Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH3:15])[C:13]=1I)(C)(C)C.[C:17]([O:21][C:22](=[O:45])[NH:23][C:24]([C:26]1[S:27][C:28]([S:43][CH3:44])=[C:29]([S:31]([C:34]2[CH:39]=[CH:38][C:37](O)=[C:36](B)[C:35]=2O)(=[O:33])=[O:32])[CH:30]=1)=[NH:25])([CH3:20])([CH3:19])[CH3:18].C(O)C.C1(C)C=CC=CC=1>C([O-])([O-])=O.[Na+].[Na+].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.CCOC(C)=O>[C:17]([O:21][C:22](=[O:45])[NH:23][C:24]([C:26]1[S:27][C:28]([S:43][CH3:44])=[C:29]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:13]3[C:12]([CH3:15])=[CH:11][N:10]=[CH:9][C:8]=3[NH2:7])[CH:35]=2)(=[O:33])=[O:32])[CH:30]=1)=[NH:25])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cncc(NC(=O)OC(C)(C)C)c1I
Reactant: Bc1c(O)ccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1O
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: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cncc2N)c1

Procedure:
(4-Iodo-5-methyl-pyridin-3-yl)-carbamic acid tert-butyl ester (106 mg, 0.32 mmol, Example 139: step b), {[4-(3-Boranyl-dihydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (145 mg, 0.32 mmol, Example 140: step a) and Pd(PPh3)4 (74 mg, 0.06 mmol) were combined in aqueous Na2CO3 (2M, 1.2 mL), ethanol (1.2 mL) and toluene (2.4 mL) and was heated to 80° C. overnight. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried MgSO4) and solvents were removed in vacuo. Purification by flash column chromatography (40% EtOAc/hexanes) afforded the title compound. ESI-MS (m/z): Calcd. for C28H34N4O6S3: 619.2 (M+1); found: 618.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 170 °C

Procedure:
The mixture of 4-bromophenol (10 g, 57.8 mmol), 4-fluorobenzaldehyde (7.17 g, 57.9 mmol), and potassium carbonate (12 g, 86.7 mmol) in DMF was heated at 170° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was poured into ice-water. The resulting solid, 4-(4-bromophenoxy)benzaldehyde, was isolated by filtration (15 g, 94%), 1H NMR (CDCl3) δ 9.95 (s, 1H), 7.85 (d, 2H), 6.62 (d, 2H), 7.17 (d, 2H), 6.96 (d, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.S(Cl)([Cl:25])(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([Cl:25])=[O:21])=[CH:5]2
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
This product is prepared by refluxing for 3 hours a solution of 10 g (34.81 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in step 1.1, and 25.4 mL (0.348 mol) of sulfonyl chloride in 174 mL of toluene. After this time, the reaction mixture is concentrated under reduced pressure. The resulting mixture is taken up twice successively in 100 mL of toluene and then concentrated under reduced pressure. The product is used in the rest of the synthesis without a further purification step.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Reactant: Cc1cccc(B(O)O)c1O
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cccc(C)c4O)n3)n2)c1
Yield: 65 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(2-hydroxy-3-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-3-methylphenylboronic acid in 65% yield using method F; δH [2H6]-DMSO 12.35,(1H, s), 8.37,(2H, m), 8.24,(2H, m), 8.17,(1H, d), 7.96,(1H, d), 7.65,(1H, s), 7.27,(1H, d), 7.02-6.86,(3H, m), 3.83,(3H, s), 8.09,(1H, s); MS 385 (MH)+; HPLC retention time (system 1) 4.31 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:9][CH:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C:4]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12].C.C(=O)(O)[O-].[Na+:26]>[Pd].O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH2:9][CH:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C:4]=1[C:11]([O-:13])=[O:12].[Na+:26]
Reactant: COC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC1=C(C(=O)[O-])N2C(=O)CC2C1
Reaction time: 0.5 h

