Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][NH:11][C:12](=[O:32])[C@H:13]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:14][N:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[O:17])[C:3]=1[F:33].Cl.[NH2:35][C@@H:36]([CH2:42][CH3:43])[C:37]([N:39]([CH3:41])[CH3:40])=[O:38].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:27]1([CH2:26][C@H:13]([CH2:14][N:15]([CH:16]=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]([NH:11][NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([NH:35][C@@H:36]([CH2:42][CH3:43])[C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[C:3]=2[F:33])=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC[C@H](N)C(=O)N(C)C
Reactant: COc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(OC)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F)C(=O)N(C)C
Temperature: 80 °C
Reaction time: 168 h
Yield: 22.4 %

Procedure:
[(2R)-3-{2-[6-Chloro-5-fluoro-2-(methyloxy)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.133 g, 0.28 mmol), (2S)-2-amino-N,N-dimethylbutanamide, hydrochloride salt (Example 83) (0.075 g, 0.45 mmol) and diisopropylethylamine (0.1 mL, 0.62 mmol) were stirred in DMSO (2 mL) overnight at 65° C. Then additional diisopropylethylamine (0.2 mL) was added, and the reaction was stirred for 7 days at 80° C. Purified by RP-HPLC to provide (2S)-2-{[6-{2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]hydrazino}-5-fluoro-2-(methyloxy)-4-pyrimidinyl]amino}-N,N-dimethylbutanamide (0.036 g, 23%). LCMS: (M+H)+=574.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:9][C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:7][C:6]=12.C[Si]([N:30]=[C:31]=[O:32])(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][CH2:12][CH:13]3[CH2:14][CH2:15][N:16]([C:31]([NH2:30])=[O:32])[CH2:17][CH2:18]3)=[CH:9][C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:7][C:6]=12
Reactant: C[Si](C)(C)N=C=O
Reactant: Clc1ccccc1-c1cc(NCC2CCNCC2)n2ncc(Br)c2n1
Solvent: ClCCl
Product: NC(=O)N1CCC(CNc2cc(-c3ccccc3Cl)nc3c(Br)cnn23)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-ylmethylamine (57 mg, 0.136 mmoles) (prepared as described in Example 460, Step B above) was dissolved in anhydrous dichloromethane (1.2 mL) and trimethylsilylisocyanate (0.091 mL, 0.679 mmoles) was added. The mixture was stirred at 25° C. for 2.5 h. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (30×2.5 cm) using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid amide (53.7 mg, 86%): FABMS: m/z 463.1 (MH+); HRFABMS: m/z 463.0647 (MH+). Calcd. for C19H21N6OBrCl: m/z 463.0649; δH (d6-DMSO) 1.09 (2H, m, CH2), 1.63 (2H, m, CH2), 1.87 (1H, m, CH), 2.60 (2H, m, CH2), 3.53 (2H, bm, CONH2), 3.91 (2H, d, CH2), 6.52 (1H, s, H6), 7.50 (2H, m, Ar—H), 7.62 (2H, m, Ar—H), 8.33 (1H, s, H2) and 8.52 ppm (1H, m, NH); δC (d6-DMSO)CH2: 30.1, 30.1, 44.2, 44.2, 47.7; CH: 36.4, 88.2, 128.1, 130.7, 131.4, 132.1, 147.9; C: 82.1, 132.1, 139.4, 145.7, 147.9, 158.1, 158.8.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][C@@H:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=2)=[CH:27][N:26]=1>CN(C)C=O>[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([NH:11][C@@H:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[O:38])=[N:35][CH:36]=2)=[CH:27][N:26]=1
Reactant: Nc1ncc(-c2ccc(C(=O)O)nc2)cn1
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc(N)nc2)cn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
N,N-Diisopropylethylamine (1.13 mL, 6.48 mmol) was added to a mixture of tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (0.250 g, 1.12 mmol), and 5-(2-aminopyrimidin-5-yl)pyridine-2-carboxylic acid (0.242 g, 1.12 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at RT for 3 h, and filtered. The filtrate was diluted with methanol (10 mL). The resulting solution was purified by RP-HPLC (pH 10) to give the desired product (182 mg, 42.3%). LCMS: (M+H)=386.2.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].[C:31](OC(=O)C)(=[O:33])[CH3:32].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ccc(C(=O)Nc2ccc(C(=O)N3CCCCc4ccccc43)cc2)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc(C(=O)N3CCCCc4ccccc43)cc2)c(Cl)c1

