Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([CH2:10]Br)=[C:6]([CH2:8]Br)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]([NH2:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:10][N:39]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:8]2)=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(Br)cc(CBr)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 90 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
4.95 g of 5-bromo-1,2-bis(bromomethyl)-3-methoxybenzene (3-19) was dissolved in 150 ml of anhydrous DMF, to which 5.50 g of potassium carbonate and 4.30 g of tritylamine, and under an argon atmosphere, the resulting mixture was stirred at 90° C. for 8 hours. The reaction solution was poured into water, and extract with chloroform and the resulting organic layer was washed with saturated salt water, and thereafter, the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and thereafter, the resulting residue was recrystallized with 2-propanol to obtain 3.35 g of 6-bromo-4-methoxy-2-tritylisoindoline (3-20).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:25]C(=O)C)=[CH:5][C:6]2[CH2:7][CH2:8][C@@H:9]3[C@@H:18]([C:19]=2[CH:20]=1)[CH2:17][CH2:16][C@@:14]1([CH3:15])[C:10]3=[CH:11][CH:12]=[C:13]1[O:21]C(=O)C.[BH4-].[Na+].C(O)(=O)C>C(O)C.C1COCC1.C(O)C.O.O>[CH3:1][O:2][C:3]1[C:4]([OH:25])=[CH:5][C:6]2[CH2:7][CH2:8][C@@H:9]3[C@@H:18]([C:19]=2[CH:20]=1)[CH2:17][CH2:16][C@@:14]1([CH3:15])[C:10]3=[CH:11][CH2:12][C@@H:13]1[OH:21]
Reactant: COc1cc2c(cc1OC(C)=O)CC[C@H]1C3=CC=C(OC(C)=O)[C@@]3(C)CC[C@H]21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc2c(cc1O)CC[C@H]1C3=CC[C@H](O)[C@@]3(C)CC[C@H]21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of the diacetate (17) (0.08 g, 0.21 mmol) in ethanol (5 mL) and THF (3 mL) was cooled to 0° C. in an ice bath. A solution of sodium borohydride (0.05 g, 1.32 mmol) in ethanol/water (10:3, 5 mL) was cooled to 0° C. in an ice bath and added to the steroid solution. The reaction mixture was stirred at 0° C. for 1 h., then allowed to warm to room temperature and stirred overnight. After that time, the reaction was diluted with water (20 mL) and neutralized with glacial acetic acid. The organic solvents were removed in vacuo under a stream of nitrogen, the residue was diluted with water (50 mL) and extracted with methylene chloride (3×). The organic fractions were washed with water (2×), brine (1×), filtered through sodium sulfate, combined and concentrated in vacuo. The residue was triturated with ether to give the pure product (18) (0.035 g, 55.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][NH2:29])=[CH:24][CH:23]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:17][CH3:18])[CH:3]=1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 72.1 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (450 mg, 1.43 mmol), O-(4-chlorophenyl)hydroxylamine hydrochloride (257 mg, 1.43 mmol) and anhydrous NaOAc (125 mg, 1.52 mmol) in EtOH (23 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). The residue was purified by radial thin layer chromatography (eluting with CH2Cl2iPE, 1:5) to afford N-{4-chloro-2-[1-(4-chlorophenoxyimino)propyl]phenyl}trifluoromethanesulfonamide 128 (455 mg, 72%), as a yellow solid. M.p. 87-88° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.18, br s, 1H; 7.71, d, J=8.8 Hz, 1H; 7.58, d, J=2.6 Hz, 1H; 7.41, dd, J=2.6 and 8.8 Hz, 1H; 7.35, d, J=8.8 Hz, 2H; 7.11, d, J=8.8 Hz, 2H; 3.02, q, J=7.6 Hz, 2H; 1.30, t, J=7.6 Hz, 3H.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][CH2:29][Cl:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
1-[2-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone (compound 314) (150 mg), 1-bromo-3-chloropropane (210 mg), and potassium carbonate (307 mg) were suspended in N,N-dimethylformamide (6 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (174 mg, 94%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH:15](O)=O.[OH-].[Na+]>>[CH2:1]([N:8]([CH3:15])[CH2:9][C@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)CNCc1ccccc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](O)CN(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
