Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O-:9])=[O:8])=[C:4]([N:10]([C@H:20]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]2)[C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[Li+].[O:28]1[C:32]2([CH2:37][CH2:36][C:35](B(O)O)=[CH:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[O:28]1[C:32]2([CH2:37][CH2:36][C:35]([C:2]3[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([N:10]([C@H:20]4[CH2:21][CH2:22][C@H:23]([OH:26])[CH2:24][CH2:25]4)[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]4)=[O:12])[CH:3]=3)=[CH:34][CH2:33]2)[O:31][CH2:30][CH2:29]1
Reactant: OB(O)C1=CCC2(CC1)OCCO2
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(Br)sc2C(=O)[O-])[C@H]2CC[C@H](O)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC4(CC3)OCCO4)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1

Procedure:
To a solution of lithium 5-bromo-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methylcyclohexanecarbonyl)-amino]-thiophene-2-carboxylate (498 mg, 1.10 mmol) and 1,4-dioxaspiro[4,5]dec-7-en-8-boronic acid (412 mg, 1.55 mmol) in DMF (6 mL) was added 2M solution of Na2CO3 (3 mL), and the mixture was deoxygenated by bubbling nitrogen through solution for 10 min. Then Pd(PPh3)4 was added to the mixture, and it was refluxed under nitrogen for 2 h. The mixture was brought to room temperature and filtered through a celite pad washing with EtOAc and H2O. Filtrate was extracted with EtOAc (4×), then aqueous fraction was separated and acidified with 2N HCl till pH 2-3. The mixture was extracted with CH2Cl2 and CH2Cl2-MeOH, organic fraction was dried over Na2SO4 and evaporated to dryness. Crude compound was recrystallized from CH3CN to afford 453 mg (82%) of 5-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid as a solid.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1>CC#N>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:35]4[N:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(c1csc(C2CCN(c3ncccn3)CC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Temperature: 180 °C
Yield: 22.8 %

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (0.054 g, 0.16 mmol) was dissolved DMSO (1 mL) and cesium carbonate (0.5 mmol) was added followed by 2-chloropyrimidine (0.18 mmol). The reaction was heated to 180° C. by microwave irradiation for 45 minutes. The reaction mixture was diluted with MeCN (1 mL) and the mixture was filtered to remove any insoluble material. The filtrate was diluted with water and the mixture separated by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a pale yellow oil (0.015 g). LCMS m/z 411.25 [M+H]+ RT=12.36 min (Analytical Method 2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][CH:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:50][CH:43]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH2:42][CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:51])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Reactant: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Product: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1)c1ccccc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 48 supra) (170 mg, 0.36 mmol) and compound (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 53 supra) (361 mg, 1.44 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude (4-{3-[2-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 110 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].[OH-].[Na+].Cl>C(#N)C>[Cl:12][C:7]1[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[C:9]([CH3:11])[N:8]=1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(C(=O)O)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of commercially available methyl-2-chloro-6-methylpyrimidine-4-carboxylate (6.00 g, 32.15 mmol) in acetonitrile (500 mL), 1M aq. solution of NaOH (48.2 mL) is added at 0° C. The mixture is stirred at 0° C. for 1 h then acidified with 25% aq. HCl (7 mL). Volatiles are evaporated and the aq. solution is extracted with ethylacetate, washed with brine, dried over Na2SO4, filtered and concentrated to give 2-chloro-6-methylpyrimidine-4-carboxylic acid (4.22 g) as a yellow crystalline solid; LC-MS: tR=0.42 min, [M+H]+=172.96; 1H NMR (D6-DMSO): δ 2.58 (s, 3H), 7.95 (s, 1H), 14.1 (s br, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+]>CO>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:22])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc(CN2CCC(=O)CC2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CN2CCC(N)CC2)cc1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To 4.25 g (21 mmol) of 1-(4-methylbenzyl)-4-piperidinone 124 in 200 mL of anhydrous methanol was added 32.2 g (420 mmol) of ammonium acetate and 25 g of 3A molecular sieves. After stirring 30 min, 5.25 g (84 mmol) of sodium cyanoborohydride was added portionwise. After stirring 16 hours, the mixture was gravity filtered and the methanol evaporated under vacuum. The residue was partitioned between ether and ice/HCl. The acidic aqueous layer was extracted twice with ether, made basic with 50% aqueous NaOH and ice, and extracted with CH2Cl2 to give 2.1 g (48%) of the title amine 125 as a thick oil. GC/MS showed a molecular ion of 204. The product was used as is without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][S:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH2:2][CH2:3][S:4][CH2:5][CH2:6][CH2:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:24])=[O:25])=[CH:21][CH:22]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)CCCSCCBr
Product: CCOC(=O)C(C)(C)CCCSCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 63 %