Procedure:
A mixture of 1-[4-(2-chloro-4-aminobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g), acetic anhydride (15 ml), acetic acid (5 ml) and a drop of sulfuric acid is stirred at room temperature for 1 hour. To the reaction mixture is added aqueous 2N aqueous sodium hydroxide solution and the mixture is extracted with chloroform. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is recrystallized from methanol/diethyl ether to give 1-[4-(2-chloro-4-acetylaminobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.28 g) as white powder, m.p. 214-243° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:20]1[CH2:24]OC[CH2:21]1>CCOC(C)=O>[Si:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]([CH3:24])[CH3:21])[N:15]=[CH:14]2)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)n1ncc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
Sodium hydride (60% oil dispersion, 211 mg, 5.28 mmol) was added to a solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-1H-indazole (Preparation 41, 1.09 g, 4.40 mmol) in THF (10 mL) and stirred at room temperature for 15 minutes. The solution was then heated at 50° C. for 18 hours, then at reflux for 8 hours. The reaction mixture was diluted with EtOAc and washed with water, 0.5 N aqueous citric acid solution and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 0 to 10% EtOAc in heptane to yield the title compound as a clear oil (261 mg, 20%):
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@H:8]([NH:12][C:13](=[O:22])[C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:25]([CH2:24][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@H:8]([NH:12][C:13](=[O:22])[C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1)([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@H](O)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NC(=O)[C@H](O)c1ccccc1)CC2
Reaction time: 5 h
Yield: 57 %

Procedure:
A mixture of 15.8 g of N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide, obtained according to Example 3(b), 7.1 ml of ethyl bromoacetate, 22 g of anhydrous potassium carbonate and 1 g of potassium iodide in 600 ml of anhydrous acetone, is heated with reflux and with stirring for 5 hours and a half. The reaction mixture is filtered, evaporated to dryness and the oil which separates is left to crystallize. The solid so obtained is purified by flashchromatography (elution with a 1/1 mixture of ethyl acetate/cyclohexane). The solid on the column is taken up and treated with 20 ml of ethyl ether, filtered and crystallized from ethyl acetate to give 11.5 g of N-[(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide, SR 58638; m.p. 115°-117° C.; [alpha]=-98.3° (methanol, c=1%). Yield: 57%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]#[N:24])=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:23]#[N:24])=[CH:14]1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: COc1ccc(C=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C=C(C#N)c2c[nH]c3ccccc23)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2.0 g (12.0 mmole) 3,4 dimethoxybenzaldehyde in 75 ml absolute ethanol are added 2.07 g (13.3 mmole) 3-indolylacetonitrile and 1.83 g (13.3 mmole) anhydrous potassium carbonate. The reaction flask is equipped with a condenser and a drying tube (using anhydrous CaSO4), and the reaction was stirred and heated. After refluxing for 24 hours, the reaction is allowed to cool to room temperature. The reaction mixture is filtered to remove the salts, and the solvent is removed by rotary evaporation. The residue is purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 3:1. The yellow solid is recrystallized from acetone-hexane to give 2-(3-indolyl)-3-(3,4-dimethoxy-phenyl)-2-propenenitrile, m.p. 139°-141° C.
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[Si:29]([O:36][CH2:37][C:38](O)=[O:39])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C)C=O>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:38](=[O:39])[CH2:37][O:36][Si:29]([C:32]([CH3:34])([CH3:33])[CH3:35])([CH3:30])[CH3:31])[CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (500 mg) in dimethylformamide (6 ml) under argon were added {[tert-butyl(dimethyl)silyl]oxy}acetic acid (225 mg), diisopropylethylamine (582 mg) and 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 542 mg). The reaction mixture was stirred at room temperature for 18 hours. Then ice-cold sodium hydrogencarbonate solution was added thereto, the mixture was filtered, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Purification by column chromatography gave 2-(3-{2-[1-({[tert-butyl(dimethyl)silyl]oxy}acetyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (150 mg, 22%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:15]I.OO.O>CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[C:12]([I:15])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: II
Agent: OO
Solvent: CO
Solvent: O
Product: Nc1ccc(Cc2ccccc2)cc1I
Reaction time: 8 h

