Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([F:26])[F:25])[CH:19]=2)[CH:17]=1)(=[O:7])=[O:6].[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28].[BH4-].[Na+].[Cl:42]CCl>CO>[ClH:42].[ClH:42].[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([F:26])[F:25])[CH:19]=3)[CH:17]=2)(=[O:7])=[O:6])=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: ClCCl
Reactant: O=CCCc1ccc([N+](=O)[O-])cc1
Reactant: NCCNS(=O)(=O)c1cc(-c2cccc(C(F)F)c2)cc2cnccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=[N+]([O-])c1ccc(CCCNCCNS(=O)(=O)c2cc(-c3cccc(C(F)F)c3)cc3cnccc23)cc1
Reaction time: 8 h
Yield: 48 %

Procedure:
Dissolve 7-(3-Difluoromethylphenyl)-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide (0.060 g, 0.16 mmol) in a mixture of dichloromethane and methanol (5:1, 15 mL). To the solution add 3-(4-nitrophenyl)-propionaldehyde (0.043 g, 0.24 mmol) as a solution in dichloromethane and stir overnight. Add sodium borohydride (0.025 g, 0.67 mmol). Evaporate the solvent and purify the residue by silica gel chromatography to give the free base of the desired compound (0.042 g, 48% yield): 1H NMR (CDCl3/CD3OD): δ9.40 (s, 1H), 8.70 (m, 2H), 8.40 (m, 2H), 8.10 (m, 2H), 7.85 (m, 2H), 7.62 (m, 2H), 7.26 (m, 2H), 6.73 (t, J=52.1 Hz, 1H), 3.00 (m, 2H), 2.64 (m, 4H), 2.42 (t, J=7.0 Hz, 2H), 1.67 (m, 2H). ESIMS: m/z 541 (M+H)+. Form the dihydrochloride salt by suspending the free base in ethyl acetate, cooling to 0° C., and adding 4M HCl in 1,4-dioxane dropwise. Filter the precipitate and wash with dichloromethane then dry in vacuum to give the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1(=[O:20])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1C=CC=CC=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:13]2=[O:20])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C1NCCCCC1C(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A mixture of 4-nitrobenzoyl chloride (50.16 g, 0.27 mol), freshly distilled ε-caprolactam (30.59 g, 0.27 mol), and 500 ml of benzene are added to a 1L three-necked round-bottom flask equipped with an overhead stirrer, condenser and a nitrogen inlet tube. The solution is heated to 90°-100° C. and after all the solids are dissolved, 160 ml of pyridine is added. White pyridine salts form immediately, the reaction solution being kept at 90°-100° C. for 1 hour. The pyridine salts are removed by filtration, and the solvent is separated from the filtrate under reduced pressure. The residue is washed with a 5 percent NaHCO3 aqueous solution and with distilled water several times before being dried. The product is then recrystallized from a mixture of ethyl acetate and hexane to obtain 67 g (95 percent) of white crystals: mp 105°-106° C.
Reaction SMILES: CC1C=CC=C(C)N=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18](Br)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1.[OH:24][CH2:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][N:32]2[CH3:35])=[CH:28][CH:27]=1>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18]([C:30]3[C:29]4[C:33](=[CH:34][C:26]([CH2:25][OH:24])=[CH:27][CH:28]=4)[N:32]([CH3:35])[CH:31]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: Cn1ccc2ccc(CO)cc21
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Temperature: 80 °C
Yield: 77.3 %

