Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8](Cl)=[O:9].O>C1COCC1>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8]([N:2]([CH3:3])[CH3:1])=[O:9]
Reactant: CNC
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of dimethylamine (2M in THF, 3 mL) and THF (2 mL) is added 2,6-dimethoxybenzoyl chloride (200.6 mg, 1 mmol) in THF (2 mL) dropwise. After the addition, the solution is stirred at RT for 1 h. Water is added and the suspension is extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound: 1H NMR (CDCl3) δ 7.26-7.22 (t, J=8.34 Hz, 1H), 6.56-6.53 (d, J=8.33 Hz, 2H), 3.79 (s, 6H), 3.12 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:16])[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH3:16][N:8]([C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:10])[C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: CN(C(=O)c1cccs1)c1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(N(C)C(=O)c2cccs2)cc1)c1ccccc1

Procedure:
The title product was prepared from thiophene-2-carboxylic acid (4-hydroxy-phenyl)-methyl-amide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (16%, oil). HPLC-MS: m/z=367.2 (M+1); Rt: 3.97 min.
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1.[CH2:19]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[C:20]#[CH:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Pd](Cl)Cl.C(#N)C>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH2:19][C:20]#[C:21][N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(I)cnc-2n1
Reactant: C#CCOC1CCCCO1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cc2c(O)n(C#CCOC3CCCCO3)cnc-2n1
Reaction time: 12 h

Procedure:
A mixture of 14.6 g of 3-iodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine, 7.6 g of 2-(2-propynyloxy)-tetrahydropyran, 798 mg (10%) of palladium chloride, 2.36 g (20%) of triphenyl phosphine, 428 mg (5%) of cuprous iodide, 45 ml of triethyl amine and 700 ml of acetonitrile is heated at reflux under nitrogen for 12 hours. There then are added to the hot reaction mixture 3.2 g of 2-(2-propynyloxy)-tetrahydropyran and reflux is continued for an additional 12 hours. After heating for a total of 24 hours under reflux, the solvent is removed under reduced pressure, and the residue filtered through silica gel using 2% methanol in methylene chloride. This filtrate is concentrated and chromatographed on silica gel eluting with 20:1 ethyl acetate:hexane mixture to give 3-(3-tetrahydropyr-2-yloxyprop-1-yn-1-yl)-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine which is further purified by recrystallization with ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:16])[CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Br:50][C:51]1[CH:52]=[C:53]([NH2:58])[C:54]([NH2:57])=[N:55][CH:56]=1>CN(C)C=O.C(OCC)(=O)C>[C:2]1([CH2:1][O:8][C:9](=[O:10])[N:11]([CH2:12][C:13]([NH:58][C:53]2[C:54]([NH2:57])=[N:55][CH:56]=[C:51]([Br:50])[CH:52]=2)=[O:15])[CH3:16])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CC(=O)Nc1cc(Br)cnc1N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a mixture of 2-[(benzyloxycarbonyl)(methyl)amino]acetic acid (0.42 g, 1.88 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.75 g, 1.97 mmol) in N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine (0.72 mL, 4.12 mmol) was added and the reaction mixture was stirred for 30 minutes at room temperature, followed by the addition of 5-bromo-2,3-diaminopyridine (0.35 g, 1.86 mmol), then stirred for 16 hours. It was diluted with ethyl acetate (50 mL), washed with aqueous lithium chloride (2×20 mL) and brine, dried over sodium sulfate, filtered and concentrated. Gradient flash chromatography (35% to 85% ethyl acetate in hexane) provided phenylmethyl{2-[(2-amino-5-bromopyridin-3-yl)amino]-2-oxoethyl}methylcarbamate (0.70 g, 96%). MS (EI) for C16H17BrN4O3: 394 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:8]1[C:7]([F:11])=[C:3]([C:2]([F:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1c(F)cccc1F
Product: O=C(O)c1c(F)ccc(S(=O)(=O)Cl)c1F
Temperature: 150 °C
Reaction time: 2 h

Procedure:
77 mmol of 2,6-difluorobenzoic acid were dissolved in 15.5 ml of chlorosulfonic acid and stirred for 2 h at 150° C. The reaction mixture was cooled to room temperature and poured into 100 ml of ice/water. The solid was filtered and dried to yield the title compound as a colorless solid. MS (m/e): 255.1 (M−H, 44%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1CCN2C(=NCCC2)CC1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>[OH-].[Na+]>[CH:19]1([NH:25][C:26](=[O:27])[NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C=NC1CCCCC1
Reactant: NCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)CCCNC(=O)NC1CCCCC1
Yield: 76 %

