Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O-:29])=[O:28])=[C:15]([S:18][C:19]4[C:20]([C:25]#[N:26])=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([OH:29])=[O:28])=[C:15]([S:18][C:19]4[C:20]([C:25]#[N:26])=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ncccc1SC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncccc1SC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirring solution of (7R)-7-[(phenylacetyl)amino]-3-(2-cyanopyrid-3-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (158 mg, 0.277 mmol) and anisole (0.4 mL) in dichloromethane (1 mL) at 0° C. was added trifluoroacetic acid (1 mL). After 1 h at 0° C., the solvent was removed with a rotary evaporator, and the residue was triturated with ether, filtered, and dried, affording 104 mg (83%) of the title compound. 1H NMR (CDCl3) δ3.15 (d, 1, J=18), 3.54 (d, 1, J=18), 3.65 (d, 1, J=16), 3.69 (d, 1, J=16), 5.07 (d, 1, J=4), 5.89 (dd, 1, J=4, 9), 6.18 (d, 1, J=9), 7.2-7.4 (m, 5), 7.53 (dd, 1, J=5, 8), 7.90 (d, 1, J=8), 8.66 (d, 1, J=5).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH:18]([CH3:20])[CH3:19])[C:10]([C:12]2[N:13]=[CH:14][N:15]([CH3:17])[CH:16]=2)=[O:11])[CH:5]=[CH:4][N:3]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.C(Cl)(Cl)[Cl:47]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[ClH:47].[ClH:47].[CH3:17][N:15]1[CH:16]=[C:12]([C:10]([N:9]([CH:18]([CH3:20])[CH3:19])[CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=3)[CH:7]=2)=[O:11])[N:13]=[CH:14]1
Reactant: ClC(Cl)Cl
Reactant: CC(C)N(Cc1ccnc(Br)c1)C(=O)c1cn(C)cn1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)N(Cc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)C(=O)c1cn(C)cn1
Product: Cl
Temperature: 150 °C

Procedure:
A mixture of N-[(2-bromopyridin-4-yl)methyl]-1-methyl-N-(propan-2-yl)-1H-imidazole-4-carboxamide (100 mg), 4-trifluoromethoxyphenylboronic acid (122 mg), tetrakis(triphenylphosphine)palladium (34 mg), potassium carbonate (82 mg), dimethylformamide (1.2 mL) and ethanol (0.4 mL) was stirred under irradiation with microwave while heating at 150° C. for 30 min. After diluting with chloroform, the mixture was washed with water and further extracted with chloroform. The organic phase was separated out, and the solvent was distilled off under reduced pressure. The resulting residue was diluted with ethyl acetate, and a small amount of NH silica gel was added thereto, followed by stirring. The NH silica gel was filtered off, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by HPLC. The resulting residue was dissolved in acetonitrile and water, and 2N hydrochloride was added thereto, followed by lyophilization to afford the title compound (94 mg).
Reaction SMILES: [C:1]([C:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][CH2:12]C)=[O:10])[N:4]=1)#[N:2].C[O-].[Na+].[Cl-:17].[NH4+:18]>>[ClH:17].[C:1]([C:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=1)(=[NH:2])[NH2:18]
Reactant: [NH4+]
Reactant: CCOC(=O)Cn1cnc(C#N)n1
Reactant: [Cl-]
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)Cn1cnc(C(=N)N)n1
Product: Cl
Yield: 54.9 %

Procedure:
Ethyl 2-(3-cyano-1H-1,2,4-triazol-1-yl)acetate (2 g, 11.2 mmol) was reacted with sodium methoxide (0.85 g, 15.68 mmol) and ammonium chloride (0.89 g, 16.8 mmol) according to the procedure as described in Example 61, Step B to give the title compound as a white solid (1.35 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].Br[C:8]1[C:12](Br)=[CH:11][S:10][CH:9]=1.O>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:8]1[C:12]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][S:10][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]Br
Reactant: Brc1cscc1Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCCc1cscc1CCCC
Yield: 64 %

