Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>>[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)cc1

Procedure:
4-(Methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)-phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 4-methylsulfonylbenzenesulfonylchloride (61 mg, 0.455 mmol) according to general method 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 551.2; Calcd: 551.10.
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.Cl[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1>CCO>[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=3)[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(N[C@H]2CC[C@@H](c3nnc4cnc5[nH]ccc5n34)C2)nc1
Temperature: 130 °C
Yield: 25.2 %

Procedure:
To a microwave vessel was added (1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.0979 g, 0.311 mmol, Example #6, Step C), EtOH (2 mL), 6-chloronicotinonitrile (0.057 g, 0.41 mmol), and TEA (0.130 mL, 0.932 mmol). The reaction mixture was heated in a CEM™ microwave at about 130° C. for about 1 h (250 psi maximum pressure, 5 min maximum ramp, 300 maximum watts). After cooling to ambient temperature, the reaction was concentrated under reduced pressure and purified by silica gel chromatography eluting with DCM/MeOH/Et2NH (970:27:3) to give 6-((1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)nicotinonitrile (0.027 g, 25%): LC/MS (Table 2, Method a) Rt=1.24 min; MS m/z: 345(M+H)+.
Reaction SMILES: B.[CH2:2]1COCC1.C[C:8]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1>[CH3:2][CH:14]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[OH:16]
Reactant: CC1(C(=O)O)CCCCC1
Reactant: C1CCOC1
Agent: B
Product: CC(O)C1CCCCC1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
A three liter, three necked round bottom flask was equipped with a thermometer, magnetic stirrer, argon inlet and outlet adapters and a one liter addition funnel containing 922 ml of 1.0 molar BH3.THF. 1-Methyl cyclohexanecarboxylic acid (119.2 g; 0.84 m) was added to the reaction vessel and dissolved in 100 ml of THF. The reaction mixture was cooled with an ice bath to 5° C. and the BH3.THF was added dropwise over 25 min maintaining the temperature between 5°-15° C. After the addition was complete, the ice bath was removed. After about five min, the reaction exothermed and foamed violently. A much slower addition rate and constant cooling should help to avoid this exotherm. The reaction was allowed to stir for two hr at RT under nitrogen, then 150 ml of methanol was added cautiously. When the foaming ceased, the reaction was concentrated in vacuo using low heat and the residue was treated with 100 ml of 5% acetic acid. After stirring for thirty min, the reaction was transferred to a one liter separatory funnel, diluted with water (slurry dissolved) and extracted three times with ether. The combined ether extracts were washed twice with saturated sodium bicarbonate, twice with brine, dried over anhydrous magnesium sulfate, filtered through celite and concentrated in vacuo (low heat) to give 79.09 g of a clear water-white oil. The oil was distilled on a Kugelrohr apparatus at 75°-130° C. (25 mm of Hg). Most distilled at 90° C. to give 72.11 g of 1-methyl-1-cyclohexylmethanol.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:22]([O-])=O)=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C:15]([CH3:17])([CH3:16])[N:8]3[CH:7]=[C:6]([C:18]([NH2:20])=[O:19])[C:5]2=[O:21])[C:11]=1[F:12].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.CO>[NH2:22][C:3]1[C:2]([F:1])=[C:11]([F:12])[C:10]2[O:13][CH2:14][C:15]([CH3:17])([CH3:16])[N:8]3[C:9]=2[C:4]=1[C:5](=[O:21])[C:6]([C:18]([NH2:20])=[O:19])=[CH:7]3
Reactant: CC1(C)COc2c(F)c(F)c([N+](=O)[O-])c3c(=O)c(C(N)=O)cn1c23
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)COc2c(F)c(F)c(N)c3c(=O)c(C(N)=O)cn1c23
Yield: 50.8 %

Procedure:
To a suspension of 10 (6.3 g, 18.6 mmol) in a mixture of water/methanol 1/1 v/v (160 mL), sodium hydrosulfite (19.4 g, 116 mmol) was added and the suspension was refluxed for 5 h until all starting material was consumed. The product was collected by filtration while the mixture was still hot and washed with warm water. The solid was dried under vacuum to give 11 (2.92 g, 51% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH2:32][C:33]1[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[CH2:41]O)=[CH:35][CH:34]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:26][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH2:41]/[CH:40]=[CH:39]/[C:36]2[CH:35]=[CH:34][C:33]([CH2:32][C:28]3[NH:29][CH:30]=[CH:31][N:27]=3)=[CH:38][CH:37]=2)=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21]
Reactant: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Reactant: OC/C=C/c1ccc(Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Temperature: 25 °C