Procedure:
A mixture of benzyl 3-methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (50 mg) and 10% palladium on powdered charcoal (50 mg) in 1:1 dioxane-H2O (5 ml) containing sodium bicarbonate (12.5 ml) is hydrogenated at 40 psi for 30 mins. The mixture is filtered and the catalyst is washed with more water (5 ml). The combined filtrate is extracted with ethyl acetate, concentrated in vacuo to ca. 2 ml, and lyophilized to yield sodium 3-methoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].CI.C(OCC)C>CN(C)C=O>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)s1
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of 5-methylthiophene-2-carboxylic acid (40.3 g, 282 mmol) in N,N-dimethylformamide (500 ml) were added potassium carbonate (43 g, 310 mmol) and methyl iodide (19.3 ml, 310 mmol). After stirring at room temperature for 4 hr, diethyl ether (1.0 L) was added, and the organic layer was washed successively with water (500 ml×3) and saturated brine (200 ml) and dried over magnesium sulfate. After filtration and concentration, methyl 5-methylthiophene-2-carboxylate (40.8 g, yield 93%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([CH:17]([CH3:19])[CH3:18])[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([CH:17]([CH3:19])[CH3:18])[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)[C@H](NS(=O)(=O)c1ccc(F)cc1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](NS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(C)C
Temperature: 70 °C
Yield: 41.7 %

Procedure:
To a solution of 7.76 g (25.6 mmol) of N-[(4-fluorophenyl)sulfonyl]-D-valine ethyl ester from Example 7a in 50 mL of anhydrous dimethylformamide was added 7.8 mL (77 mmol) of thiophenol. After purging with nitrogen for 5 minutes, 10.6 g (77 mmol) of powdered potassium carbonate was added and the reaction heated to 70° C. for 21 hours. The solution was cooled, water and ethyl acetate added and separated. The ethyl acetate layer was washed with saturated sodium bicarbonate, three times with brine, dried with sodium sulfate, filtered and concentrated to afford crude product. This was chromatographed on silica gel using 20% ethyl acetate/hexane to yield 4.2 g of N-[[4-(phenylthio)phenyl]sulfonyl]-D-valine ethyl ester, m/e=400 (M+Li).
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=S)[CH2:12][N:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:22]=1)([O-:4])=[O:3]>O1CCCC1>[NH2:1][C:13]1[CH2:12][N:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:22]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=[CH:7][C:8]=2[N:14]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCC(=S)N2
Solvent: C1CCOC1
Product: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
300 ml of 25% aqueous ammonia solution were added to a solution of 16 g of 7-nitro-5-phenyl-3H-1,4-benzodiazepine-2(1H)-thione (J. B. Hester, A. D. Rudzik & B. V. Kamdar, J.Med.Chem., 1971, 14, 1078-1081) in 850 ml of tetrahydrofuran. The solution was stirred at room temperature for 20 h. and then concentrated to about 50 ml in a vacuum. The crystalline precipitate was filtered off and recrystallized from dioxan. There were obtained 8.0 g of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine which was used in this form for the next step.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:3]=1.[C:11]1([O:17]C(Cl)=O)C=CC=CC=1.C(N(CC)CC)C.[NH2:28][C:29]1[N:34]=[C:33]([NH:35][C:36]([NH2:38])=[O:37])[CH:32]=[C:31]([Br:39])[CH:30]=1>C(#N)C>[Br:39][C:31]1[CH:32]=[C:33]([NH:35][C:36](=[O:37])[NH2:38])[N:34]=[C:29]([NH:28][C:11]([NH:10][S:7]([C:4]2[CH:3]=[C:2]([CH3:1])[S:6][CH:5]=2)(=[O:9])=[O:8])=[O:17])[CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(S(N)(=O)=O)cs1
Reactant: NC(=O)Nc1cc(Br)cc(N)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(S(=O)(=O)NC(=O)Nc2cc(Br)cc(NC(N)=O)n2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 0.089 g 5-methyl-thiophene-3-sulfonic acid amide in 4 ml acetonitrile was added at 0° C. 0.094 g phenylchloroformate and 0.127 g triethylamine. The mixture was stirred at 0° C. for 1 h. To the resulting suspension was added 0.127 g (6-amino-4-bromo-pyridin-2-yl)-urea and the mixture was heated to 60° C. for 18 h. The mixture was cooled to room temperature. The product was collected by filtration, washed with acetonitrile and dried to constant weight to yield 0.190 g of the title compound as white crystals.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])([O-])=O.[Na+].[Na+].[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)([CH3:13])([CH3:12])[CH3:11]>O.CO>[C:10]([O:14][C:15](=[O:25])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[NH:24])[NH:2][OH:3])[CH:18]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(C(=N)NO)c1

