Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2[C:20]3[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.C(O)C.[C].[Pd]>[CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]2[C:20]3[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc2scc(C#Cc3ccc(C(=O)OCc4ccccc4)cc3)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc2scc(CCc3ccc(C(=O)OCc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.2 %

Procedure:
3-[2-(4-Benzyloxycarbonylphenyl)ethynyl]-4-methoxybenzo[b]thiophene (0.2 g) was dissolved in tetrahydrofuran (3 mL)-ethanol (3 mL). To the solution was added 10% palladium-carbon powder (40 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 14 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 3-[2-(4-benzyloxycarbonylphenyl)ethyl]-4-methoxybenzo[b]thiophene (0.15 g). This material was dissolved in dichloromethane (4 mL). To the solution was added boron tribromide (0.038 mL) at −78° C., and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give 3-[2-(4-carboxyphenyl)ethyl]-4-methoxybenzo[b]thiophene (85 mg). This material was dissolved in dichloromethane (4 mL). To the solution was added boron tribromide (0.057 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hour. Then the mixture was stirred for 1 hour under ice-cooling. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-[2-(4-carboxyphenyl)ethyl]-4-hydroxybenzo[b]thiophene (80 mg). This material was dissolved in tetrahydrofuran (1 mL). To the solution were added benzyl alcohol (29 mg), triphenylphosphine (79 mg) and diethyl azodicarboxylate (40% toluene solution, 0.13 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-3/1) to give the title compound (35 mg).
Reaction SMILES: CN(C)C=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:17]12[C:23](=[O:24])[O:22][C:20](=[O:21])[CH:18]1[CH2:19]2>>[C:10]1([CH3:16])[CH:15]=[CH:14][C:13]([C:23]([C@H:17]2[CH2:19][C@H:18]2[C:20]([OH:22])=[O:21])=[O:24])=[CH:12][CH:11]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Temperature: 70 °C
Yield: 89.7 %

