Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[C:10]([CH3:14])[C:11](O)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>>[C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[C:10]([CH3:14])[C:11]([Cl:19])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C=C(C)C(=O)O)cc1
Product: CC(=O)Oc1ccc(C=C(C)C(=O)Cl)cc1
Yield: 87.7 %

Procedure:
Into 20 g of this 4-acetoxy-α-methylcinnamic acid was dropped 100 g of thionyl chloride, reaction was carried out under reflux for 2 hours, unreacted thionyl chloride was removed by distillation and the reaction product was subjected to distillation under a reduced pressure to obtain 19 g of 4-acetoxy-α-methylcinnamic acid chloride. This acid chloride was dissolved in 100 ml of acetone, 11 g of l-2-octanol and 10 g of triethylamine were added to the solution, and the reaction was carried out for 10 hours under reflux. The precipitated triethylamine hydrochloride was removed by filtration, acetone was removed from the filtrate by using an evaporator, and the ether-soluble component was extracted from the residue with diethyl ether. The unreacted acid chloride was removed, and extract was dehydrated on magnesium sulfate overnight, and subsequently, diethyl ether and remaining l-2-octanol were removed by distillation under a reduced pressure. Then, 100 ml of acetone and 100 ml of an aqueous saturated solution of sodium carbonate were added to the residue and reaction was carried out under reflux for 15 hours. The obtained product was hydrolyzed and extracted with ether again. The extract was dehydrated and ether was evaporated to obtain 15 g of 1R-methylheptyl 4-hydroxy-α-methylcinnamate.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([N+:17]([O-])=O)=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].O.NN>CO.[Ni]>[NH2:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([NH2:17])=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)NCc1cc([N+](=O)[O-])c(Cl)cc1N
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)NCc1cc(N)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of N-(2-amino-4-chloro-5-nitrobenzyl)pivalamide (2.0 g, 6.9 mmol) in methanol (20 mL), Raney Ni (2.0 g) and hydrazine hydrate (5.0 mL) were added and the reaction mass was stirred at RT for 3 h. After the completion of the reaction, the reaction mass was filtered through celite pad and obtained filtrated was concentrated to afford 1.5 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.11 (s, 9H), 3.97 (br d, 2H), 4.52 (br d, 2H), 5.44 (br s, 2H), 6.50 (d, J=11.4 Hz, 2H), 7.88 (m, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:16]([I:45])=[C:17]([NH:37][C:38](=[O:44])[O:39][CH2:40][CH:41]2[CH2:43][O:42]2)[C:18]([I:36])=[C:19]([C:22]([NH:24][CH:25]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[CH2:26][O:27][C:28](=[O:30])[CH3:29])=[O:23])[C:20]=1[I:21])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:16]([I:45])=[C:17]([N:37]2[CH:41]([CH2:43][OH:42])[CH2:40][O:39][C:38]2=[O:44])[C:18]([I:36])=[C:19]([C:22]([NH:24][CH:25]([CH2:31][O:32][C:33](=[O:35])[CH3:34])[CH2:26][O:27][C:28](=[O:30])[CH3:29])=[O:23])[C:20]=1[I:21])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(NC(=O)OCC2CO2)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2C(=O)OCC2CO)c1I
Yield: 76.2 %

