Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:29][CH2:30][CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:29][CH2:30][CH2:31][OH:32])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: NCCO
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1=C(C)NC(C=NCCO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1651 g), 2-aminoethanol (185 mg) and p-toluenesulfonic acid (catalytic amount) in dried benzene (20 ml) was refluxed under azeotropic dehydration for 1.5 hours. After cooling to room temperature, water was added to the resultant solution. The mixture was washed twice with water. The aqueous layer was extracted with diethyl ether and the extract was combined with the benzene solution. The mixed solution was dried over magnesium sulfate and then the solvent was removed from the solution to give viscous oil (1.2397 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-(2-hydroxyethyl)iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([C:18]1[CH:23]([C:24]([OH:26])=[O:25])[N:22]2[C:27](=[O:38])[CH:28]([NH:29][C:30](=[O:37])[CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C@H:21]2[S:20][CH:19]=1)=[O:17]>O1CCCC1>[CH:16]([C:18]1[CH:23]([C:24]([O:26][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:25])[N:22]2[C:27](=[O:38])[CH:28]([NH:29][C:30](=[O:37])[CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C@H:21]2[S:20][CH:19]=1)=[O:17]
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of diphenyldiazomethane (0.213 g, 1.1. mmol) in dry tetrahydrofuran (2 ml) was added dropwise with stirring to the 3-formyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid (0.352 g., 1 mmol) in dry tetrahydrofuran (10 ml) at 40°. The reagent was allowed to completely react as noted by the color changes between each addition. The reaction was stirred at 40° for two hours after the addition was completed and then the solvent was removed in vacuo. The residual oil was dissolved in chloroform, washed with 5% NaHCO3, dried over MgSO4 and concentrated to half volume. The product was precipitated by the addition of hexane.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[N:6]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[C:10]([C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([NH:1][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[S:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=1)#[N:11]
Reactant: N#Cc1cccc(-c2csc(N)n2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(C#N)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A mixture of 0.5 g of 3-(2-amino-thiazol-4-yl)-benzonitrile with 0.52 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 50 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 80 ml of 50% ethanol yielded 0.35 g of N-[4-(3-cyano-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as colorless crystals.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]([F:43])([F:42])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[F:43][C:30]([F:29])([F:42])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1OC(F)(F)F)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.8 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2-(Trifluoromethoxy)benzenesulfonyl chloride (26 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.0 mg). MS m/z 413 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([CH3:20])=[CH:9][C:8]=2[Cl:21])(=[O:3])[CH3:2].[CH2:23]([NH2:26])[CH:24]=[CH2:25]>>[C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1[NH:26][CH2:23][CH:24]=[CH2:25])=[CH:11][C:10]([CH3:20])=[CH:9][C:8]=2[Cl:21])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(C)cc(Cl)c2[nH]c1=O
Reactant: C=CCN
Product: C=CCNc1c(C(C)=O)c(=O)[nH]c2c(Cl)cc(C)cc12
Yield: 81.9 %

Procedure:
3-Acetyl-8-chloro-6-methyl-4 -methylsulfoxy -2-quinolinone (2.97 g, 0.01 mol) and allylamine (0.57g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.38g, yield: 82%).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]1([C:35]2[C:36]([O:41]C)=[N:37][CH:38]=[CH:39][CH:40]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])(=[O:23])=[O:22])[C:12]1=[O:34])=[O:4].[I-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:43][N:2]([CH3:1])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]1([C:35]2[C:36](=[O:41])[NH:37][CH:38]=[CH:39][CH:40]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])(=[O:22])=[O:23])[C:12]1=[O:34])=[O:4]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cccnc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccc[nH]c3=O)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC)c1
Yield: 59.8 %

