Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)[CH2:3]1.Cl.[C:23]12([NH2:28])[CH2:27][CH:25]([CH2:26]1)[CH2:24]2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:23]12([NH:28][C:12]3[N:11]=[C:10]([NH:9][C@@H:4]4[CH2:5][CH2:6][C@@H:7]([CH3:8])[C@H:2]([OH:1])[CH2:3]4)[C:15]([C:16]#[N:17])=[CH:14][N:13]=3)[CH2:27][CH:25]([CH2:26]1)[CH2:24]2
Reactant: NC12CC(C1)C2
Reactant: C[C@@H]1CC[C@@H](Nc2nc(S(C)(=O)=O)ncc2C#N)C[C@H]1O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@@H](Nc2nc(NC34CC(C3)C4)ncc2C#N)C[C@H]1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (446 mg, 1.437 mmol; synthesis described herein) in NMP (5 mL) was added bicyclo[1.1.1]pentan-1-amine hydrochloride (258 mg, 2.155 mmol; prepared according to Org. Lett., 13(17): 4746-4748 (2011)) and DIEA (1.255 mL, 7.18 mmol). The reaction was stirred at 80° C. for 4 h and then allowed to cool to ambient temperature. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (0-90% ethyl acetate in hexanes) to afford 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carbonitrile (381 mg, 1.216 mmol, 85% yield). MS (ESI): m/z 314.0 [M+1]+.
Reaction SMILES: [OH-].[K+].C(O)C.[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]2[N:6]=[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]3=[CH:9][C:24]=2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(CN2CCc3nc4ccccc4cc3C2)cc1
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A 10% potassium hydroxide/ethanol solution (120 ml) was added dropwise to a solution of 2-aminobenzaldehyde (26 g, 0.21 mol) and 1-benzyl-4-piperidone (40 g, 0.21 mol) in absolute ethanol (430 ml) over a period of 1 hour. After stirring overnight, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate, and the extract solution was washed with water and then dried over anhydrous sodium sulfate. The organic solvent was removed by concentration under reduced pressure, and the residue was recrystallized from ethyl acetate-isopropyl ether to obtain the desired compound (37 g, 63%) as white crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[N:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25](O)=[O:26])[CH:23]=4)=[CH:15][N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3]1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[CH:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:24][C:25]([N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:26])[CH:23]=4)=[CH:17][N:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(CC(=O)O)c4)cn3)c2)cn1
Reactant: C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(CC(=O)N5CCCCC5)c4)cn3)c2)cn1
Temperature: 50 °C
Yield: 15.1 %

Procedure:
A mixture of (4-{2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]pyrimidin-5-yl}-1H-pyrazol-1-yl)acetic acid (example 9, 110 mg; 0.31 mmol; 1.0 eq.), piperidine (52 mg; 0.61 mmol; 2.0 eq.), HATU (174 mg; 0.46 mmol; 1.50 eq.) and DIEA (152 μl; 0.92 mmol; 3.0 eq.) in DMF (2 mL) was stirred at 50° C. O/N. The reaction mixture was poured into water and extracted with DCM (three times). Combined organic phases were then concentrated under reduced pressure and the residue was recrystallised in MeOH/Ether. The solid obtained was filtered and dried under reduced pressure to give the title compound as a white solid (20 mg, 15%). 1H NMR (300 MHz, DMSO) δ 9.18 (s, 2H), 8.54 (t, J=1.6 Hz, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 8.25-8.19 (m, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.77-7.66 (m, 1H), 7.52 (t, J=7.8 Hz, 1H), 5.22 (s, 2H), 3.90 (s, 3H), 3.55-3.39 (m, 4H), 1.69-1.39 (m, 6H).HPLC (Condition A): Rt 3.16 min (purity 99.9%). MS (ESI+): 428.3
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN(C)P(=O)(N(C)C)N(C)C>C(OCC)(=O)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCOCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 7 h
Yield: 39.3 %