Procedure:
2,6-Dimethylpyridine (0.12 ml) was added to a stirred solution of methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from step (c), 273 mg, 1 mmol) and 6-(hydroxymethyl)-1-methylindole (from step (a), 161 mg, 1 mmol) in anhydrous dimethylformamide (2 ml) at ambient temperature, under a nitrogen atmosphere. The solution was heated to 80° C. for 3 hours. The reaction mixture was cooled, and partitioned between diethylether and water, separated and the organic layer dried (magnesium sulphate) and evaporated in vacuo. The residue was flash chromatographed (using diethyl ether as eluant) to give the subtitle compound as a colourless foam (273 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C([Cl:14])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1.N1C=CC=CC=1>ClCCl.CN(C=O)C>[ClH:14].[NH2:1][C:2]1[C:3]([C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccc(Cl)cn1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: Nc1ncccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a stirring suspension of 2-aminonicotinic acid (26.9 g, 194 mmol) in dichloromethane (120 mL) at 0° C., was added DMF (a few drops), followed by oxalyl chloride (20 mL, 194 mmol). The cold bath was removed, and the solution was allowed to stir for 60 min at room temperature. This solution was then transferred via cannula into a stirring solution of 2-amino-5-chloropyridine (25 g, 194 mmol) and pyridine (78 mL, 970 mmol) in dichloromethane (100 mL). After stirring overnight, the precipitate was filtered and dried to give 32.8 g of solid. The crude product was recrystallized from ethanol with activated charcoal to give the amide (12.4 g, 23%) as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[C:19]1([C:25]2[CH:26]=[C:27]([C:34](Cl)=O)[S:28][C:29]=2[C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:19]1([C:25]2[CH:26]=[C:27]([C:34]3[O:18][N:17]=[C:15]([C:13]4[S:14][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=4)[N:16]=3)[S:28][C:29]=2[C:30]([F:33])([F:31])[F:32])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: OCc1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)s1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1e) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxythiophene-2-carboximidamide (0.43 g, 1.5 mmol) that was obtained in Example 4 (4b), 4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyl chloride (0.52 g, 1.8 mmol), N,N-diisopropylethylamine (0.52 ml, 3.0 mmol), and a 1.0 M solution of tetrabutylammonium fluoride (3.0 ml, 3.0 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:2) as the eluent to afford the title compound (0.60 g) in a yield of 99% as a white crystalline solid.
Reaction SMILES: [C:1]([C:4]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH2:7][CH:8]([OH:21])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)(=[O:3])[CH3:2].[O-:27][CH2:28][CH3:29].[Na+].[Na].[CH2:32]([OH:34])[CH3:33]>C(OCC)(=O)C(OCC)=O.CCOCC>[C:28]([C:29]1[O:26][C:25]2[C:4]([C:1](=[O:3])[CH:2]=1)=[C:5]([O:6][CH2:7][CH:8]([OH:21])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1)[CH:22]=[CH:23][CH:24]=2)([O:34][CH2:32][CH3:33])=[O:27]
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1cccc(C(F)(F)F)c1
Reactant: CCO
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc(C(F)(F)F)c3)cccc2o1

Procedure:
A suspension of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3 -(m-trifluoromethylphenoxy) propane (29.6 g) in diethyl oxalate (30 ml) was added to a suspension of sodium ethoxide, prepared from sodium (6.0 g) and ethanol (60 ml) in dry ether (400 ml). The resulting solution was heated under reflux for 2 hours, cooled, and poured onto ice (200 g). After acidification with a solution of acetic acid (24 ml) in water (160 ml), the ether layer was separated, and the aqueous layer extracted with ether (3 × 50 ml). The combined extracts were evaporated under reduced pressure, and the residue dissolved in ethanol (96%, 100 ml) to which hydrochloric acid (20 drops) was added. This solution was heated under reflux for 1 hour, and the ethanol then removed under reduced pressure to give a beige solid, which was crystallized from aqueous ethanol to yield 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-3-(m-trifluoromethylphenoxy) propane (19.5 g) as white needles m.p. 70°- 75° C.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH:16]=[O:17])=[C:11]([Cl:18])[CH:10]=1)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[Cl:15][C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([Cl:18])[C:12]=1[CH:16]=[O:17])[NH:8][CH3:1]
Reactant: CN(Cc1ccccc1)c1cc(Cl)c(C=O)c(Cl)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CNc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of N-benzyl-3,5-dichloro-4-formyl-N-methylaniline (820 mg) in ethyl acetate (10 ml) was added palladium hydroxide (80 mg) under nitrogen atmosphere. This mixture was stirred under hydrogen atmosphere under atmospheric pressure at ambient temperature for one and half an hour. The precipitate was dissolved into chloroform and filtered through celite and the filtrate was concentrated in vacuo. The residual solid was suspended in diisopropyl ether and warmed at 90° C. After being stirred and cooled, the solid was collected by filtration to afford 3,5-dichloro-4-formyl-N-methylaniline (470 mg) as a pale brown solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(C[AlH]CC(C)C)C.Cl[Si:18]1([CH3:22])[CH2:21][CH2:20][CH2:19]1.O>CCCCCC>[CH3:22][Si:18]1([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:21][CH2:20][CH2:19]1
Reactant: C#CCCCCC
Reactant: C[Si]1(Cl)CCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: O
Product: CCCCCC#C[Si]1(C)CCC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 4 %