Procedure:
Butylmagnesium bromide (140 mmol) was added dropwise at 0° C. to a mixture solution of 3,4-dibromothiophene (50 mmol) and [1,3-bis (diphenylphosphino)propane]dichloronickel(II) (0.3 mmol) in 100 mL of dry diethyl ether. The resulting mixture was heated and refluxed for 6 hours. The reaction mixture was combined with water, and extracted with diethyl ether. The extract solution was derived over magnesium sulfate, and the solvent was evaporated therefrom to obtain a crude product. The crude product was purified by silica gel column chromatography and by distillation to obtain the intended product (32 mmol) in a 64% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=O)[CH2:3]1.CO[CH:13](OC)[CH2:14][NH2:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][C:2]1([CH3:1])[CH2:3][C:4]2[NH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:8])[CH2:7]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2cc[nH]c2C1
Temperature: 60 °C
Yield: 5.3 %

Procedure:
A solution of 5,5-dimethyl-1,3-cyclohexandione (30 g, 0.21 mol), aminoacetaldehyde dimethyl acetal (35 mL, 0.32 mol) and p-toluenesulphonic acid hydrate (1.5 g, 8 mmol) in toluene (250 mL) were heated at reflux for 4 h using Dean-Stark apparatus to remove the water. The toluene was evaporated and the residue dissolved in 3N HCl (250 mL). The solution was heated at 60° C. for 6 h. After this time the mixture was cooled to room temperature and extracted with DCM (6×). The combined organic layers were dried (MgSO4), evaporated and the residue chromatographed on silica gel, eluting with isohexane: EtOAc (4:1→1:1). The fractions containing the desired product were combined, evaporated and the residue triturated with ether. The title compound (1.8 g, 5%) was isolated as a cream solid. mp 177-178° C. 1H NMR (360 MHz, d6-DMSO) 8 1.02 (6H,s), 2.19 (2H,s), 2.63 (2H,s), 6.23 (1H,t, J=3.9 Hz), 6.71 (1H,t, J=3.9 Hz). MS (ES+) 164 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([O:15][CH3:23])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)C(O)C(=Cc1ccc(Cl)cc1)n1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C(=Cc1ccc(Cl)cc1)n1cncn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
The I'-A isomer (2 g) of 1-p-chlorophenyl-4,4-dimethyl-2-(1,2,4-triazole-1-yl)-1-pentene-3-ol (Compound No. 1) was dissolved in dimethylformamide (20 cc), and 65% oily sodium hydride (0.26 g) was added thereto. After stirring for 1 hour at room temperature, the reaction mixture was cooled to 10° C., and methyl iodide (1 g) was added. After standing at room temperature for 20 hours, the solvent was removed under reduced pressure, and the residue obtained was extracted with addition of ice water (100 g) and chloroform (100 cc). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The oily crude product obtained was purified by column chromatography on silica gel (acetone:n-hexane=1:10) and further recrystallized from a carbon tetrachloride/n-hexane (1:2) mixture to obtain 1.6 g of the entitled compound (m.p. 63°-66° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=O)=O.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].N1CCCCC1>C(O)C>[C:14]([C:16]1[C:17](=[O:18])[NH:19][C:4]([CH2:3][O:2][CH3:1])=[C:6]2[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH2:11]2)#[N:15]
Reactant: N#CCC(N)=O
Reactant: COCC(=O)C1CC(C)CCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COCc1[nH]c(=O)c(C#N)c2c1CC(C)CC2
Yield: 32.3 %

