Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[N:6]=1.[CH3:28][N:29]=[C:30]=[O:31].[OH-].[Na+]>O1CCCC1>[CH3:28][NH:29][C:30](=[O:31])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)[N:6]=1
Reactant: CN=C=O
Reactant: Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNC(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-amino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (1.0 g) in dry tetrahydrofuran (10 ml) was added dropwise methyl isocyanate (0.34 ml) at ambient temperature. After the addition had been completed, the reaction mixture was stirred for 3 hours. 1N Sodium hydroxide solution (3 ml) was added thereto and stirring was continued for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After removal of solvent, the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with 70% ethanol to give white powder. Recrystallization from 70% ethanol gave 2-(3-methylureido)-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:20][C:13]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=2[Cl:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: COc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2ccc(C#N)c(Cl)c2)c(Cl)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A solution of 3.0 g (19.28 mmol) of 2-chloro-4-fluorobenzonitrile and 3.06 g (19.28 mmol) of 2-chloro-4-methoxyphenol in 77 mL DMSO was combined with 5.32 g (38.57 mmol) of potassium carbonate and stirred for 2 h at 120° C. Then the mixture was evaporated to dryness in vacuo, the residue was taken up in dichloromethane and washed once with semisaturated potassium carbonate solution and twice with water. The organic phase was dried on sodium sulphate and evaporated down.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[C@H:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][CH2:36][C:35]1=[O:48]>>[Si:41]([O:40][CH2:39][C@H:38]1[CH2:37][CH2:36][C:35](=[O:48])[N:34]1[C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:20])[CH3:21])=[O:23])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1c1cc(F)ccc1CN
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO[Si](C)(C)C(C)(C)C)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (S)-1-(2-(aminomethyl)-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one, derived from reduction of intermediate 122, (R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile 1HNMR 400 MHz (DMSO) δ ppm: 8.82 (1H, broad s), 7.47 (2H, m), 7.35 (4H, m), 7.00 (1H, broad s), 5.09 (2H, s), 4.60–4.10 (3H, m), 4.02 (3H, m), 3.88 (2H, m), 3.53 (2H, broad s), 2.42–2.35 (2H, m), 1.94 (1H, m), 1.56 (3H, s), 1.55 (3H, s), 0.82 (9H, broad s), −0.01 (6H, s). LCMS (M+H)+ m/z 665.
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)(=[O:3])[NH2:2].[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:9]([O:8][CH:6]1[CH2:7][N:4]([C:1](=[O:3])[NH2:2])[CH2:5]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)N1CC(O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)[Si](OC1CN(C(N)=O)C1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 18 %

Procedure:
To a solution of 1-carbamoyl-3-hydroxyazetidine (obtained as described in Reference Example 21(1)) in dimethylformamide (100 ml) were added t-butyldiphenylsilyl chloride (18.0 ml, 66.9 mmol) and imidazole (4.55 g, 66.9 mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the resulting mixture was stirred at room temperature overnight. After checking the completion of the reaction, ethanol (1 ml) was added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-carbamoylazetidine (1.45 g, total yield 18%) as a white solid.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH:17](=O)[CH3:18].S(=O)(=O)(O)O>>[CH:17](=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][N:4]=1)[CH3:18]
Reactant: COc1cc2c(cc1OC)C(NN)=NCC2
Reactant: CC=O
Agent: O=S(=O)(O)O
Product: CC=NNC1=NCCc2cc(OC)c(OC)cc21

Procedure:
In a manner similar to that of Step C of Example 1, condensation of 1-hydrazino-6,7-dimethoxy-3,4-dihydroisoquinoline (7.2 g.) with acetaldehyde (4.3 g.) and treatment of the resulting product with sulfuric acid afforded 1-(2-ethylidenehydrazino)-6,7-dimethoxy-3,4-dihydroisoquinoline (I: X=CH3, X' =Y=Y' =H, Z=Z' =CH3O) sulfate monohydrate (5.3 g., m.p. 165°-168° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([NH:12][NH2:13])=[O:11])=[CH:5][C:4]=1[O:16][CH3:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.CCN(CC)CC>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([NH:12][NH:13][C:26](=[S:27])[NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:11])=[CH:5][C:4]=1[O:16][CH3:17]
Reactant: COc1cc(C(C)(C)C(=O)NN)ccc1Cl
Reactant: Fc1ccc(N=C=S)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)(C)C(=O)NNC(=S)Nc2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(4-chloro-3-methoxyphenyl)-2-methylpropanehydrazide hydrochloride (6.88 g, 0.02 mol) and 4-fluorophenylisothiocyanate (3.96 g, 0.03 mol, 1.05 eq.) in DCM (500 mL) at 0° C. was added Et3N (7 mL, 1.29 mol, 2.0 eq.) and the resulting solution was stirred for 1.5 h at room temperature. The reaction mixture was washed with 1M HCl, satd NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with DCM/Et2O, collected by filtration and dried to give 2-(2-(4-Chloro-3-methoxyphenyl)-2-methylpropanoyl)-N-(4-fluorophenyl)hydrazine carbothioamide (8.13 g, 83% as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.32-7.30 (d, 1H), 7.25-7.22 (m, 2H), 7.01-7.05 (t, 2H), 6.95-6.94 (d, 1H), 6.93-6.90 (dd, 1H), 3.88 (s, 3H), 1.64 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[SH:33]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[Cl:25])[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19]1)=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCC(F)(F)C1
Reactant: Fc1ccc(S)c(Cl)c1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(F)cc2Cl)C[C@H]1C(=O)N1CCC(F)(F)C1

