Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[C:33]([NH:34][C:35](=[O:39])[CH2:36][O:37][CH3:38])=[CH:32][C:31]2[C:27](=[CH:28][C:29](=[O:40])[N:30]=2)[CH:26]=1.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:39])[CH2:36][O:37][CH3:38])[NH:30][C:29](=[O:40])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: COCC(=O)Nc1cc2c(cc1F)=CC(=O)N=2
Solvent: CCO
Solvent: C1CCNCC1
Product: COCC(=O)Nc1cc2c(cc1F)/C(=C/c1[nH]c3c(c1C)C(=O)N(C[C@@H](O)CN1CCOCC1)CC3)C(=O)N2
Temperature: 25 °C
Yield: 85.7 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (40 mg, 0.125 mmol) was dissolved in 2 mL of ethanol under stirring at room temperature, and 5-fluoro-6-methoxyacetamido-2-oxoindole 13a (26.7 mg, 0.112 mmol) was then added to the solution. Upon completion of the addition, the reaction mixture was stirred until all dissolved, and piperidine (0.05 mL, 0.5 mmol) was then added to the solution. Upon completion of the addition, the reaction mixture was heated to reflux in an oil bath for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials. The reaction mixture was naturally cooled down to room temperature, and filtered under reduced pressure to give the title compound (S,Z)-N-{5-fluoro-3-[5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 13 (52 mg, yield 85.8%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH:14][CH2:15][CH2:16][OH:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:14]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:15][CH2:16][O:17][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: OCCNCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(CCc1ccccc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
Methanesulfonyl chloride (4.3 g, 0.037 mol) was added dropwise at 0° C. to a well stirred solution of 2-phenethylamino-ethanol (2.5 g, 0.015 mol, from step (i) above) and triethylamine (4.6 g, 0.045 mol) in dry dichloromethane (50 ml). The reaction mixture was stirred at room temperature for 3 h and quenched with water. The reaction mixture was extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography over silica gel using 3% methanol in dichloromethane as eluent to yield (3 g) of compound as a solid.
Reaction SMILES: [OH:1]O.[CH3:3][S:4][CH2:5][C:6]1[N:11]=[C:10]([O:12][C:13](=[O:17])[N:14]([CH3:16])[CH3:15])[C:9]([CH:18]([CH3:20])[CH3:19])=[C:8]([CH3:21])[N:7]=1>C(O)(=O)C>[CH3:3][S:4]([CH2:5][C:6]1[N:11]=[C:10]([O:12][C:13](=[O:17])[N:14]([CH3:16])[CH3:15])[C:9]([CH:18]([CH3:19])[CH3:20])=[C:8]([CH3:21])[N:7]=1)=[O:1]
Reactant: CSCc1nc(C)c(C(C)C)c(OC(=O)N(C)C)n1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1nc(CS(C)=O)nc(OC(=O)N(C)C)c1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
3.4 g (0.05 mol) of 50% strength hydrogen peroxide were added to a solution of 14.2 g (0.05 mol) of N,N-dimethyl-carbamic acid O-(2-methylthiomethyl-5-iso-propyl-6-methyl-pyrimidin-4-yl) ester in 50 ml of glacial acetic acid at 5°-10° C. The mixture was subsequently stirred at room temperature for 6 hours and the solvent was then distilled off in vacuo. The residue was dissolved in 100 ml of methylene chloride and the methylene chloride solution was washed with a solution of 10 g of potassium carbonate in 15 ml of water. The organic phase was separated off and dried over sodium sulphate. The solvent was then distilled off in vacuo. 11 g (74% of theory) of N,N-dimethyl-carbamic acid O-(2-methylsulphinylmethyl-5-iso-propyl-6-methyl-pyrimidin-4-yl) ester were thus obtained in the form of beige crystals with a melting point of 80° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]#[N:11])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:24]1([O:30][CH2:31][CH2:32][Br:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br-:33].[C:10]([C:9]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:32][CH2:31][O:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2)#[N:11]
Reactant: BrCCOc1ccccc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 66 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)acetonitrile (0.0499 g, 0.165 mmol) and 2-bromoethyl phenyl ether (0.0760 g, 0.378 mmol) in 2CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0548 g, 66.0%). EI-MS m/z 423(M+) Rt (2.20 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=1.N>>[Cl:33][C:28]1[CH:27]=[C:26]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Reactant: Fc1ccc(Br)cc1Cl
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, starting with 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (described in Example 99) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-bromo-3-chloro-4-fluorobenzene in place of 4-bromothioanisole (yield: 330 mg, 58.8%). mp 205° C. 1H NMR (300 MHz, CDCl3) δ 3.10 (s, 3H), 7.17 (d, J=9 Hz, 2H), 7.23-7.31 (m, 1H), 7.28 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.65 (ddd, J=9 Hz, 3 Hz, 1.5 Hz, 1H), 7.85 (dd, J=9 Hz, 3 Hz, 1H), 7.93 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 489 (M+H)+, 508 (M+NH4)+. Anal. calc. for C23H15Cl2N2O3S: C,56.44; H, 3.17; N, 5.73. Found: C, 56.37; H, 3.19; N, 5.64.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:24])=[C:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:5]=2[O:4][C:3]=1[C:25]([O:27]CC)=[O:26].[OH-].[K+].Cl>O>[CH3:1][C:2]1[C:6]2[C:7]([OH:24])=[C:8]([C:20]([CH3:23])([CH3:21])[CH3:22])[CH:9]=[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:5]=2[O:4][C:3]=1[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)c1oc2c(C(=O)c3ccc(Cl)cc3)cc(C(C)(C)C)c(O)c2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)oc2c(C(=O)c3ccc(Cl)cc3)cc(C(C)(C)C)c(O)c12