Procedure:
To a solution of 4-benzylbenzenamine (3.00 g, 16.4 mmol) in 16 mL MeOH was added iodine (2.49 g, 9.82 mmol) followed by hydrogen peroxide, 30% in water (1.67 mL, 16.4 mmol). The dark solution was allowed to stir overnight. The reaction was partitioned between water/brine and EtOAc. The organic layer was washed 1× brine, dried over MgSO4, filtered, and concentrated. The resulting oil was purified by ISCO (120 g, 0-10% EtOAc/hexanes) to give 4-benzyl-2-iodobenzenamine as a red oil which slowly solidified to a red solid. MS (ESI) m/z: Calculated: 309.0; Observed: 310.0 (M++1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[Na].Cl[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Cl>C(O)C>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:8])[CH3:11]
Reactant: ClCCOCCCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1
Reaction time: 0.17 h
Yield: 44 %

Procedure:
A solution of diethyl malonate (15.2 mL, 99.8 mmol) in ethanol (10 mL) was added dropwise to a solution of sodium ethoxide in ethanol [freshly prepared from sodium (2.3 g, 100 mmol) and ethanol (30 mL)] at ambient temperature and stirred for 10 min. Bis(2-chloroethyl)ether (12 mL, 102 mmol) was added dropwise then the mixture was heated at reflux overnight. It was then cooled to 10° C. before another portion of freshly-prepared sodium ethoxide in ethanol [prepared from sodium (2.3 g, 100 mmol) and ethanol (30 mL)] was added. The mixture was heated at reflux for 48 h then cooled, filtered to remove the precipitated sodium chloride then the filtrate was concentrated to dryness. Water was added to the residue which was then extracted with ether (3×25 mL). The combined ether layers were washed with water, brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure yielded tetrahydropyran-4,4-dicarboxylic acid diethyl ester (10.1 g, 44%) as a mobile oil.
Reaction SMILES: [Na].[C:2]([O:11]C)(=O)[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[SH:5].[C:13]1([NH:19][C:20](=[N:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[C:24]1([NH:23][C:20]([C:21]2[S:5][C:4]3[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=3[C:2]=2[OH:11])=[N:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccccc1S
Reactant: ClCC(=Nc1ccccc1)Nc1ccccc1
Agent: [Na]
Solvent: CO
Product: Oc1c(C(=Nc2ccccc2)Nc2ccccc2)sc2ccccc12
Temperature: 0 °C
Yield: 76.9 %

Procedure:
A solution of 2.3 g (0.1 mol) of sodium in 150 ml of methanol is mixed with 16.8 g (0.1 mol) of methyl thiosalicylate and then a solution of 24.4 g (0.1 mol) of N,N'-diphenyl-2-chloro acetamidine in 250 ml of methanol is added. After heating under reflux for 1 hour, the mixture is poured into ice water and the precipitate filtered and recrystallized from an ethanol/water solution to yield 26.5 g of yellow needles having an m.p. of 152°-153° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][CH:9]1[S:13](=[O:15])(=[O:14])[O:12][CH2:11][CH2:10]1>O1CCCC1>[CH:1]1([NH:7][CH2:11][CH2:10][CH:9]([S:13]([OH:15])(=[O:14])=[O:12])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1CCOS1(=O)=O
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: CC(CCNC1CCCCC1)S(=O)(=O)O
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of cyclohexylamine (1.50 g, 15.1 mmol) in tetrahydrofuran (15 mL) was added 2,4-butane sultone (2.04 g, 14.4 mmol). The solution stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and dried in vacuo. Yield: 59%. 1H NMR (DMSO, 500 MHz) δ ppm 8.50 (s (broad), 1H), 3.02 (m, 2H), 2.93 (m, 1H), 2.60 (m, 1H), 1.93 (m, 3H), 1.75 (m, 3H), 1.57 (m, 1H), 1.21 (m, 4H), 1.11 (m, 4H). 13C (DMSO, 125 MHz) δ ppm 56.23, 53.20, 43.09, 29.54, 29.41, 29.39, 25.40, 24.42, 17.23. ES-MS 234 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([CH3:33])[O:32][CH2:31][CH2:30][O:29]2)=[CH:24][CH:23]=1.O>O1CCOCC1>[CH3:33][C:28]1([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][O:16][N:15]=[CH:14][C:5]3[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]=3[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:23][CH:24]=2)[O:29][CH2:30][CH2:31][O:32]1
Reactant: CC1(c2ccc(CBr)cc2)OCCO1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn(C)c(Oc2ccccc2)c1C=NOCc1ccc(C2(C)OCCO2)cc1
Yield: 74.2 %