Procedure:
3.7 g of the crude 2-methoxyacetyl-4-methylcyclohexanone, 1.68 g of cyanoacetamide and 1 ml of piperidine were mixed with 50 ml of ethanol and the obtained reaction mixture was heated under reflux for four hours. The crystals thus formed were filtered and purified to give 1.5 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methoxymethyl-7-methyl-3-oxoisoquinoline. m.p.: 205°-208° C. NMRδTMSDMSO-d6 :1.01 (3H, d), 1.2-2.0 (4H, m), 2.5-2.6 (1H, m), 2.7-2.9 (2H, m), 3.28 (3H, s), 4.32 (2H, s) and 11.86 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].O1[CH:20]=[CH:19][CH2:18][C:17](=[O:21])[NH:16]1.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:19]([CH:18]1[O:25][C:24]2[C:4]([CH:5]=[CH:6][CH3:7])=[CH:12][CH:26]=[CH:22][C:23]=2[N:16]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[C:17]1=[O:21])[CH3:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CC=CON1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC=Cc1cccc2c1OC(CC)C(=O)N2C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 96 %

Procedure:
Procedure & NMR Data: 107 mg (2.5 eq, 0.58 mmol) of 4-Nitrobenzoyl chloride was added to a mixture of 37 mg (4 eq, 0.92 mmol) of NaH and 50 mg (0.23 mmol) of oxazinone P2 in THF (10 mL). 81 mg of P7 were obtained, yield 96%.
Reaction SMILES: C1COCC1.Cl[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[H-].[Na+].[CH3:20][O:21][N:22]=[C:23]([C:32]1[O:36][N:35]=[C:34]([CH3:37])[CH:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31]>O>[CH3:20][O:21][N:22]=[C:23]([C:32]1[O:36][N:35]=[C:34]([CH3:37])[CH:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][O:31][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1
Reactant: CON=C(c1cc(C)no1)c1ccccc1CO
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(c1cc(C)no1)c1ccccc1COc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
THF (7.5 ml), 2,3-dichloro-5-trifluoromethylpyridine (0.81 g, 3.75 mmol) and 60% sodium hydride (0.12 g, 3.0 mmol) were added to 2-hydroxymethylphenyl 3-methylisoxazol-5-yl ketone O-methyloxime (0.62 g, 2.5 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ether (150 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.29 g, yield: 27.2%) and isomer B (0.76 g, yield: 71.4%) of 2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)phenyl 3-methylisoxazol-5-yl ketone O-methyloxime.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])[C:15]([F:23])=[CH:14][C:11]=1[C:12]#[N:13].ClC1N=C(Cl)C(F)=CC=1C#N.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:1]([O:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]1[C:15]([F:23])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:9])[N:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1cc(F)c(NCCCO)nc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCNc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of t-butyldimethylsilyl chloride (0.73 g, 4.79 mmol) in CH2Cl2 (21 mL) was added 2-chloro-5-fluoro-6-[(3-hydroxypropyl)amino]nicotinonitrile [prepared as in Example 302] and starting from 2,6-dichloro-5-fluoronicotinonitrile] (1.0 g, 4.35 mmol), followed by Et3N (0.48 g, 4.79 mmol) and DMAP (0.01 g, 0.09 mmol). The resulting cloudy mixture was stirred at rt for 18 h, and then diluted with CH2Cl2. The organic layer was washed with water, dried (MgSO4), filtered, and then concentrated under reduced pressure. The product (1.47 g, 98%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.46 (d, 1H), 3.67 (t, 2H), 3.49 (t, 2H), 1.77 (qt, 2H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]#[N+:14][O-:15].[SH:16][CH2:17][C:18]([OH:20])=[O:19].[OH2:21]>C(COC)OC>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]([NH:14][O:15][S:16][CH2:17][C:18]([OH:20])=[O:19])=[O:21]
Reactant: O
Reactant: O=C(O)CS
Reactant: [O-][N+]#Cc1c(Cl)ccc2cc(Cl)cnc12
Solvent: COCCOC
Product: O=C(O)CSONC(=O)c1c(Cl)ccc2cc(Cl)cnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
12.0 g (50 millimoles) of 3,7-dichloroquinoline-8-nitrile oxide (compound No. 47) were suspended in 100 ml of dimethoxyethane, and 5.6 g (60 millimoles) of mercaptoacetic acid were added. The mixture was stirred for 6 hours at room temperature, after which it was freed from the solvent, water was added and the mixture was filtered under suction. 13.5 g (81%) of a product of melting point of 174° C. were obtained (compound No. 59).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[CH:10][N:9]=2)[CH:7]=1.[CH2:24]=O.O.[C:27]([BH3-])#[N:28].[Na+]>C(#N)C.C(O)(=O)C>[CH3:24][N:28]([CH3:27])[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[CH:10][N:9]=2)[CH:7]=1
Reactant: C=O
Reactant: CCCOc1ccc(N)cc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCOc1ccc(N(C)C)cc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a suspension of 2-(5-amino-2-n-propoxyphenyl)-5-(5-1H-tetrazolyl)pyrimidin-4(3H)-one (0.50 g., 1.6 mmoles) in acetonitrile (40 ml.) was added 37% formaldehyde in water (1.32 ml., 16.0 mmoles). Sodium cyanoborohydride (0.302 g., 4.8 mmoles) was then added followed by glacial acetic acid (1.67 ml. The suspension was stirred at room temperature for 15 minutes and then heated under reflux for 3 hours. The mixture was cooled in an icebath. The precipitate was recrystallized from acetonitrile to give the title compound (0.19 g., 35%), m.p. 258°-259°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.C(C(NC1C=C[C:22]([CH2:25][CH2:26][CH2:27][C:28]#[N:29])=CC=1)(C)C)#N>>[C:11]([CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]2([C:28]#[N:29])[CH2:22][CH2:25][CH2:26]2)=[CH:7][CH:6]=1)#[N:12]
Reactant: CC(C)(C#N)Nc1ccc(CCCC#N)cc1
Reactant: N#CCCCc1ccc(N)cc1
Product: N#CCCCc1ccc(NC2(C#N)CCC2)cc1

