Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:28]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][C:10]([NH:9][CH2:8][CH2:7][O:6][C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:11])[CH2:18][CH2:17]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cccc(OCCNC(=O)CC2CCNCC2)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(OCCNC(=O)CC2CCN(Cc3ccccc3)CC2)c1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
430 mg (1.58 mmol) of N-[2-(3-cyanophenoxy)ethyl]piperidine-4-carboxyamide was dissolved in 10 ml of dimethylformamide. 540 mg (3.93 mmol) of potassium carbonate and 0.16 ml (1.31 mmol) of benzyl bromide were added to the solution, and they were stirred at 50° C. for 13 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, crude 1-benzyl-N-[2-(3-cyanophenoxy)ethyl]piperidine-4-carboxyamide was obtained. The crude product was stirred in 10 ml of dioxane containing 4 N hydrogen chloride. 3.5 ml of ethanol containing 30% (w/v) of hydrogen chloride was added to the resultant mixture. After the stirring at room temperature for 3 days, the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of 10% (w/v) solution of ammonia in ethanol, and the obtained solution was stirred at room temperature for 2 days. The solvent was evaporated, and the residue was treated by the reversed-phase high-performance liquid chromatography with silica gel, containing octadodecyl group chemically bonded thereto, as the filler. After the elution with a mixed solvent of water and acetonitrile containing 0.1% (v/v) of trifluoroacetic acid, the fraction of the intended product was freeze-dried to obtain the title compound.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:33])=[C:17]([C@:19]23[CH2:27][O:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[C@H:24]2[CH2:23][S:22][C:21]([NH2:32])=[N:20]3)[CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[NH4+]>CCOC(C)=O.O>[NH2:32][C:21]1[S:22][CH2:23][C@@H:24]2[C@@H:25]([C:28]([F:31])([F:29])[F:30])[O:26][CH2:27][C@:19]2([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH2:2][F:1])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:33])[N:20]=1
Reactant: O=C(O)c1cnc(CF)cn1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(CF)cn4)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
5-(Fluoromethyl)pyrazine-2-carboxylic acid (32.6 g, 1.05 equiv) and (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (70.0 g, 1.0 equiv) were charged to a reactor and EtOAc (630 mL) was added to the mixture to give a suspension. A solution of ®T3P (146 g, 1.10 equiv, 50 wt % in EtOAc) (Archimica, Germany) was added at ambient temperature while controlling the internal temperature below 30° C. The reaction mixture was stirred at 40-45° C.>3 hours and monitored by HPLC. The reaction mixture was cooled to 15-20° C. and water (140 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (175 mL) while controlling the temperature below 30° C. EtOAc (245 mL0 was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The aqueous phase was separated and back-extracted with EtOAc (490 mL). The organic phases were combined and washed with 15% aq. NaCl (140 mL) and water (140 mL). The organic layer was filtered over Celite (1.0 Wt) and rinsed with EtOAc (140 mL). The solution was concentrated under vacuum to obtain a beige solid (quantitative crude yield) which was recrystallized from 1-propanol to afford N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide as a white solid (70.0 g).
Reaction SMILES: NN.O=C1C2C(=CC=CC=2)C(=O)[N:5]1[O:14][CH2:15][C:16]1[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]3[N:26]=[N:27][N:28]=[C:20]3[C:19]=2[N:29]=1.ClCCl.[CH3:43][C:44]([CH3:46])=O>C(O)C>[CH3:25][C:22]1[N:21]2[N:26]=[N:27][N:28]=[C:20]2[C:19]2[N:29]=[C:16]([CH2:15][O:14][N:5]=[C:44]([CH3:46])[CH3:43])[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[C:18]=2[C:23]=1[CH3:24]
Reactant: CC(C)=O
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)C(C)C)c12
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)C(C)C
Reaction time: 4 h

Procedure:
Anhydrous hydrazine (0.91 mL, 29 mmol) was added to a stirred suspension of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]-2-methylpropanamide (4.90 g, 9.71 mmol) in ethanol (100 mL). Dichloromethane (50 mL) was added. After four hours, acetone (50 mL) was added and the reaction mixture was stirred overnight. A solid was removed by filtration and washed with methanol. The filtrate was concentrated to provide a solid that was triturated with 1:1 saturated aqueous sodium bicarbonate/water. The solid was isolated by filtration, washed with water, and dissolved in chloroform (300 mL). The solution was washed with water (2×50 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to afford N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}-2-methylpropanamide that was used in the next experiment.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[CH3:13].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[CH3:13])=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)cc1C
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(C)cc1C