Procedure:
To a cold solution of 4-aminobutyric acid (2.16 g, 21 mmol) and catalytic amount of DBU in 22 mL of 1.0 N NaOH, 2.5 g (20 mmol) of cyclohexyl isocyanate were added in one time. The mixture was strongly mixed at room temperature overnight. The reaction was then acidified with concentrated HCl. The formed white solid was collected by filtration. The mixture was purified by chromatography on a silica column (8×3 cm). Elution with a mixture 50:50:1 of hexane:ethyl acetate:acetic acid gave the pure targeted product. The resulting white crystal (3.46 g; yield: 76%) had a mp of 153.0-154.0° C. [M+H]+ 281.18.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([Cl:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([Cl:12])[C:5]2[O:9][C:8]([N:18]3[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1c(Cl)cc2nc(S)oc2c1Cl
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cc2nc(N3CCN(C)CC3)oc2c1Cl

Procedure:
5,7-Dichloro-6-methyl-2-mercaptobenzoxazole (200 mg) was dissolved in chloroform (20 ml), N-methylpiperazine (0.94 ml) was added dropwise to the solution and then the mixture was stirred with heating for 29 hours. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5,7-dichloro-6-methyl-2-(4-methyl-1-piperazinyl)benzoxazole (163 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]CCCC)=[O:15])[CH:12]=2)[C:7]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[CH:6]1)[CH2:2][CH2:3][CH3:4].O[Li].O.C1COCC1.O>CO>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7]([C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ccc2c(C(=O)C(F)(F)F)cn(CCCC)c2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCn1cc(C(=O)C(F)(F)F)c2ccc(C(=O)O)cc21
Yield: 70.7 %

Procedure:
Butyl 1-butyl-3-(trifluoroacetyl)-1H-indole-6-carboxylate (0.277 g), LiOH.H2O (0.040 g), THF (1.5 mL), water (0.5 mL), and methanol (0.5 mL) were stirred overnight at room temperature. The solvents were then removed under reduced pressure and HCl (2N, 0.5 mL) was added to the residue. The residue was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated. Chromatography on silica gel using methanol/dichloromethane (6/94) gave 1-butyl-3-(trifluoroacetyl)-1H-indole-6-carboxylic acid (0.166 g). MS (ESI+) for C15H14F3N1O3+H1 m/z 314.10 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[Br:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:13][C:14]1[N:15]=[CH:16][N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11][CH3:12])[CH:18]=1
Reactant: Brc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(Br)c1

Procedure:
A mixture of 2.0 g (10.7 mmol) 2-chloro-5-nitroanisole, 1.65 g (11.2 mmol) 4-bromoimidazole and 5.21 g (16.0 mmol) cesium carbonate in 50 ml acetonitrile was refluxed overnight. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic phase was dried, evaporated and the residue purified on silica gel with ethyl acetate/heptane 3/7. After trituration with diethyl ether 707 mg (22%) of 4-bromo-1-(2-methoxy-4-nitro-phenyl)-1H-imidazole was isolated as a slightly brownish solid. MS ISP (m/e): 298.1/300.0 (100/87) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.96 (d, 2H), 7.77 (s, 1H), 7.44 (d, 1H), 7.26 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=[O:17])([O-:8])=[O:7].[CH3:19]COC(C)=O>CO>[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])([O-:8])=[O:7]
Reactant: CCOC(C)=O
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: CO
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)Cc1ccccc1[N+](=O)[O-]
Yield: 94.7 %

Procedure:
Add sulfonyl chloride (3 mL) dropwise to a solution of 2-nitrophenylacetic acid (7.0 g, 38.6 mmol) in methanol (20 mL) at 0° C., reflux the resulting mixture overnight. TLC (PE:EtOAc=3:1) shows the reaction is complete. Concentrate the reaction mixture under reduced pressure, add water, extract with ethyl acetate twice, and wash the combined organic layers with brine, dry over anhydrous sodium sulfate. Concentrate under reduced pressure to yield the crude product (7.5 g, 94.7%) which is used directly without further purification. MS: (M+1): 196.1.
Reaction SMILES: N=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:4](=[S:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.C[OH:33].O>Cl>[O:33]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:4](=[S:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1
Reactant: CO
Reactant: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C23CCCCC3)cc1
Agent: Cl
Solvent: O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCCCC3)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 9b (0.035 g, 0.08 mmol) in HCl aq., 2N (1 ml) and methanol (3 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (5 ml) and extracted with ethyl acetate (6 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-(4-oxo-2-thioxo-1-(4-methylphenyl)-1,3-diazaspiro[4.5]dec-3-yl)-2-trifluoromethylbenzonitrile, 9c, [RD48] (0.034 g, 0.076 mmol, 95%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7][CH2:6]2.[CH3:16][CH2:17][N:18]([CH:22](C)C)[CH:19](C)[CH3:20].BrCC(Cl)=[O:28].N1C2C(=CC=CC=2)C=CC=1.C(NC)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:17]([N:18]([CH3:22])[CH2:19][C:20]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:28])[CH3:16]
Reactant: O=C(Cl)CBr
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCCC2
Agent: CCNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CCN(C)CC(=O)N1CCCc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.6 %