Procedure:
360 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-isopropyloxycarbonyl-4-(3- nitrophenyl)pyridine -3carboxylic acid together with 215 mg (1 mM) of (E)-3-{4-(1-imidazolylmethyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 541 mg (97.2%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:25])[CH:10]=1.[C:32]([O:36][C:37](=[O:51])[CH2:38][CH2:39][S:40][CH2:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](O)=[O:46])([CH3:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[NH:25][C:45]([C:44]2[CH:43]=[C:42]([CH:50]=[CH:49][CH:48]=2)[CH2:41][S:40][CH2:39][CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:51])=[O:46])[CH:10]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: CC(C)Oc1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-isopropoxyphenyl)isonicotinamide (230 mg, 0.48 mmol, 1.00 equiv, 90%) in dichloromethane (8 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c (317 mg, 0.86 mmol, 2.00 equiv, 80%), EDC.HCl (206 mg, 1.07 mmol, 2.00 equiv), and 4-dimethylaminopyridine (131 mg, 1.07 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 100 mL of ethyl acetate and washed with 1×20 mL of aqueous NH4Cl, 1×20 mL of 10% sodium bicarbonate, and 1×20 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). The product was obtained as 240 mg (60%) of a brown oil.
Reaction SMILES: Cl.[C:2]1([C:8]2[NH:13][C:12]3[CH:14]=[N:15][CH:16]=[CH:17][C:11]=3[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([Cl:25])=[O:24]>>[ClH:25].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([N:10]1[C:11]2[CH:17]=[CH:16][N:15]=[CH:14][C:12]=2[NH:13][C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9]1)=[O:24]
Reactant: c1ccc(C2=NNc3ccncc3N2)cc1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Product: O=C(c1ccco1)N1N=C(c2ccccc2)Nc2cnccc21
Yield: 81.1 %

Procedure:
3.8 g (0.015 moles) of 3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with furan-2-carbonyl chloride as described in Example 2 to obtain 1-furoyl-3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 81.1%; m.p.: 245°-246° C.
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([F:19])=[CH:4][N:3]=1.[C:20](=[O:27])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH2:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:23]([O:22][C:20](=[O:27])[NH:21][C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([F:19])=[CH:4][N:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Fc1cnc(Br)c2cn(-c3c(Cl)cccc3Cl)nc12
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ncc(F)c2nn(-c3c(Cl)cccc3Cl)cc12
Temperature: 70 °C
Yield: 57 %

Procedure:
A suspension of 4-bromo-2-(2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (635 mg, 1.75 mmol), tert-butyl carbamate (614 mg, 5.25 mmol), Pd2(dba)3 (40 mg, 0.044 mmol), Xantphos (101 mg, 0.175 mmol) and potassium phosphate tribasic (742 mg, 3.5 mmol) in toluene (15 mL) and water (3 mL) was de-gassed and purged with argon and the reaction mixture was heated at 70° C. for 5 h. The mixture was cooled and partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (20% ethyl acetate in cyclohexane) to afford the title compound as a pale yellow solid (396 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 9.05 (s, 1H), 7.92 (d, J=3.1 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.72 (d, J=7.9 Hz, 1H), 1.48 (s, 9H).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[SH:10])[CH:3]=[CH:2]1.S(Cl)(Cl)(=O)=O>ClCCl>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[S:10][S:10][C:8]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:3]=[CH:2][S:1][C:9]=23)[CH:3]=[CH:2]1
Reactant: Sc1ccnc2ccsc12
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: c1cc(SSc2ccnc3ccsc23)c2sccc2n1
Temperature: 0 °C
Reaction time: 48 h
Yield: 37.7 %