Procedure:
In a 200 ml stainless steel autoclave were placed 10 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 12.8 g of morpholine and 80 ml of hexamethylphosphoric triamide and the mixture was reacted at 160° C. on an oil bath. After 7 hours, the temperature of the autoclave was lowered to room temperature and disappearance of the starting materials was confirmed by thin layer chromatography. Then, the reaction mixture was transferred from the autoclave to a 300 ml Erlenmeyer flask to which ethyl acetate was added and the resulting mixture was allowed to stand for 1 day. The crystals which formed were collected by filtration and recrystallized from dimethylformamide to give 4 g of 9-fluoro-8-morpholino-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 279°-280° C., white rhombic crystals.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[K+].[Br-].C([O-])(O)=O.[Na+].[O-]Cl.[Na+]>ClCCl.O>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]1[CH2:12][C:11](=[O:13])[CH2:10][C@@H:9]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)O[C@@H]1C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)O[C@@H]1CC(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
To a solution of 27.50 g of (1R,3S,5R)-2,2-dimethyl-propionic acid 3-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-cyclohexyl ester in 250 ml of dichloromethane was subsequently added at 0° a solution of 0.713 g of KBr and 2.656 g of NaHCO3 in 250 ml of water and 200 mg of 2,2,6,6-tetramethyl-piperidine-1-oxyl, radical. The stirred mixture was treated at 0° with 61.9 g of NaOCl (11.0%) over 1 h after which time t.l.c. showed completion of the reaction. The layers were separated, the organic layer was washed with 15% aqueous NaCl, dried over MgSO4 and evaporated to give 27.24 g of the pure (t.l.c.) title compound as a yellow oil. IR (neat): 1728s (C═O). MS (EI): 271/5 (M−tert-butyl).
Reaction SMILES: [CH3:1][C:2]1[C:3](S(C)(=O)=O)=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)=[N:6][CH:7]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[C:3]([O:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:30])[F:31])[CH:24]=2)=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(-n2cc(C(F)(F)F)cn2)nc1S(C)(=O)=O
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(-n2cc(C(F)(F)F)cn2)nc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.2 %

Procedure:
A mixture of 11.2 g (36.4 mmol) of 5-methyl-4-methylsulfonyl-2-(4-trifluoromethyl-1H -1-pyrazolyl)pyrimidine, 7.7 g (47.4 mmol) of 3-trifluoromethylphenol and 10.1 g (72.9 mmol) of K2CO3 in 200 ml of DMF is stirred at RT for 24 h. It is then poured into 200 ml of water and extracted with four times 100 ml of CH2Cl2. The combined organic phase is dried over Na2SO4, filtered and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (1:1) as eluent gives 10.2 g (72%) of 5-methyl-4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethyl-1H-1-pyrazolyl)pyrimidine as colourless crystals having a melting point of 103-105° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Cl)[N:7]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:5][C:6]1[N:7]=[C:8]([NH:1][CH2:2][CH2:3][OH:4])[CH:9]=[CH:10][CH:11]=1
Reactant: NCCO
Reactant: Clc1cccc(Cl)n1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: OCCNc1cccc(Cl)n1
Temperature: 100 °C
Yield: 98.7 %

Procedure:
2-Amino-ethanol (0.82 g, 13.5 mmol) was added to a solution of 2,6-dichloropyridine (2.0 g, 13.5 mmol) in pyridine (10 mL) at room temperature and then heated at 100° C. overnight. The reaction mixture was concentrated in vacuo to obtain a residue which was dissolved in ethyl acetate. The solution was washed with water, brine, dried over anhydrous sodium sulfate and evaporated in vacuo to afford 2-(6-chloro-pyridin-2-ylamino)-ethanol (2.3 g, 99%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:6]=2[O:7][C:8]=1[CH3:9])(=O)[CH3:2].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+].O>C(O)C>[OH:19][N:18]=[C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:6]=2[O:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CC(=O)c1c(C)oc2c([N+](=O)[O-])cccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1c(C)oc2c([N+](=O)[O-])cccc12
Yield: 72.5 %

Procedure:
A mixture of 3-acetyl-2-methyl-7-nitrobenzo[b]furan (413 mg), hydroxylamine hydrochloride (393 mg) and sodium bicarbonate (792 mg) in ethanol (10 ml) was refluxed for 30 minutes. The reaction mixture was cooled and water was added to the solution. The separated solid was collected, washed with water and dried to give 3-(1-hydroxyiminoethyl)-2-methyl-7-nitrobenzo[b]furan (320 mg).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
to a stirred solution of 4-(tert-butydimethylsilyloxy)-benzaldehyde (48.0 g, 203 mmol) in methanol (200 mL) at 0° C. was added sodium borohydride (11.6 g, 305 mmol) and the reaction was stirred at 0° C. for 45 min. Water (200 mL) was added and the methanol was removed under reduced pressure. The mixture was extracted with ether (2×200 mL) and ethyl acetate (2×200 mL). The combined organics were dried (MgSO4), filtered and concentrated under vacuum to give the crude product, which was used without further purification (48 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:23]1([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=4[CH3:21])[CH:5]=[CH:6][C:7]=3[Cl:8])=[O:33])=[CH:35][CH:36]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(-n3ccnc3)cc2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 4-(1H-imidazol-1-yl)benzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(3-(4-(1-H-imidazol-yl)benzamido)-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 500.0 (M)+
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH:40](=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:40]([N:13]([CH2:14][C@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(N[C@H](Cc1ccccc1)CN(Cc1ccccc1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)OCc1cncs1
Yield: 39.3 %