Procedure:
A solution of example 5 (0.16 mmol, 100 mg) and sodium iodide (0.32 mmol, 109 mg) in acetic acid (1 mL) was heated overnight at 40° C. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium dithionate solution, water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Chromatographic purification over silica gel (gradient from 4% to 12% MeOH in dichloromethane) yielded 59 mg (60%) of a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:47][C:48]([F:62])([F:61])[C:49]([N:51]1[CH2:60][CH2:59][C:54]2([CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:53][CH2:52]1)=[O:50]>C1COCC1>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:57]3[CH2:56][CH2:55][C:54]4([CH2:53][CH2:52][N:51]([C:49](=[O:50])[C:48]([F:61])([F:62])[F:47])[CH2:60][CH2:59]4)[CH2:58]3)=[O:18])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(O)c1ccc2c(c1)C(NC(=O)c1ccccc1Cl)CC2
Reactant: O=C(N1CCC2(CCNC2)CC1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: O=C(NC1CCc2ccc(C(=O)N3CCC4(CCN(C(=O)C(F)(F)F)CC4)C3)cc21)c1ccccc1Cl
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a suspension of 3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid (E-01) (789 mg, 2.49 mmol, 1.0 eq.) in THF (20 ml) was added HATU (1.04 g, 2.76 mmol, 1.1 equiv.) and DI PEA (2.1 ml, 12.4 mmol, 5 eq.) at 0° C. and the reaction mixture was allowed to stir for 15 min. A solution of 2,2,2-trifluoro-1-(2,8-diazaspiro[4.5]decan-8-yl)ethanone (587 mg, 2.49 mmol, 1.0 equiv.) in THF (5 ml) was then added and the reaction mixture was stirred at 25° C. for 15 h. The mixture was diluted with MC (300 ml) and washed successively with sodium bicarbonate solution (40 ml), ammonium chloride solution (50 ml), water (50 ml) and brine (50 ml). The organic layer was dried over sodium sulfate and the solvent evaporated under reduced pressure to obtain the crude material which was purified by column chromatography (silica gel; 0-3% methanol/MC) to yield the pure final product as a white solid. Yield: 72% (1 g, 1.8 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[NH:44]([C:45]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:18])[S:10][N:9]=2)=[CH:6][CH:7]=1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3ccccc3)cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.4 %

Procedure:
A mixture of 3-(4-aminophenyl)-5-(3-(3-morpholinopropyl)ureido)isothiazole-4-carboxamide (12 mg, 0.030 mmol), N,N-diisopropylethylamine (0.021 mL, 0.120 mmol), and phenyl isocyanate (0.0056 mL, 0.051 mmol) in 1.0 mL THF was stirred at rt for 19 hours. The reaction was quenched with 0.2 mL aqueous Na2CO3 solution, stirred 5 min at rt, and then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to a white solid. The solid was chromatographed eluting with CHCl3, then gradient 2.5% to 10% MeOH in CHCl3. The resulting solid was subjected to an EtOAc/NaHCO3 work-up to remove the presence of any silica gel impurity. Upon evaporation of the EtOAc layer the title compound was obtained as a white solid (12 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([F:16])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].[CH3:17][C:18]([CH3:21])([O-:20])[CH3:19].[K+]>CS(C)=O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:18]([O:20][C:13]1[C:12]([F:16])=[CH:11][C:3]([C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5])=[C:2]([F:1])[CH:14]=1)([CH3:21])([CH3:19])[CH3:17]
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Yield: 96.7 %

Procedure:
To a solution of 2,4,5-trifluoro-N-(methylsulfonyl)benzamide (Preparation 16, 1.50 g, 5.92 mmol) in DMSO (10 mL) at room temperature was added potassium t-butoxide (1.46 g, 13.0 mmol). After 18 hours the reaction mixture was diluted with EtOAc (30 mL) and 10% aqueous citric acid solution (15 mL). The pH of the aqueous layer was checked to ensure it was acidic. The organic layer was separated and washed with 10% aqueous citric acid solution (15 mL) and brine (15 mL), dried over magnesium sulphate, filtered and evaporated to yield the title compound as a cream solid (1.76 g, 97%).
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[C:12]([O:16][C:17]([N:19]1[C:27]2[CH:26]=[C:25]([CH2:28]OS(C)(=O)=O)[N:24]=[CH:23][C:22]=2[C:21]([CH3:35])([CH3:34])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>C1COCC1>[C:12]([O:16][C:17]([N:19]1[C:27]2[CH:26]=[C:25]([CH2:28][N:7]3[CH:11]=[CH:10][CH:9]=[N:8]3)[N:24]=[CH:23][C:22]=2[C:21]([CH3:35])([CH3:34])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(COS(C)(=O)=O)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cn3cccn3)cc21
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of potassium tert-butoxide (0.090 g, 0.80 mmol) in anhydrous THF (4.0 mL) was added pyrazole (0.104 g, 1.52 mmol). The reaction was stirred for 30 min. 6-Methanesulfonyloxymethyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.271 g, 0.76 mmol) was added at ambient temperature and the reaction was stirred for 1 h. A second equivalent of pyrazole (104 mg) was added, followed by potassium tert-butoxide (90 mg) and the reaction stirred for 1 h. Water (4.0 mL) was added and the reaction extracted with EtOAc (3×5.0 mL), washed with saturated brine solution (15 mL), dried over sodium sulfate, filtered and concentrated. Chromatography (SiO2, gradient elution, 0-100%, EtOAc/petrol then SiO2, gradient elution, 0-5%, MeOH/DCM). gave the title compound (0.13 g, 52%) as a pale yellow oil MS: [M+H]+=329.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)\[CH3:5].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Br:1][CH2:2][CH:3]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]1([CH3:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C/C(=C\CBr)c1cccc([N+](=O)[O-])c1
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CBr)C1(C)c1cccc([N+](=O)[O-])c1
Yield: 9.4 %

