Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:16])=[C:11]([CH:15]=2)[C:12]([NH2:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1[CH:22]=[C:21]2[C:23]([CH:26]=O)=[CH:24][S:25][C:20]2=[CH:19][CH:18]=1>>[N:1]1([C:7]2[CH:15]=[C:11]3[C:10](=[CH:9][CH:8]=2)[N:16]=[C:26]([C:23]2[C:21]4[CH:22]=[CH:17][CH:18]=[CH:19][C:20]=4[S:25][CH:24]=2)[NH:14][C:12]3=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1csc2ccccc12
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1N
Product: O=c1[nH]c(-c2csc3ccccc23)nc2ccc(N3CCCCC3)cc12

Procedure:
Compound 28 was synthesized from 5-piperidinyl-2-aminobenzamide (12) (1.6 g, 7.3 mmol) and thianaphthene-3-carboxaldehyde (16) (1.2 g, 7.3 mmol): yield 1.6 g (60%); pale yellow crystals; mp>300° C.; 1H NMR (DMSO-d6) δ 1.57-1.59 (6H, m, (CH2)2CH2NCH2CH2), 3.22-3.25 (4H, m, CH2NCH2), 7.42-7.54 (4H, m, 4×ArH), 7.63-7.67 (1H, m, 1×ArH), 8.03-8.07 (1H, m, 1×ArH), 8.66 (1H, s, 1×ArH), 8.97-9.00 (1H, m, 1×ArH), 12.30 (1H, br s, NH) ppm; MS (ESI) m/z 361; Anal. (C21H19N3OS): C, H, N.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[N:12]=[C:11]2[CH2:20][CH3:21])=[CH:6][CH:5]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1.O>CN(C=O)C>[Si:22]([O:19][C:17]1[CH:16]=[CH:15][C:14]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][Br:1])=[CH:9][CH:8]=3)[C:11]([CH2:20][CH3:21])=[N:12][C:13]=2[CH:18]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CCc1nc2cc(O)ccc2n1-c1ccc(CCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2cc(O[Si](C)(C)C(C)(C)C)ccc2n1-c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
A mixture of 1-[4-(2-bromoethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ol (step 1, 200 mg, 0.58 mmol), tert-butyldimethylsilyl chloride (100 mg, 0.7 mmol) and imidazole (47 mg, 1.45 mmol) in DMF (5 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 119 mg (45%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.20 (2H, d, J=8.4 Hz), 7.10 (2H, d, J=8.4 Hz), 7.01 (1H, d, J=2.3 Hz), 6.72 (1H, d, J=8.6 Hz), 6.52 (1H, dd, J=2.3 Hz, 8.6 Hz), 3.45 (2H, t, J=7.4 Hz), 3.07 (2H, t, J=7.4 Hz), 2.56 (2H, q, J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz), 0.79 (9H, s), 0.05 (6H, s).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:32][C:33]1[C:37]([CH:38]=O)=[CH:36][NH:35][N:34]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:38][C:37]4[C:33]([CH3:32])=[N:34][NH:35][CH:36]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: Cc1n[nH]cc1C=O
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4c[nH]nc4C)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 3-methyl-1H-pyrazole-4-carboxaldehyde (9 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CC.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH2:1]([S:13]([C:16]1[CH:21]=[C:20]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCCCCCCCS(=O)(=O)c1cc(N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
A mixture of 27.5 g of 2-dodecylsulfonyl-4-chloronitrobenzene, 5.5 g of pyrrolidine, 138 g of potassium carbonate and 70 ml of dimethylacetamide was stirred for 3 hours at 90° C. To this reaction mixture was added 210 ml of water, and the precipitated crystal was collected by filtration and recrystallized with acetonitrile to obtain 12.7 g of 2-decylsulfonyl-4-pyrrolidinonitrobenzene.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH2:11][CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCl>[Br:1][CH:11]([CH3:12])[C:4](=[O:3])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC
Reactant: BrBr
Agent: CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)CC(=O)C(C)Br
Temperature: 0 °C

