Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[CH3:23][O:24][CH:25]([CH2:28][O:29][CH3:30])[CH:26]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:26][CH:25]([O:24][CH3:23])[CH2:28][O:29][CH3:30]
Reactant: COCC(C=O)OC
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Product: COCC(C=NOCCC1=C(C)/C(=C/c2ccncc2)c2ccc(F)cc21)OC

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 2,3-dimethoxypropanal by the method of Example 1.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH2:18][OH:19])[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[H][H].Cl>O.CO.[Pd]>[NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH2:18][OH:19])[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2CO
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CN)C2CO
Yield: 77.3 %

Procedure:
(2RS,3SR)-2-Aminomethyl-3-hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (550.0 mg, 2.12 mmol) was dissolved in water (50 ml). To the solution, 10% palladium-on-carbon (500 mg) was added, followed by stirring at 80° C. for 2 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure, and the residue was dissolved in methanol. HCl--methanol solution was added thereto to convert the mixture to a hydrochloric acid salt. The salt was condensed, and recrystallized from methanol--ether. As a result, 430.1 mg of the title compound was obtained as colorless powdery crystals (78.2%).
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([O:18][C:19](=[O:38])[CH2:20][CH2:21][CH2:22][C@H:23]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:24]([O-:26])=O)([CH3:17])([CH3:16])[CH3:15].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:61]([O:63][C:64]([N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1)=[O:65])[CH3:62].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:61]([O:63][C:64]([N:66]1[CH2:67][CH2:68][N:69]([C:24](=[O:26])[C@@H:23]([NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:22][CH2:21][CH2:20][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:38])[CH2:70][CH2:71]1)=[O:65])[CH3:62]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CCC[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 2 g of (S)-2-Benzyloxycarbonylamino-hexanedioic acid 6-tert-butyl ester dicyclohexyl-ammonium salt, 1.7 g of NEM and 1.2 g of TOTU in 6 ml of DMF, 0.62 g of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 16 h. The reaction mixture was diluted saturated aqueous sodium hydrogen carbonate solution and extracted with 150 ml of ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.2 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>O1CCCC1>[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([N:19]2[CH2:20][CH2:21][C:15]3[N:14]=[C:13]([C:11]4[S:12][C:8]5[C:7]([N:23]6[CH2:24][CH2:25][O:26][CH2:27][CH2:28]6)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=5[N:10]=4)[NH:22][C:16]=3[CH2:17][CH2:18]2)=[O:44])=[CH:41][CH:40]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccc(F)cc3)CC4)nc12
Yield: 49 %

Procedure:
To a suspension of 0.037 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3 ml tetrahydrofurane were added at 0–4° C. 0.06 ml N-ethyldiisopropylamine and 0.01 μl 4-fluorobenzoylchloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.022 g (49%) (4-fluoro-phenyl)-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-methanone as yellow solid; M.p.: 205–207° C.; MS (ISP): m/e=506 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24].[NH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH:36]2[CH2:38][CH2:37]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH:36]1([NH:35][S:32]([C:28]2[CH:27]=[C:26]([NH:25][C:21]([C:20]3[CH:19]=[N:18][N:11]4[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=5)=[N:9][C:10]=34)=[O:22])[CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH2:38][CH2:37]1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC5CC5)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.6) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 548.1 [(M−H)−]; mp 244° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:19]([O-:21])=[O:20])=[C:7]([S:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH2:15])=O)[CH:8]=1.B.[ClH:23].[OH-].[K+]>C1COCC1>[ClH:23].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:19]([O-:21])=[O:20])=[C:7]([S:9][C:10]2[CH:11]=[C:12]([CH2:13][NH2:15])[CH:16]=[CH:17][CH:18]=2)[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(Sc2cccc(C(N)=O)c2)c1
Agent: B
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(Sc2cccc(CN)c2)c1
Temperature: 0 °C
Yield: 72 %