Procedure:
Compound 85 was prepared from compound 83 in a manner similar to synthesis of 84.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH:4]1[C:9]([OH:11])=[O:10].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(C)C=CC=CC=1>[OH-].[Na+].C1COCC1>[CH2:16]([O:15][C:13]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH3:2])[CH:4]1[C:9]([OH:11])=[O:10])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1CCCNC1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1CCCN(C(=O)OCc2ccccc2)C1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Methylpiperidine-2-carboxylic acid hydrochloride (28.5 g, 31.6 mmol) was dissolved in (1:1) 2 M NaOH/THF (600 mL) and cooled to 0° C. Benzyl chloroformate (31.57 ml, 222 mmol) was then added dropwise and the reaction was stirred overnight. Toluene was then added and organic layer discarded to remove unreacted chloroformate. The aqueous layer was made acidic (pH=2) with conc. HCl and the product was extracted with EtOAc, dried (MgSO4), and concentrated in vacuo to give a crude residue which was used without further purification (41.6 g, 94.5%). 1H NMR (CDCl3, 400 MHz) δ 7.40-7.37 (m, 5H), 5.19 (m, 2H), 4.95-4.72 (m, 1H), 4.14-4.03 (m, 1H), 3.36-3.25 (m, 1H), 1.93-1.53 (m, 5H), 1.20-1.05 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C1C(=O)N([I:16])C(=O)C1.C(O)(C(F)(F)F)=O>CC#N.CCOC(C)=O>[F:1][C:2]1[C:7]([I:16])=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(F)ccn1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1cc(F)c(I)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4-fluoropyridin-2-amine (336 g, 2.5 mol) and NIS (745 g, 2.75 mol) in MeCN (9 l) was treated with TFA (114 g, 1 mol). The reaction mixture was then stirred at room temperature for 8 h. The reaction mixture was diluted with EtOAc (10 l), washed with sat. aq. Na2S2O3 (2×5 l), brine (4×5 l). The combined organic layers were dried over Na2SO4, filtered and concentrated to get the crude product. The crude product was purified by recrystallization from EtOAc/pentane (1/10) to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, 1H), 6.45 (s, 2H), 6.33 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH2:34]([NH2:36])[CH3:35].C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[CH2:34]([NH:36][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21])[CH3:35]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: CCN
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 55 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.465 g, 0.951 mmol) by treatment with commercially available ethylamine (2 M in THF, 2.38 ml, 4.76 mmol) and triethylamine (1.33 ml, 9.51 mmol) in THF (5 ml) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.260 g, 55%) as an off-white solid. MS (ISP) 498.3 [(M+H)+]; mp 135° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:21](=[O:22])[C:20]2[CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=2)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@@H](O)C1(c2ccc(F)cc2F)CO1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)[C@@]1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 46.3 %

