Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH:4]([CH2:6][CH3:7])[OH:5].[N:9]#[C:10][NH2:11].[O-]CC.[Na+].O>C(O)C>[NH2:11][C:10]1[O:5][C:4]([CH2:6][CH3:7])=[C:3]([CH2:2][CH3:1])[N:9]=1
Reactant: N#CN
Reactant: CCC(=O)C(O)CC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1nc(N)oc1CC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.5 %

Procedure:
Propioin (1.03 g, 8.37 mmol) was dissolved in ethanol (15 mL). Cyanamide (0.75 g, 17.7 mmol) and sodium ethoxide (1.21 g, 17.7 mmol) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (dichloromethane:methanol=9:1) to give the title compound (369.2 mg, 29.7%) as a yellow amorphous.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[CH3:10][C:11]1[NH:12][C:13](=[O:17])[CH2:14][S:15][CH:16]=1.C(#N)C.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:10][C:11]1[NH:12][C:13](=[O:17])[CH2:14][S:15][C:16]=1[CH:24]1[CH:25]=[CH:26][N:21]([C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[CH:22]=[CH:23]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC1=CSCC(=O)N1
Reactant: c1ccncc1
Solvent: CC#N
Product: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SCC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
2,2,2-Trichloroethylchloroformate (64 ml) was added dropwise to a suspension of 5-methyl-2H-1,4-thiazin-3(4H)-one (50 g) and acetonitrile (500 ml) in pyridine (75 ml) under ice/water-cooling. The reaction mixture was further stirred at ambient temperature for 1 hour. Then, the mixture was added with ice water (about 1.5 l), was stirred for a while and was filtered. The filtration was recrystallized from ethanol to give the titled compound (120 g, yield 80.7%) as pale yellow prisms.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[C:17]([CH3:27])=[C:18]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:15][C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([O:21][CH3:22])=[O:20])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cc(Cl)nc2ccccc12
Reactant: COC(=O)c1ccc(C)c(N)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(Cl)nc3ccccc23)c1C
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
To a solution of 2-chloroquinoline-4-carboxylic acid (0.40 g, 0.0019 mol) in CH2Cl2 (8 mL) at 0° C. are added methyl 3-amino-2,4-dimethylbenzoate (0.31 g, 0.0017 mol, see preparation 10) and triethylamine (0.80 ml, 0.0058 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 2.45 ml, 0.0038 mol) is added via syringe and stirred at room temperature. After 16 hours, the reaction is diluted with water and extracted twice with dichloromethane. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is triturated with 20% diethyl ether in pentane and filtered to give the title compound as an off-white solid (0.55 g, 77%). Mass spectrum (m/z): 369.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36].[H-].[Li+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:33])[CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 104 %

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.3 g, 0.5 mmol) prepared in example 55b was reacted with LiH (0.17 g, 21.4 mmol) (Aldrich) and iodomethane (4 g, 28.2 mmol) in N,N-dimethyl-formamide (40 mL) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white solid (Yield: 0.16 g, 51.6%).
Reaction SMILES: [S:1]([O:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])([CH3:4])(=[O:3])=[O:2].P(Cl)(Cl)(Cl)=O.[CH2:16](Cl)Cl.N1[CH:24]=[CH:23][CH:22]=CC=1>C(O)(C)(C)C>[S:1]([O:5][CH:6]([CH3:10])[C:7]([O:9][C:23]([CH3:22])([CH3:24])[CH3:16])=[O:8])([CH3:4])(=[O:3])=[O:2]
Reactant: CC(OS(C)(=O)=O)C(=O)O
Reactant: c1ccncc1
Reactant: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Product: CC(OS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: -5 °C

Procedure:
0.35 mole of the S optical isomer of 2-mesyloxypropionic acid was dissolved in 25 ml of pyridine and 500 ml of t-butanol, and 65 g of phosphoryl chloride was added, with stirring, at -5° C. After a further 30 minutes stirring at -5° C., and a further 2 hours at 20° C., the mixture was poured into ice-water, and methylene chloride was added. The organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate, and water, and then evaporated to give a solid which was recrystalised from light petroleum ether to give (S) t-butyl 2-mesyloxypropionate.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[Br:13]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:13][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[F:9]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(Br)c(F)c1F
Temperature: 90 °C
Yield: 73.6 %