Procedure:
3-[(5-Methoxy-2-nitrophenyl)thio]benzamide (0.6 g, 1.97 mmol) in THF (25 ml) was treated with 1M borane in THF (10 ml, 9.86 mmol) at 0° C. with stirring. The clear solution was heated under reflux with stirring for 24 h under nitrogen. The reaction mixture was cooled, treated with 5N hydrochloric acid (20 ml) and stirred for 1 h. The mixture was cooled to 0° C., basified with solid potassium hydroxide and extracted with ethyl acetate. The extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue eluted down a silica column using 5% methanol/dichloromethane as eluent to give a yellow solid (0.414 g, 72%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]([O:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:17])[CH3:16]
Reactant: OCc1ccsc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccsc1
Yield: 85 %

Procedure:
To the solution of 0.44 g (3.8 mmol) of Thiophen-3-ylmethanol in 5 mL anhydrous methylene chloride was added 0.58 mL (4.18 mmol) of anhydrous triethylamine and kept for stirring under nitrogen atmosphere. To the solution was then added 0.01 g (0.09 mmol) of DMAP followed by the addition of 0.29 mL (4.17 mmol) acetyl chloride dropwise and kept for stirring for 3 h under nitrogen atmosphere. The resulting mixture was poured into 50 mL of water and extracted twice from 70 mL of methylene chloride. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield pale yellow liquid. The crude product was purified by silica gel column chromatography by eluting with hexane and ethyl acetate (1:1) to obtain colorless liquid. Yield: 85%. 1H NMR (400 MHz CDCl3): δ 2.08 (s, 3H), 5.11 (s, 2H), 7.09 (s, 1H), 7.31 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 20.78, 61.13, 124.28, 126.15, 127.55, 136.82, 170.56.
Reaction SMILES: [C:1]([C:4]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7]C(O)=O)(=O)[CH3:2].[C:16](OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>O>[CH3:7][O:6][C:5]1[C:4]2[C:1]([CH3:2])=[CH:16][O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1c(O)cccc1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1cccc2occ(C)c12
Temperature: 110 °C
Yield: 83 %

Procedure:
(2-Acetyl-3-hydroxy-phenoxy)-acetic acid (2.0 g, 8.9 mmol) is added to acetic anhydride (60 ml) followed by sodium acetate (10.0 g, 122.0 mmol). The mixture is stirred and heated to 110° C., under a nitrogen atmosphere, for 5 hrs. then cooled to 0° C. Water (100 ml) is added slowly, stirred while warming to ambient temperature and continued stirring overnight. The solution is extracted twice with ethyl acetate and the combined organic extracts are washed twice with sodium hydroxide (1N), then brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 25% ethyl acetate in hexane) to give the title compound (1.2 g, 83% yield).
Reaction SMILES: Cl.[C:2]1([CH:8]2[O:12][N:11]=[C:10]([C:13]3[N:14]=[C:15]([C:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=4)[S:16][CH:17]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:29]([CH2:30][C:31](O)=[O:32])[N:28]=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:2]1([CH:8]2[O:12][N:11]=[C:10]([C:13]3[N:14]=[C:15]([C:18]4[CH2:19][CH2:20][N:21]([C:31](=[O:32])[CH2:30][N:29]5[C:25]([CH3:24])=[CH:26][C:27]([C:34]([F:37])([F:36])[F:35])=[N:28]5)[CH2:22][CH:23]=4)[S:16][CH:17]=3)[CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: C1=C(c2nc(C3=NOC(c4ccccc4)C3)cs2)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CC=C(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1,2,3,6-tetrahydropyridine hydrochloride (i.e. the product of Example 13, Step C) (0.250 g, 0.720 mmol) and 5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (0.150 g, 0.720 mmol) in dichloromethane (10 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.138 g, 0.720 mmol), 1-hydroxybenzotriazole (0.024 g, 0.177 mmol), and triethylamine (0.145 g, 1.44 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with dichloromethane (30 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was separated, washed with water, dried (Na2SO4), and concentrated under reduced pressure and purified by medium-pressure liquid chromatography using 3% methanol in chloroform as eluant to give 200 mg of the title product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][OH:35])=[CH:4][N:3]=1.CO.[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH2:32][CH2:33][CH2:34][OH:35])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(CCCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-hydroxyprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (110 mg, 0.228 mmol), methanol (2 mL) and N,N-dimethylformamide (2 mL) was added sodium borohydride (26.9 mg, 0.684 mmol) under an atmosphere of nitrogen. Mixture stirred for 30 minutes at room temperature after which it was treated with 1M sodium carbonate (5 mL) and extracted with dichloromethane (3×5 mL). The organic layer was separated, dried over magnesium sulfate, and filtered, and the solvent was removed under reduced pressure. The product was purified via flash chromatography to furnish the title compound as a pale yellow powder (21.1 mg, 0.0434 mmol): LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 min particle size, 33×4.6 min; 70% 50 mM ammonium Acetate in Water to 95% Acetonitrile over 4.5 mM, 0.8 mL/min): MH+=487 RT=3.23 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (1H), 7.99 (1H), 7.70 (2H), 7.60 (1H), 7.55 (1H), 7.32-7.35 (2H), 7.21 (1H), 7.15 (1H), 7.07 (1H), 5.34 (2H), 4.04 (3H), 3.91 (3H), 3.47 (2H), 2.75 (2H), 1.83 (4H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.Br[C:24]1[S:25][C:26]2[C:32]([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[C:31]([C:41](=[O:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:30]([CH3:48])=[CH:29][C:27]=2[N:28]=1.C(Cl)[Cl:50]>>[Cl:50][C:24]1[S:25][C:26]2[C:32]([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[C:31]([C:41](=[O:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:30]([CH3:48])=[CH:29][C:27]=2[N:28]=1
Reactant: CCOC(=O)C(=O)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Reactant: ClCCl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCOC(=O)C(=O)c1c(C)cc2nc(Cl)sc2c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The above residue was dissolved in CH2Cl2 (33 mL), cooled to 0° C. and Dess-Martin periodinane (2.54 g, 5.99 mmol) was added portion-wise. After stirring for 2 h, more Dess-Martin periodinane (0.25 g, 5.99 mmol) was added. After 1 h, reaction was quenched with Na2S2O3 solution and stirred for 30 minutes. The mixture was diluted with CH2Cl2, washed with water, saturated sodium bicarbonate solution, brine and dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 20% EtOAc/Hex) to give product contaminated with ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-oxoacetate 1H NMR (400 MHz, CDCl3): δ 7.88 (s, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.49 (s, 3H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.Cl.Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>O.CS(C)=O>[N:23]1[CH:24]=[CH:25][C:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:21][CH:22]=1
Reactant: OCCCCCCSc1nc2ccccc2[nH]1
Reactant: Brc1ccncc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2[nH]c(SCCCCCCOc3ccncc3)nc2c1
Temperature: 150 °C
Reaction time: 6 h
Yield: 21.4 %