Procedure:
A solution of 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (3.00 g, 14.41 mmol), Hunig's Base (12.55 mL, 72.0 mmol), and bromo-acetylchloride (1.500 mL, 18.01 mmol) was stirred at room temperature for 2 hours, at which time quinoline was observed to still remain. Additional bromo-acetylchloride (1.500 mL, 18.01 mmol) was added, the reaction was stirred an additional 5 hours, N-ethylmethylamine (12.38 mL, 144 mmol) was added, and the reaction was maintained for 16 hours at room temperature. The reaction was poured into saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and the residue was purified by silica gel chromatography to afford N-ethyl-N-methyl-2-[6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-2-oxoethanamine (2.02 g, 45.6% yield) as a dark red solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (s, 1 H), 7.18 (s, 1 H), 3.89 (s, 3 H), 3.75 (s, 2 H), 3.30 (s, 2 H), 2.81 (t, J=6.12 Hz, 2 H), 2.36-2.47 (m, 2 H), 2.19 (s, 3 H), 1.80-1.97 (m, 2 H), 0.86-1.02 (m, 3 H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:35])[N:4]([C:8]2[C:9]([CH3:34])=[C:10]([C:14]3[C:26]4[C:25]5[C:20](=[CH:21][C:22]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:24]=5)[NH:19][C:18]=4[C:17]([C:31]([NH2:33])=[O:32])=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:5][C:6]=1[CH3:7].C([O-])=O.[NH4+]>CO.[Pd].C(Cl)Cl>[CH3:1][CH:2]1[CH:6]([CH3:7])[CH2:5][N:4]([C:8]2[C:9]([CH3:34])=[C:10]([C:14]3[C:26]4[C:25]5[C:20](=[CH:21][C:22]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:24]=5)[NH:19][C:18]=4[C:17]([C:31]([NH2:33])=[O:32])=[CH:16][CH:15]=3)[CH:11]=[CH:12][CH:13]=2)[C:3]1=[O:35]
Reactant: CC1=C(C)C(=O)N(c2cccc(-c3ccc(C(N)=O)c4[nH]c5cc(C(C)(C)O)ccc5c34)c2C)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1N1CC(C)C(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of 4-(3-(3,4-dimethyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Example 81-21, 20 mg, 0.043 mmol) and ammonium formate (27.0 mg, 0.428 mmol) in methanol (5 mL) was treated with 10% palladium on charcoal (20 mg, 0.019 mmol). The mixture was stirred under nitrogen at rt for 2 h. Additional ammonium formate (27.0 mg, 0.428 mmol) was added and the mixture was stirred at rt overnight. More ammonium formate (57 mg) and 10% palladium on charcoal (40 mg) were added, and after 6 h more additional ammonium formate (57 mg) was added. The mixture was again stirred overnight, then was diluted with DCM and filtered through Celite. The filtrate was washed with water, dried and concentrated. The residue was purified by preparative HPLC and the appropriate effluent fractions were made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The combined organic phases were washed with water, dried and concentrated to provide 4-(3-(3,4-dimethyl-2-oxopyrrolidin-1-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (11 mg, 55%), which was a mixture of diastereomers. Mass spectrum m/z 452.1 (M+H—H2O)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23].Br[CH2:30][CH2:31][CH2:32][OH:33]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:30][CH2:31][CH2:32][OH:33])=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: OCCCBr
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)c2ccc(O)cc2)cc1Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)c2ccc(OCCCO)cc2)cc1Cl)C(F)(F)F
Reaction time: 0.25 h