Procedure:
18 ml (0.23 mole) of dimethylformamide are added dropwise in the course of a few minutes, whilst stirring, to 120 g (0.90 mole) of anhydrous aluminum chloride, resulting in a strongly exothermic reaction. 8.2 g (89.0 millimoles) of toluene are then added dropwise at 60°-70° C. Thereafter, 10.0 g (89.2 millimoles) of 1,2-cyclopropanedicarboxylic acid anhydride are added, a little at a time, at the same temperature, and the mixture is stirred for a further hour at 70° C. The melt is then introduced into 1 kg of ice. The solid which has precipitated is filtered off, washed with water and dried under reduced pressure at 50° C. 16.3 g (90% of theory) of cis-2-(p-toluoyl)-cyclopropanecarboxylic acid are obtained as colorless crystals, of melting point 165°-166° C. after recrystallization from ethyl acetate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:21]([O:23][C:24]([C:26]1[C:27](=[O:49])[C:28]2[CH:33]=[N:32][C:31](S(C)(=O)=O)=[N:30][C:29]=2[N:38]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[CH2:45][CH2:44][CH2:43]3)[CH:39]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1[C:27](=[O:49])[C:28]2[CH:33]=[N:32][C:31]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:19][CH:18]=3)=[N:30][C:29]=2[N:38]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[CH2:45][CH2:44][CH2:43]3)[CH:39]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(C4CCNCC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (from the previous step, 66 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e), 100 mg, 0.24 mmol). A yellow solid was obtained (75 mg, 51%) after a preparative HPLC (32 mL/min 5-100% MeCN/H2O gradient over 10 min) purification. The Boc group was removed by treatment with TFA in CH2Cl2 (1:1 v/v) to give the title compound. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.31 (s, 1H), 8.54 (s, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.29 (br, 2H), 7.27 (s, 1H), 7.18 (d, J=7.9 Hz, 1H), 6.91 (br, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.52 (m, 2H), 3.16 (br, 2H), 2.97 (m, 4H), 2.68 (m, 1H), 2.22 (m, 2H), 1.95 (m, 2H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([NH:45][C:19]([C:15]1[S:14][C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]2=[O:22])=[N:17][C:16]=1[CH3:18])=[O:21])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.21 g, 0.66 mmol) and 4-methylmorpholine (0.08 mL, 0.72 mmol) in tetrahydrofuran (50 mL) was added isobutyl chloroformate (0.09 mL, 0.68 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 2 hours and benzylamine (0.08 mL, 0.73 mmol) was added. The reaction mixture was kept stirring for 14 hour at ambient temperature. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound as a white powder in 20% yield (0.050 g): mp 169-171° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (t, J=5.7 Hz, 1H), 7.35-7.19 (m, 10H), 4.39 (s, 2H), 4.35 (d, J=5.7 Hz, 2H), 3.96 (t, J=7.5 Hz, 2H), 3.41 (t, J=7.5 Hz, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.2, 157.8, 155.5, 151.4, 140.1, 136.7, 129.1, 128.7, 128.2, 127.9, 127.6, 127.1, 118.2, 47.3, 43.0, 42.4, 42.0, 17.5; MS (ES+) m/z 407.3 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH2:25])[CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])(O)=O.[Na+].[F:31][C:32]1[C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH:25][C:38]([C:37]3[C:32]([F:31])=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:39])[CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N)cc(C(F)(F)F)c2)CC1
Reactant: O=C(Cl)c1cccnc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(NC(=O)c3cccnc3F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine (4.37 g) was dissolved in CH2Cl2 (100 ml) and NaHCO3 (2.4 g, Baker) was added. 2-Fluoropyridine-3-carbonyl chloride (2.12 g) was added an the reaction was stirred at RT for 2.5 h. The reaction was filtered and concentrated in vacuo to yield a yellow foam. (30%) EtOAc/Hexane was added and 1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine precipitated as an off white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:16])=[C:7]([C:14]#[CH:15])[CH:8]=2)[O:3]1.Cl[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=1.[Cl-]>C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[C:22]1[CH:28]=[CH:29][C:19]([C:15]#[C:14][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[CH3:16])[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[N:20][CH:21]=1)[CH3:27]
Reactant: C#Cc1cc2c(cc1C)OC(C)(C)CC2(C)C
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Pd]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2C)OC(C)(C)CC3(C)C)nc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A solution of 300 mg (1.316 mmol) of 2,2,4,4,7-pentamethyl-6-ethynyl-chroman (Compound 9) and 245.6 mg (1.3276 mmol) of ethyl 6-chloro-nicotinate (Compound 98) in 2 ml of triethylamine was placed in a pressure tube and a stream of nitrogen was bubbled through the solution for 15 min. The tube was then flushed with argon and a finely ground mixture 100 mg (0.1425 mmol) of bis (triphenylphosphine) palladium II) chloride and 50 mg (0.2625 mmol) of cuprous iodide was added to the solution. The pressure tube was then sealed and the reaction mixture heated at 60 degrees C. for 72 h. The mixture was cooled to room temperature and the triethylamine removed under vacuum. The residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid. PMR (CDCl3): & 1.37 (6H, s), 1.38 (6H, s), 1.44 (3H, t, J~7.2 Hz), 1.85 (2H, s), 2.49 (3H, s), 4.43 (2H, q, J~7.2 Hz), 6.70 (1H, s), 7.55-7.61 (2H, m), 8.28 (1H, dd, J~8.2 Hz, 2.1 Hz), 9.22 (1H, d, J~2.1 Hz). MS exact mass, m/e 377.1982 (calcd. for C24H27O3N, 377.1991).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[C:14]([CH3:40])=[N:15][C:16]([O:19][CH2:20][C:21]3[N:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][C:36]([F:39])([F:38])[F:37])[N:23]=[N:24][C:25]=3[CH:26]([CH3:28])[CH3:27])=[CH:17][CH:18]=2)[CH3:12])=[CH:6][C:5]=1[CH3:41].[OH-].[Li+]>O1CCOCC1>[CH:26]([C:25]1[N:24]=[N:23][N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][C:36]([F:39])([F:38])[F:37])[C:21]=1[CH2:20][O:19][C:16]1[N:15]=[C:14]([CH3:40])[C:13]([N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:42])=[O:2])=[C:5]([CH3:41])[CH:6]=2)[CH3:12])=[CH:18][CH:17]=1)([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccc(CN(C)c2ccc(OCc3c(C(C)C)nnn3-c3ccccc3OC(F)(F)F)nc2C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(CN(C)c2ccc(OCc3c(C(C)C)nnn3-c3ccccc3OC(F)(F)F)nc2C)ccc1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
A solution of 4-[({6-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-2-methyl-benzoic acid methyl ester (147 mg, 0.251 mmol) in dioxane (2 mL) is treated with a solution of lithium hydroxide (378 mL, 0.756 mmol, 2.0N in water) and heated to 50° C. After 2 h, the reaction is concentrated and the residue is partitioned between Et2O and water. The aqueous layer is adjusted to pH ˜7 and is extracted with a second portion of Et2O. The combined organic layers are washed with water, dried (MgSO4), filtered, and concentrated to yield the title compound (138 mg, 97%). LC/MS (ES+): 570.0, 100%.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[N-:15]=[N+]=[N-].[Na+]>CO.C(O)C>[N+:7]1([O-:9])[O:8][N:15]=[C:2]2[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:6]=12
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Br)s1
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1cc2c(no[n+]2[O-])s1
Temperature: 70 °C
Yield: 33.7 %

