Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:18])=[N:6][CH:7]=1.C([BH3-])#N.[Na+].Cl.[CH3:32][C:33]([CH3:35])=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:33]([CH3:35])[CH3:32])[CH2:24][CH2:25]2)=[O:18])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNCC1
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)N1CCC(OC(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 67 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(piperidin-4-yloxycarbonyl)amino]benzamide (100 mg, 0.205 mmol), acetone (0.075 mL), and sodium cyanoborohydride (51 mg, 0.82 mmol) yielded, after treatment with HCl, 63 mg (67%) of the title compound as a hydrochloride salt.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:15]1[C:16]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[N:17][S:18][N:19]=1.O>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:15]1[C:16]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[N:17][S:18][N:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-butoxyethoxy)ethanol (1.46 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[O:7])=[CH:4][N:3]=1.[NH2:16][NH2:17].C1(C)C=CC=CC=1>C(O)(C)C>[NH:16]([C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[O:7])=[CH:4][N:3]=1)[NH2:17]
Reactant: COCCCNC(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COCCCNC(=O)c1ccc(NN)nc1
Reaction time: 24 h

Procedure:
A solution of 6-chloro-N-(3-methoxypropyl)nicotinamide (6.6 g, 28.9 mmol) and hydrazine (4.53 mL, 144 mmol) in isopropanol (100 mL) was heated at 80° C. for 21 h. More hydrazine (3 mL) was added and heating continued at 80° C. for 24 h. The reaction was then concentrated in vacuo to give a tan oil which was reconcentrated from toluene to give the title compound as its hydrochloride salt as a white solid in quantitative yield. MS m/z 225 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.78 (m, 2H) 3.18-3.30 (m, 5H) 3.35 (t, J=6.3 Hz, 2H) 6.68 (d, J=8.8 Hz, 1H) 7.87 (dd, J=8.8, 2.3 Hz, 1H) 7.99 (br. s., 1H) 8.20 (t, J=5.6 Hz, 1H) 8.49 (dd, J=2.4, 0.6 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CC(O)=O>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:29]([CH2:28][C:27]4[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: NCc1ccc(F)cc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(F)cc1)C3=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(O'Reilly, N. J., Derwin, W. S., Fertel, L. B., Lin, H. C., Synlett., (1990) 609-610.) A solution of 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) and 4-fluorobenzylamine (0.15 mL, 1.3 mmol) in glacial HOAc (30 mL) was refluxed at 113° C. After 4 h, the reaction was cooled to r.t., concentrated, then azeotroped with toluene. The residue was diluted with water and basified with sat'd Na2CO3 (or sat'd NaHCO3) to pH>12. The solution was extracted with CH2Cl2 and the organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was purified by using silica gel, eluting with 4:1 CH2Cl2/acetone+0.1 % MeOH, to give 101 as a light yellow oil that was converted to an HCl salt and recrystallized from MeOH/EtOAc to give a white solid (m.p. 251-253° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([C:28]([F:36])([F:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:24]=[CH:23][C:22]=3[C:21]([CH3:38])([CH3:37])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS([Cl:44])(=O)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:44])[N:11]([CH2:16][C:17]([N:19]2[C:27]3[CH:26]=[C:25]([C:28]([F:36])([F:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:24]=[CH:23][C:22]=3[C:21]([CH3:38])([CH3:37])[CH2:20]2)=[O:18])[CH2:10][C@H:9]1[CH3:39])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(C(F)(F)c4ccccc4)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(C(F)(F)c4ccccc4)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
The title compound was prepared following methods similar to those described in Preparation 351 starting from (2R,5R)-4-{2-[6-(difluoro-phenyl-methyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.37 g, 2.5 mmol), methanesulfonyl chloride (234 μL, 3.0 mmol) and TEA (582 μL, 4.0 mmol) to give the title compound (1.0 g) as a pale yellow gum. MS: [M+H]+=563.
Reaction SMILES: CN(CCN(C)C)C.[Li]C(CC)C.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:24])[CH:16]=1.CI.C1C[O:30][CH2:29]C1>>[F:14][C:15]1[CH:16]=[C:17]([CH3:24])[C:18]([C:19]([OH:21])=[O:20])=[C:22]([O:30][CH3:29])[CH:23]=1
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: C1CCOC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CI
Product: COc1cc(F)cc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of TMEDA (1.95 mL, 19.2 mmol) in anhydrous THF (8 mL) at −78° C. was slowly added a solution of sec-BuLi (1.4 M solution in cyclohexane, 18.5 mL, 25.8 mmol), followed by a solution of 4-fluoro-2-methyl-benzoic acid (44, 1.0 g, 5.88 mmol) in anhydrous THF (2 mL) at −78° C. under an atmosphere of N2. The mixture stirred at −78° C. for 2 h before a solution of methyl iodide (1.46 mL, 23.5 mmol) in anhydrous THF (2 mL) was added slowly. The mixture was stirred at same temperature for 1 h before it was warmed up to room temperature and quenched with H2O. The crude mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL). Aqueous layer was collected and acidified with 2 M HCl, followed by extraction by EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 40 g Redisep column, 20% to 50% EtOAc/hexane) to give 4-fluoro-2-methoxy-6-methyl benzoic acid as a white solid (45, 0.18 g, 16%): 1H NMR (300 MHz, CDCl3) δ 6.53-6.62 (m, 2H), 3.90 (s, 1H), 2.48 (s, 1H); MS (ESI+) m/z 185 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccncc1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3ccncc3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with commercially available 4-chloromethyl-pyridine gave the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[N:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:27][C:28]4[CH:29]=[C:30]5[C:34](=[N:35][CH:36]=4)[NH:33][CH:32]=[CH:31]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 95 °C
Yield: 62.7 %