Procedure:
Hydroxylamine hydrochloride (179 mg, 2.60 mmol) and Na2CO3 (138 mg, 1.30 mmol) was dissolved in 1 mL water. A solution of (3-cyano-phenyl)-carbamic acid tert-butyl ester (560 mg, 2.60 mmol) in 10 mL of methanol was added and the combined solution was stirred at reflux overnight. The solvent was removed and the resulting precipitate was extracted with water and ethyl acetate to yield [3-(N-hydroxycarbamimidoyl)-phenyl]-carbamic acid tert-butyl ester which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:33]=[N:34][CH:35]=2)[C:5]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.C(Cl)[Cl:37].O1CCOCC1>Cl>[ClH:1].[ClH:37].[Cl:1][C:2]1[C:3]2[N:4]([CH:33]=[N:34][CH:35]=2)[C:5]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: ClCCl
Reactant: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cncn2c1N1CCNCC1
Reaction time: 0.25 h
Yield: 199.1 %

Procedure:
To tert-butyl 4-{8-chloro-6-[1-(9H-purin-6-ylamino)ethyl]imidazo[1,5-a]pyridin-5-yl}piperazine-1-carboxylate (8.0 mg, 0.016 mmol) in methylene chloride (0.5 mL, 8 mmol), 4.0 M hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) was added. The mixture was stirred for 15 minutes. Evaporation gave the desired compound (7.5 mg, 99%). LCMS calculated for C18H21ClN9 (M+H)+: m/z=398.2. found: 397.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11]O)=[N:7][C:6]=2[CH:13]=1.C([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])C.S(Cl)([CH3:24])(=O)=O.C(#N)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][N:16]3[CH2:17][CH2:18][CH2:24][C@H:19]3[CH3:20])=[N:7][C:6]=2[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: OCCc1nc2cc(Br)ccc2s1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 2-(5-bromo-benzothiazol-2-yl)-ethanol (1.50 g, 5.8 mmol) and triethylamine (1.33 g, 11.6 mmol) in CH2Cl2 was cooled to 0° C., and mesyl chloride was added dropwise. The mixture was warmed to room temperature and stirred for 1 hr. The solvent was removed under vacuum, and to the residue was added acetonitrile (20 mL), triethylamine (1.33 g, 11.6 mmol) 2-(R)-methylpyrrolidine hydrochloride (2.83 g, 23.2 mmol) to the mixture, and the mixture was stirred at 60° C. for 1 hr. Solvents were removed under vacuum, and the residue was dissolved in 20 mL methylene chloride and washed with 10 mL water. The aqueous layer was re-extracted with 10 mL methylene chloride. The combined methylene chloride extracts were concentrated to give a crude product yield 1.9 g (100%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]1[N:24]=[N:25][S:26][C:27]=1[C:28](O)=[O:29].C(N(CC)CC)C.C(OCC)C>CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:28]([C:27]3[S:26][N:25]=[N:24][C:23]=3[CH3:22])=[O:29])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Cc1nnsc1C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1nnsc1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 31.5 %

Procedure:
Preparation of example 16 from the title compound of Example 7 (15 mg, 0.054 mmol), 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid (8 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Additional 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid (1.0 mg, 0.006 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (2.0 mg, 0.006 mmol) were added after c.a. 18 hours to drive the reaction to completion. Silica gel chromatography, also in an analogous manner, followed by diethyl ether trituration afforded the title compound (7 mg, 0.017 mmol) as a yellow powder in 32% yield.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F-:12].[K+].Cl[C:15]([F:21])([F:20])C(OC)=O>CN(C=O)C>[F:20][C:15]([F:21])([F:12])[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: [F-]
Reactant: COC(=O)c1nccnc1Cl
Reactant: COC(=O)C(F)(F)Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1nccnc1C(F)(F)F
Temperature: 115 °C
Reaction time: 5 h
Yield: 29.3 %

Procedure:
Methyl 3-chloropyrazine-2-carboxylate (2 g, 11.6 mmol), cuprous iodide (3.3 g, 17.3 mmol), potassium fluoride (1.34 g, 23 mmol) and methyl chlorodifluoroacetate (3.36 g, 18.2 mmol) were dissolved in DMF (20 ml) and stirred at 115° C. for 5 hours under argon atmosphere. The reaction solution was filtered with celite, followed by dilution of the filtrate with ethyl acetate, and washing four times with water. The filtrate was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 700 mg of the desired compound as paste state.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3]1.I[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:13][CH2:14][OH:15])[CH:4]=[CH:3]1
Reactant: OCCI
Reactant: Cn1ccc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(OCCO)c21
Reaction time: 20 h
Yield: 63.1 %

