Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:16][F:17])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][F:15])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].[Cl:18][CH:19]([Cl:24])[C:20](OC)=[O:21].C(N(CC)CC)C>CO>[F:17][CH2:16][C@@H:2]([NH:1][C:20](=[O:21])[CH:19]([Cl:24])[Cl:18])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:14][F:15])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[OH:4]
Reactant: COC(=O)C(Cl)Cl
Reactant: N[C@H](CF)[C@H](O)c1ccc(S(=O)(=O)CF)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(S(=O)(=O)CF)cc1)C(Cl)Cl
Temperature: 40 °C
Reaction time: 20 h
Yield: 76.8 %

Procedure:
A mixture of 17 (0.90 g, 3.39 mmol), methyl dichloroacetate (0.42 mL, 4.07 mmol) and triethylamine (0.71 mL, 5.09 mmol) in methanol (40 mL) was stirred at 40° C. for 20 hours. The reaction was quenched with water. Extraction with dichloromethane (2×100 mL) afforded an oily residue which was subjected to flash chromatography (SiO2, hexanes/ethyl acetate=2:1 to 1:1) to provide 0.98 g of the desired product as a white solid. 1H NMR (400 MHz, CDCl3) 4.28-4.38 (m, 1H), 4.46-4.72 (m, 2H), 5.05 (s, 1H ), 5.17 (s, 1H), 5.23 (t, J=4 Hz, 1H), 5.81 (s, 1H), 7.01 (d, J=8 Hz, 1H), 7.62 (d, J=8 Hz, 2H), 7.87 (d, J=8 Hz, 2H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26]([Cl:28])=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:32]=[C:33]([NH2:38])[CH:34]=[CH:35][C:36]=1[F:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN1CCCC1=O>COCCOCCOC>[ClH:28].[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26]([NH:38][C:33]5[CH:34]=[CH:35][C:36]([F:37])=[C:31]([Cl:30])[CH:32]=5)=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COCCOCCOC
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Product: Cl
Temperature: 190 °C
Yield: 38.8 %

Procedure:
A mixture of 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (44 mg, 0.11 mmol), 3-chloro-4-fluoro-phenylamine (154 mg, 1.1 mmol) and p-toluenesulfonic acid monohydrate (10.1 mg, 0.053 mmol), 1-methyl-2-pyrrolidinone (2.5 mL) and 2-methoxyethyl ether (2.5 ml) was heated to 190° C. for 16 hours and concentrated. The residue was purified by reverse phase HPLC, then dissolved in 2N HCl and acetonitrile and freeze-dried to give 24 mg (39%) of 5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide hydrochloride as a red solid. 1H NMR (360 MHz, DMSO-d6) δ 13.46 (s, 1H, NH), 11.79 (s, 1H, NH), 10.74 (br s, 1H, HCl), 9.33 (s, 1H), 8.83 (t, J=5.5 Hz, 1H, NH), 8.33 (s, 1H, H-vinyl), 7.74 (dd, J=2.39, 6.68 Hz, 1H), 7.38-7.47 (m, 2H), 7.35 (t, J=9.03, 1H), 6.94 (s, br, 1H), 3.96 (dt, J=5.74, 11.37 Hz, 2H, CH2), 3.80 (t, J=12.10 Hz, 2H, CH2), 3.68 (dd, J=5.99 & 11.61 Hz, 2H, CH2), 3.52 (d, br, J=12.44 Hz, 2H, CH2), 3.29-3.31 (m, 2H, CH2), 3.10-3.13 (m, 2H, CH2), and 2.23 (s, 3H, CH3). MS 526 [M+].