Procedure:
277 g of bromine are added dropwise to a solution of 250 g of ethyl 3-oxovalerate and 0.5 g of p-toluenesulphonic acid in 55 ml of methyl chloride at room temperature, while stirring. The mixture is subsequently stirred at 30° C. for one hour, ice-water is added and the organic phase is separated off. The aqueous phase is extracted once more with methylene chloride and the combined organic phases are then dried over magnesium sulphate and evaporated. The product is further processed in the crude form.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[N:17]1([C:22]2[CH:26]=[CH:25][S:24][C:23]=2[C:27](O)=[O:28])[CH:21]=[CH:20][CH:19]=[CH:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:27]([C:23]4[S:24][CH:25]=[CH:26][C:22]=4[N:17]4[CH:21]=[CH:20][CH:19]=[CH:18]4)=[O:28])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1sccc1-n1cccc1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4sccc4-n4cccc4)CC3C2)n1
Yield: 71.7 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), 3-pyrrol-1-yl-thiophene-2-carboxylic acid (58.4 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (79.0 mg, 73%). MS (ESI) mass calcd. for C21H23N5OS, 393.51; m/z found [M+H]+. 1H NMR (CDCl3): 7.42-7.39 (m, 1H), 7.04-7.01 (m, 1H), 6.85 (t, J=2.1, 2H), 6.29 (s, 1H), 6.14 (t, J=2.1, 2H), 3.88-3.73 (m, 2H), 3.66-3.52 (m, 2H), 3.50-3.41 (m, 1H), 3.32-3.20 (m, 1H), 3.00-2.86 (m, 2H), 2.80-2.66 (m, 1H), 2.60-2.47 (m, 1H), 2.34-2.25 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[NH:6][N:5]=1.[Br:14][C:15]1[C:22]([O:23][CH2:24][CH3:25])=[C:21]([CH:26](Cl)[CH3:27])[CH:20]=[C:19]([Cl:29])[C:16]=1[C:17]#[N:18]>CN(C)C=O.C(Cl)Cl>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:26]([C:21]3[CH:20]=[C:19]([Cl:29])[C:16]([C:17]#[N:18])=[C:15]([Br:14])[C:22]=3[O:23][CH2:24][CH3:25])[CH3:27])[N:5]=[C:4]([CH3:3])[C:12]=12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1Br
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1Br
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
Sodium hydride (16 mg, 0.41 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (33 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL, 40 mmol) and was stirred for 10 minutes. 2-bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (60 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL) was added and the reaction was stirred at 50° C. overnight. The mixture was diluted with methylene chloride, washed with sat'd NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product was purified by flash column chromatography eluting with CH2Cl2/MeOH 0-10%, to give 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile (0.05 gm, 60%) as a solid, LCMS calculated for C17H16BrClN6O (M+H)+: m/z=437.0, 435.0; found: 436.9, 434.7.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]([CH2:14][CH2:15]Cl)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[CH:22]=[C:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>CO>[OH:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][N:26]2[CH2:27][CH2:28][C:23](=[CH:22][C:21]3[CH:29]=[CH:30][CH:31]=[C:19]([F:18])[CH:20]=3)[CH2:24][CH2:25]2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Oc1nc(-c2ccc(F)cc2)c(CCCl)s1
Reactant: Fc1cccc(C=C2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Oc1nc(-c2ccc(F)cc2)c(CCN2CCC(=Cc3cccc(F)c3)CC2)s1
Yield: 21.4 %

