Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[OH-].[Na+].Cl[CH:14]([F:16])[F:15]>O1CCOCC1.O>[F:15][CH:14]([F:16])[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccccc1OC(F)F
Temperature: 70 °C

Procedure:
A mixture of 2-nitrophenol (6.01 g, 43.2 mmol) and sodium hydroxide (8.6 g, 216 mmol) in 50 mL of dioxane and 50 mL of water was heated to 70° C. and chlorodifluoromethane gas was introduced. The mixture was diluted with water and extracted with diethyl ether. The organic phase was washed with aqueous sodium hydroxide and then brine, dried (MgSO4) and concentrated to give 1-difluoromethoxy-2-nitrobenzene (8.21 g, 43.4 mmol) as an oil.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3[CH2:20][C:21]4[S:22][CH:23]=[CH:24][C:25]=4[C:18]=3[N:17](COCC[Si](C)(C)C)[N:16]=2)=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CO>[CH:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3[CH2:20][C:21]4[S:22][CH:23]=[CH:24][C:25]=4[C:18]=3[NH:17][N:16]=2)=[CH:13][CH:14]=1)=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(C=Cc3ccccc3)cc2)c2c1-c1ccsc1C2
Agent: Cl
Solvent: CO
Product: C(=Cc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1)c1ccccc1
Temperature: 100 °C
Yield: 90 %

Procedure:
6-(4-Styryl-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.15 g, 0.3 mmol) was dissolved in MeOH and treated with concentrated HCl (0.12 mL, 3 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-(4-Styryl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.1 g, 0.27 mmol) as yellow solid in 89% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[CH:19]([C:20](O)=[O:21])[NH:18][CH:17]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]32[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[NH:29][C:28]3=[O:37])[CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:20]([C@@H:19]2[NH:18][C@@H:17]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C@:16]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[C@H:15]2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[C:10]=2[F:38])=[O:21])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Br)c2F)c(OC)c1
Yield: 51.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 97 (0.4 g, 0.64 mmol), was reacted with diisopropylethylamine (0.43 g, 3.3 mmol), diphenylphosphinic chloride (0.31 g, 1.3 mmol), then reacted with methyl 4-amino-3-methoxybenzoate (Ark Pharm) (0.18 g, 0.99 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield 0.22 g, 51%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([N:8]2[N:12]=[N:11][C:10]([CH3:13])=[N:9]2)[CH2:4][C@H:3]1[N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][C:17]([N:38]1[CH2:42][CH2:41][C@@H:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:39]1)=[N:18][C:19]=2[NH:23][CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N[C@@H:49]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1>>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][NH:23][C:19]2[N:18]=[C:17]([N:38]3[CH2:42][CH2:41][C@@H:40]([NH:43][S:44]([CH3:47])(=[O:45])=[O:46])[CH2:39]3)[N:16]=[C:15]3[C:20]=2[N:21]=[CH:22][N:14]3[C@@H:3]2[CH2:4][C@H:5]([N:8]3[N:12]=[N:11][C:10]([CH2:13][CH3:49])=[N:9]3)[C@@H:6]([OH:7])[C@H:2]2[OH:1])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: Cc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NS(C)(=O)=O)C5)nc43)[C@H](O)[C@@H]2O)n1
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NS(C)(=O)=O)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
The title compound is prepared using a procedure analogous to that of N-{(R)-1-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(5-methyl-tetrazol-2-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-methanesulfonamide (Example 67) by replacing (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-((R)-pyrrolidin-3-ylamino)-purin-9-yl]-5-(5-methyl-tetrazol-2-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 7) with (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48). MS (ES+) m/e 674 (MH+).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[S-:11][C:12]#[N:13].[NH4+].C(O)C>O>[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH:9][C:12]([NH2:13])=[S:11]
Reactant: Cc1ccccc1NN
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1NNC(N)=S