Procedure:
To a solution of 1-heptyne (2.62 mL, 1.91 g, d=0.7328, 20.0 mmol) in n-hexane (7 mL) was added a solution of DIBAL-H (20 mL, 1.0 M in n-hexane, 20.0 mmol 1.0 equiv) at −78° C. The reaction mixture was heated at 50° C. for 2 h, then was cooled to 0° C. 1-Chloro-1-methylsilacyclobutane (2.41 g, 20.0 mmol, 1.0 equiv) was added dropwise with syringe to the reaction mixture at 0° C., which was stirred for 48 h at 50° C. Cold water (1.28 mL, 71 mmol, 3.5 equiv) was added to the action solution carefully at 0° C. The resulting white suspension was filtered through Celite and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (SiO2, pentane) and distillation to afford 2.96 g (81%) of (E)-1 as a colorless oil. 1-Methyl-(1-heptynyl)silacyclobutane (145 mg, 8%) was also isolated after column chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C1CCCCC1.[CH2:25]([O:32][C:33]1[C:34]([CH2:44][CH:45]=[O:46])=[CH:35][C:36]([Cl:43])=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([O:32][C:33]1[C:34]([CH2:44][CH:45]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[S:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[CH:3]=2)[OH:46])=[CH:35][C:36]([Cl:43])=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(-c2cccc(Br)c2)s1
Reactant: O=CCc1cc(Cl)c2cccnc2c1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc(-c2cccc(C(O)Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)c2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirring solution of 2-(3-bromo-phenyl)-5-methyl-thiophene (0.395 mmol) in tetrahydrofuran (4 mL) at −78° C. was slowly added a 2M solution of n-butyllithium in cyclohexane (0.435 mmol, 1.1 eq.). The resulting solution was stirred 30 min at −78° C. and solid [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (0.395 mmol) was added. Stirring at −78° C. was continued for 10 min and the reaction was allowed to warm to room temperature and was stirred 1 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give a yellow oil that was purified by column chromatography using 20% ethyl acetate/hexanes to give the final product as a light yellow solid (0.18 mmol, 46%). MS (ESI) m/z 486.4.
Reaction SMILES: [CH3:1][OH:2].Cl[CH2:4][N:5]([CH3:10])[S:6]([Cl:9])(=[O:8])=[O:7].C1CCCCC1>C(N(CC)CC)C>[CH3:1][O:2][CH2:4][N:5]([CH3:10])[S:6]([Cl:9])(=[O:8])=[O:7]
Reactant: CO
Reactant: CN(CCl)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: COCN(C)S(=O)(=O)Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
500 parts of methanol are added in the course of 2 minutes at 25° C. to a mixture of 400 parts of N-chloromethyl-N-methylsulfamic acid chloride and 1,000 parts of cyclohexane. 227 parts of triethylamine are then added in the course of 30 minutes at from 0° to 7° C. The reaction mixture is then stirred for one hour at 40° C., after which it is concentrated under reduced pressure. The hydrochloride which has precipitated is filtered off and the filtrate is distilled, giving 282 parts (72% of theory) of N-methoxymethyl-N-methylsulfamic acid chloride of boiling point 84°-87° C./12 mbar and nD25 =1.4536.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:4]=[CH:3][C:2]([C:36]6[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=6)=[CH:7][CH:6]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:29][CH2:30]1
Reactant: OB(O)c1ccncc1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4ccncc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Yield: 44 %

Procedure:
(11β,16α,17β)-11-(4-Bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 4-pyridinylboronic acid were applied as described in example 1 step h. Purification by HPLC followed by crystallisation (acetonitrile/water) gave the product (44% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.84-2.85 (m, 24H), 4.46 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.26-7.30 (m, 2H), 7.48-7.50 (m, 2H), 7.55-7.59 (m, 2H), 8.63-8.65 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[CH:34]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cccc(OC)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-methoxy-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.82 min; Mass spectrum (ESI+): m/z=487 [M+Na]+.
Reaction SMILES: C([N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13](=[O:18])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>O.[Pd]>[CH3:17][N:14]1[C:15](=[O:16])[C:10]2[CH2:9][NH:8][CH2:20][CH2:19][C:11]=2[NH:12][C:13]1=[O:18]
Reactant: Cn1c(=O)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c2c(c1=O)CNCC2
Yield: 179.8 %

