Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H].Br[CH2:15][C:16]1[CH:33]=[CH:32][C:19]([CH:20]=[C:21]2[CH:26]3[C:27]([CH3:29])([CH3:28])[C:23]([CH3:30])([CH2:24][CH2:25]3)[C:22]2=[O:31])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O>[CH2:3]([O:11][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[C:21]2[CH:26]3[C:27]([CH3:28])([CH3:29])[C:23]([CH3:30])([CH2:24][CH2:25]3)[C:22]2=[O:31])=[CH:32][CH:33]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCO
Reactant: [H][H]
Reactant: CC12CCC(C(=Cc3ccc(CBr)cc3)C1=O)C2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOCc1ccc(C=C2C(=O)C3(C)CCC2C3(C)C)cc1

Procedure:
A suspension of 2.1 g (50 millimols) of sodium hydride (in oil) is added in small amounts to 6.5 g (50 millimols) of octan-1-ol in 100 ml of toluene, whilst stirring. When the evolution of hydrogen has ended, 16.6 g (50 millimols) of 3-(p-bromomethylbenzylidene)-camphor are added in portions, and the mixture is then heated under reflux for 3 hours. After adding water, the toluene phase is decanted, dried and concentrated to dryness. The residual syrup is distilled under reduced pressure. 8.8 g of a yellow liquid, which boils at 240° under a pressure of 0.1 mm Hg, are thus collected.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].B(O)(O)O.C(OC(=O)C)(=O)C>C(O)(=O)C>[OH:1][CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: OB(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: OC[C@H]1OC(O)[C@H](O)[C@H]1O
Temperature: 50 °C

Procedure:
L-xylose of formula 10 (5.00 g, 33.3 mmol) and boric acid (4.53 g, 73.3 mmol) were dissolved in acetic acid (120 mL), followed by heating at 50° C. for 1 hour with stirring. Acetic anhydride (120 mL) was added thereto. The reaction mixture was heated at 50° C. for 3 days and then cooled down at room temperature, followed by extraction by using water (600 mL) and ethyl acetate (3×300 mL). The ethyl acetate extract was washed with saturated sodium_bicarbonate solution and brine, and moisture remained in the solvent was dried over magnesium sulfate. The extract was concentrated to give xylofuranose, the compound of formula 5, as a syrup (10.45 g, 32.8 mmol, 99%, α:β=1:1.8).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].F[P-](F)(F)(F)(F)F.C[N+:28](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[NH2:28][C:12]([CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:14]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CC(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (from Activate Scientific. 0.25 g, 1.2 mmol), ammonium acetate (0.14 g, 1.9 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.71 g, 1.9 mmol) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (0.43 mL, 2.5 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.156 g, 63%). LCMS calculated for C9H16N2O3Na (M+Na)+: m/z=223.1. Found: 223.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:6]C)[CH2:4]C)[CH3:2].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:10][CH2:9]1.ClCC[S:28](Cl)(=[O:30])=[O:29].Cl>ClCCl>[CH3:4][N:3]([CH3:6])[CH2:1][CH2:2][S:28]([N:8]1[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]1)(=[O:30])=[O:29]
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCS(=O)(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (3.4 mL) was added to a dichloromethane (300 mL) solution of Benzyl piperidin-4-ylcarbamate (2.2 g) at 0° C. followed by the dropwise addition of 2-chloroethanesulfonyl chloride (2.6 mL; TCI) and the resulting mixture was slowly stirred overnight with raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with chloroform, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). 30 mg of this purified compound was dissolved in methanol (1 mL) followed by the addition of dimethylamine (2 M, 0.2 mL; Ald), the resulting mixture was stirred at 100° C. for 2 hours with microwave irradiation, and then the solvent was evaporated under reduced pressure. The title compound was obtained from this residue according to the method described in Step c of Reference Example N-14.