Procedure:
0.5 g of the compound obtained in Example 26a, 0.4 g of 4-bromopyridine hydrochloride, 0.38 g of potassium hydroxide and 0.2 g of 18-crown-6-ether were added to 10 ml of DMSO and the mixture was heated to 150° C. with stirring for 6 hours. After cooling, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methylene chloride=1:3) and crystallized from acetonitrile to obtain 0.14 g of the title compound (yield: 22%).
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[NH2:3].N1C=CC=CC=1.C(#N)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([NH:3][N:2]([CH3:1])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)(=[O:5])=[O:6])=[O:27]
Reactant: CN(N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: CN(NC(=O)c1c(F)cccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
Into a 100 mL three necked round bottom flask equipped with a magnetic stirrer and condenser, under an atmosphere of nitrogen, was added 2-methyl-2-[(4-chlorophenyl)sulfonyl] hydrazine (5.4 g, 24.5 mmol), pyridine (1.93 g, 1.98 mL, 24.5 mmol), 4-dimethylaminopyridine (0.15 g, 1.2 mmol), and acetonitrile (50 mL). The mixture was cooled to 10° C. and 2-fluoro-6-chlorobenzoyl chloride (4.65 g, 23.4 mmol) was added dropwise at a rate such that the temperature did not rise above 10° C. The mixture was allowed to stir at RT overnight. The solvent was removed from the reaction mixture in vacuo to give an off white solid and the solid was diluted with methylene chloride and extracted with 1N HCl (20 mL), saturated sodium bicarbonate (20 mL), dried (Na2SO4), and the solvent removed in vacuo to give 1-(2-fluoro-6-chlorobenzoyl)-2-methyl-2-[(4-chlorophenyl)sulfonyl] hydrazine as a yellow oil which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Methyl 2-fluoro-4-hydroxybenzoate (1.4685 g, manufactured by Changzhou Fine Chemical Corp.) and potassium carbonate (3.6917 g; manufactured by Sigma-Aldrich Co.) were suspended in dehydrated DMF (21 mL; manufactured by Kanto Chemical Co., Inc.), added with benzyl bromide (1.22 mL; manufactured by Wako Pure Chemical Industries, Ltd.), and stirred at 50° C. overnight. After cooling to the room temperature, it was added to water and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=97:3→77:23) to obtain the title compound (2.2207 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N+:11]([O-:13])=[O:12].[Br:15]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([Br:15])=[C:6]([OH:10])[C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Br)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
To a solution of 3-hydroxy-2-nitrobenzoic acid methyl ester (Example 6.1) (11 g) in chloroform (220 ml) was added dropwise bromine (18.7 g). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was allowed to cool to ambient temperature and the reaction quenched by addition of aqueous sodium metabisulfite (22 g in 100 ml water) and the mixture was stirred for 15 minutes. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was crystallized from diethyl ether/heptane to give 4-bromo-3-hydroxy-2-nitro-benzoic acid methyl ester (6.6 g). 1H-NMR (400 MHz, CDCl3): 9.92 (s, 1H), 7.84 (d, 1H), 7.09 (d, 1H), 3.93 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([NH:10][C:11](=[S:13])[N:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.OO>CO>[F:1][C:2]1[C:3]2[N:4]([N:10]=[C:11]([S:13][S:13][C:11]3[N:12]=[C:3]4[N:4]([C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]4[F:1])[N:10]=3)[N:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)c2nc(=S)[nH]n12
Agent: OO
Solvent: CO
Product: COc1ncc(F)c2nc(SSc3nc4c(F)cnc(OC)n4n3)nn12
Temperature: 43 °C
Yield: 81.8 %