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.COCCN1CCNCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: COCCN1CCNCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To 10 ml of 1,4-dioxan is added 0.645 g (3.0 mmol) of methyl-4-bromobenzoate 0.519 g (3.6 mmol) of 1-(2-methoxy-ethyl-piperazine, 0.892 g (8.47 mmol) of potassium phosphate, 0.177 g (0.45 mmol) of 2-dicycohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 0.137 g (0.15 mmol) tris-(benzylideneacetone)palladium (0). The resulting reaction mixture is stirred under argon for 5 hours at 100° C., then cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate is washed once with H2O and once with brine, the organic layer separated and dried over Na2SO4. Purification of the crude product by flash chromatography (dichloromethane/methanol) yields 0.52 g of 4-[4-(2-methoxy-ethyl)-piperazin-1-yl)]benzoic acid methyl ester as a solid.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O.O>[Si:22]([O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([OH:12])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.8 %

Procedure:
To a solution of vanillic acid (2.0 g, 11.89 mmol) in N,N-dimethylformamide (50 ml), imidazole (4.04 g, 59.45 mmol) and tert-butyldimethylchlorosilane (4.48 g, 29.72 mmol) were added. The reaction was stirred at room temperature for 24 hours. he mixture was poured in water (70 ml) solution and extracted with diethyl ether (3×70 ml) The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, column FLASH 40+M™ KP-C18 HS, eluent: gradient acetonitrile/water 65/35 (600 ml), to acetonitrile/water 80/20 during 1200 ml). The product (0.70 g) was obtained.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:5]1.[CH2:21](N(CC)CC)C.S(Cl)(C)(=O)=O.[OH2:33]>C(Cl)Cl>[OH:33][CH2:21][CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:5]1
Reactant: CCN(CC)CC
Reactant: O
Reactant: OCCC1C=C(c2ccccc2F)c2ccccc2C1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: OCCCC1C=C(c2ccccc2F)c2ccccc2C1
Temperature: -10 °C

Procedure:
To a solution of 17.2 g of 3-(2-hydroxy ethyl) 3,4-dihydro 1-orthofluorophenyl naphthalene [(IV), n=2] obtained in example 11 above in 200 ml of methylene chloride, cooled to -10° C., are added 22.3 ml of triethylamine then 10 ml of mesyl chloride. It is left at -10° C., and when the reaction is finished (checked by T.L.C.), it is diluted with water, washed with a dilute hydrochloric solution, then with water, then with a dilute sodium bicarbonate solution, then with water, dried on magnesium sulfate, filtered and the filtrate is evaporated. The crude product (22.2 g) is dissolved in 100 ml of DMSO and 25 g of sodium cyanide are added. The mixture is left for a night at ambient temperature, then diluted with water, extracted with chloroform, washed with water, dried on magnesium sulfate, filtered and the filtrate is evaporated. 18 g of the expected product (oily) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[CH2:25][CH2:26][CH3:27].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
6-Bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (80 mg, 0.28 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (112 mg, 0.38 mmol) and 1-hydroxy-7-azabenzotriazole (57.7 mg, 0.42 mmol) were stirred in 3 mL of DMSO for 10 min under nitrogen. N-Methylmorpholine (0.12 ml, 1.13 mmol) was added along with EDC (81 mg, 0.42 mmol) and the mixture was stirred at room temperature overnight under nitrogen. Ice-water was added and solids crashed out. Then 10% K2CO3 was added to adjust the pH to about 8-9. Then the reaction was stirred at room temperature for 10 min and let stand for 10 min. Solids were filtered off, dissolved in DMF and water was added. Solids that precipitated out were filtered off, air-dried for 15 min and dried in vacuum oven for 2 h to give the title compound (94 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.62 (t, J=4.93 Hz, 1H) 8.37 (s, 1H) 8.20 (s, 1H) 7.69 (d, J=1.26 Hz, 1H) 5.91 (s, 1H) 5.06 (dt, J=13.14, 6.57 Hz, 1H) 4.36 (d, J=4.80 Hz, 2H) 2.14 (s, 3H) 1.48-1.56 (m, 2H) 1.47 (s, 3H) 1.45 (s, 3H) 0.89 (t, J=7.33 Hz, 3H); MS(ES) [M+H]+ 445.1, 446.9.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[F:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][C:14]2([C:17]([CH3:21])([CH3:20])[CH2:18][F:19])[CH2:16][O:15]2)=[CH:10][CH:9]=1>C(O)CC>[F:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:14]([CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:23][CH:22]=1)([OH:15])[CH2:16][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(CF)C1(COc2ccc(F)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCCO
Product: CC(C)(CF)C(O)(COc1ccc(F)cc1)Cn1cncn1
Yield: 28.7 %

Procedure:
15.2 g (0.22 mol) of 1,2,4-triazole were added to 0.46 g (0.02 mol) of sodium in 200 ml of n-propanol. The solution was heated to the boil, and 48.5 g (0.2 mol) of 2-(4-fluorophenoxymethyl)-2-(fluoro-tert.-butyl)-oxirane, dissolved in 50 ml of n-propanol, were added dropwise. The reaction solution was stirred under reflux for a further 48 hours and was concentrated, and 200 ml ethyl acetate and 100 ml of water were added to the residue. The organic phase was separated off, washed twice with water, dried over sodium sulphate and concentrated. The residue was dissolved in ether, and the solution was gassed with hydrogen chloride. The precipitate formed was filtered off under suction and washed with ether, and ethyl acetate/1N sodium hydroxide solution were added. The crude product obtained was purified over a silica gel column (mobile phase: methylene chloride/ethyl acetate, 2:1), and recrystallised from acetonitrile. 17.9 g (29% of theory) of 4-fluoro-2-(4-fluorophenoxymethyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 97° to 99° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24]O)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-5-nitrophenol (5.06 g, 29.17 mmol), (S)-(−)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol (5.87 g, 29.17 mmol), and Ph3P (7.65 g, 29.17 mmol) in 50 mL THF, cooled to −15° C., was added dropwise, over 75 min, a solution of DIAD (6.02 g, 29.75 mmol). The reaction was warmed to RT and stirred for 18 h. The reaction was concentrated to dryness. The crude residue was treated with a small mix of Et2O and hexanes and sonicated so as to triturate out bulk of impurities, which were filtered off. The filtrate was concentrated to dryness. The resulting residue was purified by silica gel column chromatography using 7% EtOAc in hexanes to elute the title compound as a thick yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O.CCOCC>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCOc2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred solution 7.94 g (48.9425 mmol) of 4,4-dimethylchroman (Compound 76) in 70 ml of nitromethane was added under argon 4.0 g (50.96 mmol) of acetyl chloride followed by 6.8 g (51 mmol) of aluminum chloride. This was stirred at room temperature for 5.5 hours and then cooled in an ice bath and treated slowly with 70 ml of 6N hydrogen chloride. The resultant mixture was stirred at room temperature for 10 minutes and then treated with 100 ml ether and the organic layer separated. The organic layer was washed with water, saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 10% ethyl acetate in hexanes). This was followed by kugelrohr distillation (95-100 degrees C; 0.15 mm) to give the title compound as a colorless oil. PMR (CDCl3): δ 1.40 (6H), 1.95-2.00 (2H, m), 2.58 (3H), 4.25-4.30 (2H, m), 6.83 (1H, d, J~18.0 Hz), 7.62 (1H, dd, J~8.0 Hz, 1.5 Hz), 8.00 (1H, d, J~1.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]C)[CH:5]=[CH:4][C:3]=1[C:10](=[O:18])[CH:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].ClC1C=C(C=CC=1)C(OO)=O.CO.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[C:10](=[O:18])[CH:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CC(C)C(=O)c1ccc(SC)cc1Br
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)C(=O)c1ccc(S)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of the sulfide obtained in step B (3.59 g) in chloroform (30 c.c.) was added m-chloroperoxybenzoic acid (1.87 g) and the suspension was stirred for 1 hr. It was than warmed up to R.T. and Ca(OH)2 (1.11 g) was added and stirred for 45 min. Insolubles were filtered off and trifluoroacetic anhydride (10 g) was added to the filtrate and the mixture heated to reflux for 1 hr. Volatiles were removed in vacuo to yield a residue to which was added a solution of MeOH (50 c.c.) and triethylamine (50 c.c.); the mixture was then concentrated in vacuo to dryness and this process was repeated 3 times. The residue was finally taken up in ethyl acetate (100 c.c.) and washed with 1N HCl (3×25 c.c.), brine, dried and evaporated to dryness to yield the title compound as an oil which was used immediately in the following step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]#N)=[CH:13][CH:12]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:33])[C:30](O)=[O:31])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@H:29]([OH:33])[C:30]([N:8]([C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17][C:14]2[CH:15]=[N:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)=[O:31])=[CH:27][CH:28]=1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Reactant: Cc1ccc(N)cn1
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2ccc(F)cc2)cn1

Procedure:
In analogy to example 47, steps 2, 3 & 4, 6-Methyl-pyridin-3-ylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (4-Fluoro-phenyl)-oxo-acetic acid were successively coupled and reduced to give after separation by chromatography on a chiral column (+ve rotation) the target compound. MS(m/e): 434.1 [M+H]+.