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:13]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[N:12]=[C:11]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO.O1CCCC1.[OH-].[Na+].O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[N:13]([CH2:14][C:15]3[CH:34]=[CH:33][C:18]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=4)=[CH:17][CH:16]=3)[N:12]=[C:11]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:43])([F:44])[F:42])=[CH:37][CH:36]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3/C=C/c3ccccc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3/C=C/c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Methyl 3-(4-{[4-({5-[(E)-2-phenylvinyl]-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)benzyl]oxy}phenyl)propanoate (250 mg, 0.419 mmol) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and 2 N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and neutralized with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure to give the title compound (220 mg, yield 90%) as colorless crystals. MS: m/z 583 (MH+), 1H NMR (DMSO-d6) δ: 2.45 (2H, t, J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz), 5.00 (2H, s), 5.65 (2H, s), 6.86 (2H, d, J=8.5 Hz), 7.09 (2H, d, J=8.5 Hz), 7.22-7.46 (10H, m), 7.64 (2H, d, J=7.4 Hz), 7.77 (2H, d, J=8.2 Hz), 8.05 (2H, d, J=8.0 Hz), 12.05 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[N:10][C:9]=2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:43][C:44]1[CH:45]=[CH:46][C:47]([CH3:63])=[C:48]([NH:50][C:51]2[CH:52]=[C:53]3[C:58](=[CH:59][CH:60]=2)[N:57]=[CH:56][N:55]([CH3:61])[C:54]3=[O:62])[CH:49]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([F:14])([F:15])[F:16])=[N:10][C:9]=2[C:17]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([CH3:63])=[C:48]([NH:50][C:51]3[CH:52]=[C:53]4[C:58](=[CH:59][CH:60]=3)[N:57]=[CH:56][N:55]([CH3:61])[C:54]4=[O:62])[CH:49]=2)=[O:19])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reactant: O=C(O)c1nc(C(F)(F)F)oc1-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2nc(C(F)(F)F)oc2-c2ccc(F)cc2)cc1Nc1ccc2ncn(C)c(=O)c2c1
Yield: 27 %

Procedure:
To a flask containing DCM (3 mL) at 0° C. was added 5-(4-fluorophenyl)-2-(trifluoromethyl)oxazole-4-carboxylic acid (S-68) (17 mg, 0.06 mmol), EDC (10.6 mg, 0.07 mmol), HOAt (10.9 mg, 0.08 mmol), and DIPEA (0.043 mL, 0.25 mmol). The resulting solution was allowed to react at 0° C. for 1 hr, at which point 6-((5-amino-2-methylphenyl)amino)-3-methylquinazolin-4(3H)-one (HGM-7) (17.3 mg, 0.06 mmol) was added. The reaction was allowed to react for 18 hours at ambient temperature at which point saturated sodium bicarbonate (5 mL) was added and extracted with DCM (2×10 mL) then EtOAc (2×10 mL). The organic extracts were washed with brine, combined, dried over Na2SO4, and concentrated. The crude material was fractionated by SiO2 chromatography (stepwise gradient of DCM to 10% MeOH, the desired product elutes in 6% MeOH) (9 mg, 27% yield). 1HNMR (400 MHz, CDCl3/MeOD): d 8.29 (m, 2H), 7.98 (s, 1H), 7.62 (d, 1H, J=2.4 Hz), 7.57 (m, 2H), 7.51 (s, 1H), 7.42 (dd, 1H, J=2.8, 9.2 Hz), 7.39 (dd, 1H, J=2.4, 8.4 Hz), 7.24 (d, 1H, J=8.0 Hz), 7.19 (t, 2H, J=8.4 Hz), 3.58 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][NH:50][CH3:51])[CH3:46]>C(N(CC)CC)C.C1COCC1>[CH2:45]([O:47][C:48](=[O:52])[CH2:49][N:50]([C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=1)[CH3:51])[CH3:46]
Reactant: CCOC(=O)CNC