Procedure:
A suspension of 25.0 g (90 mmol) of ethyl 2-bromo-3-nitro-5-thiophenecarboxylate (Tetrahedron 21 (1965) 1061) and 29.0 g (450 mmol) of sodium azide in 300 ml of methanol is stirred at room temperature for 4 hours in 300 ml of ethanol. The mixture is poured into 4 l of ice-water, the precipitate is filtered off and the residue is heated at 70° C. for 3 hours in 700 ml of toluene. Subsequent purification by flash chromatography yields 6.5 g (34%) of ethyl thieno[2,3-c][1,2,5]oxadiazole-5-carboxylate-1-oxide and -3-oxide, m.p. 72°-74° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.[O-:21][S:22]([O-:24])=[O:23].[Na+:25].[Na+].CCO>O>[Na+:25].[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:22]([O-:24])(=[O:23])=[O:21])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCc1ccc(OCc2ccccc2)cc1

Procedure:
Following the procedure described for 11.1 using 10.4 (0.95 g, 2.85 mmol), Na2SO3 (0.50 g, 4.0 mmol) and EtOH (25 mL)/H2O (7 ml) mixture, the crude 11.4 was obtained and used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[C:32]([N+:34]([O-])=O)[CH:33]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=1[O:29][CH3:30])=[O:8])([O-])=O>CN(C=O)C.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:31]=[C:32]([NH2:34])[CH:33]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=1[O:29][CH3:30])=[O:8]
Reactant: COC(=O)/C=C/c1ccc(OCCCCCCOC(=O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c(OC)c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(OCCCCCCOC(=O)c2cc(N)cc(N)c2)c(OC)c1
Yield: 62.9 %

Procedure:
5 g (9.7 mmol) of 6-{2-methoxy-4-[(1E)-3-methoxy-3-oxoprop-1-enyl]phenoxy}hexyl 3,5-dinitrobenzoate are dissolved in a mixture of 84 ml of DMF and 9 ml of water. 15.7 g (58 mmol) of ferric chloride hexahydrate are added. 6.31 g (97 mmol) of zinc powder are added portionwise within 30 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Filtration of the residue on silica gel using toluene:ethyl acetate (1:3) as eluant and yielded 2.7 g (61%) of 6-{2-methoxy-4-[(1E)-3-methoxy-3-oxoprop-1-enyl]phenoxy}hexyl 3,5-diaminobenzoate as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1c(Cl)cnc2[nH]ccc12
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
5-Chloro-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 9.2 mmol) in THF (15 mL) at 0° C. was treated dropwise with TBAF (10.1 mL, 10.1 mmol). After 30 minutes, the reaction was quenched with saturated aqueous NaHCO3 and extracted into CH2Cl2. The combined organic fractions were dried (MgSO4), filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel using 1.2% MeOH:CH2Cl2 to provide 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridine (1.4 g, 89% yield).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=O)[C:36]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)([CH3:42])[CH2:35][CH2:34]2.[Cl-].[NH4+]>C(OCC)C.CCCCCC>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[CH:2][O:3][CH3:4])[C:36]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)([CH3:42])[CH:35]=[CH:34]2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C2(C)CCc3cc(OC)ccc3C2=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: COC=C1c2ccc(OC)cc2C=CC1(C)c1ccc(OC)cc1

