Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][CH:12]([CH3:18])[CH:13](OC)OC)=[S:10])[CH:5]=[CH:6][CH:7]=1>O.Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([CH3:18])[N:11]=[C:9]2[SH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(C)NC(=S)Nc1cccc(Br)c1
Agent: Cl
Solvent: O
Product: Cc1cn(-c2cccc(Br)c2)c(S)n1
Yield: 68.9 %

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)pyridine (example A.31) (400 mg, 1.09 mmol) and 4-methyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole [in situ prepared by the following sequence: Step 1) A mixture of commercially available 3-bromophenylisothiocyanate (10.06 g, 47.0 mmol) and 2-aminopropionaldehyde dimethylacetal (5.96 mL, 47.0 mmol) in EtOH (50 mL) was refluxed for 1 h. Evaporated to dryness to give 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methylethyl)-thiourea as an off-white solid (15.69 g, 100%). Step 2) A mixture of the above prepared 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methyl-ethyl)-thiourea (15.69 g, 47 mmol) in H2O (85 mL) and 37% HCl (8.5 mL) was refluxed for 4.5 h. Removed from oilbath, added ice and ice water (total volume: 250 mL), the precipitate was filtered off, washed several times with ice water and dried in vacuum at 60° C. to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole-2-thiol as a light orange solid (8.71 g, 69%). Step 3) To a suspension of the above prepared 1-(3-bromophenyl)-4-methyl-1H-imidazole-2-thiol (6.00 g, 22 mmol) in acetic acid (20 mL) and water (5 mL) was added dropwise 35% H2O2 (13.4 mL, 156 mmol) within 15 min keeping the internal temperature below 60° C. Stirred at 23° C. for 30 min, poured onto ice, destroyed excess H2O2 by addition of sat. Na2SO3-sol., adjusted pH with 32% NaOH-sol. until pH 9 is reached, extracted with EtOAc (3×100 mL), the combined organic layers were washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a red oil, which was purified by silica gel column chromatography with EtOAc to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole as a brown oil (3.80 g, 72%). Step 4) A mixture of the above prepared 1-(3-bromo-phenyl)-4-methyl-1H-imidazole (0.313 g, 1.31 mmol), bis(pinacolato)diboron (0.364 g, 1.438 mmol), potassium acetate (0.389 g, 3.96 mmol) and PdCl2(PPh3)2 (0.023 g, 3 mol %) in DMF at 100° C. for 2 h; then addition of Pd(OAc)2 (0.007 g, 3 mol %) and dppf (0.018 g, 3 mol %) and stirred at 100° C. overnight. This solution obtained was used directly.] according to the general procedure VI. Obtained as an off-white solid (0.140 g, 32%). MS (ISP) 394.0 [(M+H)+]; mp 126-132° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[CH2:14]([O:13][C:11]([NH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)O)NC(=O)OCc1ccccc1
Temperature: 2.5 °C
Yield: 44.3 %

Procedure:
Into a 2000-mL 4-necked round-bottom flask was placed a solution of 3-aminobutanoic acid (100 g, 969.75 mmol, 1.00 equiv) in water (1000 mL), followed by the addition of potassium hydroxide (136 g, 2.42 mol, 2.50 equiv) in several batches. To this was added benzyl chloroformate (247 g, 1.45 mol, 1.50 equiv) dropwise with stirring at 0-5° C. The resulting solution was stirred at 25° C. for 5 h. The reaction progress was monitored by LCMS. The resulting solution was extracted with 3×250 mL of dichloromethane and the aqueous layers were combined. The pH value of the water phase was adjusted to 3 with hydrogen chloride (2 mol/L). The precipitates were collected by filtration and dried to afford 102 g (44%) of 3-[[(benzyloxy)carbonyl]amino]butanoic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([F:23])[CH:25]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2cccc(F)c2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 3-fluorobenzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-fluorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 452.1 (M)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[N:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[N:10]=[C:11]([S:14][CH3:15])[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:31])C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[N:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[N:10]=[C:11]([S:14]([CH3:15])=[O:31])[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCOC(=O)c1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reaction time: 24 h
Yield: 67.6 %