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)c1ccccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-fluorobenzoyl)benzoic acid (3.00 g), 1-hydroxybenzotriazole (2.07 g), 1,3-dicyclohexylcarbodiimide (3.00 g) and anhydrous THF (50 ml) was stirred at room temperature for 1 hour. To this mixture were added N-methylglycine ethyl ester hydrochloride (2.84 g) and triethylamine (2.58 ml), followed by stirring at room temperature for 16 hours and with heating and refluxing for 4 hours. After the solvent was distilled off, ethyl acetate was added to the residue, and the insoluble crystals were separated by filtration. The filtrate was washed successively with water, aqueous sodium hydrogen carbonate, water, dilute hydrochloric acid and water and then dried, after which the solvent was distilled off, to yield N-[2-(4-fluorobenzoyl)benzoyl]-N-methylglycine ethyl ester as a colorless oily substance (4.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[C:15]([OH:18])(=O)[CH3:16].C([BH3-])#N.[Na+].[CH2:23]1[CH2:27]OC[CH2:24]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:24]2[CH2:16][CH2:15][O:18][CH2:27][CH2:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C2CCOCC2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 8.05 mmol) stirring in anhydrous THF (20 mL) and water (0.2 mL) was added glacial acetic acid (1.45 mL, 24.2 mmol), followed by sodium cyanoborohydride (758 mg, 12.1 mmol). The reaction mixture was stirred at 60° C. for 12 h, quenched with 10% aqueous NaHCO3 (50 mL), extracted with EtOAc and dried (MgSO4) to give a colourless oil which was purified by silica chromatography to give 4-(tetrahydro-pyran-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.54 g, 25%), as a white solid. BOC-deprotection was carried out as in Reference Example 3 to give the title compound (0.30 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][S:7]([C:10]1[S:14][C:13]([NH2:15])=[N:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].[CH3:17][CH:18]([CH3:29])[CH2:19][CH2:20][NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][CH2:23]1.C1(N(CCC2C=CC=CC=2)C(=O)NC2SC(SC[C:46](O)=[O:47])=CN=2)CCCCC1>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][S:7]([C:10]1[S:14][C:13]([NH:15][C:46]([N:21]([CH2:20][CH2:19][CH:18]([CH3:29])[CH3:17])[C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)=[O:47])=[N:12][CH:11]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: CCOC(=O)CNS(=O)(=O)c1cnc(N)s1
Reactant: CC(C)CCNC1CCC(C)CC1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CNS(=O)(=O)c1cnc(NC(=O)N(CCC(C)C)[C@H]2CC[C@H](C)CC2)s1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
An equimolar mixture of 1,1-carbonyldiimidazole, (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester and DMAP (5 mol %) in THF was heated for 5 h at 50-60° C. and then cooled to room temperature. Then (3-methyl-butyl)-(4-methyl-cyclohexyl)-amine (1 equivalent; prepared following the procedure described in the preparation of [2-(3-cyclohexyl-3-phenethylureido)-thiazol-5-ylsulfanyl]-acetic acid) was added and the reaction is stirred overnight at room temperature. The reaction mixture was quenched with water. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude product was dissolved in MeCN and purified using HPLC to give {2-[3-(3-methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid ethyl ester as crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[CH2:15]([N:14]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1)[CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: CNCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CN(Cc1ccccc1)c1cnc2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-Dichloroquinoxaline (0.500 g, 2.5 mmol) was dissolved in DMSO (10 mL) at RT and N-methyl-1-phenylmethanamine (1.53 g, 12.56 mmol) was added to the reaction mixture. The reaction mixture was stirred at RT for 16 hrs. After completion of reaction (checked by TLC), water (100 mL) was added to the reaction mixture and it was extracted with ethyl acetate (50 mL×3). The organic layer was washed with water (10 mL), brine (10 mL) and dried over Na2SO4. The organic layer was concentrated under vacuum to give the crude