Stir a mixture of 3.5 g (21.2 mmol) (2R)-1-(benzylamino)propan-2-ol [F. L. Delft, Synthesis 1997, 4, 450-454], 1.85 ml (2.0 g, 23.3 mmol) of a 35% aqueous formaldehyde solution and 3.6 ml (4.4 g, 95.3 mmol) formic acid for 16 h under reflux. After cooling to room temperature, first neutralize with 45% sodium hydroxide solution and then adjust to a pH value of 9. Extract with ethyl acetate. Wash the organic phase three times with 10 ml water each time, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation, and dry. 3.08 g (78% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:12]([CH:13]=[O:14])=[CH:11][N:10]([CH3:15])[N:9]=1.[CH3:33][Mg]Br.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:12]([CH:13]([OH:14])[CH3:33])=[CH:11][N:10]([CH3:15])[N:9]=1
Reactant: C[Mg]Br
Reactant: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(COc2nn(C)cc2C(C)O)ccc1OCc1nc(-c2ccccc2)oc1C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carbaldehyde (0.45 g) in tetrahydrofuran (10 mL) was slowly added methylmagnesium bromide (3.0 M diethyl ether solution, 0.5 mL) at 0° C., and the mixture was stirred for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)ethanol (0.38 g, yield 81%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 94-95° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1>CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CO
Product: Nc1cc([N+](=O)[O-])cnc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a stirred suspension of 2-Amino-3,5-dinitropyridine (2) (1.62 g, 8.8 mmol) in MeOH (75 mL) was added an aqueous solution of (NH4)2S (20%, 15 mL, 44 mmol) dropwise at room temperature over 20 minutes. The mixture was stirred for an additional 30 minutes at room temperature and then heated at reflux for 30 minutes. The solution was cooled to room temperature and the solid collected by filtration, rinsed with cold MeOH (2×20 mL), and dried in vacuo at room temperature to give 3 as a red solid (0.812 g, 5.27 mmol, 60%). 1H NMR (500 MHz, DMSO-d6) δ 5.31 (s, 2H), 6.98 (s, 2H), 7.35 (d, J=2.55 Hz, 1H), 8.28 (d, J=2.91 Hz, 1H). EIMS M+1 155.1.
Reaction SMILES: [OH-].[K+].CO.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]#[N:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N+:24]([O-])=[O:25])[CH:18]=1>O.C(O)(=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13](=[C:22]1[CH:21]=[C:20]([CH3:23])[C:19](=[N:24][OH:25])[CH:18]=[C:17]1[Cl:16])[C:14]#[N:15]
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC1=CC(=C(C#N)c2ccc(Cl)cc2Cl)C(Cl)=CC1=NO
Reaction time: 2 h

Procedure:
To a stirred solution of 75 parts of potassium hydroxide in 240 parts of methanol, are added 27 parts of 2,4-dichlorobenzeneacetonitrile. Then there is added a solution of 25.5 parts of 1-chloro-4-methyl-3-nitrobenzene in 40 parts of methanol (exothermic reaction: temperature rises to 40° C). Stirring is continued for 2 hours while meantime the mixture is allowed to cool to 20° -25° C. 1000 parts of water are added. Upon the addition of a mixture of acetic acid and water (1:1 by volume), an oil is precipitated. The supernatant aqueous phase is decanted and the oil is taken up in methylbenzene. The solution is evaporated. The oily residue is triturated in a mixture of 2,2'-oxybispropane and petroleumether, yielding 2,4-dichloro-α-[2-chloro-4-(hydroxyimino)-5-methyl-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:35])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[N:23][C:22]=3[Cl:34])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:36](O)[CH2:37]C>>[Cl:34][C:22]1[N:23]=[CH:24][N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([CH:36]=[CH2:37])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:35])=[O:20]
Reactant: CCCO
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Product: C=Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (320 mg, 0.513 mmol), potassium vinyl trifluoroborate (69.2 mg, 0.513 mmol) and TEA (0.214 ml, 1.539 mmol) in n-propanol (3 ml) was added 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (84 mg, 0.103 mmol) and the reaction mixture was stirred at 100° C. for 4 hours. The mixture was adsorbed onto silica gel and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (246 mg, 0.431 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 7.95 (s, 1H), 7.40-7.55 (m, 1H), 7.22-7.39 (m, 2H), 6.99 (s, 1H), 6.72-6.81 (m, 1H), 6.64 (dd, 1H), 5.89 (d, 1H), 5.46 (s, 2H), 5.32 (d, 1H), 4.45 (d, 2H), 3.35 (t, 2H), 0.72 (t, 2H), −0.12 (s, 9H).