Procedure:
8-Cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (1.2 g, 3.6 mmol) was dissolved in CH2Cl2 (20 mL) and treated with 2-benzenesulfonyl-3-phenyl-oxaziridine (1.13 g, 4.32 mmol) at room temperature and stirred for 1 day. Following concentration under reduced pressure, the crude reaction mixture was chromatographed on silica gel eluting with ethyl acetate to give 8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a white solid (0.85 g, 68%). MS (APCI); M++1: Calc'd, 350.1. Found 350.0.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[C:27]1[CH:36]=[CH:35][C:30]([C:31](OC)=[O:32])=[CH:29][CH:28]=1)=[O:20].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:32][CH2:31][C:30]1[CH:29]=[CH:28][C:27]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][N:21]2[C:19](=[O:20])[CH2:18][C@H:3]2[N:4]([S:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:15])=[CH:16][CH:17]=3)(=[O:10])=[O:9])[CH:5]=[CH:6][NH:7][C:2]2=[O:1])=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc([C@H]2CCCCN2C(=O)CC2C(=O)NC=CN2S(=O)(=O)c2ccc(C)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)N2CCCCC2c2ccc(CO)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of (R)-methyl 4-(1-(2-(3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetyl)piperidin-2-yl)benzoate (0.562 g, 1.10 mmol) in CH2Cl2 stirred in dryice-acetone bath under N2 was added DIBAL (1.0M solution in CH2Cl2, 5.50 ml, 5.50 mmol) via syringe over 15 min, and stirred for 30 min. The cold bath was removed and after 2 h MeOH (6.0 ml) was added followed by Na2SO4 (12.0 g) and sat'd NH4Cl aq. (0.30 ml). After 30 min the mixture was filtered and the filtercake was washed with CH2Cl2/MeOH (10/1). The filtrate was concentrated under reduced pressure and the residue was chomatographed on silica (CH2Cl2→CH2Cl2/MeOH=20/1) to yield the product. MS 482.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: CO
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)ccc1N
Yield: 76 %

Procedure:
2-Amino-5-bromobenzoic acid (80 g, 0.37 mmol) was dissolved in MeOH (600 mL) and a solution of H2SO4 (50 mL) was slowly added. The reaction mixture was refluxed for 72 h, then concentrated. NaOH solution was added to adjust the pH to 10-11. The mixture was extracted with EtOAc (3×500 mL). The combined organic layer was dried over MgSO4, concentrated to afford the desired compound (65 g, yield: 76%) as a colorless oil, which is used directly in the next step without purification.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23](=[O:38])[CH2:24][NH:25][CH2:26][C:27]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:12]>C(OCC)(=O)C>[CH3:12][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:20])[CH3:21])[C:14]=1[NH:22][C:23](=[O:38])[CH2:24][N:25]([C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[CH2:26][C:27]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:10]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(CC1(c2ccccc2)CCCC1)C(=O)Nc1ccccc1
Reaction time: 96 h

Procedure:
Phenylisocyanate (0.092 g) was added to a solution of the product of Example 6 (0.250 g) in a few mL ethyl acetate at room temperature. The reaction mixture was allowed to sit 4 days at room temperature, concentrated, and the resulting white solid collected by filtration from a slurry in hexane. 0.30 g (94%). NMR (CDCl3) δ 1.14 (12H, d), δ 1.59-2.10 (8H, m), δ 3.04 (2H, m), δ 3.61 (2H, s), δ 4.12 (2H, bs), δ 5.55 (1H, s), δ 6.77-7.51 (13H, m), δ 8.26 (1H, bs). IR (KBr) 2963, 2871, 1668, 1599, 1534, 1501, 1446, 1312, 1240, 703 cm-1.
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([OH:12])=O)[CH2:4][F:5].[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][C:27]([NH2:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:7]([O:6][CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH:8]=2)=[N:26]1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
Reactant: Cc1cc(N)nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2cc(OCc3ccccc3)cc(OC(CF)CF)c2)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A solution of 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (2.96 mmol) in DMF (5 mL) was treated with 1,5-dimethyl-1H-pyrazol-3-ylamine (3.11 mmol), DIPEA (5.93 mmol) and HATU (3.85 mmol) and stirred at RT overnight. The mixture was poured into water (100 mL) and extracted with ethyl acetate (3×75 mL). The organics were washed with brine, dried (MgSO4) and evaporated in vacuo before chromatography on solica, eluting with 50-100% ethyl acetate in isohexane, to give the desired compound as a colourless glass (784 mg). 1H NMR δ (d6-DMSO): 2.81 (s, 3H), 3.67 (s, 3H), 4.66 (m, 2H), 4.78 (m, 2H), 5.04 (m, 1H), 5.69 (s, 2H), 6.43 (s, 1H), 6.85 (t, 1H), 7.28 (m, 1H), 7.32 (m, 1H), 7.35 (m, 1H), 7.41 (m, 2H), 7.47 (m, 2H), 10.64 (s, 1H); m/z 416 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:20]([O:22][CH3:23])=[O:21])([C:6]4[C:11]3=[CH:10][CH:9]=[C:8]([N+:17]([O-])=O)[CH:7]=4)[C:4]=2[CH:3]=1>C(O)C>[NH2:17][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]3[CH2:16][C:5]([C:20]([O:22][CH3:23])=[O:21])([C:4]4[C:13]3=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=4)[C:6]=2[CH:7]=1
Reactant: COC(=O)C12CC(c3ccc(Cl)cc31)c1ccc([N+](=O)[O-])cc12
Solvent: CCO
Product: COC(=O)C12CC(c3ccc(N)cc31)c1ccc(Cl)cc12
Temperature: 0 °C
Yield: 75.6 %