Procedure:
A solution of 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-chloro-6-methoxyquinazoline (0.285 g, 0.753 mmol), 5-hydroxy-7-azaindole (0.111 g, 0.828 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (0.114 g, 0.828 mmol) in DMF (1.6 ml) was stirred and heated at 95° C. under nitrogen for 3 hours. The mixture was cooled and filtered and the filtrate was evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol (saturated with ammonia). The fractions containing the expected product were combined and evaporated and the residue was triturated under diethyl ether, filtered and dried under vacuum to give 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline (0.225 g, 62%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.N>O>[O:22]=[C:19]1[CH:20]=[CH:21][N:2]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=3)=[CH:5][CH:4]=2)[CH:17]=[CH:18]1
Reactant: O=c1ccocc1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Agent: Cl
Agent: N
Solvent: O
Product: O=C1CCC(c2ccc(-n3ccc(=O)cc3)cc2)=NN1

Procedure:
A stirred mixture of 6-(4-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone hydrochloride (1.5 g), 4H-pyran-4-one (0.7 g), and water (20 ml), was heated under reflux for 41/2 hours. The resultant solid was dissolved in the minimum of hot water and the solution was neutralised with ammonia to give the crude product. Recrystallisation from water gave the title compound, 0.73 g, m.p. 270°-272° C.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:14][NH2:15])[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:2]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:14][NH:15][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([C:26]4[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=4)[CH:30]=3)[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN1CCC(CN)(c2cccc(-c3ccccc3)c2)CC1
Product: CN1CCC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2cccc(-c3ccccc3)c2)CC1
Yield: 31 %