product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@@H:5]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[N:23]1[CH:28]=CC=CC=1.C[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[C@@H:5]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:30]([CH2:28][NH2:23])(=[O:32])=[O:31])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(NS(=O)(=O)CN)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(S)-Ethyl-2-tert-butyloxycarbonylamino-3-(4-aminophenyl)propionate (0.103 g, 0.33 mmol) was dissolved in CH2Cl2 (1 mL) in a two-necked flask fitted with a thermometer and nitrogen line. The flask was cooled to 0° C. and pyridine (1.1 eq, 0.36 mmol, 0.030 mL) was added via syringe. Methanesulfonyl chloride (1.1 eq, 0.36 mmol, 0.028 mL) was then added dropwise at such a rate as to maintain the temperature <10° C. After addition was complete, the ice bath was removed and the bright yellow solution was allowed to warm to room temperature, turning bright orange and then pink in color as it stirred over the next two hours. The solution was poured into 1 M aqueous CuSO4 and the organic portion was separated. It was washed once again with aqueous CuSO4, then dried over MgSO4, filtered, and concentrated to a colorless oil (0.11 g, 84%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH2:16][C@H:15]([O:18][NH2:19])[CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ClC([O:25][C:26](Cl)(Cl)Cl)=O.C.[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:26]([NH:19][O:18][C@H:15]2[CH2:16][CH2:17][N:13]([S:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)(=[O:11])=[O:12])[CH2:14]2)=[O:25])=[CH:34][CH:33]=1
Reactant: NO[C@H]1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)C1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NO[C@H]1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)C1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
A solution of (S)—O-(1-(4-(trifluoromethoxy)phenylsulfonyl)pyrrolidin-3-yl)hydroxylamine (250 mg, 0.76 mmol) in tetrahydrofuran (10 ml) was added over 30 minutes to a suspension of trichloromethyl chloroformate (227 mg, 1.15 mmol) and activated charcoal (20 mg) in tetrahydrofuran (35 ml) at 0° C. over 30 minutes. After stirring at room temperature for 18 hours, the reaction mixture was filtered over silicagel and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (15 ml), 4-fluoroaniline (93.6 mg, 0.84 mmol) and N,N-diisopropylethylamine (296 mg, 2.3 mmol) were added and the whole was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (50 ml), washed with H2O (20 ml×2), brine (20 ml×2), dried over Na2SO4 and concentrated in vacuo. The residual solid was recrystallized from diethyl ether to give (S)-1-(4-fluorophenyl)-3-(1-(4-(trifluoromethoxy)phenylsulfonyl)pyrrolidin-3-yloxy)urea as a white solid (127 mg, 36%): LCMS: 464 [M+1]+. 1H NMR (DMSO-d6) δ: 1.85 (m, 1H), 2.09 (m, 1H), 3.25 (m, 3H), 3.53 (d, 1H), 4.36 (s, 1H), 7.07 (t, 2H), 7.47 (d, 2H), 7.56 (d, 2H), 7.92 (d, 2H), 8.63 (s, 1H), 9.45 (s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH2:20])=[C:14]([O:21][CH3:22])[CH:13]=2)=[CH:6][N:5]=1.Cl.[N:24]([O-])=O.[Na+].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>O>[NH2:3][C:4]1[N:9]=[C:8]([NH2:10])[C:7]([CH2:11][C:12]2[CH:13]=[C:14]([O:21][CH3:22])[C:15]([N:20]=[N:24][N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[C:16]([O:18][CH3:19])[CH:17]=2)=[CH:6][N:5]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N
Reactant: CCNCC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCN(CC)N=Nc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC

Procedure:
A solution of 7 g. of 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-pyrimidine dihydrochloride in 60 ml. of 1N hydrochloric acid and 40 ml. of water was treated during 5 minutes with stirring and ice-cooling with a solution of 1.52 g. of sodium nitrite in 10 ml. of water. The solution was stirred at 0° C. for 30 minutes and 14.6 g. of diethylamine were then added. After stirring with ice-cooling for 2 hours, the precipitate was removed by filtration with suction, washed with water and recrystallized from methanol, whereby there was obtained 2,4-diamino-5-[4-(3,3-diethyl-1-triazeno)-3,5-dimethoxy-benzyl]-pyrimidine having a melting point of 196°-197° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Br[C:14]1[CH:23]=[N:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:20]2[CH:21]=[N:22][CH:23]=[CH:14][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccncc1Br