Procedure:
prepared by reaction of 3-chloro-3-(2,4-dimethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.96 min; [M+H]+=262.3.
Reaction SMILES: [CH2:1]([N:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])(=[O:6])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[S:34][C:35]2[CH2:62][CH2:61][CH2:60][CH2:59][C:36]=2[C:37]=1[C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[CH:51][CH:50]=2)=[CH:43][CH:42]=1)=[O:39]>CN(C=O)C.ClCCl.N1C=CC=CC=1>[CH2:1]([N:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH:32][C:33]1[S:34][C:35]2[CH2:62][CH2:61][CH2:60][CH2:59][C:36]=2[C:37]=1[C:38]([NH:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:53]([O:55][CH3:56])=[O:54])=[CH:57][CH:58]=2)=[CH:45][CH:46]=1)=[O:39])=[O:11])(=[O:6])=[O:5])[CH3:2]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 319 mg of 3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoic acid, 0.10 mL of oxalyl chloride, 2.5 mL of dichloromethane, and one drop of DMF was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated under reduced pressure. A mixture of the obtained crude product and 2.5 mL of dichloromethane was added to a mixture of 0.050 mL of pyridine, 250 mg of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, and 2.5 mL of dichloromethane, followed by stirring at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 320 mg of methyl 4-(2-{4-[({2-[(3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate as a yellow foamed solid.
Reaction SMILES: BrCC(N[C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=O.Cl.NC(C)CO.C(N(CC)CC)C>C(O)C>[ClH:20].[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[C:7]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:6]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CC(N)CO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
A mixture of 79.4 g. (225 mmole) of 2-(2-bromoacetamido)-5-chlorobenzophenone, 25 g. of 2-aminopropanol hydrochloride, 95 ml. of triethylamine and 500 ml. of ethanol was stirred overnight at room temperature, and then at reflux for 5 hours. The solution was concentrated under reduced pressure to a residue which was partitioned between ether and water. The organic layer was washed with water, dried and treated with hydrogen chloride to give 18 g. of a colorless solid. Recrystallizations from ethanol-ether gave prisms of 5-chloro-2-[2-hydroxy-2-propylamino)acetimido]-benzophenone, hydrochloride, m.p. 183°-186°.
Reaction SMILES: [CH3:1][C:2]1[O:7][C:5](=[O:6])[CH2:4][CH:3]=1.[CH3:8][NH2:9]>>[CH2:1]=[C:2]1[N:9]([CH3:8])[C:5](=[O:7])[CH2:4][CH2:3]1.[CH3:8][N:9]1[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]1=[O:6]
Reactant: CC1=CCC(=O)O1
Reactant: CN
Product: C=C1CCC(=O)N1C
Product: CC1CCC(=O)N1C

Procedure:
Wedler, et al. (Journal. f. prakt. Chemie (1990) 332:557–562) discuss a process for producing 5-hydroxy-1,5-dimethyl-2-pyrrolidone by reacting α-angelica lactone with methylamine. Dehydration of this product resulted in the formation of the unstable 5-methylene-N-methyl-2-pyrrolidone, rather than the desired 1,5-dimethyl-2-pyrrolidone.
Reaction SMILES: O.C(O)(C(F)(F)F)=O.[OH-].[Na+].[CH:11]([O:14][P:15]([CH2:21][O:22][C:23]1([CH2:26][O:27]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:25][CH2:24]1)(=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])([CH3:13])[CH3:12]>CC(C)=O>[OH:27][CH2:26][C:23]1([O:22][CH2:21][P:15](=[O:20])([O:14][CH:11]([CH3:13])[CH3:12])[O:16][CH:17]([CH3:18])[CH3:19])[CH2:25][CH2:24]1
Reactant: CC(C)OP(=O)(COC1(COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(C)=O
Product: CC(C)OP(=O)(COC1(CO)CC1)OC(C)C
Temperature: 25 °C

Procedure:
The compound of formula (10) obtained in Example 3 (59.15 g, 116.3 mmol) was dissolved in acetone [59.2 ml, 1 ml/g with respect to the compound of formula (10)], H2O (5.9 ml, 327.8 mmol) and TFA (26.52 g, 232.6 mmol) were added, and the mixture was stirred at room temperature. After the portion of the compound of formula (10) was confirmed 7% or less by HPLC, 3N aqueous NaOH solution [75 ml, 2.6 ml/g with respect to the compound of formula (10)] was added thereto, and acetone was removed therefrom by distillation under reduced pressure. The solid produced during the reaction was filtered off, and the filtrate was extracted twice with methylene chloride [118.3 ml×2, 2 ml/g with respect to the compound of formula (10)]. Thus obtained organic layer was concentrated under reduced pressure to give the title compound (2) [31.71 g, Purity 98%, Yield with respect to the compound of formula (10) 102.4%].
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].II.[Cl:20]Cl>ClC=C(Cl)Cl>[Cl:20][C:15]1[C:2]([CH3:1])=[C:3]([CH:12]=[C:13]([CH3:17])[C:14]=1[CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: ClCl
Reactant: Cc1cc(C)c(C(=O)c2ccccc2)cc1C
Agent: II
Solvent: ClC=C(Cl)Cl
Product: Cc1cc(C(=O)c2ccccc2)c(C)c(Cl)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
33.6 parts of 2,4,5-trimethylbenzophenone and 0.1 part of iodine are dissolved in 150 parts of trichloroethylene. 19.2 parts of chlorine is passed into this solution at 0° to 5°C over a period of 3 hours. The mixture is stirred for another 5 hours at ambient temperature and then distilled at subatmospheric pressure. 26 parts (67.2% of theory) of 3-chloro-2,4,5-trimethylbenzophenone is obtained at 155° to 165°C at 0.1 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1F.C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:42][CH2:41]2)[CH2:36][CH2:35]1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:44][CH2:45]2)[CH2:36][CH2:35]1
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)c(Cl)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 104.4 %