Procedure:
Thieno[3,2-b]pyridine-7-thiol (1.00 g, 5.9 mmol) was dissolved in dichloromethane (40 mL). The solution was cooled to 0° C. and sulfuryl chloride (1M in dichloromethane, 2.9 mL, 2.9 mmol) was added dropwise and the reaction stirred while warming to ambient temperature. The solution stirred for 5 hours at ambient temperature and then concentrated to dryness. The residue was left standing under open air for two days. The residue was then diluted in dichloromethane and was neutralized with saturation NaHCO3 solution. The organic layer was separated, dried, and concentrated. The residue was triturated with ether and the solid was filtered and dried to provide the title compound (0.37 g, 46% yield) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6](Cl)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cu](C#N)[C:23]#[N:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:23]#[N:24])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: N#C[Cu]C#N
Solvent: Cc1ccccc1
Product: N#CC(c1ccccc1)(c1ccccc1)c1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
2-(4-Chlorophenyl) 2,2-diphenylacetonitrile was synthesized by carefully triturating 1.50 g (4.8 mmol) of 4-chlorotrityl chloride with 1.00 g (11 mmol) of copper cyanide and the resulting mixture was heated for 4 hours at 150° C. without a solvent. After cooling 50 ml of toluene was added, the mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was recrystallized from petroleum ether (40–60° C.) to give 0.66 g (45%) of the triarylmethyl acetonitrile derivative.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][CH:6]=2>CO.C1COCC1.[Pd]>[CH3:1][N:2]([CH3:15])[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=2)[CH2:4]1
Reactant: CN(C)C1=Cc2cc([N+](=O)[O-])ccc2C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C1Cc2ccc([N+](=O)[O-])cc2C1
Yield: 82.1 %

Procedure:
To a solution of 5-nitro-2-indanone (885 mg, 5 mmol) in THF (15 mL) was added dimethylamine (2N in THF, 5 mL, 10 mmol) dropwise. The reaction mixture was stirred at r.t. for 5 h. Water was added and the reaction mixture was extracted with EtOAc. Combined organic layers were washed with water and brine and dried over Na2SO4. The concentrated crude product was filtered through a short pad of silica gel (EtOAc:hexane=1:1) and the filtrate was concentrated to give dimethyl-(5-nitro-1H-inden-2-yl)-amine as a dark red solid (1.0 g, 98%). Dimethyl-(5-nitro-1H-inden-2-yl)-amine (1.0 g, 4.9 mmol) was hydrogenated using Pd/C (10% dry, ca. 300 mg) and H2 in MeOH:THF (1:1, 30 mL) at 1 atm at r.t. for 5 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. The concentrated filtrate was further purified via short silica gel column chromatography (EtOAc: MeOH=6:4) to give the title compound as a yellow solid (830 mg, 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(OCc2ccccc2)cc1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1CC1CCCCC1
Temperature: 55 °C

Procedure:
4-Benzyloxy-2-cyclohexylmethylphenol (1,77 mmol) was dissolved in anhydrous DMF (4 mL), followed by the addition of ethyl bromoacetate (0.29 mL, 2.65 mmol), and cesium carbonate (0.75 g, 2.30 mmol). The mixture was then heated for 18 h (55° C.). The reaction mixture was then cooled and concentrated in vacuo. The crude residue was partitioned between ethyl acetate (70 mL) and water (40 mL). The organic layer was washed with brine, dried (Na2SO4), and removed in vacuo to give the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cc(OCc2ccccc2)ccn1
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(COc2ccnc(Nc3ccccn3)c2)cc1
Yield: 72.7 %

Procedure:
Compound I (2.325 mg, 8.80 mmol), 2-aminopyridine (911 mg, 9.68 mmol), tBuOK (1.481 g, 13.20 mmol), (±)-BINAP (219 mg, 0.35 mmol) and Pd2(dba)3 (201 mg, 0.22 mmol) were stirred in toluene (35 mL) at 90° C. under Ar(g) for 17 h. The reaction mixture was then diluted with CH2Cl2 (20 mL) and silica was added followed by the removal of the solvent under reduced pressure. The resulting dry loaded material was purified by silica gel column chromatography eluting with hexane/EtOAc (60:40 then 50:50) to furnish II as a yellow oil (1.773 g, 73%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[CH:25]([CH2:29][C:30]([OH:32])=[O:31])[C:26](O)=[S:27]>C(COC)OC>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[CH:25]1[CH2:29][C:30](=[O:31])[O:32][C:26]1=[S:27]
Reactant: O=C(O)CC(C(O)=S)c1nc2ccccc2s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: O=C1CC(c2nc3ccccc3s2)C(=S)O1
Reaction time: 1.5 h