Procedure:
The title compound was prepared in analogy to example 68/69 step 8 using (1R,2R,4R)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 186 step 3) and 2-chloro-4-fluorothiophenol. Light yellow oil (88%). MS (EI): 436.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:18])=[CH:5][CH:4]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>C1COCC1>[C:34]([O:33][C:31](=[O:32])[CH2:30][CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=2)[C:9]1=[O:18])([CH3:37])([CH3:36])[CH3:35]
Reactant: COc1ccc(CN2C(=O)CCc3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(CC(=O)OC(C)(C)C)Cc3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
The 1-(4-methoxy-benzyl)-3,4-dihydro-1H-quinolin-2-one (7.86 mmol) obtained in the previous step is dissolved in 10 mL of anhydrous THF. A solution of freshly prepared LDA (9.43 mmol) in 3.5 mL of anhydrous THF is added dropwise at −78° C. The reaction mixture is stirred at −78° C. for 10 minutes, warmed up to 0° C. for 15 minutes, and then cooled down to −78° C. again before it is transferred dropwise through a double-ended needle to a solution of tert-butyl bromoacetate (10.2 mmol) in 5 mL of anhydrous THF. The resultant solution is stirred at −78° C. for 1 hour before it is allowed to warm up to 0° C. within another hour and then quenched with MeOH. After removal of the solvent, the residue is purified by silica gel chromatography (hexane/EtOAc) to give [1-(4-methoxy-benzyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid tert-butyl ester as a light yellow oil. Yield: 53%. 1H NMR (400 MHz, CDCl3): δ 7.13 (m, 4H), 6.96 (t, 1H), 6.90 (d, 1H), 6.83 (d, 2H), 5.25 (d, 1H), 4.95 (d, 1H), 3.76 (s, 3H), 3.13 (m, 1H), 3.00-2.85 (m, 3H), 2.41 (dd, 1H), 1.48 (s, 9H). MS: (ES+): 404.2 [M+23].
Reaction SMILES: Cl[C:2]1[CH:19]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:20])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=3.[CH3:21][C:22]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:23]=1[NH2:24]>CC(O)C>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:17][CH3:18])[C:6]1=[CH:19][C:2](=[N:24][C:23]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:22]=3[CH3:21])[NH:3][C:4](=[O:20])[N:5]1[CH2:14][CH2:13]2
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)[nH]c(=O)n1CC2
Temperature: 25 °C

Procedure:
2-Chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one, prepared according to Preparation 1, (38.5 g, 0.13 mol) and 2,4,6-trimethylaniline (52.7 g, 0.39 mol) in propan-2-ol (31) was stirred and heated at reflux, under nitrogen, for 24 h. After cooling to room temperature, the solution was evaporated in vacuo and the residue was purified by column chromatography on silica gel, eluting with CH2Cl2/MeOH, initially 98:2, changing to 96:4 once the product began to elute from the column. The title compound was obtained with a slight impurity, just above the product on tic). Yield 34.6 g, 67%.
Reaction SMILES: [Mg].[CH2:2]([C:4]1[C:12]2[N:11]3[C@H:13]([CH3:18])[CH2:14][NH:15][C:16](=[O:17])[C:10]3=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3].[H][H].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO>[CH2:2]([C:4]1[C:12]2[N:11]3[C@H:13]([CH3:18])[CH2:14][NH:15][C:16](=[O:17])[C@@H:10]3[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: [H][H]
Reactant: CCc1cccc2cc3n(c12)[C@H](C)CNC3=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Mg]
Solvent: CO
Product: CCc1cccc2c1N1[C@H](C)CNC(=O)[C@@H]1C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Magnesium turnings (87 mg, 3.6 mmol) were added to a solution of (R)-6-Ethyl-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (82 mg, 0.36 mmol) in methanol (4 mL). After hydrogen gas started to evolve, the reaction mixture was kept at 10-20° C. and stirred for 2 h to dissolve the magnesium completely. Then the reaction mixture was poured onto 3 mL ice-cold 1 M aq. HCl, neutralized with 1 M aq. potassium phosphate solution (pH 6.85), and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield the title compound (80 mg, 97%). White solid. ISP-MS: m/e=231.2 ([M+H]+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.C([OH:15])C>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[O:15])[S:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: CCO
Agent: Cl
Product: O=c1[nH]c2ccc(Cl)cc2s1