Procedure:
A mixture of 15.9 g. (0.1 moles) of o-tolylhydrazine hydrochloride, 15.2 g. (0.2 moles) of ammonium thiocyanate, 300 ml. of ethanol and 30 ml. of water are heated at reflux temperature for 24 hours, the solvent is removed by distillation at atmospheric pressure, and sufficient water added to cause precipitation. The aqueous suspension is filtered and the solid residue recrystallized from aqueous ethanol affording 15 g. (85%) of 1-(o-tolyl)-3-thiosemicarbazide, m.p. 158°-160° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]=[CH:5][C:4]1=[O:57])[CH3:2].C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH2:6][CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-azido-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone (55 mg, Example 31), tetrakistriphenylphosphine palladium (10 mg), and acetic acid (10 μl) in 3 ml of dry toluene was stirred for 5 min at room temperature under nitrogen atmosphere. To this yellow solution was added tributyltin hydride (40 μl) and stirred an additional 45 min at room temperature. The brown colored reaction mixture was subjected to column chromatography on silica gel (eluted first with hexane and then with 50% ethyl acetate/hexane) to give 50 mg of the title compound (Mass and 1H NMR data were consistent with the proposed structure).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([S:14]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[F:18])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 2,4-dichloro-5-(chlorosulfonyl)benzoate (1 g, 3.15 mmol) in N,N-dimethylacetamide (10.5 mL) was added 2-fluoroaniline (1.215 mL, 12.60 mmol) dropwise over 1 minute at room temperature. The mixture was stirred at room temperature for 1 hour, and then it was diluted with ethyl acetate (35 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (38 mL) was added, and the mixture concentrated to give ethyl 2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH3:20])C.[OH-].[Na+]>C1COCC1>[CH3:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[C:12](=[O:11])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(C)cc1C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)CC#N)c(C)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.6 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 12 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of 2,4-dimethyl-benzoic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(2,4-dimethyl-phenyl)-3-oxo-propionitrile in the amount of 2.0011 gms.
Reaction SMILES: O[C@H:2]([C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[CH3:32])[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.CS([Cl:37])(=O)=O.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:37][C@@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:25](=[CH:30][CH:31]=1)[C:26](=[O:29])[O:27][CH2:28]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1=C(N2CCC3(CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCN(C[C@@H](Cl)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Reaction time: 0.33 h

Procedure:
To a solution of 8-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (Example 7) (1.1 g, 2.5 mmol) and methanesulfonyl chloride (0.584 mL, 7.49 mmol) in DCM (30 mL) was added triethylamine (1.22 mL, 8.74 mmol) and N,N-dimethylpyridin-4-amine (0.031 g, 0.250 mmol) at −10 to −15° C. (ice-NaCl). The mixture was stirred at the same temperature for 20 min, quenched with NH4Cl aqueous. The organic layer was separated, and the aqueous was extracted with DCM (30 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give product was used in the next step without further purification. LCMS: 459.05 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH:13]1([C:3]2[C:2]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:9]=[C:8]3[C:4]=2[CH2:5][C:6](=[O:12])[N:7]3[CH3:11])[CH2:15][CH2:14]1
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=O)Cc2c1ccc(Br)c2C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2C1CC1
Temperature: 130 °C

Procedure:
To 5-bromo-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one, prepared as described in Example 40c, (320 mg, 1.202 mmol), was added 3-pyridine boronic acid (CAS#1692=25-7, 177 mg, 1.443 mmol), 1,2-dimethoxyethane (7.5 mL), and 2 M aqueous sodium carbonate (1.503 ml, 3.01 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3—Pd(0) (Biotage), 0.11 mmol/g loading, (328 mg, 0.036 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 130° C. for 4 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 10 to 100%) to furnish 4-cyclopropyl-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one, HRMS: (ESI) m/z 265.1342 (M+H)+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.12-0.24 (m, 2H), 0.68-0.78 (m, 2H), 1.86-2.00 (m, 1H), 3.19 (s, 3H), 3.59 (s, 2H), 6.80 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.34 (dd, J=7.7, 4.9 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 8.53 (d, J=4.6 Hz, 1H), 8.63 (s, 1H).