Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CC1CCC(CCN)CC1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(CCNS(=O)(=O)c2ccc(C#N)cc2)CC1
Yield: 95 %

Procedure:
by the reaction of 4-cyanobenzenesulphonyl chloride with ethyl 4-(2-aminoethyl)-cyclohexylacetate hydrochloride in methylene chloride in the presence of triethylamine. Yield 95% of theory, colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Br[CH2:27][CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:27][CH2:28][N:29]1[C:30](=[O:39])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]1=[O:38])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg), 2-(2-bromo-ethyl)-isoindole-1,3-dione (229 mg) and potassium carbonate (125 mg), and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (83 mg, yield 55%).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([N:45]3[CH2:46][CH2:47][CH:42]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:43][CH2:44]3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)[CH:9]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(N4CCC(c5ccccc5)CC4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) was treated as described in general procedure R using 4-phenylpiperidine (162 mg, 1 mmol) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[C:3]=1[CH3:12].[CH3:13][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([CH3:12])[C:4]=1[Cl:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1c(N)ccc(C(=O)O)c1Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(N)c(C)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a suspension of 4-amino-2-chloro-3-methyl-benzoic acid (0.64 g, 3.45 mmol) in toluene (10 mL) and methanol (10 mL) at 0° C. was added drop-wise trimethylsilyldiazomethane (3.45 mL, 2 M in hexane, 6.90 mmol). The reaction mixture was stirred at 0° C. for 30 min during which the reagents dissolved. The reaction mixture was quenched by the addition of acetic acid (1 mL) then washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a beige solid (0.66 g, 96%). 1H NMR (CDCl3, 400 MHz) 2.26 (3H, s), 3.86 (3H, s), 6.55 (1H, d, J=8.8 Hz), 7.60 (1H, d, J=8.8 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(Cl)cc23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(Cl)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,6-dichloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-chloro-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=[O:13])[CH2:7][CH2:6]2.[Li+].CC([N-]C(C)C)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([O:13][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH2:7][CH2:6]2
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc2c(c1)CCC(=O)C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(O[Si](C)(C)C)C2

Procedure:
6-Methoxy-3,4-dihydronaphthalen-2(1H)-one (25 g) was treated with LDA (110 ml) in dry THF (500 ml) at −78° C. for 5 minutes. Then TMSCl (21.64 g) was added and after 30 minutes the cooling bath was removed. After 1 hour at room temperature the solvent was evaporated in vacuo and the residue was dissolved in heptane and filtered to eliminate the solid particulate. Finally the heptane was evaporated in vacuo.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1.Cl[CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:13])[F:15])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:23]([CH3:25])=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a8) and commercially available (2-chloromethoxy-ethyl)trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Yield: 81.1 %

Procedure:
To a solution of 5-bromo-2-hydroxybenzaldehyde (5 g, 24.9 mmol) in acetone (200 mL) were added benzyl bromide (5.11 mL, 29.9 mmol), potassium iodide (KI, 2.07 g, 12.45 mmol) and potassium carbonate (K2CO3, 5.17 g, 37.4 mmol), followed by mixing at 70° C. for 2 hours under a reflux condition. The product thus obtained was diluted in ethyl acetate (EtOAc), washed with brine, and dried over magnesium sulfate (MgSO4) to concentrate it. The concentrate was purified using silica column chromatography (10% ethyl acetate/hexane) to afford the title compound (5.88 g, 81%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Reactant: BrCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc(-c2ccn(CCc3ccccn3)n2)sc1C(=O)NCc1ccccc1
Temperature: 90 °C
Yield: 42.1 %