Procedure:
Ethyl 3-methyl-4-hydroxy-5-tert-butyl-7-p-chlorobenzoylbenzofuran-2-carboxylate, compound 17 (0.322 g, 0.79 mmol) was suspended in a solution of potassium hydroxide (0.151 g, 2.69 mmol) in water (15 mL) and heated to reflux for 2.5 hours. The resulting solution was cooled in an ice bath and acidified with 2N HCl. The product precipitated and 3-methyl-4-hydroxy-5-tert-butyl-7-p-chlorobenoylbenzofuran-2-carboxylic acid, compound 18 was collected by filtration and allowed to air dry. mp 214°-216° C.; 1H NMR (DMSO-d6) d 1.44 (9H, s), 2.78 (3H, s), 5.78 (1H, s), 7.6 (2H, d, J=8 Hz), 7.62 (1H, s), 7.74 (2H, d, J=8 Hz).
Reaction SMILES: [Cl:1][N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.[CH3:9][S:10][CH3:11].N1C=CC=C1.CCOCC>ClCCl>[Cl-:1].[CH3:9][S+:10]([CH3:11])[C:3]1[NH:2][CH:6]=[CH:5][CH:4]=1
Reactant: CSC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: c1cc[nH]c1
Solvent: ClCCl
Product: C[S+](C)c1ccc[nH]1
Product: [Cl-]
Reaction time: 2 h
Yield: 37 %

Procedure:
To a solution of N-chlorosuccinimide (40 g, 0.3 5 moles) in anhydrous dichloromethane (3 l), cooled to -30° to -40° C. and maintained in a nitrogen atmosphere, was added, with good stirring, a solution of dimethyl sulfide (20.5 g, 0.66 moles) in dichloromethane (125 ml) over a 1 hour period, the temperature being maintained at -30° to -40° C. After a further hour at this temperature, a solution of pyrrole (20 g, 0.3 moles) in dichloromethane (125 ml) was added over a 1 hour period maintaining a temperature of -30° to -40° C. The solution was stirred for a further 2 hours at -30° to -40° C. and then ether (ca 6 l) was added with strong agitation until the precipitation of the product was complete. The solid was collected by filtration, washed three times with ether and dried in vacuo to give a white solid of dimethyl 2-pyrrolylsulfonium chloride (40 g, 83%) which after crystallization from dichloromethane had mp 115°-116° C. dec.
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:21]1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31]([O-])=[O:32])=[CH:23][N:22]=1)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>ClCCl>[CH:1]([C@@H:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:21]1[N:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[C:24]([CH2:31][OH:32])=[CH:23][N:22]=1)([CH3:3])[CH3:2].[CH:1]([C@H:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:21]1[N:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[C:24]([CH2:31][OH:32])=[CH:23][N:22]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C1c2cc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)[O-])c(C(F)(F)F)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)[C@@H]1c2cc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(CO)c(C(F)(F)F)n1
Product: CC(C)[C@H]1c2cc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(CO)c(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 6.97 %
Yield: 7.84 %