Reaction SMILES: [CH2:1]=[O:2].[OH-].[Na+].[CH:5]1([CH:11]=[O:12])[CH2:10][CH2:9][CH:8]=[CH:7][CH2:6]1>O>[OH:12][CH2:11][C:5]1([CH2:1][OH:2])[CH2:10][CH2:9][CH:8]=[CH:7][CH2:6]1
Reactant: C=O
Reactant: O=CC1CC=CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC1(CO)CC=CCC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a 5-liter volume four-necked flask provided with a stirrer, a thermometer, a Dimroth condenser and a dropping funnel, 633.3 g (purity 92%, 19 mol) of paraformaldehyde dissolved in 1004.0 g of water was charged, 465.6 g of sodium hydroxide (purity 98.5%, 11.5 mol) dissolved in 1397.0 g of water were dropwise added. Next, the mixture was cooled in an ice bath to 10° C. and 880.7 g of 3-cyclohexene-1-carboaldehyde (purity 97%, 7.8 mol) was dropwise added over 1 hour to the mixture. After dropwise addition, the solution temperature was increased to 20° C. The mixture was stirred at that temperature for 1 hour, then the flask was immersed in a hot water bath and was further stirred at 55° C. for 1 hour. Next, the reaction mixture was cooled down to 15° C. in a water bath and the precipitated solid was obtained by filtration. The solid thus obtained was washed with water to obtain a wet crude crystal of 4,4-bis[(hydroxy)methyl]cyclohexene (II) in an amount of 1396.0 g.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]#[N:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH2:24][CH2:25]Cl)[CH2:21][CH2:22][Cl:23].Cl.Cl>CN(C)C=O.CCOCC>[ClH:23].[C:17]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:25][CH2:24][N:20]([CH3:19])[CH2:21][CH2:22]1)#[N:18]
Reactant: N#CCc1ccccc1Sc1ccccc1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CCC(C#N)(c2ccccc2Sc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.6 g of 99% sodium hydride are added portionwise to a solution of 4.4 g of 2-(phenylthio)phenylacetonitrile in 50 ml of dimethylformamide. The resulting reddish brown mixture is stirred for 30 minutes before adding dropwise a solution of 4.0 g of mechlorethamine hydrochloride in 50 ml of dimethylformamide, maintaining gas evolution at a slow rate. After total addition, the mixture is stirred at 80°-85° C. for 15 hours. Thereafter, 100 g of ice are added before the mixture is extracted thrice with ether. The combined ether extracts are dried over potassium carbonate and then the solvent is removed under vacuum leaving a brownish oil. The oil is dissolved in a small amount of ether and passed through, with additional ether, an alumina column which is packed in ether. The effluent is concentrated leaving an oil which is converted to its hydrochloride which is recrystallized from an acetone-ether mixture, leaving 4-cyano-1-methyl-4-(2-phenylthiophenyl)piperidine hydrochloride.