Procedure:
A solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (0.1 g, 0.33 mmol) in dimethyl sulfoxide (5 mL) was treated with 2-(2-bromo-ethyl)-pyridine (0.089 g, 0.33 mmol) and potassium carbonate (0.140 g, 1.0 mmol), and the reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue, was purified by preparative thin layer chromatography over silica gel eluting with (5% methanol, 95% methylene chloride) to provide 4-methyl-2-[1-(2-pyridin-2-yl-ethyl)-1H-pyrazol-3-yl]-thiazole-5-carboxylic acid benzylamide (56 mg, 43% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=4.0 Hz, 1H), 7.50-7.57 (m, 1H), 7.29-7.42 (m, 5H), 7.21 (s, 1H), 7.12-7.19 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 6.01 (bs, 1H), 4.62 (d, J=8.0 Hz, 2H), 4.61 (t, J=8.0 Hz, 2H), 3.36 (t, J=8.0 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=404.2; Rt=1.25 min; HRMS (M+H)+=404.15.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C@H:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:44]I.O>C1COCC1>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C@H:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[O:26][CH3:44])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2[C@@H](O)C2CCCCC2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of (S)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (1.81 g, 3.04 mmol) in THF (20 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 254.4 mg, 6.4 mmol). The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and methyl iodide (1.31 g, 9.2 mmol) was added. The mixture was stirred at room temperature for 5 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+M Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound as a colorless oil (1.77 g, 96%). 1H NMR (400 MHz, CDCl3) δ ppm 0.93-1.14(m, 5H) 1.18 (d, J=10.79 Hz, 1H) 1.43-1.54(m, 1H) 1.59-1.65(m, J=4.56 Hz, 2H) 1.68-1.74 (m, J=2.49 Hz, 1H) 1.90 (d, J=12.03 Hz, 1H) 3.06 (s, 3H) 4.08 (d, J=7.05 Hz, 1H) 4.21 (s, 3H) 4.71 (d, J=15.77 Hz, 1H) 4.71 (s, 2H) 4.88 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.49 (d, J=8.30 Hz, 1H) 7.55 (d, J=8.30 Hz, 1H) 7.66 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 609.2, Found: 610.5 (M+1). [α]D20=36.49 deg (c=10.05 mg/mL, acetone) Determination of absolute configuration of (S)-(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxymethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.Br[CH2:30][C:31]1[CH:32]=[C:33]([F:39])[C:34]([F:38])=[C:35]([F:37])[CH:36]=1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([CH2:30][C:31]3[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([F:39])[CH:32]=3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: Fc1cc(CBr)cc(F)c1F
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3cc(F)c(F)c(F)c3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 5-(bromomethyl)-1,2,3-trifluorobenzene in the same manner as in Example 32.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26]Br>[OH-].[Na+]>[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: COC(CBr)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(SCC(OC)OC)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
15.0 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 50 ml of 2 N sodium hydroxide solution, 15.4 g of bromoacetaldehyde-dimethylacetal (2,2-dimethoxy-1-bromoethane) are added under nitrogen and the mixture is heated to 80° while stirring. The mixture is stirred at 80° for 2.5 hours, cooled to room temperature, extracted by shaking with 100 ml of toluene, the organic layer is removed and the aqueous phase is subsequently shaken with 50 ml of toluene. The organic phases are combined, washed twice with 30 ml of 2 N sodium hydroxide solution each time and then with 30 ml of 2 N hydrochloric acid, dried over magnesium sulphate, concentrated by evaporation under reduced pressure and carefully dried. The crude product is crystallised from hexane/methanol (50 ml+5 ml). 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-acetaldehyde-dimethylacetal having a melting point of 60°-61° is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:39]([N:38]([CH3:42])[CH3:37])=[O:40])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)N(C)C)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL) was added dimethylcarbamic chloride (39 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to afford 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)-N,N-dimethylpiperidine-1-carboxamide as a white solid.
Reaction SMILES: [H][H].[C:3]1([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1>[C:3]1([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Reactant: [H][H]
Solvent: C1CCOC1
Product: c1ccc(CCc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
In Example 5, hydrogenation reaction was conducted under the same condition as Example 1 for THF diluted solution concentration of the substance to be reduced, its flow rate, and hydrogen 9 flow rate, using 1,2-diphenylacetylene as the substance to be reduced. The reaction time was within five minutes. The analytical result of the reaction product by 1H-NMR showed almost complete hydrogenation of 1,2-diphenylacetylene, and 1,2-diphenylethane was obtained at about 100% yield (See FIG. 6.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[S:37]([CH3:36])(=[O:39])=[O:38])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)CCCCN(Cc1ccc(CNC(=O)OC(C)(C)C)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (198.3 mg) obtained in Example 23-4 was dissolved in anhydrous dichloromethane (4.0 ml) and added with triethylamine (0.142 ml) and methanesulfonyl chloride (0.060 ml), and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the resultant was washed with water and dried with anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (192.0 mg) as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])(C)C)=[CH:15][CH:14]=2)=[N:7][CH:6]=1)[CH3:2].[CH3:24][CH:25]([CH3:37])[CH2:26]CCC1C=CC(C#C)=CC=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:22][CH2:24][CH:25]([CH3:37])[CH3:26])=[CH:17][CH:18]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: C#Cc1ccc(CCCC(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C(C)(C)C)cc2)nc1
Product: CCOC(=O)c1ccc(C#Cc2ccc(CCCC(C)C)cc2)nc1