Procedure:
A solution of oxiranylmethyl [3,5-bis[[[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]amino]carbonyl]-2,4,6-triiodophenyl]carbamate of Example 3a (12.1 g, 12.4 mmol) in freshly distilled anhydrous pyridine (120 ml) was heated at 75° C. for 45 minutes. Pyridine was removed under diminished pressure at 45° C. and the residue was co-evaporated twice with toluene (75 ml). The solid thus obtained was dissolved in ethyl acetate (250 ml) and the solution was washed with H2O (1×100 ml). The organic layer was dried (MgSO4). It was then filtered and the solvent removed to obtain the title compound as a yellow solid (9.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(F)c2)c1C(=O)OC
Yield: 112.5 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.4 g, 6.7 mmol) in acetone (30 mL) and potassium carbonate (2.8 g, 20 mmol) was added 3-fluorobenzyl bromide (0.89 mL, 7.0 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (50 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-fluoro-benzyloxy)-phthalic acid dimethyl ester (2.4 g, 113% crude yield). The product was used in the next step without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)O1.Br[C:21]1[N:25]=[CH:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[CH:28][CH:27]=2)[N:22]=1.C([O-])(O)=O.[Na+].O1CCOCC1>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.O>[F:39][C:33]([F:38])([O:32][C:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH:24]=[N:25][C:21]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)=[N:22]2)=[CH:27][CH:28]=1)[C:34]([F:37])([F:36])[F:35]
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A microwave vial was charged with methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (147 mg, 0.561 mmol), 3-bromo-1-(4-(pentafluoroethoxy)phenyl)-1H-1,2,4-triazole (200 mg, 0.559 mmol), NaHCO3 (94 mg, 1.2 mmol), and Pd(PPh3)4 (39 mg, 0.034 mmol). Dioxane (3.8 mL) and water (1.2 mL) were added, the reaction vial was capped, and the reaction was heated at 140° C. for 30 min in a Biotage Initiator® microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and allowed to stand overnight. A white solid formed, which was filtered and air-dried to give the title compound as a white solid (146 mg, 62%): mp 192-195° C., 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.28 (d, J=9.0 Hz, 2H), 8.19-8.12 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 7.45-7.38 (m, 2H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −85.90, −87.86; ESIMS m/z 414 ([M+H])+.
Reaction SMILES: [CH3:1][O:2][C:3](=[CH2:6])[CH:4]=O.[CH3:7][N:8]([CH3:10])[NH2:9]>CCOCC>[CH3:1][O:2][C:3]([CH:4]=[N:9][N:8]([CH3:10])[CH3:7])=[CH2:6]
Reactant: CN(C)N
Reactant: C=C(C=O)OC
Solvent: CCOCC
Product: C=C(C=NN(C)C)OC
Yield: 66.1 %

Procedure:
6.4 g of 2-methoxyacrolein are stirred for 1 hour at 30°-35° C. with 4.4 g of N,N-dimethylhydrazine in 50 ml of ether, dried at 20° C. with Na2SO4 and then the solvent is removed. Distillation at 74°-76° C./13 mbar gives 6.2 g of pure 2-methoxy-4-dimethylamino-4-azabutadiene. (b) 10.8 g of 2-methoxy-4-dimethylamino-4-azabutadiene and 15 g of 2-tert.-butylisothiazolin-3-one-1,1-dioxide are stirred for 11/2 h at 80°-85° C. in 250 ml of toluene. The crude bicyclic compound of formula IVb is further processed in the crude state as described in Example 4. ##STR16## The compounds listed in Table 1 are obtained in an analogous manner.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(C)(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in an analogous manner to Example 61e. Product isolated as a white solid (0.011 g, 11%). MP: 165-167° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 10.94 (s, 1H), 8.65 (d, 1H, J=8.6 Hz), 8.10 (d, 1H, J=1.5 Hz), 8.09-8.07 (m, 1H), 7.53-7.39 (m, 3H), 7.12-7.06 (m, 1H), 6.64 (s, 1H), 6.13 (br s, 1H), 3.86 (s, 3H), 3.57-3.48 (m, 2H), 2.90-2.73 (m, 10H), 1.69 (t, 3H, J=18.6 Hz), 1.30-1.24 (m, 3H). MS: 545.21 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.CN(C=O)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])[C:21]1=[O:23])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)N1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 48 h

Procedure:
Dissolve 4.76 g of the lysine derivative, 1.64 g. of N-hydroxysuccinimide and 3.24 g dicyclohexylcarbodiimide in 250 ml. of DMF. Store this reaction mixture at 0° C. for two days. Concentrate the reaction in vacuo and dissolve the residue in ethyl acetate. Filter and purify the product by silica gel chromatography. Isolate the purified 3-(S)-t-butoxycarbonylamino-1-(1-methoxycarbonylethyl)perhydroazepin-2-one.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH:20]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[Si](C)(C)CC[Si]4(C)C)=[CH:26][CH:27]=3)O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1N=CC(C(C2C3C(=NC=C(Cl)C=3)N(S(C3C=CC=CC=3)(=O)=O)C=2)O)=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[N:24][CH:23]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: CC[SiH](CC)CC
Agent: Nc1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[6-(2,2,5,5-tetramethyl-[1,2,5]azadisilolidin-1-yl)-pyridin-3-yl]-methanol and (6-amino-pyridin-3-yl)-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (118, 119, 1.70/1.25 g mix, 2.41 mmol) in 25.0 mL of dichloromethane, triethylsilane (3.00 mL, 18.8 mmol) and trifluoroacetic acid (1.50 mL, 19.5 mmol) were added and the reaction stirred at room temperature overnight. The reaction was concentrated under vacuum, combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane to provide the desired compound (120, 0.70 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].[CH3:17][O-:18].[Na+].O>CO>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([O:18][CH3:17])[CH:6]=1)(=[O:4])=[O:3]
Reactant: C[O-]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Yield: 70.3 %