Procedure:
from ethyl 8-bromo-2,2-dimethyl-6-thiaoctanoate and 4-chlorobenzenesulphonamide; yield 63% of theory; colourless oil;
Reaction SMILES: Cl[C:2]1([NH2:20])[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].O.[NH2:22][NH2:23]>CO>[NH:22]([NH:20][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:16]=2[N:17]=[CH:18][N:19]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[NH2:23]
Reactant: NN
Reactant: NC1(Cl)N=CN=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Solvent: CO
Product: NNNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 6-chloroadenosine (1 g, 3.5 mmol) and hydrazine monohydrate (5 mL) in MeOH (10 mL) was stirred at 50° C. for 1 hr. The reaction mixture was allowed to cool to room temperature and was then concentrated in vacuo to provide a crude residue which was suspended in MeOH and (10 mL) and stirred at room temperature. The solid product that separated out from the suspension was filtered, washed with MeOH and dried in vacuo to provide N6-hydrazinoadenosine (970 mg) which was used without further purification.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@H:14]([N:20]1[CH:33]=[CH:32][C:23]3[N:24]([CH3:31])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:22]=3[C:21]1=[O:34])[CH2:13]2>ClCCl>[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[CH:14]([N@@+:20]1([O-:6])[CH:33]=[CH:32][C:23]3[N:24]([CH3:31])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=4[C:22]=3[C:21]1=[O:34])[CH2:13]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c2ccccc2c2c(=O)n([C@@H]3CN4CCC3CC4)ccc21
Solvent: ClCCl
Product: Cn1c2c(c3ccccc31)C(=O)[N@@+]([O-])(C1CN3CCC1CC3)C=C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
m-Chloroperoxybenzoic acid (1.2 g, 7.0 mmol) was added in small portions at 0° C. to a solution of (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)1,2-dihydro-5-methyl-1-oxopyrido[4,3-b]indole (1.8 g, 5.8 mmol), from Example 3, in dichloromethane (50 mL). The reaction mixture was stirred for additional 0.5 hour at 0° C. The solvent was removed under reduced pressure and the residue was purified by column chromatography (10% methanol in dichloromethane and 1% ammonium hydroxide) to afford 0.75 g (62% yield) of (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-1,2-dihydro-5-methyl-1-oxopyrido[4,3-b]indole N-oxide, as an amorphous solid, m.p 98°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([NH:20][CH2:21][O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].Cl[C:38]([O:40][CH3:41])=[O:39]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:31]([F:32])([F:34])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:29]=[CH:28][C:17]([C:18]([N:20]([CH2:21][O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:38](=[O:39])[O:40][CH3:41])=[O:19])=[C:16]([CH3:30])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCOCC(F)(F)F
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(COCC(F)(F)F)C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 12.6 %

Procedure:
In a solution of 0.50 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-yl]-2-methyl-N-(2,2,2-trifluoroethoxymethyl)benzoic acid amide in 10 mL of N,N-dimethylformamide, 0.0825 g of 60% oily sodium hydride was added under cooling with ice and with stirring, and stirred at room temperature for 10 minutes. Then, 0.268 g of methyl chloroformate was added, and continued to stir at the same temperature for 30 minutes. After the completion of the reaction, the reaction was poured in 50 mL of water, extracted with ethyl acetate (50 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.07 g of the aimed product as colorless resinous substance.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)#[N:2].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:26](O)=[O:27]>>[C:1]([C:3]1[O:4][C:5]2[C:6](=[C:8]([CH:26]=[O:27])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:7]=1)#[N:2]
Reactant: COc1cccc2cc(C#N)oc12
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1ccc(C=O)c2cc(C#N)oc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of 2-cyano-7-methoxybenzofuran (4.17 g), hexamethylenetetramine (3.38 g), and trifluoroacetic acid (62 ml) was stirred at 60 to 70° C. for one hour. The mixture was concentrated and the residue was purified by silica gel column chromatography (toluene/ethyl acetate=20/1) to give Compound IIi (1.02 g, 21%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N+](C1C=CC([O:16][C:17]([O:19][CH:20]2[CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:24][C:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:22][CH2:21]2)=O)=CC=1)([O-])=O>CN(C)C=O>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:17]([O:19][CH:20]2[CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:24][C:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:22][CH2:21]2)=[O:16])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(O)c1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Temperature: 70 °C
Yield: 47.4 %