Procedure:
1-Chloro-2-fluoro-4-(methyloxy)-5-nitrobenzene (2.0 g, 9.7 mmol), from a different batch than previously described, was dissolved in DMSO (50 mL) and K2CO3 (6.7 g, 49 mmol), and phenylmethyl 4-(4-piperidinyl)-1-piperazinecarboxylate bis(trifluoroacetate) salt (5.1 g, 9.7 mmol) were added. Reaction was stirred overnight. Poured into H2O and extracted (2×) with EtOAc. Combined organic layers were back-extracted (5×) with H2O and then dried over MgSO4, filtered, concentrated on to silica gel and flash chromatographed to give the title compound of step C (4.95 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (s, 1H), 7.00-7.52 (m, 5H), 6.76 (s, 1H), 5.03 (s, 2H), 3.90 (s, 3H), 3.54 (d, J=12.1 Hz, 2H), 3.17-3.47 (m, 4H), 2.76 (t, J=11.4 Hz, 2H), 2.23-2.63 (m, 5H), 1.82 (d, J=11.5 Hz, 2H), 1.54 (qd, J=11.7, 3.0 Hz, 2H).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH:6]1[C:19]2[C:10](=[S+:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1.[C-:20]#[N:21].[K+]>O.C(Cl)Cl>[C:20]([CH:18]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:19]1=[CH:6][CH:7]=[CH:8][CH:9]=2)#[N:21]
Reactant: [C-]#N
Reactant: c1ccc2[s+]c3ccccc3cc2c1
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: N#CC1c2ccccc2Sc2ccccc21
Reaction time: 1 h
Yield: 91.2 %

Procedure:
8.0 g (27.0 mmol) of thioxanthylium perchlorate [C. C. Price et al, J. Amer. Chem. Soc. 85, 2278 (1963)] are added to a well-stiffed mixture of 3.5 g (53.8 mmol) of potassium cyanide in 4 ml of water and 30 ml of methylene chloride under a nitrogen atmosphere. After one hour, the mixture is dried over potassium carbonate and filtered and the flitrate is concentrated on a vacuum rotary evaporator. Crystallization of the residue from isopropanol gives 5.5 g (91%) of 9-cyano-thioxanthene, melting point 103°-105° C., colourless needles (compound (103), Table I).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:37])[O:33][CH:34]([CH3:36])[CH3:35])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([NH:31][C:32]([O:33][CH:34]([CH3:36])[CH3:35])=[O:37])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)Nc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)OC(=O)Nc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06) and Isopropyl 1H-indol-5-ylcarbamate (intermediate 78).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH:23]=O)[CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:26]1([C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH3-]C#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][N:35]2[CH2:36][CH2:37][C:32]([OH:38])([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:33][CH2:34]2)[CH2:10][C:11]([N:13]2[C:17]3[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[CH:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CCC(CC(=O)n1ccc2ccccc21)c1ccc(Cl)c(Cl)c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
1-[3-(3,4-dichlorophenyl)-1,5-dioxopentyl]-1H-indole (740 mg), in MeOH/THF (1:1, 30 mL) was treated sequentially with molecular sieves 3A (880 mg), 4-phenyl-4-hydroxypiperidine HCl (880 mg) and NaBH3CN (130 mg). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was with quenched with water (20 mL) and diluted with CH2Cl2 (50 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×50 mL) The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude oil. Silica gel chromatography eluting with 1-2% MeOH/CH2Cl2 gave the title compound (600 mg). Mass spectrum (CI): 521.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[S:9](=[O:26])(=[O:25])[CH2:10][C:11]3[C:15]([C:16]([OH:18])=O)=[N:14][N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C1COCC1>[CH3:1][O:2][C:3]1[C:8]2[S:9](=[O:26])(=[O:25])[CH2:10][C:11]3[C:15]([C:16]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[O:18])=[N:14][N:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1cccc2c1S(=O)(=O)Cc1c(C(=O)O)nn(-c3ccccc3)c1-2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc2c1S(=O)(=O)Cc1c(C(=O)N3CCOCC3)nn(-c3ccccc3)c1-2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 6-methoxy-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylic acid 5,5-dioxide (0.20 g, 0.54 mmol) in THF (20 mL) is added triethylamine (0.20 mL, 1.63 mmol) followed by 50% propane phosphonic acid anhydride in EtOAc (0.70 mL, 0.347 g, 1.09 mmol). The reaction mixture is cooled to 0° C. and then morpholine (0.049 g, 0.59 mmol) is added and the reaction mixture is stirred overnight at room temperature. The solvent is removed under reduced pressure and the residue is diluted with EtOAc. The organic layer is washed with 10% NaHCO3 then brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography (eluent 1 to 2% MeOH in DCM) to afford the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.59-7.58 (m, 3H) 7.46-7.42 (m, 3H) 7.25 (d, J=8.60 Hz, 1H), 6.35 (d, J=7.92 Hz, 1H), 4.82 (s, 2H), 3.95 (br, 2H), 3.90 (s, 3H), 3.65 (br, 4H), 3.59 (br, 2H). MS (ESI+): 440.0. HPLC (max plot) 96.0%; Rt 4.81 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=0.866 min, m/z=444.2; 1H NMR (CDCl3) 1.04-1.16 (d, 6H), 1.50 (d, 3H), 2.14-2.25 (m, 4H), 2.45 (m, 1H), 2.57 (s, 3H), 2.83 (m, 1H), 5.65 (m, 1H), 7.04 (d, 2H), 7.20-7.33 (m, 9H), 8.45 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([CH3:12])=[N:7]2.[CH3:14]I.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([CH2:12][CH3:14])=[N:7]2
Reactant: CI
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2cccc(Br)c2nc1Cl
Temperature: -78 °C
Reaction time: 0.12 h
Yield: 54.3 %

