Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.Cl.[C:11]([O:15][C:16](=[O:26])[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:11]([O:15][C:16](=[O:26])[NH:17][CH:18]1[CH2:19][CH2:20][CH:21]([CH2:24][NH:25][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)[CH2:22][CH2:23]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2Br)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (1.1 g, 4.83 mmol) was dissolved in DMA (25 mL). To this solution was added tert-butyl-trans-4-aminomethylcyclohexylcarbamate hydrochloride (1.54 g, 5.80 mmol), followed by DIEA (1.98 mL, 11.4 mmol). The reaction was stirred at 25° C. for 18 h. The reaction was worked up by removal of the volatiles in vacuo. The crude was purified via flash chromatography (SiO2, 10-25% EtOAc-Hexanes) to afford 1.32 g (65%) of {4-[(5-bromo-2-chloro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C-:19]#[N:20].[Na+]>CN(C=O)C>[C:19]([C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:20]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N
Temperature: 0 °C
Yield: 82.7 %

Procedure:
A solution of 6.6 g of 5-chloro-1-(4-bromophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 30 ml of DMF with 2 g of sodium cyanide was heated at approximately 95° C. for 3 hours. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration. The product was recrystallized from 3A alcohol to afford 5.3 g of 5-cyano-1-(4-bromophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. mp=104°-105° C.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6]C(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56](O)=[O:57])[CH:51]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:56]([C:52]1[CH:51]=[C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:55]=[CH:54][CH:53]=1)=[O:57]
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: O=C(O)c1cccc(-c2ccccc2CSCCOc2ccccc2)c1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1cccc(-c2ccccc2CSCCOc2ccccc2)c1
Yield: 86 %

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (1.0 g, 2.74 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.45 g, 2.79 mmol, 1.02 eq.) followed by 3-(dimethylamino)propylamine (0.34 g, 3.29 mmol, 1.2 eq.) as described. When complete, the reaction was worked up leaving a yellow oil. The oil was purified via silica gel flash chromatography using 10% 2M NH3 in methanol in chloroform as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo leaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide (1.06 g, 86% yield). The free base was converted to the oxalate salt by adding oxalic acid (0.26 g, 1.2 eq.) in EtOAc dropwise to an EtOAc solution of the free base. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide oxalate (1.08 g) was collected by filtration as a white solid.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:10])[N:4]=[C:5]([O:8][CH3:9])[NH:6][CH:7]=1.N12CCCN=C1CCCCC2.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=2)=[N:27][CH:28]=1>C(#N)C.CCOC(C)=O>[I:1][C:2]1[C:3]([O:10][C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH3:22])=[CH:28][N:27]=3)=[CH:35][CH:34]=2)=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: Cc1ccc(Nc2ccc(O)cc2)nc1
Reactant: COc1nc(=O)c(I)c[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ncc(I)c(Oc2ccc(Nc3ccc(C)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 5-iodo-2-methoxypyrimidin-4(1H)-one (0.12 g, 0.46 mmol) and (1H-benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(V) (0.24 g, 0.55 mmol) in acetonitrile (4 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL, 0.91 mmol). The reaction mixture was stirred at room temperature for 30 min before 4-(5-methylpyridin-2-ylamino)phenol (0.27 g, 1.37 mmol) was added. The reaction mixture was stirred at room temperature for an additional 1 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give N-(4-(5-iodo-2-methoxypyrimidin-4-yloxy)phenyl)-5-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 435.1 (M+1).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=[CH2:20])[CH2:17][S:18](=O)[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:39]C(=O)C)(=[O:38])[CH3:37]>C(Cl)(=O)C.C1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH2:20][O:39][C:36](=[O:38])[CH3:37])=[CH:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)Cl
Product: CC(=O)OCC1=CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 85 °C

Procedure:
To 10 ml. of benzene were added 500 mg. (1 millimole) of p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide. To the resulting slurry were added 2 ml. of acetic anhydride and 2 drops of acetyl chloride. The resulting mixture was refluxed at 85° C. for about 15 hours. The resulting reaction mixture then was treated as in Example 1 to obtain p-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].C(N(CC)CC)C>ClCCl.CS(C)=O.[Cl-].[Na+].O>[O:13]=[C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19]1)[CH2:11][CH2:10][CH2:9][CH:8]=[O:7]
Reactant: O=C(CCCCO)N1CCN(c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCCC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of 1.11 mL (12.8 mmol) oxalyl chloride in 35 mL of dichloromethane is cooled to −80° C. under argon atmosphere. 2.33 mL (32.7 mmol) of dimethylsulfoxide in 9.33 mL of dichloromethane is introduced dropwise over 10 minutes. After 5 minutes a solution of 1.84 (7 mmol) 5-hydroxy-1-(4-phenylpiperazin-1-yl)pentan-1-one in 8 mL dichloromethane and 2 mL dimethylsulfoxide is added over the course of 10 minutes. The reaction mixture is stirred for another hour at −80° C. before 5 mL of triethylamine is added and the mixture is allowed to warm up to room temperature. 50 mL of saturated brine solution is added for hydrolysis. The organic phase is separated, extracted three times with a saturated solution of sodium chloride, dried over sodium sulfate and the solvent is evaporated. The crude product is obtained in almost quantitative yield.