Procedure:
A heterogeneous mixture composed of 76.0 g (0.380 mol) of 8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c ]pyrimidine-2(3H)-thione and 400 g of methanol at 24° C. was prepared and 45.3 g (0.400 mol) of ice cold 30 percent by weight hydrogen peroxide solution was added with stirring. An exothermic reaction took place raising the temperature to 43° C. The mixture was allowed to react for about 75 min and then another 13.0 g (0,115 mol) of ice cold 30 percent by weight hydrogen peroxide solution was added with stirring. The mixture was allowed to react for another 30 m in and then the solids present were recovered by vacuum filtration. These solids were dried and were then slurried with methanol. The slurry was heated to reflux, cooled to 35°-45° C., and filtered to recover the insoluble solids. The solids were dried under reduced pressure at 40° C. to obtain 61.9 g of the title compound (80 percent of theory) as an off-white solid. The compound is a white powder melting at 201°-208° C. (dec.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:25])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.Br[C:27]1[C:28]([CH:45]=[O:46])=[N:29][N:30]([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:25][C:11]1[N:12]=[CH:13][C:14]([C:27]2[C:28]([CH:45]=[O:46])=[N:29][N:30]([CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]3)[CH:31]=2)=[CH:15][C:10]=1[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4o3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(C=O)n2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
A suspension of 3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.3 g), tert-butyl 4-(4-bromo-3-formyl-pyrazol-1-yl)piperidine-1-carboxylate (0.362 g), potassium carbonate (0.335 g) and tetrakis(triphenylphosphine) palladium (0.093 g) in degassed acetonitrile (50 mL) was stirred at reflux overnight. The resulting suspension was cooled to room temperature, filtered, washed with dichloromethane (3×20 ml) and the filtrate concentrated and the crude product was purified by flash chromatography on silica gel eluting with 5 to 90% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (0.370 g) as a solid. NMR Spectrum: (DMSOd6) 1.44 (s, 9H), 1.87 (dd, 1H), 1.92 (dd, 1H), 2.09-2.18 (m, 2H), 2.97 (bs, 2H), 4.04-4.16 (m, 2H), 4.52-4.61 (m, 1H), 7.41-7.49 (m, 2H), 7.80 (dd, 1H), 7.82 (bs, 2H), 7.85 (dd, 1H), 8.48 (s, 1H), 8.56 (d, 1H), 8.65 (d, 1H), 9.99 (s, 1H); Mass spectrum: M+H+ 489.