Procedure:
1.0 Gram (0.0043 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dioxane, and 0.14 g (0.0058 mole) of sodium hydride was added. Thereafter, 1.1 g (0.0043 mole) of 2-(4-bromomethylphenyl)-2-methyl-1,3-dioxolane was added to this solution which was then heated under reflux for 3 hours. After completion of the reaction, the reaction solution was poured into 200 ml of cold water and extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.3 g of the desired compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:1][CH2:2][CH2:3][C:4]2[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=2)(=[O:22])=[O:21])=[CH:18][CH:19]=1)(=[O:12])[CH3:11]
Reactant: Cn1cccc1CCN
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCc2cccn2C)cc1

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and p-acetamidobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][NH:18]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1>CO>[CH2:1]([N:8]1[CH2:16][CH2:17][NH:18][CH:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/CN(CCNC(c1ccccc1)(c1ccccc1)c1ccccc1)Cc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1
Temperature: 50 °C

Procedure:
To a solution of Example 12B (160 g, 326 mmol) in methanol (652 mL) was added 4 MHCl in dioxane (408 mL, 1630 mmol) and the mixture was heated at 50° C. for 3 hours. The solvent was then evaporated and water was added. A solid precipitates. The water layer was decanted and washed once with ethyl acetate. The solid was dissolved in ethyl acetate and extracted with water once. The water layers were combined and treated with 1N NaOH (1 L) until pH=10. The free amine was extracted twice with dichloromethane, dried over sodium sulfate and concentrated to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.34-7.20 (m, 5H), 3.57 (s, 3H), 3.42 (q, J=13.4 Hz, 2H), 2.96 (qd, J=2.7 Hz, 6.9 Hz, 1H), 2.78 (dt, J=2.9 Hz, 11.9 Hz, 1H), 2.69-2.60 (m, 2H), 2.55 (d, J=10.8 Hz, 1H), 2.30 (dd, J=3.2 Hz, 6.7 Hz, 2H), 1.92 (td, J=2.8 Hz, 10.6 Hz, 1H), 1.68 (t, J=10.0 Hz, 1H); MS (ESI) m/z 249.0 (M+H)+.
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][C@@:14]2([C:26]([OH:28])=O)[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:11][CH:10]=1.[NH2:31][CH2:32][CH:33]([OH:40])[CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2([C:26]([NH:31][CH2:32][CH:33]([OH:40])[CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])=[O:28])[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(Cc1ccc(Br)cc1)C(=O)O
Reactant: CCC(C)(C)CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(Br)cc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methylmorpholine (6.4 mL, 58.6 mmol) was added to an ambient temperature solution of 2-(4-bromobenzyl)-1-(tert-butoxycarbonyl)proline (5.0 g, 13 mmol), 1-amino-4,4-dimethylhexan-2-ol (1.89 g, 13 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (3.0 g, 15.6 mmol), and hydroxybenzotriazole (2.1 g, 15.6 mmol) in dichloromethane (51 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with water. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo to afford tert-butyl 2-(4-bromobenzyl)-2-{[(2-hydroxy-4,4-dimethylhexyl)amino]carbonyl}pyrrolidine-1-carboxylate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([F:29])=[CH:24][N:23]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:18][C:24]3[C:25]([F:29])=[CH:26][N:27]=[C:22]([Cl:21])[N:23]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Cl)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 4-(N-benzylpiperazino)aniline and 2,4-dichloro-5-fluoropyrimidine gave N4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 2.81 (m, 4H), 3.37 (m, 6H), 6.85 (br, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.40 (m, 5H), 7.50 (d, J=9.3 Hz, 2H), 8.02 (d, J=2.7 Hz, 1H); LCMS: ret. time: 20.56 min, purity: 97.75%; MS (m/e): 398.00 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[N:8]=1.[CH2:16](O)[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:14][C:13]([C:9]1[N:8]=[C:7]([Br:6])[CH:12]=[CH:11][CH:10]=1)=[O:15])[CH3:17]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(Br)n1

Procedure:
Sulfuric acid (1.46 mL) was added to a mixture of 2-bromo-6-pyridine-carboxylic acid, ethanol (15 mL) and toluene (30 mL). The reaction heated to reflux for 16 h. The mixture was partitioned between chloroform and a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with chloroform (2 x) and the combined organic layers were dried over sodium sulfate, filtered and concentrated to yield a cloudy orange oil. The oil was purified by silica gel chromatography with 9:1 hexane:ethyl acetate. The title product was obtained as an oily white solid (1.31 g).