Reaction SMILES: [CH:1]1([C:7](=[O:29])/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:13]3=[N:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([C:7](=[O:29])[CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=4)(=[O:21])=[O:20])[C:13]3=[N:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(/C=C/C(=O)C4CCCCC4)cnc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CCC(=O)C4CCCCC4)cnc32)cc1
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a solution of (E)-1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)prop-2-en-1-one (0.050 g, 0.12 mmol) in EtOAc (5 mL) was added palladium (10% on carbon, 0.0065 g, 0.0061 mmol). The reaction mixture was purged with hydrogen and a hydrogen atmosphere was maintained via balloon. After about 1 h at ambient temperature, the reaction mixture was filtered and concentrated under reduced pressure to provide 1-cyclohexyl-3-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)propan-1-one as an oil (0.050 g, 100%): LC/MS (Table 2, Method a) Rt=2.94 min; MS m/z: 412 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[N+:12]([O-])=O>CCO.[Pd]>[CH3:1][O:2][N:3]([CH3:16])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12]
Reactant: CON(C)C(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CON(C)C(=O)c1ccc(F)cc1N
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of N-methoxy-N-methyl-4-fluoro-2-nitro-benzamide (1.15 g, 5.04 mmol) and 5% palladium charcoal (190 mg) in EtOH (30 mL) was shaken overnight under hydrogen atmosphere (3 atm). The mixture was filtered and concentrated under reduced pressure to give N-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.9 g, 90%).
Reaction SMILES: [Na].[O:2]=[S:3]1(=[O:17])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]([CH2:13][C:14]([O-])=[O:15])=[N:4]1.C([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C@H:27]2[CH2:38][C@@H:24]1[CH2:25][CH2:26]2)=O)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[O:2]=[S:3]1(=[O:17])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]([C:13]2[C:14](=[O:15])[N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C@@H:28]3[C@H:23]([C:21]=2[OH:20])[C@@H:24]2[CH2:38][C@H:27]3[CH2:26][CH2:25]2)=[N:4]1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2cnccc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cnccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
The crude sodium-(1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-acetate, (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 61, 0.149 g, 0.51 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.194 g, 0.51 mmol) were combined and dissolved in anhydrous N,N-dimethylformamide (1 mL). The mixture was stirred at 25° C. for 1 h. Triethylamine (0.35 mL, 2 6 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling, the mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (2×25 mL) and saturated aqueous brine solution (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 75% to 100% ethyl acetate in hexanes) followed trituration of the resulting oil with a 1:1 mixture of hexanes and diethyl ether (2 mL) afforded the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.0184 g, 0.039 mmol, 7.7% over two steps), as a pale yellow powder. LC-MS (ESI) calculated for C23H21FN4O4S 468.13, found 469.2 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ: 1.01-1.54 (6H, m), 2.35 (1H, d, J=3.7 Hz), 2.46 (1H, s), 2.53 (1H, s), 3.26 (1H, d, J=9.5 Hz), 4.23 (1H, d, J=15.8 Hz), 4.94 (1H, d, J=15.0 Hz), 7.08-7.13 (3H, m), 7.24-7.28 (2H, m), 8.44 (1H, d, J=4.8 Hz), 8.67 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][NH:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH2:18]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:24]([O:26][CH3:27])=[O:25]>N1C=CC=CC=1.C(Cl)Cl>[CH3:27][O:26][C:24]([N:16]1[C:17]2[CH2:18][CH:19]3[N:11]([S:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)(=[O:9])=[O:10])[CH:12]([CH2:22][N:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20]3)[C:13]=2[CH:14]=[N:15]1)=[O:25]
