Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[N:26]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:30][C:27]4[CH:28]=[CH:29][O:25][N:26]=4)[CH2:21]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccon1
Reactant: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)C2)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[4(4-fluorophenyl)-1-pyrrolidin-3-yl-1H-imidazol-5-yl]pyrimidin-2-amine (C18) (300 mg, 0.925 mmol) and isoxazole-3-carbaldehyde (90 mg, 0.93 mmol) in toluene (5 mL) was added triethylamine (0.5 mL, 3.6 mmol), and the mixture was heated at 80° C. for 16 hours. After cooling to room temperature, the reaction was treated with sodium triacetoxyborohydride (500 mg, 2.36 mmol) and stirred for an additional 3 hours at 80° C. Solvents were removed in vacuo, and the residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by preparative thin layer chromatography on silica gel (Eluant: ethyl acetate) provided the product as a solid. Yield: 60 mg, 0.15 mmol, 16%. LCMS m/z 406.6 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.10 (m, 1H), 2.50-2.59 (m, 2H), 2.84 (dd, J=10.5, 6.7 Hz, 1H), 3.09 (dd, J=10.4, 2.4 Hz, 1H), 3.16 (m, 1H), 3.85 (AB quartet, JAB=14.0 Hz, ΔνAB=23.1 Hz, 2H), 5.29 (m, 1H), 6.40 (d, J=4.9 Hz, 1H), 6.55 (br s, 1H), 7.07 (dd, J=8.7, 8.7 Hz, 2H), 7.41 (dd, J=8.5, 5.5 Hz, 2H), 8.12 (d, J=5.2 Hz, 1H), 8.21 (s, 1H), 8.63 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[N+:11]([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[NH2:11]
Reactant: COC(=O)c1ccc(O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc(O)cc1N
Yield: 96.1 %

Procedure:
To a stirred solution of 4-hydroxy-2-nitrobenzoic acid methyl ester (4.410 g, 22.369 mmol) in methanol (80 ml) under nitrogen at room temperature was added ammonium formate (5.642 g, 89.475 mmol) and 5% Pd/C (450 mg). After 5 hours the reaction mixture was filtered through celite and rinsed. The filtrate was concentrated and the residue partitioned between EtOAc (150 ml) and water (40 ml). The layers were shaken, separated and the organic layer washed with water (3×30 ml), brine (2×30 ml), dried over Na2SO4, filtered, concentrated and dried to give 2-amino-4-hydroxy-benzoic acid methyl ester (3.593 g, 21.494 mmol, 96%) as an off-white solid, dec. 113-118° C. 1H NMR (DMSO-d6) δ 3.70 (s, 3H), 5.98 (dd, 1H), 6.10 (s, 1H), 6.59 (s, 1H), 7.54 (d, 1H), 9.81 (s, 1H); mass spectrum [ES(−)], m/z 166 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].[NH4+].C(O)C.CN(C)C=O>[Fe].O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(N)c2)cc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
After adding 1 g of 2-amino-4-(4-nitrophenoxy)pyridine to a mixture of 2.0 g of iron powder, 4.0 g of ammonium chloride, 30 ml of ethanol, 30 ml of dimethylformamide and 15 ml of water, the mixture was vigorously stirred at 100° C. for 10 minutes. The reaction solution was filtered with celite and the solvent was distilled off under reduced pressure to obtain 0.53 g of the target substance as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38]CC[CH2:35][O:34]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].Cl[C:41]1C=C(NC2C=CC(F)=CC=2)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC1COC(C)(C)O1)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH:31]3[CH2:35][O:34][C:33]([CH3:38])([CH3:41])[O:32]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3)cc2Cl)c1
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: CC1(C)OCC(CN=[N+]=[N-])O1
Product: Cc1ccc(-c2cn(CC3COC(C)(C)O3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 432 (2.75 mmol) and compound 410 (2.75 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 20:80 to 65:35 as the eluent to afford the title compound as foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C([Sn](CCCC)(CCCC)[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)CCC.[F-].[K+]>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C.C(Cl)(Cl)Cl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: Cl[Pd]Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C1Cc2cc(-c3cccnc3)ccc2N1
Temperature: 25 °C
Yield: 17.5 %