Reaction SMILES: C([N:8]1[CH2:48][CH2:47][C:11]2[N:12]=[C:13]([C:26]3[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]4[C:27]=3[C:28]([CH3:46])=[N:29][N:30]4[S:36]([C:39]3[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C@@H:19]([O:22][CH3:23])[C:18]([CH3:25])([CH3:24])[CH2:17]3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>C1COCC1.O.[OH-].[OH-].[Pd+2]>[CH3:46][C:28]1[C:27]2[C:31](=[CH:32][CH:33]=[C:34]([CH3:35])[C:26]=2[C:13]2[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C@@H:19]([O:22][CH3:23])[C:18]([CH3:25])([CH3:24])[CH2:17]3)[C:10]3[CH2:9][NH:8][CH2:48][CH2:47][C:11]=3[N:12]=2)[N:30]([S:36]([C:39]2[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=2)(=[O:37])=[O:38])[N:29]=1
Reactant: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(Cc2ccccc2)CC3)CC1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CNCC3)CC1(C)C
Temperature: 40 °C
Reaction time: 2.25 h

Procedure:
To a solution of (R)-6-benzyl-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (3.0 g, 4.51 mmol) in THF (24 mL) and water (6 mL) was added acetic acid (1.30 mL, 22.6 mmol). The solution was warmed to 40° C. and Pd(OH)2 20% on carbon (0.792 mg, 1.13 mmol) was added. The mixture was then stirred under a hydrogen atmosphere for 2.25 h. The mixture was then allowed to cool to rt and was filtered over Celite®, washing with EtOAc and MeOH. The filtrate was then basified with aqueous 1 N NaOH and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduce pressure. The residue was then purified via FCC (0-15% MeOH/DCM; with 10% NH4OH in DCM) to obtain the title compound. MS (ESI+) m/z 575.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([NH:32][CH:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[O:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1CCC(NC(=O)CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (120.0 mg, 0.29 mmol) from example 210 and N-methyl-4-amino-piperidine (40.2 mg, 0.35 mmol). The title compound was obtained as a solid (30.0 mg, 21% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.14 (1H, m), 8.99 (2H, m), 8.48 (1H, s), 7.90 (1H, m), 3.77 (2H, m), 3.48 (1H, m), 2.69 (2H, m), 2.15 (3H, s), 1.92 (2H, m), 1.67 (2H, m), 1.44 (2H, m). MS m/z: 502.15, 504.12 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[C:15]([C:16]#[N:17])=[C:14]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[N:13]=[C:12]([S:30][CH3:31])[N:11]=1>O1CCCC1>[CH3:31][S:30][C:12]1[N:13]=[C:14]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)[C:15]([C:16]#[N:17])=[C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:11]=1
Reactant: CSc1nc(Cl)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
A solution of 56 mg (0.55 mmol) of 2,2,2-trifluoroethanol in 5 ml of tetrahydrofurane was cooled to 0° C. and treated under an argon atmosphere with 23 mg (0.52 mmol) of sodium hydride (55% dispersion in oil). The mixture was kept at 0° C. during 10 min, then a solution of 200 mg (0.58 mmol) of 4-chloro-2-methylsulfanyl-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile in 5 ml of tetrahydrofurane was added and, thereupon, the mixture was warmed to room temperature and stirring continued during 36 hours. For the working-up, the reaction mixture was evaporated and the residue obtained was directly chromatographed on silica gel using a 9:1 mixture of hexane and ethyl acetate as the eluent yielding 142 mg (0.35 mmol, 60% of theory) of the 2-methylsulfanyl-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=409.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:22]=[C:23]=[N:24][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[N:24][C:23]#[N:22]
Reactant: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (379 mg, 1.28 mmol) in anhydrous DCM (10 mL) was added TiCl4 (1 M solution in DCM, 2.6 mL, 2.6 mmol) dropwise within 15 min at rt. The mixture was stirred for another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (0.525 g, 0.63 mL, 2.82 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give N-(6-bromospiro[chroman-2,1′-cyclohexane]-4-ylidene)cyanamide as a light brown solid (410 mg), which was used in the next step without further purification. MS ESI +ve m/z 319 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([F:18])[CH:11]=1.FC1C=CC(C(C2C=CC(C(F)(F)F)=CC=2)O)=CC=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[OH:15])=[C:12]([F:18])[CH:11]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=Cc1ccc(Cl)cc1F