Procedure:
4.081 gm (0.02 mol) of 2,6-dichloro-benzothiazole were refluxed for 4 hours in 100 ml of a mixture of equal parts of ethanol and concentrated hydrochloric acid. After distilling the reaction mixture with 100 ml of water, the resulting precipitate was filtered off and washed thoroughly with water. For further purification the precipitate was taken up in aqueous 10% sodium hydroxide, the solution was filtered, and the filtrate was extracted twice with 100 ml each of ether. The aqueous phase was acidified with hydrochloric acid, and the resulting precipitate was collected by suction filtration, washed with water and recrystallized once from ethanol and once from toluene, each time in the presence of activated charcoal. 3.1 gm (83% of theory) of crystals with a melting point of 212°-213° C. were obtained. According to mixed melting point determination, elemental analysis, and thin-layer chromatography, the product was identical to the product obtained in Example 6.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([C:13]([OH:15])=O)[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17].[CH3:29][C:30]1[C:31]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[N:32][C:33]([CH3:36])=[CH:34][N:35]=1>>[CH3:29][C:30]1[C:31]([N:37]2[CH2:38][CH2:39][N:40]([C:13]([CH:5]3[CH2:4][N:3]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:26])([F:28])[F:27])(=[O:18])=[O:17])[C:2](=[O:1])[N:6]3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:15])[CH2:41][CH2:42]2)=[N:32][C:33]([CH3:36])=[CH:34][N:35]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1
Reactant: Cc1cnc(C)c(N2CCNCC2)n1
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4C(F)(F)F)C(=O)N3c3ccccc3)CC2)n1

Procedure:
In analogy to example 1, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid (example 11) was coupled with 3′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (CAS [59215-42-8]) to give the title compound as a colorless solid. MS: 589.0 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:25][CH2:24][C:19]3(OCC[O:20]3)[CH2:18][CH2:17]2)[CH3:15])=[CH:4][CH:3]=1.Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:16]2[CH2:17][CH2:18][C:19](=[O:20])[CH2:24][CH2:25]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCC(=O)CC1
Temperature: 85 °C

Procedure:
To a solution of 8-[1-(4′-Chloro-biphenyl-2-yl)-ethyl]-1,4-dioxa-8-aza-spiro[4.5]decane (3.1 g, 8.66 mmol) in dioxane-water (1:1 60 mL) is added HCl 37% (10.5 mL, 346 mmol). The reaction is then heated up to 85° C. for 26 hours. The solvent is then removed under vacuum and the aqueous phase is basified to pH=9 using sodium hydroxide 4N and then extracted with DCM. The organic layer is then washed with brine. The combined organic phase is then dried on MgSO4 and concentrated to afford 1-[1-(4′-Chloro-biphenyl-2-yl)-ethyl]-piperidin-4-one. The crude material is used without further purification. Found m/z ES+=314.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 7.57 (1H, d, J=7.1 Hz), 7.32 (1H, t), 7.30 (2H, d, J=8.6 Hz), 7.22 (1H, t), 7.15 (2H, d, J=8.6 Hz), 7.09 (1H, d, J=6.1 Hz), 3.58 (1H, m), 2.63 (2H, m), 2.52 (2H, m), 2.25 (4H, t, J=6.1 Hz), 1.24 (3H, d, J=6.6 Hz).
Reaction SMILES: C([Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[CH:21][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.[CH3:30][N:31]1[CH:35]=[C:34]([S:36]([N:39]2[CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]2)(=[O:38])=[O:37])[N:33]=[CH:32]1>>[OH:28][C@@H:27]([CH2:29][NH:46][CH2:45][CH:42]1[CH2:41][CH2:40][N:39]([S:36]([C:34]2[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=2)(=[O:38])=[O:37])[CH2:44][CH2:43]1)[CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: Cn1cnc(S(=O)(=O)N2CCC(CN)CC2)c1
Product: Cn1cnc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3ccc(O)cc3)CC2)c1
Yield: 10.6 %

