochloride (0.15 g, 0.3 mmole) in toluene (5 mL) and saturated sodium carbonate (2 mL) was added isoxazole-5-carbonyl chloride (0.04 g, 0.31 mmole). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried (magnesium sulfate), and concentrated to give 4-(4-{ethyl-[2-(4-methanesulfonyl-phenyl)-1-methylethyl]amino}butyl)-1-(isoxazole-5-carbonyl)-[1,4]diazepan-5-one as a hygroscopic hydrochloride salt (0.14 g) in ethyl acetate/diethyl ether, 316, M+H=505.