Procedure:
In 2 ml of methanol were stirred 773 mg of 2-hydroxy-5-(2-chloroethyl)-4-(4-fluorophenyl)thiazole, 683 mg of 4-(3-fluorobenzylidene)piperidine hydrochloride and 1.04 ml of N,N-diisopropylethylamine at 80° C. for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was separated with ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by a flash column chromatography (silica gel; ChromatorexNH NHDM1020 (manufactured by Fuji-Davison Chemical Co.), eluent; hexane-ethyl acetate =1:1), and recrystallized from hexane-ethyl acetate to give 265 mg of 2-hydroxy-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene)piperidin-1-yl]ethyl]thiazole.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([F:24])[CH:13]=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].CC(C)([O-])C.[Li+].ClC[C@@H](O)[CH2:34][N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[CH2:43]([N:35]([CH2:34][C@@H:4]1[O:3][C:1](=[O:2])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:14]([F:24])[CH:13]=2)[CH2:5]1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (0.33 g, 1 mmol) was added under nitrogen atmosphere to 5 mL of DMF (N,N-dimethyl formamide), and mixture was cooled to −10˜0° C. A solution of lithium tert-butoxide (2.5 mL, 2.5 mmol) in tetrahydrofuran was added dropwise. The mixture was warmed to room temperature (25° C.) naturally and stirred for 2 hours. (S)-1-chloro-3-(dibenzylamino)propan-2-ol (0.32 g, 1.1 mmol) was then added and the mixture was stirred at room temperature for 20 hours. Saturated ammonium chloride solution and ethyl acetate were added to separate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to provide 0.42 g of white solid in 88% yield.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[C:29]2[CH:30]=[CH:31][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:33][CH:34]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(R)-4-[6-(4-tert-Butyl-cyclohexyloxy)-5-(4-trifluoromethoxy-phenyl)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.2041 g, 0.0003768 mol) was dissolved in ethanol (4.00 mL, 0.0685 mol) in a capped 40 mL EPA vial equipped with a magnetic stir bar. 4.2 M lithium hydroxide, monohydrate in water (2.00 mL, 0.00840 mol) was added and the mixture was stirred overnight at 80° C. HPLC analysis showed that the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure. The product was partitioned between water and methylene chloride. The combined organic phase was dried over MgSO4, filtered, concentrated and purified by flash chromatography [0-50% of 2M NH3 solution in MeOH (10% in methylene chloride) and methylene chloride to give the title compound in 69% yield. MS: m/z=499.23 [M−NH2]+. 1H NMR (MeOD) δ: 7.93-7.96 (m, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.47-7.52 (m, 1H), 7.38-7.45 (m, 6H), 4.06-4.16 (m, 1H), 3.72 (d, J=10.8 Hz, 1H), 3.67 (d, J=10.8 Hz, 1H), 1.99-2.07 (m, 2H), 1.76-1.84 (m, 2H), 1.51 (s, 3H), 0.91-1.24 (m, 5H), 0.86 (s, 9H)
Reaction SMILES: S(=O)(=O)(O)O.[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]([O-:17])=[O:16])[CH:9]=1.C([O-])(O)=O.[Na+].[CH2:23](O)[CH3:24]>>[CH2:23]([O:16][C:15]([C:10]1[CH:9]=[C:8]([Br:7])[CH:13]=[C:12]([CH3:14])[N:11]=1)=[O:17])[CH3:24]
Reactant: CCO
Reactant: Cc1cc(Br)cc(C(=O)[O-])n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cc(Br)cc(C)n1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Sulfuric acid (5 mL) is added to a suspension of 4-bromo-6-methyl-pyridine-2-carboxylic acid potassium salt (5.03 g, 15.5 mmol) in ethanol (150 mL). The clear solution is heated to 70° C. and stirred for 18 h. The mixture is neutralised with NaHCO3 and sat. aq. NaHCO3 solution and then extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 3:2 to give 4-bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (2.42 g) as a yellow oil; LC-MS: tR=0.86 min, [M+1]+=243.96.
Reaction SMILES: Cl.[Cl:2][C:3]([Cl:11])([Cl:10])[C:4]1[CH:5]=[NH+:6][CH:7]=[CH:8][CH:9]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:2][C:3]([Cl:11])([Cl:10])[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Cl)c1ccc[nH+]c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: ClC(Cl)(Cl)c1cccnc1
Yield: 80.2 %

Procedure:
The 3-trichloromethylpyridinium hydrochloride salt (2836 g, 12.17 moles) was placed in a 22-liter pot with 2800 ml of methylene chloride and 2600 ml of water. A solution of 1000 g of sodium carbonate in 4300 ml of water was then added slowly so that the gassing could be controlled. The temperature was maintained with an ice bath between 15°-20° C. The lower organic phase was then separated and was dried with magnesium sulfate. The mixture was filtered and the methylene chloride was removed by rotary evaporation. The concentrated material was distilled at 77°-79° C. and 0.5 mm Hg giving 1918 g of the desired 3-trichloromethylpyridine product. The yield was 80%.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[S:59][C:60]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)=[CH:61][N:62]=4)=[O:57])=[CH:51][N:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[S:59][C:60]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)=[CH:61][N:62]=4)=[O:57])=[CH:51][N:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cn3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cn3)cc2C1=O
Yield: 59 %

Procedure:
The compound of example 637 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 636.
Reaction SMILES: Br[CH:2]1[CH2:4][CH2:3]1.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])([O-:7])=[O:6]>>[CH:2]1([O:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N+:5]([O-:7])=[O:6])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrC1CC1
Product: O=[N+]([O-])c1ccccc1OC1CC1