Procedure:
(1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (31.5 g) and 40 g of 3,5-dinitrobenzoyl chloride were dissolved in 500 ml of methylene chloride and, under ice-cooling, 24.1 ml of triethylamine was added dropwise thereinto. After the reaction mixture was stirred at room temperature for 3.5 hours, the resultant mixture was washed successively with 150 ml of water and with 150 ml of 5% aqueous solution of sodium bicarbonate. The resultant was dried over magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration and washed with methylene chloride. The mother liquor and the washing were collected and the solvent was distilled off under reduced pressure. To the residue were added 25 ml of ethyl acetate and 300 ml of methanol, and the mixture was cooled with ice. The precipitated crystals were collected by filtration and recrystallized from a mixture of 25 ml of ethyl acetate and 250 ml of methanol to give 28.7 g of [(1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethyl]3,5-dinitrobenzoate as colorless needles.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([C:14]([C:16]2([N:19]3[CH:23]=[N:22][C:21]([Cl:24])=[N:20]3)[CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]2([C:16]3([N:19]4[CH:23]=[N:22][C:21]([Cl:24])=[N:20]4)[CH2:17][CH2:18]3)[CH2:4][O:15]2)=[CH:25][CH:26]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ccc(C2(C3(n4cnc(Cl)n4)CC3)CO2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2.5 g (83 mmol) of sodium hydride (80% strength) and 17.6 g (80 mmol) of trimethylsulphoxonium iodide are initially introduced under a nitrogen atmosphere and 60 ml of absolute dimethyl sulphoxide are added dropwise at 10° C. The mixture is stirred for 1 hour at 20° C. and then 20 g (71 mmol) of 1-(4-chlorobenzoyl)-1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropane dissolved in 30 ml of absolute dimethyl sulphoxide are added at 10° C. After 48 hours at 20° C., the mixture is warmed to 40° C. for 1 hour and the reaction solution is then poured into water. The mixture is extracted with ethyl acetate, the combined organic phases are washed with water and dried over sodium sulphate, and the solvent is evaporated in vacuo. 21 g of the title compound (100 % of theory) remain in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](SC)=[C:10]([C:14]#[N:15])[C:11]([NH2:13])=O)[CH:5]=[CH:6][CH:7]=1.[OH2:18].[NH2:19][NH2:20]>C(O)C>[NH2:13][C:11]1[NH:20][N:19]=[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:10]=1[C:14]([NH2:15])=[O:18]
Reactant: CSC(Nc1cccc(Cl)c1)=C(C#N)C(N)=O
Reactant: NN
Reactant: O
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Temperature: 75 °C
Yield: 83 %

Procedure:
3-((3-chlorophenyl)amino)-2-cyano-3-(methylthio)acrylamide (6.00 g) was suspended in 100 mL of ethanol and hydrazine hydrate (1.478 mL, 1.5 eq.) was added drop wise to the reaction. Reaction was then heated at 75° C. until the starting material was no longer present and confirmed via HPLC. Once starting material was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide as an off white to yellow powder. Product was allowed to dry under vacuum for 1 hr (4.40 g, 83% yield).