Procedure:
A suspension of (methoxymethyl)triphenylphosphonium chloride (25.7 g) in diethyl ether (400 ml) was stirred under an argon atmosphere and cooled in an ice-bath while a solution of n-butyl-lithium in hexane (1.6M, 46 ml) was added slowly over 10 minutes. The reaction mixture was then stirred at that temperature for 1 hour. A solution of 6-methoxy-2-(4-methoxyphenyl)-2-methyltetralone (8.9 g ) in diethyl ether 150 ml) was added to the reaction, and it was then stirred at room temperature for 16 h, saturated ammonium chloride solution (300 ml) was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted twice with diethyl ether (200 ml). The organic extracts were combined, dried and evaporated to dryness. The resulting gum was subjected to flash column chromatography on silica (K60) using toluene as eluting solvent to give 6-methoxy-1-methoxymethylene-2-(4-methoxyphenyl)-2-methylnaphthalene as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:30]1(B(O)O)[CH2:33][CH2:32][CH2:31]1.C1(C)C=CC=CC=1>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:30]3[CH2:33][CH2:32][CH2:31]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CCC1
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C2CCC2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 12.5 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (4.8 g), bis(tricyclohexylphosphine)palladium (II) dichloride (515 mg), tripotassium phosphate (16 g) and cyclobutylboronic acid (2.6 g) were added toluene (39 mL) and water (2 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(5-cyclobutyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (560 mg). 4-(5-cyclobutyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (560 mg) was dissolved in chloroform (1.5 mL), 4N hydrogen chloride/ethyl acetate (1.5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (8 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (350 mg).
Reaction SMILES: [H-].[Na+].[N:3]1[C:8]2[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[NH:12][C:13](=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:19](I)[CH3:20].O>CN(C)C=O>[CH2:19]([N:12]1[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[S:9][C:8]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:13]1=[O:14])[CH3:20]
Reactant: O=C1Nc2ccccc2Sc2ncccc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)c2cccnc2Sc2ccccc21
Temperature: 50 °C

Procedure:
Sodium hydride (1.05 g of a 50% suspension in mineral oil) was added to a suspension of pyrido[2,3-b][1,5]benzothiazepin-5(6H)-one (4.0 g, 0.0175 mol) in 100 ml of dimethylformamide and the resulting mixture stirred until the evolution of gas stopped, at which time the mixture was heated to 50° C. for 30 min. After cooling to room temperature, ethyl iodide (5.46 g, 0.035 mol) was slowly added and the reaction mixture allowed to stir for 2 hours. Crushed ice was added to decompose unreacted sodium hydride. Water was then added and the product was extracted with ether, dried (anhydrous sodium sulfate) and concentrated in vacuo. After washing the solid residue with hexane, it was recrystallized from ethyl acetate/hexane to give 0.66 g (14% of theory) of product as yellow crystals, m.p. 148°-149° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=[CH:14]3)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[F:41])[NH2:37]>C(Cl)Cl>[Cl:33][C:34]1[CH:35]=[C:36]([NH:37][C:21]([C:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][C:7]4[CH:8]=[N:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=4)=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:22])[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: COc1ccc(Oc2ccc3c(C(=O)Cl)cccc3c2)cn1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(Cl)c4)cccc3c2)cn1
Reaction time: 16 h

Procedure:
To a stirred solution of 6-(6-methoxypyridin-3-yloxy)-1-naphthoyl chloride hydrochloride salt (225 mg, 0.64 mmol) and DIPEA (0.22 mL, 1.285 mmol) in DCM (5 mL) at RT was added 3-chloro-4-fluoroaniline (93.5 mg, 0.64 mmol). After stirring for 16 h, the reaction mixture was directly purified by silica gel chromatography (elution hexanes/EtOAC:85/15 to 35/65) to give the title compound as a tan solid. MS (ESI, pos. ion) m/z: 423.1 (M+1). Mass Calc'd for C23H16ClFN2O3: 422.84.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=O)[C@H:15]2[C@@:10]([CH3:24])([C@@H:11]([CH3:23])[CH2:12][C:13]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CO.Cl>C1COCC1>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@@:10]([CH3:24])([C@@H:11]([CH3:23])[CH2:12][C:13]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:14]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1Cc2c(Cl)cccc2[C@H]2C(=O)N(Cc3ccccc3)C[C@@]21C
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1Cc2c(Cl)cccc2[C@H]2CN(Cc3ccccc3)C[C@@]21C
Temperature: 70 °C
Yield: 23.7 %

Procedure:
(3aR*,4S*,9bR*)-2-Benzyl-6-chloro-3a,4-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-1-one (229 mg, 0.674 mmol) was dissolved in THF (2.6 ml). Borane THF (2 M solution) (6.74 mmol, 6.74 ml) was added and the reaction mixture was heated to 70° C. overnight. MeOH and 5 N aq HCl (4 ml) were then added and the resulting solution was heated at 70° C. for a further 2 hours. The organic solvents were removed in vacuo and the reaction mixture was basified using 4 N NaOH. The aqueous mixture was extracted with DCM (×3) and the combined organic extracts were dried over magnesium sulphate, filtered and concentrated in vacuo to afford a residue that was purified by silica column chromatography (eluting with heptane—heptane: 30% ethyl acetate) to give (3aR*,4S*,9bR*)-2-benzyl-6-chloro-3a,4-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (52 mg). m/z: 326.3 [M+H]+.