Procedure:
In a similar manner as in Example 1, bromocyclopropane was reacted with o-nitrophenol to yield 2-cyclopropoxynitrobenzene; which was reduced to the corresponding aniline; reacted with N-methylolpyrrolidone to form the corresponding N-methylenepyrrolidonyl derivative; and acetylated with chloroacetyl chloride to form the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12]CCOCC)=O)=[N:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][CH2:22][CH2:23][NH2:24])[CH3:20]>C1COCC1>[CH2:19]([O:21][CH2:22][CH2:23][NH:24][C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][C:6]=2[N:7]=1)=[O:12])[CH3:20]
Reactant: CCOCCN
Reactant: CCOCCOC(=O)c1nc2cc(Cl)ccc2o1
Solvent: C1CCOC1
Product: CCOCCNC(=O)c1nc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A mixture of 2-ethoxyethyl 5-chlorobenzoxazol-2-carboxylate (10 g) and 3.5 g of ethoxyethylamine in 10 ml of THF was stirred at room temperature for 2 hours. The precipitated product was filtered and washed well with hexane to give 9 g of product; mp 110°-111° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8](F)=[CH:9][CH:10]=2)[N:5]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:4]=1)[CH3:2].[C-:19]#[N:20].[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CS(C)=O>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([C:19]#[N:20])=[CH:9][CH:10]=2)[N:5]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:4]=1)[CH3:2]
Reactant: [C-]#N
Reactant: CCc1nn(C2CCOCC2)c2nc(F)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1nn(C2CCOCC2)c2nc(C#N)ccc12
Temperature: 150 °C
Yield: 74 %

Procedure:
A mixture of 3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine (2.92 g, 0.0117 mol), sodium cyanide (3.9 g, 0.079 mol), tetra-N-butylammonium bromide (7.6 g, 0.023 mol) and dimethyl sulfoxide (60 mL) was heated at 150° C. for 2 hours. After cooling, the product was extracted using ethyl acetate (300 mL). The extract was washed with water (5×50 mL) and brine (50 mL), and then concentrated to provide the crude product as a brown solid, which was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient over 15 minutes (flow rate 20 mL/min) to afford 2.22 g (73.9%) of 3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carbonitrile as an off-white solid, which was used without further purification. LC/MS (EI) tR 3.57 (Method E), m/z 257.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(Br)cc1
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C(=O)N1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
A solution of 2-(4-bromophenyl)propanoic acid (215 mg, 0.94 mmol) in dichloromethane (4 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (152 g, 0.94 mmol). This mixture was allowed to stir at room temperature for 15 minutes. Pyrrolidine (67 mg, 0.94 mmol) was then added and the stirring continued for 1 hour at room temperature. Most of the solvent was removed under reduced pressure and the residue added to a 5 g pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (189 mg, 71%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:23]([OH:24])[C@@H:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:21]([CH2:33][OH:34])[O:20][C@H:10]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:23]([OH:24])[C@@H:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:21]([CH2:33][O:34][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[O:20][C@H:10]1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Compound 16 (569 mg, 1.20 mmol) was dissolved by addition of pyridine (17 mL). Pivaloyl chloride (188 μl, 1.57 mmol) was added to the solution, and the mixture was stirred at −5° C. for 1 hour. Pivaloyl chloride (188 μl, 1.57 mmol) was further added thereto, and the mixture was stirred at −5° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, and filtered through Celite, and the filtrate was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:AcOEt=10:1) to obtain Compound 17 (648 mg, 96.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:14]=[C:13]([NH:15][NH2:16])[N:12]=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:20][C:21](=[O:29])[C:22]([C:27]#[N:28])=[CH:23]OCC)[CH3:19]>C(O)C>[CH2:18]([O:20][C:21]([C:22]1[CH:23]=[N:16][N:15]([C:13]2[CH:14]=[C:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])[CH3:8])[N:10]=[CH:11][N:12]=2)[C:27]=1[NH2:28])=[O:29])[CH3:19]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CN(C(=O)OC(C)(C)C)c1cc(NN)ncn1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cc(N(C)C(=O)OC(C)(C)C)ncn2)c1N

Procedure:
A mixture of (6-hydrazino-pyrimidin-4-yl)-methyl-carbamic acid tert-butyl ester (4.0 g, 16.7 mmol), 2-cyano-3-ethoxy-acrylic acid ethyl ester (3.02 g, 17.5 mmol) and ethanol (25 mL) is heated to reflux for 4 hours. The reaction mixture is then concentrated and triturated with water (10 mL). White precipitate forms. After filtration, the undissolved solid is further washed with water, then air-dried to give 5-amino-1-[6-(tert-butoxycarbonyl-methyl-amino)-pyrimidin-4-yl]-1H-pyrazole-4-carboxylic acid ethyl ester as white powder.