Procedure:
To a solution of 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (25 mg, 0.05 mmol) in dichloromethane (1 mL) was added DIBAL-H (0.25 mg, 0.25 mmol, 1M in toluene) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 1 h. The reaction was quenched with sat. NH4Cl (5 mL) at −78° C. and then extracted with dichloromethane (30 mL×3). The combined organic layers were concentrated, purified by preparative TLC on silica gel eluting with PE/EtOAc 1:1 and then by SFC separation to afford (R)-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol (1.80 mg, 7.84% yield, isomer 1) as a colorless oil and (S)-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)methanol (1.60 mg, 6.97% yield, isomer 2) as a colorless oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[C:20]1([C@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:20]1([C@H:26]([NH:28][C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:3]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A solution of 252A (22 g, 81 mmol) and toluene (400 mL) was treated with (R)-1-phenylethanamine (12.5 mL, 97 mmol) and p-TsOH (1.5 g). The reaction mixture was heated to reflux with a Dean-Stark trap for 23 hours. The mixture was cooled to room temperature, washed with saturated aqueous NaHCO3 (2×200 mL) and brine (2×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was filtered through a pad of silica (100% CH2Cl2) and concentrated to provide 14.7 g (yield: 49%) of Compound 252B as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C.C=C(C)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:18]([C:17]1[CH:20]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[Cl:21])[CH2:3][C:4]2([CH3:9])[CH3:5])=[O:11]
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: COC(=O)c1ccc(N)cc1
Agent: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Br)ccc1Cl)N2
Temperature: 85 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a stirred solution of 4-amino-benzoic acid methyl ester (8.25 g, 50 mmol) and 5-bromo-2-chloro-benzaldehyde (13.2 g, 60 mmol) in acetonitrile (200 mL) were added isobutene (14 mL, 0.2 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.65 g, 7.5 mmol). The resulting mixture was stirred at 85° C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(5-bromo-2-chloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (6.99 g, 33%) as a light yellow solid: MS (ESI) M+1=422.0.
Reaction SMILES: O=[C:2]1[CH:8]([CH2:9][C:10]([OH:12])=O)[CH2:7][CH2:6][S:5][C:4]2[S:13][CH:14]=[CH:15][C:3]1=2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:10](=[O:12])[CH2:9][CH:8]3[CH2:7][CH2:6][S:5][C:4]4[S:13][CH:14]=[CH:15][C:3]=4[C:2]3=[N:24]2)=[CH:19][CH:18]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CC1CCSc2sccc2C1=O
Solvent: CCO
Product: O=C1CC2CCSc3sccc3C2=NN1c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 31.9 %

Procedure:
A solution of 3.7 g of 4-oxo-4,5,6,7-tetrahydrothieno-[2,3-b]thiepin-5-acetic acid and 2.6 g of 4-chlorophenylhydrazine in 50 ml of ethanol is refluxed under heating for 6.5 hours. Then, the reaction mixture is concentrated under reduced pressure. The resulting residue is dissolved in 40 ml of acetic acid and the solution is refluxed under heating fo 1.5 hours. After cooling, the reaction mixture is concentrated under reduced pressure, the residue is subjected to column chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 1.7 g of 2-(4-chlorophenyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as pale brown crystals, melting at 134°-135° C.
Reaction SMILES: C[SH:2].[H-].[Na+].[CH3:5][C:6]([CH:8]([N:10]([C:19](=O)CCl)[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:9])=[S:7].Cl[CH2:24][C:25](Cl)=O>O1CCCC1.C(OCC)C>[CH3:5][C:6]([CH:8]([N:10]([C:19](=[S:2])[CH2:24][CH3:25])[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18])[CH3:9])=[S:7]
Reactant: O=C(Cl)CCl
Reactant: CS
Reactant: CC(=S)C(C)N(C(=O)CCl)c1c(C)cccc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=S)N(c1c(C)cccc1C)C(C)C(C)=S
Reaction time: 48 h

Procedure:
While passing in nitrogen and stirring, 3.1 g of methyl mercaptan are introduced into a suspension of 2.8 g of 55% sodium hydride in 150 ml of tetrahydrofurane and subsequently 18 g of N-(1'-methylthiocarbonylethyl)-N-chloroacetyl-2,6-dimethylaniline (prepared by chloroacetylating the intermediate obtained in Example 1a) with, for example, chloroacetyl chloride) in 50 ml of tetrahydrofurane were added dropwise. Stirring was continued for 48 hours at room temperature and the reaction mixture was diluted with 300 ml of diethyl ether, washed three times with water, dried over sodium sulphate and filtered. After recrystallisation from diethyl ether/petroleum ether, compound 2 had a melting point of 88°-92° C.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH3:14])[N:8]=[CH:9]2)=[C:2]=[S:3].[OH:15][CH2:16][CH2:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][NH:19]1>C(O)C>[OH:15][CH2:16][CH2:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][N:19]1[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH3:14])[N:8]=[CH:9]2
Reactant: OCCC1Cc2ccccc2CN1
Reactant: Cc1cc2c(N=C=S)cccc2cn1
Solvent: CCO
Product: Cc1cc2c(NC(=S)N3Cc4ccccc4CC3CCO)cccc2cn1
Temperature: 20 °C
Reaction time: 17 h
Yield: 99.5 %