Procedure:
A mixture of 5-bromooxindole (0.95 g, 4.48 mmol), 3-(tri-n-butylstannyl)pyridine (1.65 g, 4.48 mmol), tetraethyl ammonium chloride (2.23 g, 13.4 mmol) and bis(triphenylphospine palladium (II) chloride (0.16 g, 0.22 mmol) in acetonitrile (20 mL) was heated at reflux over night. After cooling to ambient temperature the mixture was diluted with chloroform (100 mL) and a potassium fluoride solution (10%, 250 mL) was added. The mixture was filtered through Celite and the layers were separated. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified on a silica gel column using chloroform/ethanol, (50:1), as the eluent affording 165 mg (18% yield) of the title compound as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.64 (br s, 1 H), 7.97 (d, J=2 Hz, 1 H), 7.66 (dd, J=5, 1 Hz, 1 H), 7.21-7.10 (m, 1 H), 6.73 (s, 1 H), 6.73-6.65 (m, 1 H), 6.65-6.54 (m, 1 H), 6.08 (d, J=8 Hz, 1 H), 2.69 (s, 2 H); MS (ES) m/z 211 (M++1).
Reaction SMILES: [CH:1]([Si:4]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][C:10](=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:8]1)([CH3:3])[CH3:2]>[Pd].CO>[CH:21]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:18]([CH3:20])[CH3:19])[O:5][CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:12]1)([CH3:22])[CH3:23]
Reactant: COC(=O)C=C1CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC1
Reaction time: 3 h
Yield: 85.1 %

Procedure:
A mixture of 10.3 g (30.2 mmol) of the unsaturated ester from Step D and 600 mg of 5% palladium on carbon in 150 mL of methanol was stiffed under an atmosphere of hydrogen for 3 h. The catalyst was filtered off and the filtrate concentrated to give 8.8 g (85%) of the title compound as a mixture of cis and trans isomers. 1H NMR (500 MHz, CDCl3) δ 3.68 (s, 3H), 3.57 (d, 0.6H, J=6.7 Hz), 3.39 (d, 1.4H, J=6.2 Hz), 2.32 (d, 0.6H, J=4.4 Hz), 2.21 (d, 1.4H, J=3.9 Hz), 1.82–1.60 (m, 4H), 1.54 (m, 1H), 1.45 (m, 1H), 1.1–1.05 (m, 21H), 1.01 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[N:29])=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[N:30]([Si](C)(C)C)=[N+:31]=[N-:32].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]4[N:30]=[N:31][NH:32][N:29]=4)=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(Nc3ccc(Cc4nn[nH]n4)cc3)c21
Temperature: 110 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A 8-mL vial was charged with 2-[4-[[2-(3-Chlorophenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]acetonitrile (17 mg, 0.04 mmol, 1 eq.), azido(trimethyl)silane (0.2 ml, excess) and tetrabutylammonium fluoride hydrate (50 mg, 0.19 mmol, 4.6 eq.). The mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture was partitioned between dichloromethane (8 ml) and 2N HCl (4 ml). The organic layer was separated and washed with sodium bicarbonate solution (5 ml) and dried over Na2SO4. Removal of solvent under reduced pressure gave a residue, which was purified using a preparation TLC plate and 3% of methanol in dichloromethane as mobile to give the title compound as white solid (13 mg, 70% yield). MW=467.93. 1H NMR (400 MHz, methanol-d4) δ 8.32 (s, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.46 (m, 2H), 7.38 (d, J=8.4 Hz, 2H), 4.38 (s, 2H), 3.63 (d, J=5.6 Hz, 2H), 3.14 (d, J=6.4 Hz, 2H), 2.54 (m, 2H).
Reaction SMILES: [Na].Cl[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1.[CH3:15][OH:16]>C(OCC)C>[CH3:15][O:16][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1
Reactant: CCc1cc([N+](=O)[O-])c(Cl)nc1C
Reactant: CO
Agent: [Na]
Solvent: CCOCC
Product: CCc1cc([N+](=O)[O-])c(OC)nc1C
Temperature: 50 °C
Yield: 80 %