Procedure:
To a solution of 1-methyl-1-H-indol-7-ol (Chemstep, CAS: 47577-33-4, 0.98 g, 6.8 mmol) and 2-iodoethanol (Fluka, 1.60 g, 8.6 mmol)) in DMF abs. (10 mL) was added potassium carbonate (1.84 g, 13 mmol). The reaction mixture at rt for 20 h, then at 70° C. for 24 h, quenched with ice/water, extracted with ethyl acetate. The organics were washed, dried and concentrated, the residue chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the desired compound (0.82 g) as a creamy solid. MS (ISP): m/e 192.3 (M+H)+
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1.[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>CN(C=O)C.O.C1COCC1>[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][S:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Oc1cc(O)nc(S)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1cc(O)nc(SCc2cccc(F)c2F)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium hydroxide (5.67 g) was added dropwise to a suspension of 2-mercaptopyrimidine-4,6-diol (14.56 g) in DMF (78 ml) and H2O (39 ml) and the mixture stirred for 30 min. A solution of 2,3-difluorobenzyl bromide (20.86 g) in THF (16 ml) was then added dropwise and the mixture stirred for 18 h. The reaction was then cooled to 0° C. and the precipitate was filtered and washed with H2O (4×100 ml) before drying in vacuo to afford the subtitle compound as a cream solid. Yield: 22.4 g.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:4]=1[C:2]#[N:3])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride and acetyl chloride in 100% yield as a yellow syrup. MS 290 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[N:21][N:22]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:23]=3)[S:18][C:11]=12)[NH2:5].[N:31]1[CH:36]=[CH:35][CH:34]=C[CH:32]=1.ClC(OC1C=CC=CC=1)=[O:39].C1(N)CC1>CN(C=O)C.CCOC(C)=O.CCOCC>[CH:36]1([NH:31][C:32]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:16]=[C:17]([C:19]5[N:20]=[N:21][N:22]([CH2:24][CH2:25][N:26]6[CH2:27][CH2:28][CH2:29][CH2:30]6)[CH:23]=5)[S:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)=[O:39])[CH2:34][CH2:35]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccncc1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4cn(CCN5CCCC5)nn4)sc23)c(F)c1
Agent: NC1CC1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4cn(CCN5CCCC5)nn4)sc23)c(F)c1)NC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a stirred solution of 361 (98 mg, 0.231 mmol) and pyridine (0.057 mL, 3 eq, 0.9 mmol) in DMF (5 mL) at 0° C. under nitrogen was added phenyl chloroformate (0.072 ml, 2.5 eq, 0.577 mmol) and the reaction mixture was stirred at 0° C. for 2 hrs. Cyclopropylamine (66 mg, 5 eq, 1.154 mmol) was added and the reaction mixture was heated at 55° C. for 5 hrs. The reaction mixture was then diluted with EtOAc, washed sequentially with sodium bicarbonate solution, saturated ammonium chloride solution and brine, then dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluent EtOAc to 30% MeOH in EtOAc) to afford the title compound 362 (50 mg, 42% yield) as a while solid after additional trituration with Et2O. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.8 (s, 1H), 8.71 (s, 1H), 8.48 (d, J=5.48 Hz, 1H), 7.91 (s, 1H), 7.70 (m, 1H), 7.36 (m, 1H), 7.18 (d, J=8.99 Hz, 1H), 6.61 (d, J=5.48 hz, 1H), 6.55 (s, 1H), 4.55 (m, 2H), 2.93 (m, 2H), 2.50 (m, 1H), 1.67 (m, 4H), 0.65 (m, 2H), 0.41 (m, 2H). MS (m/z): 508.54.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:2]=2[F:1])[CH:18]=1)[CH3:13]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1cc(Br)ccc1F
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
2-Fluoro-5-bromobenzoic acid (123 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[CH3:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C>[F:21][C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:34]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12)=[O:35])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4])([F:22])[CH3:20]
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC(F)(F)c1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(F)(F)c1cccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)-1-propanol (0.40 g, 1.42 mmol) in acetonitrile (10 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.28 g, 1.49 mmol) and 1-hydroxybenzotriazole monohydrate (0.22 g, 1.49 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.49 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, 2:1) and recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (0.50 g, 78%) as colorless crystals.