Procedure:
Prepared from t-butyl-[4-(2S)-oxiranylmethoxy-phenoxy]-diphenylsilane (0.404 g, 1.0 mmol) and [1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-ylmethyl amine (0.650 g, 1.8 mmol) according to the procedure used in example 37 to give 0.045 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](SC)[N:11]=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1.[F:23][C:24]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1>>[F:23][C:24]1[C:25]([C:10]2[N:11]=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]4[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH:4]=3)[N:9]=2)=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CSc1nncc(-c2ccc(F)c(-c3ncccc3F)c2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(F)cc1F
Product: Fc1cnc(-c2nncc(-c3ccc(F)c(-c4ncccc4F)c3)n2)c(F)c1

Procedure:
A solution of 5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-methylsulfanyl-[1,2,4]triazine and 3, 5-difluoro-2-tributylstannylpyridine were coupled together by the method of Example 36 to give 3-(3,5-difluoro-pyridin-2-yl)-5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-[1,2,4]triazine: δH (500 MHz, CDCl3) 7.34 (1H, m), 7.40-7.48 (2H, m), 7.56-7.60 (1H, m), 8.43-8.46 (1H, m), 8.54 (1H, dd, J 2.4, 6.6 Hz), 8.61 (2H, m), 9.78 (1H, s); m/z (ES+) 384.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]3)C(=O)C2=CC=CC=C12.O.NN.Cl>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]2
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc2[nH]c(=O)ccc2c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCOc1ccc2[nH]c(=O)ccc2c1
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a suspension of 6-(3-phthalimidopropoxy)carbostyril (300 g) in ethanol (3 liters) is added hydrazine monohydrate (46 g), and the mixture is refluxed for 8 hours. After the mixture is allowed to cool, the precipitated crystals are collected by filtration, suspended in water, and the suspension thus obtained is acidified with conc. hydrochloric acid, and stirred for one hour. The insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure to remove the solvent. The residue is neutralized to pH 7 with a 15% aqueous sodium hydroxide solution. The precipitated crystals are collected by filtration, and washed successively with ethanol and diethyl ether, and dried to give 6-(3-aminopropoxy)carbostyril (140 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH:24][C:25]([CH:27]5[CH2:29][CH2:28]5)=[O:26])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:29][CH2:28][CH2:27][C:25]5=[O:26])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2)C1CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 67 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-cyclopropanecarboxamidomethylindoline (90 mg) obtained in Example 159, activated manganese dioxide (450 mg) and chloroform (10 ml) were treated as in Example 285 to give the title compound (60 mg) as a white powder (yield: 73%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11](O)([CH3:13])[CH2:10][C@H:9]1[C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:33])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:33])([CH3:13])[CH2:10][C@H:9]1[C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(O)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (865 mg, 2.1 mmol) in CH2Cl2 (60 mL) under nitrogen at −78° C. was added DAST (550 μL, 4.16 mmol) and the solution was slowly allowed to reach RT and stirred for 1 h. The reaction mixture was poured into cold aqueous saturated NaHCO3 solution and extracted with CH2Cl2 (×2). The combined organic layers were dried (Na2SO4), filtered and concentrated to give the desired material which was used in the next step without further purification. TLC, Rf (EtOAc)=0.75; MS (UPLC/MS): 389.3/391.3 [M+H]+, 411.3/413.2 [M+Na]+, 333.2/335. [MH−tBu]+, 289.2/291.2 [MH−Boc]+, 387.2/389.4 [M−H]−, 433./435.2 [M+HCOO]−; tR (HPLC conditions f): 2.2 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:16])=[CH:4][C:3]=1[O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(Oc2ccccc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1Oc1ccccc1

Procedure:
For example, 4-fluoro-3-phenoxy-toluene, when reacted with N-bromosuccinimide in the presence of a radical initiator, for example azodiisobutyronitrile, optionally using a diluent, for example carbon tetrachloride, optionally using a diluent, and 100° C., gives 4-fluoro-3-phenoxy-benzyl bromide. From this, 4-fluoro-3-phenoxy-benzaldehyde can be prepared in a Sommelet reaction, that is to say by reaction with hexamethylenetetramine in the presence of a diluent, for example methylene chloride, at temperatures between 0° and 50° C., followed by reaction with aqueous acetic acid and thereafter with hydrochloric acid, at temperatures between 80° and 120° C. The reaction of 4-fluoro-3-phenoxy-benzaldehyde with sodium cyanide in aqueous acetic acid at 20° C. gives α-cyano-4-fluoro-3-phenoxy-benzyl alcohol. The reaction sequence described above is outlined in the following equations: ##STR11##