Procedure:
A solution of 96 g of 6-benzyl-3-methyl-5,6,7,8-tetra-hydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione from c) in 1.5 1 of glacial acetic acid was debenzylated by hydrogenolysis for 6 h on 14.6 g of 10% palladium/activated charcoal at 25° C. and 3.5 bar. After the catalyst had been filtered off, the filtrate was concentrated under reduced pressure. The above preparation was repeated. The two crude products were combined, dissolved in water and precipitated, with stirring, by the addition of 33% sodium hydroxide solution to pH 6.9. The precipitate was washed with water and dried at 60° C. under reduced pressure to give 115.3 g of 3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].C1(NC2CCCCC2)CCCCC1>CC(C)=O>[S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)([O:7][CH2:6][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=[CH:9][C:8]=1[N+:12]([O-:14])=[O:13])(=[O:17])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CO
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)OCc2c([N+](=O)[O-])cccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A solution was prepared containing 2 grams of the 2,6-dinitrobenzyl alcohol and 2.37 grams of tosyl chloride in 15 ml of dry acetone (20 degrees Centigrade). A solution of dicyclohexyl amine (2.25 ml in 5 ml of dry acetone) was added dropwise to the 2,6-dinitrobenzyl alcohol mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then treated as described above for the preparation of 2,6-dinitrobenzyl alcohol. After recrystallization, 2.3 grams of 2,6-dinitrobenzyl tosylate was obtained.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N+:16]([CH2:19][CH2:20][CH2:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)[NH:10][N:9]=1)[CH3:7].[BH4-].[Na+]>CO>[CH2:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:30])[CH2:15][CH:14]=2)[NH:10][N:9]=1)[CH3:7]
Reactant: CCc1cc(-c2cc[n+](CCCC(=O)c3ccc(F)cc3)cc2)[nH]n1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: CCc1cc(C2=CCN(CCCC(O)c3ccc(F)cc3)CC2)[nH]n1
Temperature: 0 °C

Procedure:
To a 2.2 g. portion of 4-(3-ethyl-5-pyrazolyl)-1 -(3-p-fluorobenzoylpropyl)pyridinium perchlorate, prepared as described in Example 2, in 100 ml. of methanol is added portionwise with stirring 2.2 g. of sodium borohydride. The mixture is stirred for 2 hours and then poured into ice water causing formation of a white solid which was collected and recrystallized from methanol, m.p. 140.5°-141.5° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(C)(C)C#N)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(O)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
Add anhydrous dichloromethane (400 mL) to 2-(4-methoxy-phenyl)-2-methyl-propionitrile (11.93 g, 68.1 mmol) and cool to −78° C. under nitrogen. Then add boron tribromide (33.0 mL, 349 mmol) and stir at −78° C. for 30 minutes. Remove the dry ice/acetone bath and allow the reaction to warm to room temperature. Stir for 3 h and then pour the reaction onto ice. Extract with ethyl acetate (2× 150 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 35% ethyl acetate/hexanes to yield 9.79 g (89%) of 2-(4-hydroxy-phenyl)-2-methyl-propionitrile: TLC: Rf in 40% ethyl acetate/hexanes: 0.38; 1H NMR (CDCl3): 7.34-7.32 (m, 2H), 6.86-6.83 (m, 2H), 5.23 (s, 1H), 1.70 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>O1CCCC1>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([NH:16][S:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=3)(=[O:29])=[O:28])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N1CCc2ccc(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)cc2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g (2.68 mmol) of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-amine and 947 mg (3.87 mmol) of 4-(trifluoromethyl)benzenesulfonyl chloride were dissolved in 20 ml of tetrahydrofuran at room temperature, and 1.62 ml (11.62 mmol) of triethylamine were added dropwise to the solution, which was stirred at room temperature overnight. After evaporation of the solvent, 20 ml of water were added and acidified with 1 mol of hydrochloric acid, and the aqueous phase was extracted with 50 ml of diethyl ether. The residue obtained after drying with sodium sulfate and after removal of the solvent was separated by column chromatography (cyclohexane/ethyl acetate 6:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[C:13]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[C:26](Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O-].[Na+].CO>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][O:18][CH3:26])[CH:14]=[C:13]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1cc(CO)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
20 mg of (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanol (Example 140) was dissolved in methylene chloride, and 59 mg of carbon tetrabromide and 47 mg of triphenylphosphine were added under ice-cooling, and the mixture was stirred for 30 minutes. Subsequently, 90 μl of 9.8 M sodium methoxide/methanol solution was added thereto, and the mixture was stirred overnight. The reaction solution was diluted with ethyl acetate and was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 7 mg of the objective compound as yellow powder.