Procedure:
To a solution of 1-methylsulfonyl-3,5-dinitro-benzene (2.0 g; 8 mmol) in methanol (15 ml) a solution of sodium methoxide (0.5 g; 10 mmol) in methanol (5 ml) was added. The mixture was refluxed for 2 hours. Water was added and the precipitate washed with a diisopropylether/ethanol mixture. 1.3 g (5.62 mmol; 70% yield) of 1-methylsulfonyl-3-methoxy-5-nitro-benzene were obtained as a yellow solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:20][CH2:21][CH2:22]Br)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:12]([O:20][CH2:21][CH2:22][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCCBr)c1ccccc1
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(C)=O
Yield: 92.4 %

Procedure:
A mixture of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 15.7 g.), 2-bromoethyl benzoate (27.5 g.), potassium carbonate (20.7 g.), N,N-dimethylformamide (25 ml.) and ethyl acetate (25 ml.) was treated in a similar manner to that of Example A-(1) to give ethyl 2-(2-benzoyloxyethoxyimino)-3-oxobutyrate (syn isomer, 28 g.).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[C:18](=O)(O)[O-].[Na+].COS(OC)(=O)=O>CC(C)=O>[CH3:18][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1
Reactant: O=C([O-])O
Reactant: BrCc1ccc(-c2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1c(-c2ccc(CBr)cc2)nc2ccccc21
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 143.6 g (0.5 mole) of 2-(4-bromomethylphenyl)benzimidazole and 42.0 g (0.5 mole) of sodium bicarbonate in 85% aqueous acetone is added 66.0 g (0.5 mole) of dimethylsulfate dropwise. The mixture is stirred at 40° C. for about 3 hours until thin-layer chromatography indicates that the reaction is complete. The solvent is removed in vacuo, and the solid product is washed with water to eliminate sodium salts and purified by recrystallization from benzene.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:14][C:13]=1[F:30])=[O:11].CS(O[CH2:36][CH2:37][C:38]([F:41])([F:40])[CH3:39])(=O)=O>>[F:40][C:38]([F:41])([CH3:39])[CH2:37][CH2:36][O:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:10]([C:12]3[N:17]=[CH:16][C:15]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[CH:14][C:13]=3[F:30])[O:11][C:2]=2[CH:7]=1
Reactant: CC(F)(F)CCOS(C)(=O)=O
Reactant: C[C@@H](COc1cnc(C(=O)Nc2ccc(O)cc2O)c(F)c1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCCC(C)(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl [(1S)-2-({6-[(2,4-dihydroxyphenyl)carbamoyl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate and 3,3-difluorobutyl methanesulfonate, and in the same manner as in Example 2, steps C-D, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19](=O)[CH:20]=[CH:21][N:22](C)C)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.O.[NH2:32]N>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:32][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C
Reactant: NN
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 36 above, with compound 3-(4-chlorophenyl)-6-(3-dimethylaminoacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine monohydrate.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:6]=1.[C:18]([C:21]1[CH:22]=[CH:23][C:24]([F:30])=[C:25](B(O)O)[CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[F:30][C:24]1[CH:25]=[CH:26][C:21]([C:18](=[O:20])[CH3:19])=[CH:22][C:23]=1[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)c2)cc1
Reactant: CC(=O)c1ccc(F)c(B(O)O)c1
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: [K+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(F)c(-c2cn(-c3ccc(OC(F)(F)F)cc3)cn2)c1
Reaction time: 0.33 h
Yield: 88 %