Procedure:
To a suspension of methyl 2-chloro-7-nitro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in example 35b) (7.36 g, 22.32 mmol) in ethanol (150 mL) was added stannous chloride dihydrate (25.2 g, 112 mmol, 5 eq). The reaction was heated to reflux at which time it became homogeneous. After heating for 2.5 h, the solution was cooled to 0° C. and quenched with ice followed by 10% NaOH (200 mL). The aqueous phase was extracted with ethyl acetate (3×150 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to a solid. The reaction product was purified by flash chromatography over silica gel (400 mL, eluent: 25% ethyl acetate in hexane) to yield 5.06 g (76%) of the title compound. TLC analysis (Rf 0.16, 30% ethyl acetate in hexane). MS (CI, CH4) m/z 300 (M+1,100), 302 (33), 328 (M+29,9), 264 (12), 182 (11), 121 (11), 89 (44)
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:9]2[O:10][C:11](=[O:18])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:17]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].C(N(CC)CC)C.Cl.[Cl:29][CH2:30][CH2:31][N:32]1[CH2:38][CH:37]2[CH2:39][CH2:40][CH:34]([CH2:35][CH2:36]2)[CH2:33]1>>[ClH:29].[ClH:1].[CH:37]12[CH2:39][CH2:40][CH:34]([CH2:35][CH2:36]1)[CH2:33][N:32]([CH2:31][CH2:30][N:14]1[CH2:15][CH2:16][C:17]3[C:8]4[CH:7]=[CH:6][C:5]([O:19][CH3:20])=[C:4]([O:3][CH3:2])[C:9]=4[O:10][C:11](=[O:18])[C:12]=3[CH2:13]1)[CH2:38]2
Reactant: COc1ccc2c3c(c(=O)oc2c1OC)CNCC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c3c(c(=O)oc2c1OC)CN(CCN1CC2CCC(CC2)C1)CC3
Yield: 8.8 %

Procedure:
Prepared by the method described in Example 9 from 1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one hydrochloride (6.0 g, 0.020 moles), triethylamine (4.0 g, 0.040 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (5.4 g, 0.024 moles). Recrystallization from 95% ethanol and then from methanol yielded the product (0.85 g) as the dihydrochloride, mp 255°-258° C.
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][CH:9]3[CH2:17][C:18](=O)[NH:19][CH2:20][CH2:21][N:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C1C=CC=CC=1>>[C:1]1([CH:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][CH:9]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][N:8]23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC2Cc3ccccc3C(c3ccccc3)N2CCN1
Solvent: O=C(Cl)c1ccccc1
Product: c1ccc(C2c3ccccc3CC3CCNCCN32)cc1

Procedure:
(7 RS,12aRS)-1,4,5,7,12,12a-hexahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinolin-2(3H)-one [M.P. 232°-234°] was produced in analogous manner to Examples 1 (a) and (b) using benzoyl chloride instead of p-anisolyl chloride. Reduction analogous to Example 1 gave (7 RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline (M.P. of maleate 204°-205°).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:2]=1.Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:11][CH2:10]2)[CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: c1cncc(C(OC2CCNCC2)c2ccsc2)c1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2cccnc2)c2ccsc2)CC1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(3-pyridyl)-3-thienylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(3-pyridyl)-3-thienylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:13][CH2:14][CH2:15][OH:16].II.C(OCC)(=O)C>C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][S:13][CH2:14][CH2:15][OH:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCS
Reactant: SCCc1ccc2c(c1)OCO2
Agent: II
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: OCCSSCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
35 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 75 g of 2-mercaptoethanol were dissolved in 150 ml of ethanol, followed by the addition of 43 g of iodine. The obtained mixture was stirred at a room temperature for 30 minutes, followed by the addition of 2 l of ethyl acetate and 2 l of water. The mixture was separated into two phases. The ethyl acetate layer was washed with water twice, then with 1 l of a 1% aqueous solution of sodium hydrogensulfite twice and finally with water thrice, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (benzen/ethyl acetate=10:1) to obtain 11.5 g of the title compound as a colorless oil.
Reaction SMILES: CO[C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19].[CH3:29][O-:30].[Na+]>>[CH2:26]([CH:23]([N:22]1[C:7]2[N:8]=[C:9]([O:30][CH3:29])[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[CH3:19])[C:6]=2[CH:5]=[CH:4][C:3]1=[O:28])[CH2:24][CH3:25])[CH3:27]
Reactant: C[O-]
Reactant: CCC(CC)Nc1nc(SC)nc(-c2ccc(F)cc2C)c1/C=C/C(=O)OC
Agent: [Na+]
Product: CCC(CC)n1c(=O)ccc2c(-c3ccc(F)cc3C)nc(OC)nc21