Procedure:
This compound was synthesized from (4-([1,1′-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 31%) as an off white solid. 1H NMR (400 MHz, MeOD) δ 8.39 (m, 1H), 8.23-8.21 (m, 1H), 7.90-7.88 (m, 1H), 7.64-7.54 (m, 4H), 7.49-7.47 (m, 3H), 7.39-7.36 (m, 2H), 7.31-7.28 (m, 1H), 3.60 (m, 2H), 2.79-2.76 (m, 2H), 2.42-2.30 (m, 4H), 2.23 (m, 3H), 2.11-2.06 (m, 2H). MS (ESI) m/z: Calculated for C29H27F3N4O2: 520.21. found: 521.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.O.[NH2:10][NH2:11]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][NH2:11])=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ccc(Br)cn1
Reaction time: 16 h
Yield: 95.5 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (10 g, 56.8 mmol) in EtOH (120 ml) was added hydrazine hydrate (14.22 g, 284 mmol), the mixture was heated to reflux and stirred overnight (16 hr). The solvent of the reaction mixture was evaporated about half under reduced pressure, then cooling in an ice bath there precipitation was occurred, filtered and washed the product with a minimum of EtOH and water, dried in vacuum to obtain pure desired product as white powder (10.2 g, yield 91%). LCMS (method A): [M+H]+=188.1, 190.1, tR=0.62 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:13]2[C:12]3[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=3)[O:16][CH2:15][C@H:14]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
(+,-) cis 4-(7-Benzyloxy-3-phenyl-chroman-4-yl)-phenol (0.5 g, 1.22 mmol), methyl bromoacetate (0.37 g, 2.44 mmol), 18-crown-6 (0.48 g, 1.83 mmol), and potassium carbonate 0.25 g, 1.83 mmol) was slurried in toluene (25 ml), and stirred at 100° C. for 75 min. After cooling the reaction mixture was filtered through a 1.6×6 cm silica column, eluted with 10% tetrahydrofuran in toluene and evaporated.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:3][OH:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4′-Bromo-biphenyl-4-carboxylic acid methyl ester, 7.8 g (27.9 mmol) in 150 mL of tetrahydrofuran was cooled to 0° C. via ice-water bath. Lithium aluminum hydride, 1.1 g (27.9 mmol) was added to the solution in one portion. The reaction mixture stirred at 0° C. for 1 h. The mixture was slowly quenched with 10 mL of isopropyl alcohol, then with 10 mL of water. The aqueous mixture was extracted with 3×50 mL portions of ethyl acetate. The organic layers were combined, washed with sat. aq. NaCl, and dried (MgSO4). The solution was concentrated to afford the desired product in 7.01 g (100%) as a white solid. The material was taken to the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:16][CH2:15][C@H:14]([CH2:17][N:18]4[CH2:23][CH:22]=[C:21]([C:24]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[NH:26][CH:25]=5)[CH2:20][CH2:19]4)[O:13][C:9]3=2)[N:4]=1)[CH3:2].Cl.[H][H]>[Pd].CO>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:16][CH2:15][CH:14]([CH2:17][N:18]4[CH2:19][CH2:20][CH:21]([C:24]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[NH:26][CH:25]=5)[CH2:22][CH2:23]4)[O:13][C:9]3=2)[N:4]=1)[CH3:2]
Reactant: CCc1ccc2c3c(ccc2n1)OC[C@H](CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1ccc2c3c(ccc2n1)OCC(CN1CCC(c2c[nH]c4ccccc24)CC1)O3
Yield: 75.3 %