Product: COC(=O)c1ccncc1NCc1ccc(C(F)(F)F)cc1
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield from 4-(trifluoromethyl)benzylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.95 (d, 1H, J=5.0 Hz), 7.93 (br s, 1H), 7.65 (d, 1H, J=5.0 Hz), 7.60 (d, 2H, J=8.1 Hz), 7.47 (d, 2H, J=8.1 Hz), 4.58 (d, 2H, J=5.9 Hz) 3.91 (s, 3H). [M+H] calc'd for C15H13F3N2O2, 311. Found 311.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N+:24]([O-])=O)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:5].O>CN(C=O)C.[Pd]>[NH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:15][CH:16]=1
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Pd]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)Nc1cc(Oc2ccc(N)c3ccccc23)ccn1

Procedure:
To a solution of 2-methoxy-N-(4-(4-nitronaphthalen-1-yloxy)pyridin-2-yl)acetamide (50.0 g, 142 mmol) in DMF (500 mL) under nitrogen was added palladium on carbon (10% w/w Pd/C, 5.0 g, 14.15 mmol) and the mixture was purged with hydrogen and maintained under a slight positive hydrogen atmosphere for 48 hr. The catalyst was removed by filtration through celite and the pad washed with DMF (2×100 mL) and then DCM (100 mL). The solvents were removed in vacuo to afford a dark brown residue which was treated with water (150 mL) and the mixture evaporated. Toluene (100 mL) was added and evaporated to remove residual water. After drying overnight under vacuum, the material was triturated from diethyl ether (250 mL) to give the title compound, Intermediate B1, as a green solid (43.3 g, 85%): m/z 324 (M+H)+ (ES+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[F:1][C:2]1[CH2:3][C:4]([N+:11]([O-:13])=[O:12])([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])C1(O)C=C(F)C(F)=C(F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Trifluorophenol (14.81 g, 0.1 mol) was dissolved in glacial acetic acid (50 mL) and cooled to 4° C. while concentrated nitric acid (5 mL, 70%) was added dropwise over 15 min, during which time the color of the mixture becomes yellow. Upon complete addition of HNO3, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 min. TLC analysis of an aliquot extracted into ethyl acetate indicates that a new non-polar spot was formed and the complete consumption of starting material. The mixture was then diluted with ethyl acetate (200 mL), transferred to separatory funnel, and washed copiously with water (3×100 mL). The organic layer was finally washed with brine, dried over anhyd MgSO4, and evaporated under reduced pressure to afford crude product as a yellowish oil. (17.3 g, 90%). This crude material was used directly in the subsequent reaction described in Intermediate 6. 1H NMR (400 MHz, CDCl3): 6.84 (m, 1H, ArH), 10.28 (brs, 1H, OH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]2[N:9]([CH2:12][CH3:13])[N:10]=[CH:11][C:3]=12.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>>[Cl:8][C:6]1[N:5]=[C:4]2[N:9]([CH2:12][CH3:13])[N:10]=[CH:11][C:3]2=[C:2]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[N:7]=1
Reactant: CCn1ncc2c(Cl)nc(Cl)nc21
Reactant: COc1cccc(N)c1
Product: CCn1ncc2c(Nc3cccc(OC)c3)nc(Cl)nc21

Procedure:
4,6-Dichloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidine 5b was reacted with m-anisidine using General Procedure B to give (6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3-methoxy-phenyl)-amine, which was reacted with indazole boronic acid pinacol ester using General Procedure A to give 147. NMR (CDCl3): 1.62 (3H, t), 3.88 (3H, s), 4.62 (2H, q), 6.89 (1H, dd), 7.17 (1H, d), 7.32 (1H, s), 7.40 (1H, t), 7.51 (1H, s), 7.55 (1H, t), 7.64 (1H, d), 8.45 (1H, d), 9.16 (1H, s), 10.20 (1H, br). MS: MH+ 386.19 (100%)