Procedure:
To a solution of 1-[(E)-3-bromo-1-methyl-1-propenyl]-3-nitrobenzene (Preparation 4, 4 g, 15.6 mmol) in dichloromethane (5 ml) was added rhodium (II) acetate dirner (100 mg, 0.22 nmnol). To the mixture was added dropwise at room temperature over 4.5 h a solution of ethyl diazoacetate (3.1 ml, 2.84 g, 25 mmol) in dichloromethane (15 ml). The mixture was filtered, concentrated in vacuo, and the residue purified by silica column (100 g) chromatography, eluting with 2:1 hexane/dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo, then purified further by preparative HPLC (Condition 1). Combination and evaporation of appropriate fractions gave the title compound as a colourless oil (0.5 g, 11%).
Reaction SMILES: C(O[C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)C.[CH3:35][S:36][Si](C)(C)C.C(NC(C)C)(C)C>C(Cl)Cl>[C:9]([O:8][C@H:7]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]([S:36][CH3:35])[C@@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=[O:11])[CH3:10]
Reactant: CS[Si](C)(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CS[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
A mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-galactose (680 mg, 1.425 mmol), methylthiotrimethylsilane (0.8 ml, 5.64 mmol), and trimethyl silyl triflate (0.32 ml, 1.66 mmol) in CH2Cl2 was stirred at room temperature for 2 days. Diisopropylamine (~1 ml) was added, diluted with CH2Cl2 (~50 ml) and washed with saturated NaHCO3 solution and water, respectively. The organic layer was dried (Na2SO4) and evaporated to dryness. Column chromatography (heptane-EtOAc) gave pure 20 (630 mg, 95%) as an amorphous powder, having [α]D24 +25° (c1, CHCl3).
Reaction SMILES: [Cl:1][C:2]1([C:9]([OH:11])=O)[C:4]([CH3:6])([CH3:5])[C:3]1([Cl:8])[Cl:7].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1([C:9]([Cl:14])=[O:11])[C:4]([CH3:6])([CH3:5])[C:3]1([Cl:8])[Cl:7]
Reactant: CC1(C)C(Cl)(Cl)C1(Cl)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC1(C)C(Cl)(Cl)C1(Cl)C(=O)Cl