Agent: OC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Product: OC(c1ccc(F)cc1)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 4.60 g (26.28 mmol) of 4-bromofluorobenzene and 5.00 g (31.53 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 4.45 g (66% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([NH2:20])[CH3:19])[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].CS([C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36][C:35](=[O:38])[N:34]3[CH2:39][CH:40]=[C:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:42]=[C:33]23)[CH:29]=[CH:28][N:27]=1)(=O)=O.O>CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([CH3:10])([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([NH:20][C:26]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][C:35](=[O:38])[N:34]4[CH2:39][CH:40]=[C:41]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[N:42]=[C:33]34)[CH:29]=[CH:28][N:27]=2)[CH3:19])[CH:12]=1)[CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(N)Cc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)c1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(Cc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Temperature: 100 °C

Procedure:
To a mixture of {1-[3-(2-amino-propyl)-phenyl]-1-methyl -ethyl}-carbamic acid tert-butyl ester (0.19 g, 0.65 mmol) and 1-(2-methanesulfonyl-pyrimidin-4-yl) -8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (0.26 g, 0.72 mmol) in NMP (2 mL) was heated to 100° C. for 17 h. The mixture was poured into water (15 mL) and extracted with ethyl acetate. The organic extracts were combined, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and chromatographed on silica gel using 0-4% MeOH/CH2Cl2 to afford a light yellow oil. M+1=596.
Reaction SMILES: [N+](=C)=[N-].[C:4]([CH:7]([CH2:20][CH2:21][CH2:22][CH:23]([OH:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:6])[CH3:5].[C:30](O)(=O)C>CCOCC>[C:4]([CH:7]([CH2:20][CH2:21][CH2:22][CH:23]([OH:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:30])=[O:16])=[CH:18][CH:19]=1)(=[O:6])[CH3:5]
Reactant: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O
Reactant: CC(=O)O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCC(O)CCCC(CCCc1ccc(C(=O)OC)cc1)C(C)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 4-(4-acetyl-8-hydroxytridecyl)benzoic acid (10.8 g., 0.03 mole) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 4-(4-acetyl-8-hydroxytridecyl)benzoate, a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].[BH4-].[Na+].[ClH:21].C([O-])(=O)C.[Na+]>O.C(O)C>[ClH:21].[CH2:14]([NH:18][CH:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[C:8]=2[OH:12])[CH2:4][CH2:5]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: Cc1cc(C)c2c(c1O)C(=O)CC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: CCCCNC1CCc2c(C)cc(C)c(O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 Milliliters of ethanol solution containing 1.76 g of 4,6-dimethyl-7-hydroxy-1-indanone and 14.6 g of n-butylamine was refluxed by heating for 8 hours. The reaction mixture was cooled to a room temperature, then 1.0 g of sodium borohydride was added thereto. The mixture was further stirred at a room temperature for 1 hour. The reaction mixture was concentrated to dryness and the residue obtained was dissolved in 100 ml of water. Then the solution was acidified by adding a concentrated hydrochloric acid, and the pH of the solution was adjusted to about pH=9 by adding a saturated sodium acetate aqueous solution. The precipitate formed was extracted with ethyl acetate, washed with water and dried. The solvent was removed by evaporation, the residue obtained was dissolved in 100 ml of ethanol, and changed to hydrochloride by adding ethanol being saturated with hydrogen chloride gas. Recrystallized from ethanol-ether to obtain 1.89 g of 1-n-butylamino-4,6-dimethyl-7-hydroxyindane hydrochloride in the form of colorless needle-liee crystals. Melting point: 143°-144° C.