Procedure:
Sodium metal (100 mg, 4.3 mmol) was dissolved in methanol (5 mL) under a nitrogen atmosphere. A solution of 2-chloro-3-nitro-5-ethyl-6-methylpyridine (677 mg, 3.37 mmol) in methanol (5 mL) was added dropwise. The reaction was warmed at 50° C. for four hours. The reaction was cooled, diluted with diethyl ether, the ether layer washed with water, dried (Na2SO4), filtered through a pad of charcoal and evaporated to yield 535 mg (80%) of product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.O[C:17]1[N:22]=[CH:21][C:20]2[C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH2:25][C:19]=2[CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:17]2[N:22]=[CH:21][C:20]3[C:23](=[O:29])[N:24]([CH:26]([CH3:27])[CH3:28])[CH2:25][C:19]=3[CH:18]=2)=[CH:6][CH:7]=1
Reactant: CC(C)N1Cc2cc(O)ncc2C1=O
Reactant: Cn1nnc(-c2ccc(F)cc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N1Cc2cc(OCc3c(-c4ccc(F)cc4)nnn3C)ncc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 18.9 %

Procedure:
To a solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (251 mg, 1.21 mmol) in THF (30 mL) was added 6-hydroxy-2-isopropyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (232 mg, 1.21 mmol) and triphenylphosphine (413 mg, 1.58 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (624 μL, 1.58 mmol) was added and the reaction mixture was stirred for 72 h at room temperature. Concentration and purification by chromatography (silica, 20 to 50% ethyl acetate in heptane) afforded the title compound (87 mg, 19%) as a white solid. MS: m/e=382.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3Br)[CH2:25][CH2:24]2)[CH2:4][CH2:3][CH2:2]1.C(OC([N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1)=O)(C)(C)C>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[C:47]3[CH:48]=[N:44][NH:45][CH:46]=3)[CH2:25][CH2:24]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1Br
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1-c1cn[nH]c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A mixture of 6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine (100.00 mg; 0.18 mmol; 1.00 eq.), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (77.63 mg; 0.26 mmol; 1.50 eq.), and in dioxane 2 ml and water 0.15 ml was degas, added Pd(t-Bu3)2 13 mg, stirred at 50° C. for overnight. Added methanol 5 ml, 4.0M HCl in dioxane 5 ml, stirred at RT for 4 hr, removed off solvent and purified by prep HPLC, collected title compound 15 mg, yield 12.7%. LC-MS: (M+1=556, obsd.=556).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:11][CH2:10]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:18]=2)[C@@H:6]1[O:32][C:33](=[O:35])[CH3:34])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[O:42]1[CH2:46][CH2:45][C@@H:44](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:43]1>CN(C=O)C.O>[C:33]([O:32][C@@H:6]1[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:10][CH2:11]2)[O:8][C@H:7]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C@H:44]3[CH2:45][CH2:46][O:42][CH2:43]3)=[CH:29][CH:30]=2)[CH:18]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O[C@H]3CCOC3)cc2)c1
Temperature: 60 °C

Procedure:
To a solution of Acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester (120 mg, 0.22 mmole) in DMF (3 mL), cesium carbonate (85 mg, 0.27 mmole), Toluene-4-sulfonic acid (R)-(tetrahydro-furan-3-yl)ester (65 mg, 0.27 mmole) was added at room temperature and heated at 60° C. for 6 hours. The reaction mixture was diluted with water (20 mL), and extracted with dichloromethane (2×50 mL). Crude (5S,6S,7R,8S)-5-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)phenyl)-4-oxaspiro[2.5]octane-6,7,8-triyl triacetate obtained after the removal of solvent used for next step without purification.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([N+:14]([O-])=O)[CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[NH4+].[Cl-].O>C(O)C.[Fe]>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[NH2:14])(=[O:3])=[O:4]
Reactant: COc1c(C)cc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1c(C)cc(N)cc1S(N)(=O)=O