Procedure:
4-Bromo-1-(4-trifluoromethoxyphenyl)-1H-imidazole (200 mg, 0.651 mmol), 5-acetyl-2-fluorophenylboronic acid (178 mg, 0.977 mmol), tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.007 mmol), a 2 N aqueous solution of potassium carbonate (0.651 mL) and dioxane (8 mL) were combined and added to a microwave vessel. The reaction mixture was heated in the microwave with stiffing to 150° C. for 20 min. LC-MS indicated 88% anticipated product; TLC (1:1 hexanes:EtOAc) indicated the presence of starting material plus 3 other materials. EtOAc and water were added to the reaction mixture. The aqueous layer was extracted with EtOAc and the organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by chromatography with gradient elution (100% hexanes to 100% EtOAc) resulting in 90 mg of an off-white solid. ESIMS 265.0 (M+H); mp 129° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH:2]1[CH2:10][C:11]([OH:13])=O.S(Cl)(Cl)=O.C[N:19]([CH:21]=O)C>C1(C)C=CC=CC=1>[S:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]1[CH2:10][C:11]([NH:19][C:21]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)=[O:13]
Reactant: O=C(O)CC1Sc2ccccc2S1
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(CC1Sc2ccccc2S1)Nc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(benzo[1,3]dithiol-2-yl)acetic acid (1.35 g) in toluene (30 mL) were added thionyl chloride (0.600 mL) and DMF (catalytic amount) at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added acetonitrile (30 mL), and then was added dropwise a solution of aniline (1.54 g) in acetonitrile (10 mL) under ice-cooling. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 3 hours, and then concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (50 mL), and the mixture was stirred at room temperature for 0.5 hour. The formed crystals were collected by filtration, washed with water, filtered, and then dried to obtain 2-(benzo[1,3]dithiol-2-yl)-N-(phenyl)acetamide (1.83 g) as a white crystal.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:49][C:50]([C:52]1[C:60]2[N:59]=[C:58]([NH2:61])[NH:57][C:56]=2[CH:55]=[C:54]([S:62]([CH2:65][CH3:66])(=[O:64])=[O:63])[CH:53]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[C:60]2[NH:59][C:58]([NH:61][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:57][C:56]=2[CH:55]=[C:54]([S:62]([CH2:65][CH3:66])(=[O:64])=[O:63])[CH:53]=1)=[O:51])[CH3:48]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: CCOC(=O)c1cc(S(=O)(=O)CC)cc2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(S(=O)(=O)CC)cc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12

Procedure:
0.30 g (1.5 mmol) of isoquinoline-3-carboxylic acid and 800 mg (2.1 mmol) HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.28 g (0.94 mmol) of 2-amino-6-ethylsulfonyl-1H-benzoimidazole-4-carboxylic acid ethyl ester as described in general procedure A to produce 6-ethylsulfonyl-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 453 (M+1)+.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]=[C:22]1[C:27]2=[CH:28][NH:29][C:30]([CH:31]=O)=[C:26]2[CH2:25][CH2:24][O:23]1>>[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[CH:31][C:30]2[NH:29][CH:28]=[C:27]3[C:22](=[O:21])[O:23][CH2:24][CH2:25][C:26]=23)(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3ccccc3)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)Nc3ccccc3)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid phenylamide was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([N:29]3[CH2:32][CH2:31][CH2:30]3)=[O:28])=[C:23]([F:33])[CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=1>>[CH3:41][C:38]1[CH:39]=[CH:40][C:35]([NH:34][C:6]([C:8]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:28])=[C:23]([F:33])[CH:22]=3)[C:11]3[CH2:12][C:13]([CH2:16][OH:17])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)c(F)c2)c2c(c1)OC(C)(CO)C2
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)c(F)c3)c3c(c2)OC(C)(CO)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (240a) and 2-amino-5-methyl-pyridine. 1H NMR (400 MHz, CDCl3) δ 9.01 (br. s., 1 H) 8.23 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.62 (dd, J=8.59, 1.77 Hz, 1 H) 7.53 (t, J=8.08 Hz, 1 H) 7.15 (s, 1 H) 7.11 (s, 1 H) 6.80 (dd, J=8.59, 2.27 Hz, 1 H) 6.63-6.73 (m, 1 H) 4.22 (t, J=7.71 Hz, 2 H) 4.15 (t, J=7.71 Hz, 2 H) 3.74 (d, 1 H) 3.61 (d, J=11.87 Hz, 1 H) 3.18 (d, J=16.67 Hz, 1 H) 2.79 (d, J=16.67 Hz, 1 H) 2.28-2.38 (m, 5 H) 1.46 (s, 3 H); LCMS for C27H26FN3O5 m/z 492.00 (M+H)+.
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[CH:5][C:6]=1[Br:7].[CH3:8][O:9][N:10]=[C:11]1[C:19]2[C:14](=[CH:15][C:16](B(O)O)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1>>[CH3:8][O:9][N:10]=[C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:2]3[O:3][CH:4]=[CH:5][C:6]=3[Br:7])=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: CON=C1CCc2cc(B(O)O)ccc21
Reactant: Brc1ccoc1Br
Product: CON=C1CCc2cc(-c3occc3Br)ccc21
Yield: 30 %

Procedure:
The title compound (1.6 g, 30%) was prepared from 2,3-dibromofuran and the product of Example 5 Step 6 using the method of Example 15 Step 1; 1H NMR (CDCl3) 7.88 (2H, m), 7.72 (1H, d, J 8.3 Hz), 7.42 (2H, d, J 3.1 Hz), 4.01 (3H, s), 3.17 (2H, m), 2.92 (2H, m).