Procedure:
To a solution of 3.00 g of 2,3-difluoro-6-nitroaniline in 30 ml of dimethylformamide, 6.14 g of N-bromosuccinimide was added, followed by an hour's stirring at 90° C. Water was added to the reaction liquid which then was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (ethyl acetate/hexane=1/6) to provide 3.21 g of the title compound.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[S:14][CH:13]=[CH:12][CH:11]=1)=O)C.[C:16]([CH:21]=[C:22]1[NH:26][CH2:25][CH2:24][NH:23]1)([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:6]1[CH:8]([CH2:9][C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[C:21]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:22]2[NH:23][CH2:24][CH2:25][N:26]2[C:5]=1[CH3:4])=[O:17])[CH3:20]
Reactant: CCOC(=O)CC(=O)C=Cc1cccs1
Reactant: CCOC(=O)C=C1NCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(C)N2CCNC2=C(C(=O)OCC)C1Cc1cccs1
Yield: 72 %

Procedure:
Boiling a solution of 7.4 g of then-2-ylideneacetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 60 ml of ethanol for 6 hours yields 5-methyl-7-(then-2-yl)-1,2,3,7-tetrahydroimidazolo[1,2-a]pyridine-6,8-dicarboxylic acid diethyl ester of melting point 134°C (ethanol).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[O:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:20](=[O:21])[C:19]3[C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[CH:16]=[C:15]([O:26][CH2:27][CH2:28][CH3:29])C=3NC=2)=[CH:7]1.[H-].[Na+].CI>C(OCC)(=O)C.O>[O:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:20](=[O:21])[C:19]3[C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[CH:16]=[C:15]([O:26][CH2:27][CH2:28][CH3:29])[C:3]=3[N:2]([CH3:1])[CH:4]=2)=[CH:7]1
Reactant: CCCOc1cc2ccccc2c2c(=O)c(-c3ccoc3)c[nH]c12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: CCCOc1cc2ccccc2c2c(=O)c(-c3ccoc3)cn(C)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
To a DMF solution (5 ml) of 2-furan-3-yl-5-propoxy-4H-benzo[f]quinolin-1-one (300 mg, 0.94 mmol) was added sodium hydride (60% oil base, 61 mg, 1.4 mmol), and then the mixture was stirred at room temperature for 5 minutes. Methyl iodide (181 mg, 1.27 mmol) was added thereto and the resulting mixture was stirred at room temperature for 62 hours. Water and ethyl acetate were added to the reaction mixture and the resulting mixture was subjected to separation. The thus-obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:ethyl acetate=90:1→80:1). The purified product was concentrated under reduced pressure to recrystallize the residue from ethyl acetate-n-hexane, giving a pale gray powder of 2-furan-3-yl-4-methyl-5-propoxy-4H-benzo[f]quinolin-1-one (130 mg, yield: 42%).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:17])([F:16])/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].C1(C)C=CC(S([CH2:27][N+:28]#[C-:29])(=O)=O)=CC=1>O1CCCC1>[F:7][C:8]([F:16])([F:17])[C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:27][NH:28][CH:29]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]cc1C(F)(F)F
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium t-butoxide (8.11 g, 0.075 mol) in tetrahydrofuran at -60° C. is treated dropwise with a mixture of ethyl 4,4,4-trifluorocrotonate (10.5 g, 0.063 mol) and p-tolylsulfonylmethylisocyanide (12.2 g, 0.063 mol) in tetrahydrofuran over a 1 hour period, stirred at -60° C. for 30 minutes, allowed to warm to room temperature and quenched with water. The reaction mixture is extracted with ether and ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and concentrated in vacuo to give a solid residue. Recrystallization from 1,2-dichloroethane affords the title compound as a tan solid, 7.3 g (56%), mp 163° to 164° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([SH:15])[CH2:13][SH:14]>CCO>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]2[S:15][CH2:12][CH2:13][S:14]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: SCCS
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C2SCCS2)cc1
Yield: 85.1 %

Procedure:
Following the general procedure employed in Example 1, 38.58 gm (0.255 moles) of 4-nitrobenzaldehyde and 24.71 gm (0.262 moles) of 1,2-ethanedithiol gave, after crystallization from absolute EtOH, 49.23 gm (0.2169 moles) of an orange colored solid (85% yield) m.p. 80°-82° C. Elemental analysis for C9H9NO2S2 :
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[OH-].C([P+](CCCC)(CCCC)CCCC)CCC.Br[CH2:31][CH2:32][O:33][CH3:34].Cl>C1COCC1>[CH3:34][O:33][CH2:32][CH2:31][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: COCCBr
Reactant: Cc1cc(C(=O)O)ccc1O
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)O)cc1C
Temperature: 0 °C
Yield: 6.7 %