Procedure:
The 1,2,2-trichloro-2,2-dimethylcyclopropanecarboxylic acid (3.0 g) synthesized in Example k and thionyl chloride (1.0 ml) were mixed, and reacted at 60° C. The reaction mixture was distilled under reduced pressure to give the desired 1,2,2-trichloro-3,3-dimethylcyclopropanecarboxylic acid chloride (2.8 g) represented by the following formula. ##STR26##
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:19]=4[CH3:34])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:35][C:36]([CH3:38])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:20]2[C:19]([CH3:34])=[C:18]([C:7]3[C:6]4[C:5]5[C:13](=[CH:14][C:2]([NH:1][CH:36]([CH3:38])[CH3:35])=[CH:3][CH:4]=5)[NH:12][C:11]=4[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=3)[CH:23]=[CH:22][CH:21]=2)=[O:33])=[CH:31][CH:30]=1
Reactant: CC(C)=O
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(N)ccc3c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(NC(C)C)ccc3c12
Temperature: 40 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A suspension of 7-amino-4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1-carboxamide (Example 54-5, 1 g, 2.210 mmol), acetone (3.4 mL, 20 eq.), and acetic acid (0.443 mL, 7.74 mmol) in 1,2-dichloroethane (220 mL) was treated with sodium triacetoxyborohydride (1.639 g, 7.74 mmol) and stirred at 40° C. for 4 h. Additional sodium triacetoxyborohydride (520 mg, 1.1 eq) and acetic acid (0.19 mL, 1.5 eq) were added and the mixture was stirred overnight. The mixture was treated with NaHCO3 (aq) and the organic phase was separated, washed with brine, dried and concentrated. The residue was purified by preparative HPLC. The appropriate effluent fractions were made basic with NaHCO3 (aq) and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was triturated with methanol to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(isopropylamino)-9H-carbazole-1-carboxamide as an off-white solid (520 mg, 48%). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (1 H, s), 10.09 (1 H, s), 8.07 (3 H, dd, J=8.8, 5.3 Hz), 7.77 (1 H, d, J=7.9 Hz), 7.27-7.51 (5 H, m), 7.17 (1 H, d, J=6.2 Hz), 6.73-6.88 (2 H, m), 6.60 (1 H, d, J=8.3 Hz), 6.23 (1 H, dd, J=8.8, 2.2 Hz), 5.49 (1 H, d, J=7.9 Hz), 3.53 (1H, dd, J=13.8, 6.4 Hz), 1.90 (3 H, s), 1.04-1.21 (6 H, m). Mass spectrum m/z 495.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[S:16][C:15]([CH3:17])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[Li]CCCC.CN([CH:28]=[O:29])C>C1COCC1.CCCCCC>[CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[S:16][C:15]([CH3:17])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:28]=[O:29])[CH:8]=2)[S:3]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C2=CC(C)(C)Sc3ccc(Br)cc32)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C=O)cc32)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cold (−78° C.) solution of 2,2-dimethyl-4(2-methyl-thien-5-yl)-6-bromo-thiochrom-3-ene (Compound T, 430 mg, 1.2 mmol) in THF (12 mL) was added n-BuLi in hexane (1.6 M solution, 1 mL). The mixture was gradually warmed to ambient temperature over 1 hour and recooled to −78° C. To this solution was added DMF (220 mg, 3 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction was quenched by adding water (10 mL) and ethy lacetate (100 mL). The organic layer was washed with brine (10 mL), dried and the solvent was removed by distillation to obtain the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23](O)=[O:24])[C:10]2=[O:26])=[O:5])[CH3:2].S(Cl)([Cl:29])=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:13][CH:12]=[C:11]([C:23]([Cl:29])=[O:24])[C:10]2=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(=O)OCC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)Oc1cc2occ(C(=O)Cl)c(=O)c2cc1OC(=O)OCC

Procedure:
6,7-Bis(ethoxycarbonyloxy)chromone-3-carboxylic cid (1.1 g) was dissolved in benzene (20 ml) and thionyl chloride (2 ml) was added dropwise at room temperature with stirring. Then, the mixture was refluxed with stirring. The reaction mixture was concentrated, and n-hexane was added to the concentrate to crystallize it. The resulting crystals were collected by filtration, washed with n-hexane and dired to afford the desired product (980 mg).
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C.[NH2:94][C:95]1[C:96]([C:112]([NH:114][CH3:115])=[O:113])=[N:97][C:98]([C:101]2[C:102]([C:110]#[N:111])=[N:103][N:104]([CH2:106][CH2:107][CH2:108][OH:109])[CH:105]=2)=[CH:99][CH:100]=1>>[C:110]([C:102]1[C:101]([C:98]2[N:97]=[C:96]([C:112](=[O:113])[NH:114][CH3:115])[C:95]([NH:94][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:100][CH:99]=2)=[CH:105][N:104]([CH2:106][CH2:107][CH2:108][OH:109])[N:103]=1)#[N:111]
Reactant: CNC(=O)c1nc(-c2cn(CCCO)nc2C#N)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4C#N)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 69 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 236 mg, 0.520 mmol) and 3-amino-6-[3-cyano-1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 52C, 164 mg, 0.546 mmol) to afford 259 mg of the title compound (69%). 1H NMR (400 MHz, CD3OD) δ 9.17 (br. s., 1H), 8.47 (s, 1H), 8.38 (s, 1H), 7.91 (d, J=9.1 Hz, 1H), 7.68 (br. s., 1H), 7.08 (s, 1H), 6.98 (d, J=7.8 Hz, 1H), 4.52 (t, J=6.9 Hz, 2H), 4.08 (quin, J=7.3 Hz, 4H), 3.88 (s, 2H), 3.61 (t, J=6.1 Hz, 2H), 3.33-3.42 (m, 2H), 2.99 (s, 3H), 2.17 (quin, J=6.5 Hz, 2H), 1.26 (t, J=7.1 Hz, 7H). MS (ESI): m/z=718.47 [M+H]+. UPLC: tR=1.39 min (UPLC-TOF: polar—2 min).