Procedure:
5-Isothiocyanato-3-methylisoquinoline (8.8 g) is added to a solution of (RS)-3-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline (7.8 g) in ethanol (150 cc). A white precipitate rapidly forms. After stirring for 17 hours at a temperature of about 20° C., the mixture is evaporated to dryness at 40° C. under reduced pressure (30 mm Hg). (RS)-3-(2-Hydroxyethyl)-N-(3-methylisoquinol-5-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (16.5 g) is thus obtained in the form of pale yellow crystals.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[F:23][C:24]([F:43])([F:42])[CH2:25][O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1.Br[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:54])[F:53]>>[F:43][C:24]([F:42])([F:23])[CH2:25][O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:53])([F:54])[F:55])[N:35]=2)[N:32]=1
Reactant: O[C@H]1CCN(c2nc(OCC(F)(F)F)nc3[nH]nnc23)C1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: O[C@H]1CCN(c2nc(OCC(F)(F)F)nc3nn(Cc4ccccc4C(F)(F)F)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from (S)-1-[5-(2,2,2-Trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol and 1-(bromomethyl)-2-(trifluoromethyl)benzene. MS (m/e): 463.4 (MH+).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][N:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].[OH-].[Li+]>C1COCC1.O>[C:16]([O:15][C:13]([NH:12][CH:11]1[CH2:10][CH2:9][N:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:7][CH:6]1[C:4]([OH:5])=[O:3])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1CN(c2ccc(OC)c(OC)c2)CCC1NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)C(C(=O)O)C2)cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 24 %

Procedure:
To a solution of rac-4-tert-butoxycarbonylamino-1-(3,4-dimethoxy-phenyl)-piperidine-3-carboxylic acid ethyl ester (170 mg) in 2 ml THF, were added 1 ml NaOH 1M and lithium hydroxide (100 mg). The suspension was stirred 22 h at RT., diluted with water and extracted twice with tert-butylmethylether. The aqueous layer was acidified to pH 4, saturated with NaCl and then the product was extracted with 3 portions of AcOEt. The organic layers were dried over MgSO4, filtered, evaporated and chromatographed (silica gel, AcOEt) to provide the title compound (38 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24]O)=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].O1CCCC1.CS(Cl)(=O)=O.O.[NH3:41]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24][NH2:41])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: OCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reactant: N
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: NCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
{2-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoro-methyl)-1,3-thiazol-5-yl}methanol (1.05 g) was added to tetrahydrofuran (30 mL). Then, tetrahydrofuran solution (10 mL) comprising methanesulfonyl chloride (0.3 g) was added dropwise thereto under ice cooling. After the dropwise addition was completed, the reaction solution was stirred at room temperature for one hour. The resulting solution was added dropwise to a mixture solution, which was separately prepared to contain 28% ammonia water (50 mL), tetrahydrofuran (100 mL), and methanol (100 mL), under ice cooling. After stirring the mixture at room temperature for 12 hours, the reaction solution was poured over ice water, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (0.4 g, 45%).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=[O:11])[CH:5]=[CH:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].[C-:14]#[N:15].[K+].C(O)C.CCCCCC>C(O)(=O)C>[C:14]([CH:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:12][CH3:13])=[O:11])#[N:15]
Reactant: CCN(CC)C(=O)C=CCC(C)C
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCN(CC)C(=O)CC(C#N)CC(C)C
Temperature: 32.5 °C
Reaction time: 18 h

Procedure:
Added 3.46 grams of compound N,N-diethyl-5-methylhex-2-enamide (formula-4-a) to a mixture of 0.863 gram of potassium cyanide and 3.5 grams of ethanol. Stirred the reaction mixture for 18 hours at 25-40° C. Added 4.45 ml of hexane to the reaction mixture. Added 0.875 gram of glacial acetic acid to the reaction mixture at 35° C. Quenched the reaction mixture with water. Separated the organic and aqueous phases. Extracted the aqueous phase with hexane. Washed the organic layer with water. Distilled the organic phase under reduced pressure to get the title compound as a residue
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[Br:22][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([O:13][CH3:14])[CH:4]=2)[C:9](=[O:12])[NH:8][CH:7]=1
Reactant: COc1cc2cc[nH]c(=O)c2cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc2c(Br)c[nH]c(=O)c2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of 7-fluoro-6-methoxyisoquinolin-1(2H)-one (1.5 g, 7.7 mmol) in acetonitrile (3 ml) was added NBS (1.382 g, 7.7 mmol) at room temperature under argon atmosphere. The reaction mass was stirred at the same temperature for 2 h. The reaction mass was cooled to room temperature and precipitated solid was filtered to get crude compound (1.25 g, 59.2%). The crude compound was taken to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.59 (s, 1H), 7.93-7.91 (d, J=8 Hz, 1H), 7.56 (s, 1H), 7.29-7.27 (d, J=8 Hz, 1H), 4.03 (s, 3H); MS: MS m/z 272.03 (M++2).