Procedure:
The reduction of 3-aminosulfonyl-4-methoxy-5-methylnitrobenzene (0.740 g, 3 mmol) using iron powder (0.81 g, 15 mmol), NH4Cl (0.81 g, 15 mmol) in ethanol (100 mL):water (25 mL) at 60° C. for 1 hour followed by filtration through a pad of Celite gave aqueous alcoholic solution. Concentration of it followed by dilution with water afforded a solid mass, which was isolated by filtration to give 3-aminosulfonyl-4-methoxy-5-methylaniline. 1H NMR (DMSO-d6): δ 6.90 (bs, 1H), 6.55 (bs, 1H), 5.1 (bs, 2H), 3.65 (s, 3H), 2.15 (s, 3H), LCMS: purity: 94%, MS (m/e): 217 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cncc(Br)c1
Reactant: OCc1ccccc1
Product: Brc1cncc(OCc2ccccc2)c1
Yield: 56 %

Procedure:
3,5-Dibromopyridine was reacted with one equivalent of benzyl alcohol to give 3-benzyloxy-5-bromopyridine (56%) using the procedure described in the first paragraph of Note c. immediately above. That product was reacted with n-butyl-lithium using the procedure described in the second paragraph of Note c. except that the reaction was carried out at -110° C. The organometallic reagent so formed was reacted with tetrahydropyran-4-one using the procedure described in that Note; the product was methylated and that product was hydrogenolysed using the procedures also described in Note c. immediately above. There was thus obtained 4-(5-hydroxypyrid-3-yl)-4-methoxytetrahydropyran in 47% yield from 3-benzyloxy-5-bromopyridine.
Reaction SMILES: C([O-])=O.[NH4+].[F:5][C:6]([F:24])([F:23])[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12][CH2:11]1)=[O:8]>[Pd].CO>[F:24][C:6]([F:5])([F:23])[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8]
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)C(F)(F)F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(NC1CCNCC1)C(F)(F)F
Temperature: 5 °C

Procedure:
A 500 mL, three-necked round-bottomed flask under nitrogen was charged with 4 g of 10% Palladium on Carbon, and 100 mL of methanol. The suspension was cooled to 5° C. and 10 g of ammonium formate was added in one batch (evolution of gas was observed). A solution of 10 g (35 mmol) of the 4-trifluoroacetamido-1-benzylpiperidine in 100 mL of methanol was then added dropwise gradually. The resulting reaction mixture was refluxed for 2.5 hr. and then at room temperature overnight. The catalyst was filtered off through Celite under a blanket of nitrogen and washed with ethanol. The filtrate was concentrated under reduced pressure to give 6.9 g (quantitative yield) of a light yellow solid of the title compound.
Reaction SMILES: C(O)(=O)C.C(=O)C.[CH:8]([O:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([N:21]([C:37](=O)[CH3:38])[CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16]2[CH:40]=[CH:41][C:42]([Cl:44])=[CH:43][C:15]1=2)=[O:13])([CH3:10])[CH3:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH:8]([O:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([N:21]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:24]=2)[CH2:37][CH3:38])[C:16]2[CH:40]=[CH:41][C:42]([Cl:44])=[CH:43][C:15]1=2)=[O:13])([CH3:9])[CH3:10]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
Add acetic acid (0.05 mL, 0.078 mmol) and acetaldehyde (34 mg, 0.78 mmol) to a solution of 5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (see example 3) (40 mg, 0.078 mmol) in dimethylformamide (1 mL). Stir at room temperature for 2 h. Add sodium triacetoxyborohydride (33 mg, 0.16 mmol) and stir the mixture at room temperature for 2 h. Add saturated solution of sodium bicarbonate and extract with ethyl acetate (3×10 mL). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica cartridge, eluting with hexanes/ethyl acetate (10:1), to afford the title compound (11 mg, 26%). MS (ES+): 537 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]=[C:15](Cl)[C:16]([F:18])=[CH:17][C:12]=2[C:11](=[O:20])[N:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:16]([F:18])=[CH:17][C:12]=2[C:11](=[O:20])[N:10]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cc(F)c(Cl)nc2n(Cc2ccccc2)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(Cc2ccccc2)c(=O)n1OCc1ccccc1
Yield: 78.6 %

