Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:5][C@H:6]([NH:20][C:21](=[O:47])[C@@H:22]([NH:30][S:31]([C:34]2[CH:35]=[N:36][C:37]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[B:7]2[O:11][C@@H]3C[C@@H]4C[C@H]([C@]3(C)[O:8]2)C4(C)C)[CH2:4][CH2:3][CH2:2]1.CC(C)CB(O)O>CO>[CH:1]1([CH2:5][C@@H:6]([B:7]([OH:11])[OH:8])[NH:20][C:21](=[O:47])[C@@H:22]([NH:30][S:31]([C:34]2[CH:35]=[N:36][C:37]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC1(C)[C@@H]2C[C@H]3OB([C@H](CC4CCC4)NC(=O)[C@H](Cc4ccccc4)NS(=O)(=O)c4ccc(Oc5ccccc5)nc4)O[C@@]3(C)[C@H]1C2
Agent: CC(C)CB(O)O
Solvent: CO
Product: O=C(N[C@@H](CC1CCC1)B(O)O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
Into a 20 mL vial was added (25)-N-{(1R)-2-cyclobutyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}-2-{[(6-phenoxypyridin-3-yl)sulfonyl]amino}-3-phenylpropanamide (31.2 mg, 0.047 mmol), (2-methylpropyl)boronic acid (10.4 mg) 1N hydrochloric acid (0.107 mmol), methanol (0.285 mL and hexanes (0.285 mL.) The mixture was stirred at room temperature overnight, then the hexane layer was separated and discarded. The remaining solvent was removed in vacuo and the residue purified by preparative TLC on silica plates using 10% MeOH in CH2Cl2 to give 18.4 mg (74% yield) of desired product as a white solid. 1H NMR (CD3OD, 300 MHz, δ): 8.36 (s, 1H); 7.95-7.84 (m, 1H); 7.52-7.39 (m, 2H); 7.33-7.06 (m, 10H); 6.95-6.83 (m, 1H); 4.25-4.13 (m, 1H); 3.09-2.94 (m, 1H); 2.93-2.78 (m, 1H); 2.46-2.32 (m, 1H); 2.26-1.93 (m, 3H); 1.92-1.71 (m, 2H); 1.64-1.37 (m, 3H); 1.37-1.22 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][CH:8]=[C:9]3[C:18]([N:17]=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[C:15]4[C:19](O)=[O:20])=[N:10]3)=[C:5]2[CH:4]=[CH:3]1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:15]1[C:16]2[C:11](=[N:10][C:9]3[C:18]([N:17]=2)=[C:5]2[CH:4]=[CH:3][N:2]([CH3:1])[C:6]2=[CH:7][CH:8]=3)[CH:12]=[CH:13][CH:14]=1)=[O:20]
Reactant: CN(C)CCN
Reactant: Cn1ccc2c3nc4c(C(=O)O)cccc4nc3ccc21
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(ccn4C)c3nc12

Procedure:
3-Methyl-3H-pyrrolo[3,2-α]phenazine-10-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 3-methyl-3H-pyrrolo[3,2-α]phenazine-10-carboxylic acid and N,N-dimethylethylenediamine
Reaction SMILES: B(F)(F)F.[CH3:5][CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][Cl:8].[C:16](Cl)([CH3:19])([CH3:18])[CH3:17]>O>[CH3:5][CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][Cl:8].[CH3:5][CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[CH2:7][Cl:8]
Reactant: CC(C)(C)Cl
Agent: CC(CCl)Cc1ccccc1
Agent: FB(F)F
Solvent: O
Product: CC(CCl)Cc1ccc(C(C)(C)C)cc1

Procedure:
BF3 is passed for 30 minutes into a mixture of 84 parts by weight of 2-methyl-3-phenyl-propyl chloride and 50 ml of BF3 ·2H2O at room temperature. 56 parts by weight of tert.-butyl chloride are then added dropwise at room temperature. The mixture is refluxed for 4 hours and is then allowed to cool; the crude product is introduced into water and extracted with chloroform. The organic phase is separated off, washed with water, dried over Na2CO3 and distilled. 30 parts by weight of 2-methyl-3-phenyl-propyl chloride, boiling point 105° C./16 mm Hg, and 45 parts by weight of 2-methyl-3-(p-tert.-butylphenyl)-propyl chloride, boiling point 80° C.-81° C./0.02 mm Hg, are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:30])[N:24]=[CH:23][N:22]=1>O1CCCC1.ClCCl>[Cl:20][C:21]1[C:26]([C:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][CH3:12])=[CH:4][CH:3]=2)=[O:28])=[C:25]([Cl:30])[N:24]=[CH:23][N:22]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1ccc(NC(=O)c2c(Cl)ncnc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
4-Amino-N-methylbenzenesulfonamide (244 mg, 1.31 mmol) was dissolved in tetrahydrofuran (12 ml) and triethylamine (402 μl, 2.88 mmol) was added. Then a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (300 mg, 1.42 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dropwise added. After 2 h more triethylamine (202 μl, 1.44 mmol) and 4,6-dichloropyrimidine-5-carbonyl chloride (150 mg, 0.71 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude was purified by flash chromatography (0% to 60%, hexane-ethyl acetate) using a SP1® Purification System to give 238 mg (50% yield) of the title compound. Purity 100%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][NH:15]2)=[C:11]([NH:18][C:19]([C:21]2[N:22]=[C:23]([CH3:26])[S:24][CH:25]=2)=[O:20])[CH:10]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[CH:38][NH:39]3)O1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:39]1[C:40]2[C:36](=[C:35]([C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:18][C:19]([C:21]4[N:22]=[C:23]([CH3:26])[S:24][CH:25]=4)=[O:20])[CH:10]=3)[CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:38]1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)cs1
Temperature: 150 °C
Yield: 36.1 %