Procedure:
Using the same general procedure as described for Compound 3, but using instead 4-(4-methylpentyl)phenylethyne (Compound 26), the title compound was synthesized as a yellow solid. PMR (CDCl3): & 0.91 (6H, d, J~6.6 Hz), 1.20-1.30 (1H, m)., 1.47 (3H, t, J~7.2 Hz), 1.51-1.72 (3H, m), 2.63 (2H, t, J~7.8 Hz), 4.45 (2H, q, J~7.2 Hz), 7.22 (2H, d, J~8.4 Hz), 7.53-7.64 (3H, m), 8.30 (1H, dd, J~8.1 Hz, 2.1 Hz), 9.23 (1H, d, J~2.1 Hz).
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9]([CH:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][OH:26])[C:15]=2[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH2:1]([N:8]([CH3:27])[C:9]([CH:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])[C:15]=2[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CCCc2c1c1ccccc1n2CCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)C1CCCc2c1c1ccccc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 31.8 %

Procedure:
To a solution of 9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid benzyl-methyl-amide (28) (36 mg, 0.1 mmol) in dichloromethane (2 mL) was added pyridine (7.91 g, 1.0 mmol, 8.1 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (57 mg, 0.5 mmol, 0.04 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×10 mL) and water (2×10 mL), dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (20-80% B, 4 g, 45 CV, 18 mL/min) to afford 14 mg (32%) of methanesulfonic acid 2-[4-(benzyl-methyl-carbamoyl)-1,2,3,4-tetrahydro-carbazol-9-yl]-ethyl ester as a yellow oil. The structure was confirmed by 1H NMR (CDCl3) δH 1.10-2.40 (5H, m), 2.51 (1.5H, s, OSO2CH3), 2.54 (1.5H, s, OSO2CH3), 2.70-2.90 (2H, m), 3.08 (1.5H, s, NCH3), 3.15 (1.5H, s, NCH3), 3.40-3.70 (1H, m), 4.10-4.80 (4H, m), 7.00-7.50 (9H, m).
Reaction SMILES: [CH2:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:5]#[N:6])[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH2:5][NH2:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C#N)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C=CCC(CN)c1ccc(OC)cc1
Yield: 89.6 %

Procedure:
A solution of (±)-2-allyl-2-(4-methoxyphenyl)acetonitrile (159.7 g., 0.852 mole) in diethyl ether (200 ml.) was added dropwise during 20 minutes to a stirred, slowly refluxing mixture of lithium aluminum hydride (LiAlH4, 42.2 g., 1.11 moles) in diethyl ether (800 ml.). The mixture was refluxed for an additional 1.25 hours and then cooled in an ice-H2O bath. The excess LiAlH4 was decomposed by the slow dropwise addition of H2O until gaseous evolution ceased, and a granular precipitate formed. The mixture was filtered and the filter cake thoroughly washed with diethyl ether. Concentration of the filtrate gave the title product (146 g., 90%) as a cloudy oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:9]=2[C:23]([F:26])([F:25])[F:24])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:34]1[CH:39]=[CH:38][N:37]([CH2:40][CH:41]2[CH2:43][CH2:42]2)[C:36](=[O:44])[C:35]=1[C:45]#[N:46]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:41]1([CH2:40][N:37]2[CH:38]=[CH:39][C:34]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[C:9]([C:23]([F:24])([F:25])[F:26])[CH:10]=3)=[C:35]([C:45]#[N:46])[C:36]2=[O:44])[CH2:42][CH2:43]1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)c(C(F)(F)F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(NC3CCOCC3)c(C(F)(F)F)c2)ccn(CC2CC2)c1=O
Yield: 83.6 %

Procedure:
To a solution of intermediate 17 (0.63 g, 1.69 mmol) in 1,4-dioxane (3 ml) and a saturated solution of Na2CO3 (3 ml) was added intermediate 8 (0.42 g, 1.69 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.19 mg, 0.17 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 3 (0.59 g, 9%).