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(1-ethyl-propylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and sodium methoxide to afford the title compound 8-(1-ethyl-propyl)-4-(4-fluoro-2-methyl-phenyl)-2-methoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 0.89 (m, 6H), 2.02 (m, 2H), 2.22 (s, 3H), 2.33 (m, 2H), 3.39 (m, 2H), 4.09 (s, 3H), 5.35 (m, 0.5H), 5.62 (m, 0.5H), 6.41 (br d, 1H, J=9.6 Hz), 7.03 (m, 2H), 7.28 (m, 2H). LC MS (m/e)=356 (MH+). Rt=2.50 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([C:19](OC)=[O:20])[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19][OH:20])[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)CN2Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CN(Cc2ccccc2)c2ncc(CO)cc2N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Methyl 4-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate (600 mg, 2.02 mmol) was taken up in tetrahydrofuran (25 mL) in an inert environment. To the stirred suspension at room temperature was added NaH (60% dispersion in mineral oil, 121 mg, 3.03 mmo) and stirred 30 min. The reaction was then cooled to −78° C. and lithium aluminum hydride (3 mL, 2M in THF) was added. The reaction was stirred at a temperature between −20 and −10° C. for 2 h. The reaction was then cooled back to −78° C. and MeOH (1 mL) followed by water (1 mL) was added. The reaction was allowed to stir at ambient temperature for 2 h and then poured into ethyl acetate (200 mL) and water (100 mL). The biphasic mixture was stirred vigorously and then filtered through a medium frit. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine (100 mL), dried with sodium sulfate and concentrated to afford the title compound (540 mg, 99%) as a white solid. [M+H] calc'd for C15H15N3O2, 270; found, 270.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:42])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37].[BH4-].[Na+].[Cl-].[Na+]>C(O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:42])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:40])([F:41])[C:36]([F:37])([F:38])[F:39]
Reactant: CN(CCCCCCCC(F)(F)C(F)(F)F)CCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CN(CCCCCCCC(F)(F)C(F)(F)F)CCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
89 mg of 11β-fluoro-3-hydroxy-7α-{6-[methyl-(8,8,9,9,9-pentafluorononyl)amino]hexyl}oestra-1,3,5(10)-trien-17-one are dissolved in 2 ml of ethanol and treated with 22 mg of sodium borohydride. After stirring at room temperature for 1 hour, the solvent is for the most part stripped off in vacuo, the residue is treated with sodium chloride solution, and the mixture is extracted 3 times with methylene chloride, dried over magnesium sulphate and concentrated in vacuo. Preparative thin-layer chromatography using methylene chloride/methanol=9/1 as an eluent leads to 53 mg of 11β-fluoro-7x-{5-[methyl-(8,8,9,9,9-pentafluorononyl)amino]hexyl}oestra-1,3,5(10)-triene-3,17β-diol are obtained as a foam, [α]D=+32° (c=1.0 in chloroform).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.C[N-]OC.[Li][CH2:16][CH2:17][CH2:18][CH3:19]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](=[O:10])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:2]=1
Reactant: [Li]CCCC
Reactant: O=C(O)Cc1cccnc1
Agent: C[N-]OC
Product: CCCCC(=O)Cc1cccnc1

Procedure:
In another example of the general procedure (scheme 2), readily available pyridin-3-yl-acetic acid (10) is converted to the N-methyl-N-methoxyamide derivate (12), which is reacted with BuLi to produce 1-pyridin-3-yl-hexan-2-one (13). N,N-dimethylformamide dimethylacetal treatment of 13 furnished the enamine (14) which is converted to the pyrazol (15). The synthesis of 3-(4-Butyl-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (16) is illustrated in scheme 2 according to the two step sequence shown in scheme 1.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10])=[O:5].Cl.[NH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([NH:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:10])=[O:5]
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: NN1CCOCC1
Agent: Cl
Product: Cc1ccc(C(=O)NN2CCOCC2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
Compound 424 (50 mg, 0.12 mmol) and N-amino-morpholine hydrochloride (35 mg, 0.25 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 67/33 to 100/0) provided the title compound. 13C NMR (DMSO-d6) δ 194.5, 168.2, 158.9 (dd), 155.8 (dd), 149.5, 139.1, 138.2, 133.7, 133.7, 132.9, 131.3, 129.3, 127.5, 126.5 (dd), 126.5, 124.3 (dd), 114.8, 112.0 (dd), 111.9, 105.1 (dd), 66.0, 19.7