Procedure:
3-Aminophenol (1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-5-(4-nitrophenoxycarbonyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (2.5 g) in anhydrous dimethylformamide (30 cc). The solution obtained is heated at 70° C. for 5 hours, then cooled to a temperature in the region of 20° C. and poured into distilled water (300 cc). The mixture is extracted with dichloromethane (2×150 cc). The organic phases are combined, washed with distilled water (3×20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The oil obtained is purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate/triethylamine (60:35:5 by volume)], collecting 25-cc fractions. The fractions 10 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(3-hydroxyphenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (1.1 g), m.p. 170° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].B.CSC.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:5]=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: B
Agent: c1cc[nH+]cc1
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1ccc(C=O)cc1O
Reaction time: 18 h
Yield: 33.4 %

Procedure:
To a solution of 3-hydroxy-4-methylbenzoic acid (15.22 g, 0.1 mole) in THF (250 mL) was added borane.dimethylsulfide (32.0 mL of a 10.0 M solution, 0.32 mole) dropwise. Upon completion of addition, the reaction was stirred for 18 hrs. It was then quenched dropwise by the slow addition of aqueous 10% HCl (250 mL) and extracted with ethylacetate (3×250 mL). The organics were combined, dried with MgSO4 and concentrated. The resulting residue was taken up in CH2Cl2 (500 mL) and pyridinium dichromate (45.15 g, 0.12 mole) was added. The resulting mixture was stirred for 48 hrs. It was then filtered through Celite and concentrated. The resulting residue was chromatographed (silica gel, ether:hexanes, 30:70) to afford 4.55 g of 3-hydroxy-4-methylbenzaldehyde as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[N:9]2[N:10]=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[C:7](=[O:26])[N:6]([CH3:27])[CH2:5]1)=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH2:14]([O:13][C:12]1[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:10][N:9]2[CH:4]([C:2]#[N:1])[CH2:5][N:6]([CH3:27])[C:7](=[O:26])[C:8]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(N)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of ethyl 7-aminocarbonyl-3-benzyloxy-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (273 mg, 0.733 mmol) in anhydrous THF under an atmosphere of nitrogen was added Burgess reagent ((methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt, 349 mg, 1.47 mmol). The reaction was stirred at room temperature for 2 hours and then heated to 50° C. for 45 minutes. Additional Burgess reagent (4.89 g, 10.26 mmol) was added in portions and the reaction was heated to 60° C. overnight. The solvent was removed in vacuo, and the resulting residue was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated and the aqueous was extracted twice more with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford the title product. 1H NMR (400 MHz, d6-DMSO) δ 7.49-7.47 (m, 2H), 7.40-7.31 (m, 3H), 6.23 (t, J=4.0 Hz, 1H), 5.23 (dd, J=10.8, 24.6 Hz, 2H), 4.33-4.23 (m, 3H), 4.13 (dd, J=3.8, 13.8 Hz, 1H), 3.09 (s, 3H), 1.27 (t, J=7.2 Hz, 3H); ES MS (M+H)=355.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][N:11](C)C)[CH:5]=[CH:6][CH:7]=1.[NH2:26]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:14])=[CH:10][NH:11][N:26]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CN(C)C=C(C(=O)c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: Nc1c[nH]nc1-c1cccc(Cl)c1
Yield: 80 %