Procedure:
To a solution of 4-hydroxy-3-methyl-benzoic acid (2.0 g, 13 mmol) in THF (24 mL) was added tetrabutylphosphonium hydroxide (18 mL of 40% w/v, 26 mmol). The reaction mixture was cooled to 0° C. and then 1-bromo-2-methoxy-ethane (1.8 g, 1.2 mL, 13 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was acidified using 1M HCl and the aqueous layer was extracted with ethyl acetate. The organics were dried over sodium sulfate and concentrated in vacuo to yield 4-(2-methoxyethoxy)-3-methylbenzoic acid (182 mg, 6%). ESI-MS m/z calc. 210.2. found 209.2 (M-H)−; Retention time: 0.96 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[N:5][C:4](=[C:8](Cl)Cl)[N:3]=1.[CH2:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[CH3:12].[OH2:19]>>[Cl:1][C:2]1[N:3]=[C:4]([C:8]([N:13]([CH2:11][CH3:12])[C:14]([NH:16][CH2:17][CH3:18])=[O:15])=[O:19])[NH:5][C:6]=1[Cl:7]
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Reactant: O
Reactant: CCNC(=O)NCC
Product: CCNC(=O)N(CC)C(=O)c1nc(Cl)c(Cl)[nH]1
Temperature: 100 °C
Yield: 66 %

Procedure:
21.8 g (0.1 mol) of 4,5-dichloro-2-dichloromethyleneimidazole were added to a solution of 26 g (0.22 mol) of N,N'-diethylurea in 150 ml of water and the mixture was heated to 100° C. while stirring. After cooling, the product was filtered off, washed with water and dried. In this way, 18.5 g (66% of theory) of 4,5-dichloro-imidazol-2-oyl-N,N'-diethylurea with a melting point of 159° C. were obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:45][C:46](=[O:50])[CH2:47][NH:48][CH3:49])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([N:48]([CH3:49])[CH2:47][C:46]([OH:45])=[O:50])=[O:36])=[CH:38][CH:39]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N(C)CC(=O)O)cc2)cc1

Procedure:
The product from Example 233 and N-methylglycine ethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.13-13.26 (br.s, 1 H), 8.94 (s, 1 H), 7.23 (m, 7 H), 6.99 (m, 7 H), 6.82 (d, J=8.7 Hz, 2 H), 4.12 (s, 1 H), 4.04 (s, 2 H), 3.96 (m, 5 H), 3.01 (s, 3 H), 3.01 (s, 2 H), 2.82 (s, 1 H), 2.50 (m, 1 H), 2.37 (m, 4 H), 1.92 (m, 2 H); MS (ESI+) m/z 646 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33]O)[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][S:43][CH3:42])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reaction time: 1 h

Procedure:
The compound (150 mg) of Example 147 was dissolved in tetrahydrofuran (10 mL) and triethylamine (1.50 mL) and methanesulfonyl chloride (0.70 mL) were added under ice-cooling, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to this reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was dissolved in a mixed solvent of N,N-dimethylformamide (5.0 mL) and tetrahydrofuran (4.0 mL). Sodium methanethiolate (180 mg) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=90:10) to give the title compound (123 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:11](O)(=[O:13])C.C(OC=O)=O.O>O1CCCC1>[CH:11]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:13]
Reactant: CC(=O)O
Reactant: NC1Cc2ccccc2C1
Agent: O=COC=O
Solvent: C1CCOC1
Solvent: O
Product: O=CNC1Cc2ccccc2C1