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CNCC1c1cn[nH]c1C2
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CC2Cc3c(cnn3C(=O)OC)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
12-(4-Chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene (204 mg, 0.602 mmol) was dissolved in pyridine (1 mL) and cooled to 0° C. Methyl chloroformate (0.139 mL, 1.80 mmol) was added over 15 minutes and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (10 mL), washed with aqueous HCl (5 mL, 1 N) and aqueous NaHCO3 (5 mL), dried (Na2SO4), filtered and concentrated under vacuum to give 275 mg of 12-(4-chloro-benzenesulfonyl)-4,5,10,12-tetraaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene-5,10-dicarboxylic acid dimethyl ester as a brown oil. Retention time (min)=1.704, method [1], MS(ESI) 455.1 (M+H).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH:12]([C@H:25]1[O:30][CH2:29][C@@H:28]([NH:31][C:32](=O)[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:27][CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO>C1COCC1>[CH:12]([C@H:25]1[O:30][CH2:29][C@@H:28]([NH:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:27][CH2:26]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cc1ccc(F)cc1)N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: Fc1ccc(CCN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
Into a suspension of NaBH4 (0.21 g, 3.33 mmol) in dry THF (20 ml) was added BF3.Et2O drop wise at 0° C. The mixture was stirred for 1.5 Hours at room temperature and cooled to 0° C. A solution of cis-N-(6-benzhydryl-tetrahydropyran-3-yl)-2-(4-fluorophenyl)-acetamide 17 (0.17 g, 0.42 mmol) in dry THF (10 ml) was added dropwise into the solution. The mixture was refluxed overnight and cooled to room temperature. Methanol was added to quench the reaction followed by removal of solvent in vacuo. To the residue was added 20 ml 10% HCl/MeOH and the mixture refluxed for 1 hour. The reaction mixture was cooled down to room temperature and solid NaHCO3 was added at 0° C. to pH 9. The aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic phases were dried over anhydrous Na2SO4, and the solvent was removed in vacuo. Flash chromatography gave 16p Cis-(6-benzhydryl-tetrahydropyran-3-yl)-[2-(4-fluorophenyl)-ethyl]-amine (0.13 g, yield 81%).
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[NH4+:17].[NH4+].O.C(OCC)(=O)C>CN(C)C=O>[NH2:17][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2nc1Cl
Temperature: 60 °C
Reaction time: 72 h
Yield: 26.8 %

Procedure:
2,3-Dichloroquinoxaline (9.90 g, 50.0 mmol) and ammonium carbonate (24.3 g, 300 mmol) were suspended in N,N-dimethylformamide (50 mL) in a stainless steel sealed tube and the mixture was stirred at 60° C. for 72 hours. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3). Further, slurry purification was performed using diisopropyl ether, to give 2-amino-3-chloroquinoxaline (2.41 g, yield: 27%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[N+:17]([CH3:20])([O-:19])=[O:18].C(N(CC)CC)C>CO>[OH:2][CH:1]([C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=[C:5]([CH:4]=1)[C:13]([O:15][CH3:16])=[O:14])[CH2:20][N+:17]([O-:19])=[O:18]
Reactant: COC(=O)c1cc(C=O)cc(C(=O)OC)c1
Reactant: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(C(=O)OC)cc(C(O)C[N+](=O)[O-])c1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a solution of 2.45 g (11.0 mmol) of dimethyl 5-formylisophthalate in 30 mL of methanol was added 1.48 mL (27.6 mmol) of nitromethane and 1.53 mL (11.0 mmol) of triethylamine (TEA). The solution was stirred at 22° C. for about 16 h, evaporated then coevaporated with xylenes. The residue was purified by flash chromatography on silica gel, eluting first with 5% ethyl acetate/hexane and then gradually increasing to 20% ethyl acetate/hexane which gave dimethyl 5-(1-hydroxy-2-nitroethyl)isophthalate as a solid.