Reaction SMILES: [C:1]([O:5]C)(=O)[CH:2]=[CH2:3].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][CH2:13][C:14]2=[O:17])=[CH:10][CH:9]=1.[CH3:18][C:19](C)([O-])C.[K+].[OH-].[K+]>C1COCC1.CC(C)([O-])C.[K+]>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13]3([CH2:3][CH2:2][C:1](=[O:5])[CH2:19][CH2:18]3)[C:14]2=[O:17])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: C=CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Temperature: 20 °C
Reaction time: 6 h
Yield: 61.7 %

Procedure:
Methyl acrylate (6.6 L, 73 mol) was charged gradually in three equal portions (each 2.2 L, 24.6 mol) to a mixture of 6-bromo-1-indanone (8.00 kg, 37.9 mol), THF (16 L) and potassium tert-butoxide (210 g, 1.87 mol) at approximately 20-30° C. Additional potassium tert-butoxide (86 g, 0.77 mol), dissolved in THF (0.39 L), was charged after the first portion of methyl acrylate. More potassium tert-butoxide (86 g, 0.77 mol), dissolved in THF (0.39 L), was charged after the second portion of methyl acrylate. Further potassium tert-butoxide (4.64 kg, 41.3 mol) solution in THF (21 L) was then charged gradually at approximately 20-30° C. Solvent (21.5 L) was distilled off at approximately 65° C. and then a mixture of water (49 L) and 50%. aq KOH (2.3 L, 30 mol) was added over approximately 10 min. at below 60° C. The reaction was held at 60° C. for approximately 6 h., then cooled to 20° C. over 1 h. and then filtered after holding at 20° C. for approximately 12 h. The solids were washed with a mixture of water (8 L) and THF (4 L), and then dried to give the title compound (7.47 kg, at 92% w/w NMR assay, 23.4 mol, 62% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.78-1.84 (m, 2H), 1.95 (td, 2H), 2.32-2.38 (m, 2H), 2.51-2.59 (m, 2H), 3.27 (s, 2H), 7.60 (d, 1H), 7.81 (m, 1H), 7.89 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:40])[CH:3]([NH:20][C:21]1[CH:39]=[CH:38][C:24]([C:25]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([O:35]CC)=[O:34])[CH2:28]2)=[O:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:11]2)=[CH:6][C:5]=1[CH3:19].C1COCC1.[OH-].[Na+]>C(O)C>[CH3:1][CH:2]([CH3:40])[CH:3]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([OH:35])=[O:34])[CH2:28]2)=[O:26])=[CH:38][CH:39]=1)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:11]2)=[CH:6][C:5]=1[CH3:19]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(c3ccc(-n4cc5c(n4)CCCC5)cc3C)C(C)C)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a mixture of ethyl (3R)-1-(4-((2-methyl-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)propyl)amino)benzoyl)piperidine-3-carboxylate (152.3 mg), THF (0.56 mL) and ethanol (0.56 mL) was added 1M aqueous sodium hydroxide solution (0.561 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, the reaction mixture was neutralized with 1M hydrochloric acid (0.561 mL), and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (140.4 mg).
Reaction SMILES: [NH2:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[CH:7]=3)=[CH:4][C:3]=1[F:21].[Br:22]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[C:7]=3[Br:22])=[CH:4][C:3]=1[F:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(N)c(Cl)c1C2
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(N)c(Cl)c1C2
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A solution of 7-amino-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.36 g, 4.42 mmol) in anhydrous CH2Cl2 (13 mL) was cooled in an ice bath, placed under a nitrogen atmosphere, treated with N-bromosuccinimide (0.787 g, 4.42 mmol) and stirred at 0–5° C. for one hour. The reaction mixture was filtered through a pad of silica gel and the pad was washed with EtOAc. The filtrate and washings were evaporated under vacuum. The residue was purified by flash chromatography on a Biotage 40M column using 10:1 hexanes-EtOAc as eluting solvent. The product containing fractions were evaporated under vacuum to afford 7-amino-4-bromo-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.08 g, 63%) as a yellow solid.