Procedure:
The product from Example 26D (87.5 mg, 0.155 mmol), benzaldehyde (19 μl, 0.186 mmol), acetic acid (11 μl, 0.181 mmol), and sodium triacetoxyborohydride (53 mg, 0.248 mmol) were processed as described in Example 27 to provide the title compound (40 mg, 39%). 1H NMR (CDCl3) δ 8.72 (s, 2H), 7.80 (s, 2H), 7.32-6.95 (m, 15H), 5.21 (s, 4H), 4.65 (br s, 2H), 3.93 (br s, 2H), 3.56 (s, 2H), 2.78 (dd, 2H), 2.66 (br s, 2H), 2.45 (d, 4H); MS (ESI+) m/z 656 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[C:9]([O:8][C:7]([NH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:2]1)=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (6.0 g, 32.2 mmol) and DIEA (12.5 g, 16.8 mL, 96.6 mmol) in dichloromethane (60 mL) cooled to 0° C. on an ice-bath was added benzyl chloroformate (8.7 g, 7.2 mL, 48.3 mmol), and the resulting mixture stirred at 0° C. for 2 hours. The mixture was diluted with dichloromethane (30 mL) and washed successively with cold aqueous 10% HCl, water, saturated sodium bicarbonate solution and brine. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography silica gel (Biotage, 65M; 20% ethyl acetate/hexanes) to afford (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (10 g, 97%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:11][C@H:12]1[C@@H:16]([CH2:17]O)[CH2:15][N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13]1)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:27]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])([CH3:29])[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CCOCC.CCCCCC>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:11][C@H:12]1[C@@H:16]([CH2:17][N:30]([CH:27]([CH3:29])[CH3:28])[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:32])=[O:33])[CH2:15][N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13]1)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)N(C[C@@H]1CN(Cc2ccccc2)C[C@@H]1CO)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)N(C[C@@H]1CN(Cc2ccccc2)C[C@@H]1CN(C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ((3S*,4R*)-1-benzyl-4-hydroxymethyl-pyrrolidin-3-ylmethyl)-isopropyl-carbamic acid tert-butyl ester (0.60 g, 1.66 mmol), N-isopropyl-2-nitro-benzenesulfonamide (0.49 g, 1.99 mmol), and PPh3 (0.52 g, 1.99 mmol) in toluene (15 mL), is added dropwise diisopropyl azodicarboxylate (0.39 mL, 1.99 mmol) at 0° C. under a nitrogen atmosphere. The solution is stirred for 1 h at room temperature, and then heated at 65° C. for 1 h. The reaction mixture is concentrated. The crude material is used purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 3:7) to give the crude product. To the solid product is added a mixture of Et2O/hexane (1:1) and the resulting suspension is filtered. The solid is washed with Et2O/hexane (1:1) solution, and then the combined filtrate is concentrated to give a titled product. TLC, Rf (AcOEt)=0.61. MS (LC-MS): 589.3 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.39 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:20][CH2:19]1)[C:10]([S:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])([F:12])[F:11].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:19][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[C:10]([S:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])([F:12])[F:11]
Reactant: CCOCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 26.4 %

Procedure:
Using 2-(2,4-difluorophenyl)-1-(2-ethyoxyethyl)thio-1,1-difluoro-2,3-epoxypropane (3.1 g, 0.01 mol), DMSO (30 ml), 1,2,4-triazole (1.7 g, 0.025 mol) and potassium carbonate (3.4 g, 0.025 mol), 2-(2,4-difluorophenyl)-1-(2-ethoxyethyl)thio-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0 g, yield: 25.0%) was obtained as colorless crystals by similar procedures to Example 14.
Reaction SMILES: [Li+].CCC[CH2-].C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].[C:21](=[O:23])=[O:22]>C1COCC1>[Cl:13][C:14]1[C:19]([C:21]([OH:23])=[O:22])=[CH:18][N:17]=[CH:16][C:15]=1[F:20]
Reactant: Fc1cnccc1Cl
Reactant: O=C=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cncc(F)c1Cl
Temperature: -78 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
N-Butyllithium, 1.6 M in hexanes (9.50 mL, 15.21 mmol) was added to THF (20 mL) and cooled to −78° C. To this solution was added diisopropylamine (2.167 mL, 15.21 mmol) followed by 4-chloro-3-fluoropyridine (2 g, 15.21 mmol) and the solution stirred for 6 h at −78° C. The reaction mixture was then poured on to crushed dry ice and stirred until the reaction mixture warmed to room temperature. The reaction was quenched by addition of aqueous ammonium chloride solution and acidified to pH=2 using conc. HCl and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate and concentrated under reduced pressure to afford the 4-chloro-5-fluoronicotinic acid (1.7 g, 9.68 mmol, 64% yield) as a pale yellow solid. LCMS (ESI) m/e 175.9 [(M+H)+, calcd for C6H4ClFNO2 176.0]; LC/MS retention time (Method F): tR=0.57 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:22](=[O:23])[NH:21][C:12]3[N:13]=[C:14](S(C)=O)[N:15]=[C:16]([CH3:17])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][NH2:25]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:22](=[O:23])[NH:21][C:12]3[N:13]=[C:14]([NH:25][CH3:24])[N:15]=[C:16]([CH3:17])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: COc1ccc(-c2cc3c(C)nc(S(C)=O)nc3[nH]c2=O)cn1
Solvent: C1COCCO1
Product: CNc1nc(C)c2cc(-c3ccc(OC)nc3)c(=O)[nH]c2n1
Temperature: 110 °C
Yield: 60.5 %