Procedure:
To a solution of 2-aminoindan (19.95 g) in tetrahydrofuran is added an solution of 2M acetic acid-formic acid anhydride in tetrahydrofuran under ice cooling, and the mixture is reacted at room temperature. To the reaction mixture is added water, and then, the solvent is distilled off, and the residue is extracted with ethyl acetate. After distilling off the solvent, the residue is recrystallized from ethyl acetate - n-hexane to give 2-formylaminoindan (19.02 g).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[CH:28]=[N:27][CH:26]=[CH:25][N:24]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cnccn2)c(F)c2oc(C3CC3)nc2c1C#N
Yield: 79 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (200 mg, 0.68 mmol) was dissolved in toluene (4 ml), then 2-tributylstannylpyrazine (300 mg, 0.81 mmol) and 2,6-di-tert-butylcresol (2 mg) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) were added, followed by heating under reflux for 15 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, followed by removing tin-derived side products with n-hexane and by elution with a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain 2-cyclopropyl-7-fluoro-5-methyl-6-(pyrazin-2-yl)-1,3-benzoxazole-4-carbonitrile (158 mg, 79%) as a yellow white solid. This was dissolved in dimethyl sulfoxide (3.2 ml), triethylamine (189 μl, 1.34 mmol) and (3S)-3-(dimethylamino)pyrrolidine (102 μl, 0.81 mmol) were added, followed by stirring at 90° C. under nitrogen atmosphere for 14 hours. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform/methanol (20:1, v/v) to obtain the entitled compound (121 mg, 58%) as a pale brown solid.
Reaction SMILES: [O:1]=[C:2]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:4]2([CH2:9][CH2:8][CH:7]([NH:10][C:11]([C@H:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[O:12])[CH2:6][CH2:5]2)[O:3]1.[Cl:25][C:26]1[C:27]([CH3:36])=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>C(#N)C>[Cl:25][C:26]1[C:27]([CH3:36])=[C:28]([S:32]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([C:11]([NH:10][CH:7]3[CH2:8][CH2:9][C:4]4([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:2](=[O:1])[O:3]4)[CH2:5][CH2:6]3)=[O:12])[CH2:14]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C1OC2(CCC(NC(=O)[C@H]3CCCNC3)CC2)c2ccccc21
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=O)NC2CCC3(CC2)OC(=O)c2ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A mixture of (3S)-N-(3-oxo-3H-spiro[2-benzofuran-1,1′-cyclohexan]-4′-yl)piperidine-3carboxamide (11 mg, 0.03 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (6.8 mg, 0.03 mmol), and triethylamine (10.5 μL, 0.075 mmol) in acetonitrile (0.2 mL) was stirred at r.t. for 2 hours. The mixture was purified by flash column to yield 10.2 mg of final product was obtained. Yield: 65%. LCMS: 517.0 (M+H)+; 539.1 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:6]([CH2:12]Cl)=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[Si]([O:36][C:37]1[CH:38]=[C:39]([C:43]2[C:51]3[C:46](=[N:47][CH:48]=[N:49][C:50]=3[NH2:52])[NH:45][N:44]=2)[CH:40]=[CH:41][CH:42]=1)(C(C)(C)C)(C)C>CN(C=O)C>[NH2:52][C:50]1[N:49]=[CH:48][N:47]=[C:46]2[N:45]([CH2:12][C:6]3[N:5]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:4](=[O:22])[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[Br:1])[N:7]=3)[N:44]=[C:43]([C:39]3[CH:40]=[CH:41][CH:42]=[C:37]([OH:36])[CH:38]=3)[C:51]=12
Reactant: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2n[nH]c3ncnc(N)c23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1cccc(O)c1)nn2Cc1nc2cccc(Br)c2c(=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 5-bromo-3-(2-chlorobenzyl)-2-(chloromethyl)quinazolin-4(3H)-one (2) (100 mg, 0.25 mmol) and potassium carbonate (42 mg, 0.30 mmol) in DMF (2.5 mL) was added a solution of 3-(3-(tert-Butyldimethylsilyloxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (6) (94 mg, 0.28 mmol) in DMF (2.5mL) and the reaction mixture was stirred at RT for 18 hr. Potassium carbonate (3×35 mg, 0.75 mmol) was added in three portions over 30 hr. after which the solvent was removed in vacuo and the crude material was purified by flash column chromatography, eluting with 4.5% methanol in DCM, to afford the title compound, Intermediate A, (94 mg, 64%) as a off-white solid: Rt 2.01 min; m/z 588/590 (M+H)+, (ES+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].CS(C)=O.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([S:22]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of indole (11.7 g, 0.1 mol) in THF is added to a stirred mixture of NaH (60% dispersion in mineral oil, 4.2, g 0.105 mol), DMSO and THF. The reaction mixture is stirred for 1 h at room temperature, cooled to 0° C., treated with phenylsulfonyl chloride (13.3 mL, 0.15 mol), stirred at ambient temperatures for 3 h, quenched with water and extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is crystallized in ethanol and filtered. The filtercake is air-dried to give 1-phenylsulfonylindole. A portion of this 1-phenylsulfonylindole (257 mg, 1.0 mmol) and cyclohexylcarbonyl chloride (0.175 mL, 1.3 mmol) in methylene chloride is treated with tin tetrachloride (97 μL, 1.9 mmol) at room temperature, shaken for 6 h, quenched with saturated NaHCO3 and extracted with ethylacetate. The extracts are combined and concentrated in vacuo to give a residue. The residue is suspended in isopropanol, treated sequentially with concentrated HCl (50 μL) and aminoguanidine bicarbonate (100 mg, 0.5 mmol), heated at 80° C. for 4 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product 37.7 mg (17% yield), identified by HPLC1 and mass spectral analyses.