Procedure:
A solution of 6.18 parts of dicyclohexylcarbodiimide in 30 parts by volume of dimethoxyethane is added dropwise, over 1.5 hours, to a stirred solution of 8.49 parts of benzothiazol-2-ylthio succinic acid prepared as in Example 1A in dimethoxyethane (70 parts by volume). The reaction is exothermic and the temperature is maintained at 25°-27° with cooling. When the addition is complete, stirring is continued for a further 1.5 hours and the precipitated dicyclohexylurea is removed by filtration. The filtrate is evaporated in vacuo and the residual solid is recrystallised from a mixture of dichloromethane and cyclohexane to give benzothiazol-2-ylthio succinic anhydride m.p. 129°-129° (with decomposition).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[SH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][C:15]([O-:17])=[O:16].[Na+].[OH-].[Na+].Cl>O.C(O)C>[C:15]([CH2:14][S:12][C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[N:10][N:9]=1)([OH:17])=[O:16]
Reactant: Sc1nncn1-c1ccccc1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CSc1nncn1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
Into 500 ml of ethanol were suspended 53 g (0.3 mol) of 4-phenyl-3-mercapto-1,2,4-triazole and 44.1 g (0.36 mol) of sodium chloroacetate. Thereto was added an aqueous solution prepared by dissolving 15.5 g (0.36 mol) of sodium hydroxide (purity, 93%) into 60 ml of water. This mixture was kept at 50° C. for 3 hours to-react the reactants. The reaction mixture was allowed to cool to room temperature, neutralized by dropwise adding 31 ml (0.36 mol) of concentrated hydrochloric acid, and then cooled to 10° C. or lower with ice. The resulting precipitate was taken out by filtration. To the precipitate was added 1.5 l of ethanol. This mixture was heated, and the insoluble matter was taken out by filtration. Thereafter recrystallization was conducted with cooling to obtain 32.3 g (0.14 mol) of the desired mercaptoacetic acid derivative. Yield, 45.8%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30]S[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.CO.O[O:35][S:36]([O-:38])=O.[K+]>O>[Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][S:36](=[O:38])(=[O:35])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1[nH]cc(Cl)c2c1c(-c1ccc(N3CCSCC3)cc1)nn2-c1c(F)cccc1F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1[nH]cc(Cl)c2c1c(-c1ccc(N3CCS(=O)(=O)CC3)cc1)nn2-c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 17.8 %

Procedure:
To a mixture of 7-chloro-1-(2,6-difluorophenyl)-3-(4-(thiomorpholin-4-yl)phenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (30 mg) obtained in Example 236 in a mixed solvent of methanol (3 mL) and water (0.15 mL) was added Oxone (registered trademark) (80 mg) at room temperature. The reaction mixture was stirred at 80° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with THF. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (5.7 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])=O.Cl.[NH2:18]O>C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7])#[N:18]
Reactant: COc1c(C=O)cc(C(=O)O)cc1C(C)C
Reactant: NO
Agent: Cl
Solvent: O=CO
Product: COc1c(C#N)cc(C(=O)O)cc1C(C)C
Yield: 99.9 %

Procedure:
3-formyl-5-isopropyl-4-methoxybenzoic acid (15.85 g) was dissolved in formic acid (80 mL), and hydroxylamine hydrochloride (5.45 g) was added to the solution, and the mixture was refluxed for 19 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (15.62 g) as a brown solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[N:6]=1.C[Sn](C)(C)[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[N:24][CH:25]=1>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.C1(C)C=CC=CC=1>[OH:27][CH2:26][C:23]1[N:24]=[CH:25][C:20]([C:2]2[S:3][CH:4]=[C:5]([N:7]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]3=[O:17])[N:6]=2)=[CH:21][CH:22]=1
Reactant: C[Sn](C)(C)c1ccc(CO)nc1
Reactant: O=C1c2ccccc2C(=O)N1c1csc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1c1csc(-c2ccc(CO)nc2)n1
Temperature: 160 °C
Yield: 68.3 %

Procedure:
A mixture of 2-(2 bromothiazol-4-yl)-isoindole-1.3-dione (10.0 g, 32.3 mmol) and (5-trimethylstannyl-pyridin-2-yl)-methanol (12.2 g, 26.9 mmol) in abs. toluene (50 mL) was placed in sealed tube, degassed and filled with tetrakis(triphenylphosphine)palladium(0) (932 mg, 0.8 mmol). The reaction mixture was heated at 160° C. for 1.5 hr and filtered while the reaction mixture was hot. After being cooled to room temperature for 2 hr, a solid was filtered through fritted funnel, washed with toluene (30 mL) and dried on vacuum to provide the title compound (6.2 g, 75%) as a pale yellow solid. MS-ESI m/z 338.02 (M+H)+.