Procedure:
Sodium hydride (0.06 g of a 60% dispersion in oil) was added to a solution of (R)-N-[2-chloro-4-(4-hydroxyphenylsulphinyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 89) (0.5 g) in DMF (5 ml) at 0° C. The mixture was stirred for 15 minutes then 3-bromopropanol (0.12 ml) was added as a solution in DMF (3 ml). The mixture was stirred at ambient temperature for 16 hours. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-10% methanol/DCM to give the title compound (0.34 g) as a gum. NMR (CDCl3): 1.25 (dd, 2H), 1.7 (s, 3H), 1.8 (s, 1H), 3.8-3.9 (m, 2H), 4.1-4.2 (m, 2H), 5.1 (s, 1H), 6.95 (d, 2H), 7.4 (d, 1H), 7.5 (d, 2H), 7.6-7.65 (m, 1H), 8.45-8.55 (m, 1H), 9.3 (s, 1H); MS (ESP−): 464.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](N)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.N(OCCC(C)C)=O.[I-:20].[Na+]>C1COCC1.C(OCC)C.CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:20])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: [I-]
Reactant: Nc1n[nH]c2ncc(F)cc12
Agent: CC(C)CCON=O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Fc1cnc2[nH]nc(I)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 g (65.75 mmol) of 5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine were initially charged in THF (329 ml), and the mixture was cooled to 0° C. 16.65 ml (131.46 mmol) of boron trifluoride diethyl ether complex were then added gradually. The reaction mixture was cooled further to −10° C. A solution of 10.01 g (85.45 mmol) of isopentyl nitrite in THF (24.39 ml) was then added gradually, and the mixture was stirred for a further 30 min. The mixture was diluted with cold diethyl ether (329 ml) and the resulting solid was filtered off. The diazonium salt thus prepared was added in portions to a solution at 0° C. of 12.81 g (85.45 mmol) of sodium iodide in acetone (329 ml), and the mixture was stirred at RT for 30 min. The reaction mixture was poured onto ice-water (1.8 l) and extracted twice with ethyl acetate (487 ml each time). The collected organic phases were washed with saturated aqueous sodium chloride solution (244 ml), dried, filtered and concentrated. This gave 12.1 g (86% purity, 60% of theory) of the desired compound in solid form. The crude product was converted without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[CH3:19][C:20]1[N:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:27][CH2:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:19])[N:25]=2)[N:7]=1
Reactant: Cc1cccc(CO)n1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(COc2nc(N)nc(-c3ccc(C)o3)c2C#N)n1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 6-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CCCCCCC>CO>[O:2]1[C:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[CH:23][N:22]=[CH:21]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCCC
Product: N#Cc1ccc(-c2cnco2)cc1
Yield: 97 %

Procedure:
To a solution of 4-Formyl-benzonitrile (5 g, 38.17 mmol) and tosylmethyl isocyanide (TosMIC) (from Aldrich, 8.33 g, 42 mmol) in MeOH (200 mL) was added K2CO3 (6.85 g, 49.62 mmol) and the mixture was stirred at reflux for 1 h. The solvent was then evaporated and saturated aqueous NaHCO3 was added. The resultant suspension was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4 and concentrated to leave a yellow solid. Trituration with heptane afforded a solid that was collected by filtration and dried under vacuum to give the title compound (6.3 g, 97%). m.p.=140° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22](=O)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]([CH:29]1[CH2:32][NH:31][CH2:30]1)=[O:28].C(O)C.C([BH3-])#N.[Na+]>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH:22]([N:31]2[CH2:32][CH:29]([C:27]([O:26][CH3:25])=[O:28])[CH2:30]2)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CC(=O)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1CN(C(C)c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Temperature: 25 °C

Procedure:
1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethanone (68 mg, 0.00021 mol) and Azetidine-3-carboxylic acid methyl ester (23.9 mg, 0.000207 mol) was dissolved in Ethanol (0.50 mL, 0.0086 mol) and was heated to reflux for 2 hours. After cooling down to rt, Sodium cyanoborohydride (32.4 mg, 0.000516 mol) was added and was heated to reflux for 1 hour. After cooling down to rt and concentration, the mixture was dissolved into DCM and quenched with NEt3 and concentrated. The residue was chromatographed with MeOH/CH2Cl2 to give product (57.2 mg, 65%). LCMS 1.66 min, at m/z 425.30 ([M+1], 100%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:26]=3)[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:26]=3)[CH:16]=2)=[CH:13][CH:14]=1
Reactant: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2-c1cccc(OCCCn2ccnc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2-c1cccc(OCCCn2ccnc2)c1

Procedure:
0.9 g of 5-(4-benzyloxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 20 h in 40 ml of THF in the presence of 0.15 g of 10% palladium/carbon. After filtration through Celite and chromatography of the residue on silica gel (methylene chloride/methanol 9:1) 5-(4-hydroxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine (Rf=0.2 silica gel, methylene chloride/methanol 9:1) is obtained.