Procedure:
A mixture of 2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1,3-dione (255 mg, 0.719 mmol, 1 eq) and hydrazine (0.15 mL, 4.8 mmol, 6.6 eq) in 10 mL ethanol was stirred under reflux for 2 hours. The ethanol and excess hydrazine were removed under vacuum. The crude product was purified by flash chromatography on silica gel (50 to 100% ethyl acetate in heptanes) to yield 111.4 mg (80%) of 3-(3-chlorophenyl)-1H-pyrazol-4-amine LCMS (ESI) m+H=194.0; 1H NMR (400 MHz, CD3OD) δ: 7.75 (broad, 1H), 7.65 (broad, 1H), 7.41 (t, 1H), 7.32 and 7.30 (overlapping s and s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:6]=2[CH:19]=1.C1(C)C=CC=CC=1>ClCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:19]=1
Reactant: Cc1cc(C)c2oc(=O)n(CC(=O)OC(C)(C)C)c2c1
Agent: ClCl
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2oc(=O)n(CC(=O)O)c2c1

Procedure:
A solution of the tert-butyl (5,7-dimethyl-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate from Step B in CH2 Cl2 (0.7 mL) and CF3 CO2H (0.3 mL) was stood at ambient temperature for 2 h. Toluene (5 mL) was added and the mixture was concentrated in vacuo to give the title compound as a dark solid. MS: m/z=222 (M+1).
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[S:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[CH2:25][CH2:24]2)=[CH:8][CH:7]=1>O1CCCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[NH:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][N:31]([C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[C:2]([NH:1][CH3:4])=[S:3])[CH2:27][CH2:28]2)=[CH:10][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)cc1
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)N(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1nccs1
Yield: 44.5 %

Procedure:
A mixture of 1.1 parts of isothiocyanatomethane, 6.76 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[2-thiazolylamino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine and 90 parts of tetrahydrofuran was stirred and refluxed for one week. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from methanol, yielding 3.5 parts (44.5%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N'-methyl-N-(2-thiazolyl)thiourea; mp. 188.5° C. (compound 104).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([Cl:29])[CH:28]=1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:24]=[C:23]([Cl:22])[CH:28]=[C:27]([Cl:29])[CH:26]=3)[CH2:35][CH2:34]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: Cc1nc2ccccc2cc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 65 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:24]([CH3:27])(=[O:26])=[O:25])[CH3:2].N.C([N:32](C(C)C)CC)(C)C>CO>[NH2:32][C:18]1[S:19]/[C:15](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:4]3[O:3][CH2:1][CH3:2])/[C:16](=[O:23])[N:17]=1
Reactant: CCOc1c(S(C)(=O)=O)cnc2ccc(C=C3SC(SCC)=NC3=O)cc12
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: CO
Product: CCOc1c(S(C)(=O)=O)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 41c was used, starting from 5-(4-ethoxy-3-methanesulfonyl-quinolin-6-ylmethylene)-2-ethylsulfanyl-thiazol-4-one (example 74e), ammonia in methanol, and DIEA (diisopropylethylamine) to give 2-amino-5-[1-(4-ethoxy-3-methanesulfonyl-quinolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 378 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([O:29][Si](C(C)(C)C)(C)C)=[C:24]([Cl:37])[C:23]=4[CH3:38])[CH:19]=[CH:20][CH:21]=3)=[CH:13][C:8]=2[O:7][CH2:6]1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:39])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([OH:29])=[C:24]([Cl:37])[C:23]=4[CH3:38])[CH:19]=[CH:20][CH:21]=3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[Si](C)(C)C(C)(C)C)c(Cl)c4C)c3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O)c(Cl)c4C)c3)ccc21
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a solution of methyl{(3S)-6-[(4′-{[tert-butyl(dimethyl)silyl]oxy}-3′-chloro-2′,6′-dimethylbiphenyl-3-yl)methoxy]-2,3-dihydro-1-benzofuran-3-yl}acetate (2.01 g, 3.54 mmol) in tetrahydrofuran (20 mL) was added 1 M tetrabutylammonium fluoride tetrahydrofuran solution (3.9 mL, 3.9 mmol) at room temperature, and the mixture was stirred at the same temperature for 3 hr under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50) to give the title compound (1.41 g, yield 88%) as a colorless oil.