Procedure:
To a mixture of 0.25 g (0.59 mmole) of (2S)-8-ethyl-2-[(4-(1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl)methyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline and 0.2 g of 10% palladium on carbon in 100 mL of methanol was added 0.2 mL of concentrated HCl. The mixture was treated with 60 psi of hydrogen in a Parr apparatus for 15 hours. It was then filtered through celite and concentrated to an oil in vacuum. Ethyl acetate (300 mL) was added and the mixture was washed with 300 mL portions of saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. Column chromatography on silica gel with 0-2% methanol/chloroform as eluant gave 0.19 g of the title compound as the free base. Recrystallization from ethanol with the addition of 0.052 g of fumaric acid gave 0.15 g of the (S)-enantiomer of the title compound as an off-white fumarate (m.p. 169-172° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)=[C:5]([C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[C:6]#[N:7])[CH3:2].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([Cl:34])[C:25]=1[NH:35][NH2:36].Cl>C(O)C>[NH2:7][C:6]1[N:35]([C:25]2[C:24]([Cl:23])=[CH:29][C:28]([C:30]([F:31])([F:33])[F:32])=[CH:27][C:26]=2[Cl:34])[N:36]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=1[C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=1
Reactant: CCOC(OCC)=C(C#N)C(=O)c1cccc(C(F)(F)F)c1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
An aliquot of the above solution of step A containing approximately two millimoles of 3,3-bis-ethoxy-2-(3-trifluoromethylbenzoyl)acrylonitrile was reacted with 0.49 g (2.0 mmol) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 10 mL of ethanol under reflux overnight. The cooled mixture was poured into dilute hydrogen chloride (HCl) and the product was extracted into ethyl acetate (EtOAc), washed with water and brine, and dried over magnesium sulfate (MgSO4). Chromatography on silica gel with 4:1 hexane/EtOAc gave the title product, 320 mg (31%), m.p. 77°-78° C. from pentane.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([O-:33])=[O:32])=[C:29]3[C:24]([CH:25]4[CH2:34][CH:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH2:4]1)[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([OH:33])=[O:32])=[C:29]3[C:24]([C@H:25]4[CH2:34][C@H:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:18])=[O:19])[CH2:4]1)[CH3:2]
Reactant: CCN1CCCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)[O-])OCC2CC32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CCCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OC[C@@H]2C[C@H]32)C1
Temperature: 100 °C
Yield: 45 %

Procedure:
A mixture of methyl (1aR,7bS))-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 221, 0.071 g) and lithium hydroxide monohydrate (0.059 g) was suspended in dioxane (5 mL) and water (2 mL) and the mixture was stirred and heated at 100° C. for 25 hours. Further lithium hydroxide monohydrate (0.116 g) was added and the mixture was heated at 100° C. for a further 18 hours. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%) and saturated with sodium chloride. The mixture was extracted with DCM and the organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18), eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 25-60% to give (1aR,7bS)-5-[2-(1-ethyl-piperidin-3-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.032 g) as a white solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([F:21])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25](I)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[C:27]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=2[F:21])[CH:28]=1
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: Fc1ccc(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2F)c(F)c1
Temperature: 80 °C
Yield: 28 %

Procedure:
A solution of 2-(4-(ethylsulfonyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 45, 1.77 g, 5.64 mmol), 4-chloro-1-fluoro-2-iodobenzene (1.28 g, 5.00 mmol), and sodium carbonate (1.59 g, 15.00 mmol) in dioxane (40 mL) and water (10 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (577 mg, 0.50 mmol) was added and the mixture was degassed twice more, and the reaction warmed to 80° C. for 2 hours. The reaction was cooled and diluted with EtOAc (50 mL) and water (50 mL), the layers separated and the aqueous extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4 and the solvent removed in vacuo. The crude was purified by silica gel column chromatography eluting with EtOAc:heptane 1:19 to 1:1 to give the title compound as a colourless oil 28% yield, 443 mg.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19].O>ClCCl>[CH2:11]([O:10][C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([O:1][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of ethyl 4-hydroxycyclohexane carboxylate (5.0 g, 29.03 mmol) in dichloromethane (200 mL) was added imidazole (4.97 g, 73 mmols) and tert-butylchlorodiphenylsilane (15.96 g, 15.2 mL, 58.0 mmol). The reaction mixture was allowed to stir at room temperature over night. The reaction mixture was poured into water (125 mL) in a separatory funnel and the phases were separated. The aqueous phase was extracted with dichloromethane (2×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel eluting with ethyl acetate in heptanes (0-10%) afforded 10.55 g (89%) of the title compound.