Procedure:
To a solution of 6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (147 mg, 0.445 mmol) in 1,4-dioxane (2.5 mL) was added methylamine (1.1 mL, 2.0 M in THF, 2.2 mmol). The mixture was sealed and heated at 110° C. microwave for 10 min. The mixture was concentrated under reduced pressure to give a solid. The crude solid was washed with water and EtOAc, recrystallized from DMSO/EtOAc to give the title compound (80 mg, 61%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([NH:18]C(OC(C)(C)C)=O)=NS(C(F)(F)F)(=O)=O)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.C[OH:36]>>[C:6]([NH:8][C:9]([NH2:18])=[O:36])([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: CO
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(N)=O
Reaction time: 7 h
Yield: 62 %

Procedure:
To a solution of amine 90 (300 mg, 0.62 mmol) and Goodman's reagent (392 mg, 1.00 mmol) in MeOH (60 mL) was added DIPEA (0.45 mL, 2.5 mmol) at room temperature. The reaction mixture was stirred for 7 h and then concentrated. The residue was dissolved in CHCl3 (200 mL) and washed with saturated NaHCO3 (2×100 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 90:9:1 CHCl3/CH3OH/NH4OH) to afford Boc-urea 92 (280 mg, 62%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.67 (t, J=7.8 Hz, 2H), 7.57 (s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.19 (s, 2H), 4.18 (t, J=5.4 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H), 2.82 (t, J=6.3 Hz, 2H), 2.12 (t, J=5.7 Hz, 2H), 1.85-1.70 (m, 4H), 1.54 (s, 9H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[N:3]1[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:14]([C:13]4[CH:12]=[CH:11][C:10]([CH2:9][N:3]5[C@H:2]([CH3:1])[CH2:6][CH2:5][S:4]5(=[O:7])=[O:8])=[CH:19][CH:18]=4)=[O:16])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COC(=O)c1ccc(CN2[C@H](C)CCS2(=O)=O)cc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CN3[C@H](C)CCS3(=O)=O)cc2)CC1
Yield: 79.6 %

Procedure:
Using methyl (R)-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoate (79 mg) described in Preparation Example 42 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (61 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (104 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2
Reactant: CCCCCCC(O)c1ccc2cc(OC)ccc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
To a stirred solution of the 1-(6-methoxy-2-naphthyl)heptan-1-ol (101.1 g, 371 mmol) in CH2CL2 (1000 mL) under N2 was added pyridinium chlorochromate (120.02 g, 556.74 mmol). The reaction was stirred for a total of 3 h and then poured onto an alumina column (2000 g, basic Brockman activity, 60-325 mesh). Column was eluted with CH2Cl2. Product was collected, filtered, rotovap'd and dried in vacuo to give the product as a white solid (81.5 g, 301.44 mmol, 81%) with mp 69-72° C. 177 mg of crude ketone was recrystallized from methanol to give the desired product as a white solid (105 mg) mp 70-72° C.; 1H NMR (DMSO-d6) δ 0.86 (m, 3H), 1.25-1.40 (m, 6H), 1.60-1.70 (m, 2H), 3.07 (t, J=7.3 Hz, 2H), 3.90 (s, 3H). 7.24 (d, J=9 Hz, 1H), 7.39 (s, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 8.02 (d, J=8.9, 1H) 8.58 (s, 1H); IR (solid) 2910, 2870, 1660, 1630, 1470, and 1180 cm−1; mass spectrum [EI], m/z271 (M+H)+;