Procedure:
LDA(Aldrich) (1.7M in heptane/THF/ethylbenzene; 0.60 mL, 1.01 mmol) was added (dropwise, over 1 min) to a solution of 5-bromo-3-chloro-2-methylquinoxaline (126e) (238 mg, 0.92 mmol) in THF (8.0 mL) in an oven-dried flask under argon at −78° C., and the resulting solution was stirred at −78° C. for 7 min. Methyl iodide (0.12 mL, 1.85 mmol) was then added, and the resulting solution was stirred at −78° C. for 15 min, then warmed to 23° C. and stir at 23° C. for 16 h. The reaction mixture was subsequently cooled to 0° C., water (0.5 mL) was added, and the reaction mixture was concentrated onto silica gel and chromatographically purified (silica gel, 0-15% EtOAc/hexanes) to provide 5-bromo-3-chloro-2-ethylquinoxaline (136 mg, 0.50 mmol, 54% yield) as a light-orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (1H, d, J=3.1 Hz), 8.02 (1H, d, J=2.3 Hz), 7.60 (1H, t, J=8.0 Hz), 3.20 (2H, q, J=7.4 Hz), 1.44 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 271.0/272.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([NH2:13])[CH:3]=1.N1C=CC=CC=1.[O:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[CH2:30][C:31](Cl)=[O:32])[CH3:21]>C(Cl)Cl.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][C:31](=[O:32])[CH2:30][C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[O:20][CH3:21])[CH:3]=1
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Reactant: CCCc1nc(N)cc(N)c1C#N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1nc(NC(=O)Cc2cc(OC)ccc2OC)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a solution of 23 mg (0.13 mmol) of 4,6-diamino-2-propyl-nicotinonitrile (Example 68B) and 50 mg (0.63 mmol) of pyridine in 1 mL of CH2Cl2 was added 35 mg (0.16 mmol) of (2,5-dimethoxyphenyl)acetyl chloride (Example 68A). The mixture was stirred at ambient temperature for 10 minutes then diluted with 3 mL of water. The mixture was extracted with ethyl acetate (3×3 mL), then the combined ethyl acetate layers were back extracted with saturated NaHCO3(aq.) (1×3 mL), and brine (1×3 mL), dried over MgSO4, filtered, and concentrated to an oil. This was suspended in 5 mL of toluene, then concentrated under reduced pressure to remove some pyridine. The product was purified via silica gel chromatography, eluting with 60:40 ethyl acetate:hexanes to provide 21 mg (46%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.27 (s, 1H), 7.34 (s, 1H), 6.83 (m, 5H), 3.70 (m, 6H), 3.65 (s, 2H), 2.64 (m, 2H), 1.68 (m, 2H), 0.93 (t, 3H, J=7.3 Hz); MS (ESI) m/e 355 (M+H)+, 353 (M−H)−.