Procedure:
Following the procedure of Example X-2, the reaction of 1-benzyl-3-benzyloxy-7-chloro-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example P-2, 142 mg, 0.345 mmol) with pyrrolidine (0.070 mL, 0.828 mmol) in dichloromethane (3 mL) afforded 121 mg of the title compound as a solid, mp 171-172° C.
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:30])[NH:7][C:8]2[CH:28]=[CH:27][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:29])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([NH:5][C:6]([NH:7][C:8]2[CH:28]=[CH:27][C:11]([C:12]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)=[O:13])=[CH:10][C:9]=2[F:29])=[O:30])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NC3CCC3)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1F)NC1CCC1
Yield: 7.5 %

Procedure:
tert-Butyl 4-(4-(3-cyclobutylureido)-3-fluorobenzoyl)piperazine-1-carboxylate (2.8 g, 66.67 mmol), trifluoracetic acid and dichloromethane were stirred for 20 hours then concentrated under reduced pressure. The residue was taken up in dichloromethane/methanol, loaded on to a strong cation exchange column and washed with dichloromethane/methanol. Elution of the column with 2M ammonia in methanol gave the title compound (1.6 g). MS (ESI) m/z: 321.4 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH3:15])[N:8]=[C:7]([S:16]([CH3:18])=O)[C:6]2=[O:19].[C:20]([O:23]C(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:23][CH2:18][S:16][C:7]1[C:6](=[O:19])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([CH3:15])[N:8]=1)(=[O:22])[CH3:21]
Reactant: COc1cc2c(=O)c(S(C)=O)nn(C)c2cc1OC
Reactant: CC(=O)OC(C)=O
Product: COc1cc2c(=O)c(SCOC(C)=O)nn(C)c2cc1OC

Procedure:
A mixture of 11 g of 6,7-dimethoxy-1-methyl-3-(methylsulfinyl)-4(1H)-cinnolinone and 100 ml of acetic anhydride was refluxed for 2 hours. The solution was chilled, and the crystalline precipitate was filtered off, washed with Skelly B, and recrystallized from CH3CN, mp. 229°-33°, yield 11 g (87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:16]=2F)[CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[CH:4][CH:3]=1.[H-].[Na+].O.C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@@H:9]2[C:15]3[C:16](=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[F:21])[O:12][CH2:11][C@H:10]2[CH2:13][OH:14])=[CH:4][CH:3]=1
Reactant: OCC(CO)C(Sc1ccc(Cl)cc1)c1c(F)ccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC[C@@H]1COc2c(F)ccc(F)c2[C@H]1Sc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
2-[(4-Chloro-phenylsulfanyl)-(2,3,6-trifluoro-phenyl)-methyl]-propane-1,3-diol (6.2 g, 14.8 mmole) was dissolved in 150 mL THF and NaH (60% in oil, 2 g) was added. The reaction was stirred at 60° C. for four hours. 300 mL of water and 400 mL of EtOAc were added. The organic layer washed with brine (100 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography (EtOAc/hexane from 0/100 to 50/50 in 45 minutes). Yield: 5.0 g, 85%. 1H NMR (CDCl3 400 MHz) δ 7.45 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 6.97 (m, 1H), 6.58 (m, 1H), 4.62 (dd, J=11.7 and 2.2 Hz, 1H), 4.50 (br, 1H), 4.43 (td, J=11.7 and 2.2 Hz, 1H), 3.67 (m, 1H), 3.48 (m, 1H), 2.25 (m, 1H), 1.50 (t, J=5.1 Hz, 1H).