Reaction SMILES: CC([O-])=O.[K+].CC1(C)C(C)(C)OB([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[N:19][C:18]=23)O1.Cl[C:25]1[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][N:26]=1>O1CCOCC1>[N:16]1[N:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]2=[C:14]([C:25]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][N:26]=2)[CH:15]=1
Reactant: CC1(C)OB(c2cnn3cccnc23)OC1(C)C
Reactant: Nc1ccnc(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Nc1ccnc(-c2cnn3cccnc23)c1
Temperature: 120 °C
Yield: 31 %

Procedure:
A suspension of 10 ml 1,4-dioxane and 8 ml 4N KOAc (5.9 g) with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (13 g, 3.68 g) and 2-chloro-4-aminopyridine (3.68 g) was purged with nitrogen for 30 min. Then, to the suspension was added Pd(PPh3)4 (867 mg) and the reaction mixture was heated at 120° C. in microwave for 20 min. Upon cooling, the precipitated solid was filtered and used without further purification (1.0 g, 31% yield).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[S:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17]2)(=[O:13])=[O:12].[O:24]=[C:25]1[C:30]2=[CH:31][NH:32][C:33]([CH:34]=O)=[C:29]2[CH2:28][CH2:27][O:26]1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[S:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[CH:34][C:33]1[NH:32][CH:31]=[C:30]2[C:25](=[O:24])[O:26][CH2:27][CH2:28][C:29]=12)(=[O:13])=[O:12]
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCc4ccccc4C3)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCc4ccccc4C3)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CCOc1ccccc1C(=O)c1ncc(Cl)cc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
4-Chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide was hydrolyzed using 4 M HCl in dioxane (12 mL) and water (4 mL) at 100° C. to provide 4-chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. Product was purified by HPLC. MS m/z 519.1 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH:4]=[CH:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C1(C=CC(O)=CC=1)O>C(#N)C>[CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH:4]1[CH2:16][CH:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]1[N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)CC=CN1CCCCC1
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: CCOC(=O)C1CC(CC(C)(C)C)C1N1CCCCC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
1-(4,4-Dimethyl-1-pentenyl)piperidine (1146 g) and acetonitrile (910 mL) were mixed. After an addition of ethyl acrylate (549 mL) and hydroquinone (553 mg) to the mixture, the mixture was stirred at 90° C. overnight. The reaction mixture was concentrated in vacuo to give the title compound (1470 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][C:34]1[N:38]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[C:37]([CH3:45])=[N:36][N:35]=1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:42]5[CH2:41][CH2:40][CH:39]([N:38]6[C:34]([CH3:33])=[N:35][N:36]=[C:37]6[CH3:45])[CH2:44][CH2:43]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:31])[F:32])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: Cc1nnc(C)n1C1CCNCC1
Product: Cc1nnc(C)n1C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(3,5-dimethyl-[1,2,4]triazol-4-yl)-piperidin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-(3,5-Dimethyl-[1,2,4]triazol-4-yl)piperidine following General Procedure B.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([N:11]1[C:19]2[C:18]([F:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:13]([C:21]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:39])[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=3)[CH:26]=[N:27][CH:28]=2)=[O:22])=[CH:12]1)([CH3:10])[CH3:9])(C)(C)C>C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:30]([NH:29][C:25]2[CH:26]=[N:27][CH:28]=[C:23]([C:21]([C:13]3[C:14]4[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=4[N:11]([C:8]([CH3:10])([CH3:9])[CH2:7][OH:6])[CH:12]=3)=[O:22])[CH:24]=2)=[O:39])=[N:33][CH:34]=1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cn3)c2)c2cncc(F)c21
Solvent: C1CCOC1
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cn3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of N-(5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridine-3-carbonyl}-pyridin-3-yl)-2-(5-chloro-pyridin-2-yl)-acetamide (Preparation 5, 30 mg, 62 μmol) in THF (5 mL) 4M dioxane-HCl (0.5 mL) was added and stirred at room temperature for 4 hours. The reaction was evaporated in vacuo and triturated with pentane-ether to afford the title compound as a white solid in 100% yield, 24.3 mg.