Procedure:
2M Sodium carbonate solution (0.059 ml), Pd(dppf)Cl2 (5 mg), and water (1 ml) were added to solution of N-(6-bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (40 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (35 mg) (Frontier Scientific) in 1,4-dioxane (1 ml). The reaction vessel was sealed and heated under microwave irradiation at 150° C. for 15 min. After cooling, water (4 ml) was added, and then the mixture was extracted into DCM (3×10 ml). The organic layers were combined and the solvent evaporated. The residue was dissolved in methanol:DMSO (0.5 ml, 1:1) and purified by mass directed preparative HPLC (Method A) to give title compound (16 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13](=[O:35])[NH:14][O:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:10][C:9]=2[CH:36]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O.O>[C:16]([O:15][NH:14][C:13]([C:11]1[S:10][C:9]2[CH:36]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[CH:12]=1)=[O:35])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc2cc(C(=O)NOC(c3ccccc3)(c3ccccc3)c3ccccc3)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc(C(=O)NOC(c3ccccc3)(c3ccccc3)c3ccccc3)sc2c1
Reaction time: 1.5 h

Procedure:
To a solution of 2-trityloxycarbamoyl-benzo[b]thiophene-6-carboxylic acid methyl ester (4.12 g, 8.35 mmol) in THF/MeOH (50/10 mL) was added 2 N NaOH (16 mL). After 1.5 h, added an additional 5 mL of 3 N NaOH. After another 1 h, added an additional 16 mL of 2 N NaOH, and stirred overnight. The solution was diluted with EtOAc (100 mL) and H2O (100 mL) and washed with EtOAc. The aqueous fractions were acidified with 5% citric acid, and extracted with EtOAc. The combined organic fractions were dried, filtered, and concentrated to yield the desired acid, which was used without further purification. MS (EI): cal'd (M−), 478.1, exp (M−), 478.6.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CI.[H-].[Na+].[C:23](OCC)(=O)C>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:23])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(C)=O
Reactant: Oc1ccc(OCCCCCn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(OCCCCCn2ccnc2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 1.87 g p-[5-(1-imidazolyl)pentyloxy]phenol and 0.46 ml methyl iodide in 18 ml anhydrous N,N-dimethylformamide, was added under ice cooling and with stirring 290 mg of 60% sodium hydride in oil, and stirring was continued at room temperature for five minutes. Ethyl acetate was added to the reaction mixture, the precipitate which separated out was filtered off, and the filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography [chloroform/methanol/28% ammonia water (50:1:0.1)], affording 2.0 g of 1-[5-(1-imidazolyl)pentyloxy]-4-methoxybenzene as oil.
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:15]=2[C:30]=1[Cl:31])=[O:9])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[Cl:31][C:30]1[C:15]2[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])=[N:17][CH2:18][C:19](=[O:22])[N:20]([CH3:21])[C:14]=2[CH:13]=[CH:12][C:11]=1[NH:10][C:8]([NH:7][CH2:6][CH2:5][OH:4])=[O:9]
Reactant: CC(=O)OCCNC(=O)Nc1ccc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(NC(=O)NCCO)c2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
600 mg of 2-[3-[6-chloro-5-(o-fluorphenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]ethyl acetate dissolved in 35 ml of absolute methanol are treated with 830 mg of sodium methylate and stirred at room temperature for 1 hour. The mixture is buffered with a small amount of acetic acid and concentrated. The residue is treated with methylene chloride/10% sodium bicarbonate solution, the aqueous solution is extracted with methylene chloride and the organic solution is dried over sodium sulphate, filtered and concentrated. The residue is purified on a 30 g silica gel column with ethyl acetate/methanol (10:1) as the eluting agent and crystallised from ethanol/ether. There is obtained 1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which, according to the melting point, mixed melting point and IR spectrum, is identical with a sample prepared in another manner (see Example 13).
Reaction SMILES: CN.CN[CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11].C(N)CCC.C(NCCCC)CCC.C(NCC1N=CNC=1C)CCC.C(N(CC1N=CNC=1C)CCCC)CCC.[NH2:54][CH2:55][CH2:56][SH:57].[ClH:58]>>[ClH:58].[ClH:58].[NH2:54][CH2:55][CH2:56][S:57][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11]
Reactant: NCCS
Reactant: CNCc1nc[nH]c1C
Agent: CCCCN(CCCC)Cc1nc[nH]c1C
Agent: CCCCNCc1nc[nH]c1C
Agent: CN
Solvent: CCCCN
Solvent: CCCCNCCCC
Product: Cc1[nH]cnc1CSCCN

Procedure:
By the same procedure, using methylamine in place of dimethylamine, 4-(N-methylaminomethyl)-5-methylimidazole is prepared. In the same way, using butylamine and dibutylamine, 4-(N-butylaminomethyl)-5-methylimidazole and 4-(N,N-dibutylaminomethyl)-5-methylimidazole are prepared. Refluxing these intermediates with cysteamine by the above procedure and treating with hydrochloric acid gives 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:16]1[C:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[NH:22][C:21](=[O:27])[CH:20]=[CH:19]2)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:42][CH2:43][NH:44][C:45](=[O:53])[O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:16]1[C:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[N:22]([CH2:42][CH2:43][NH:44][C:45](=[O:53])[O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:21](=[O:27])[CH:20]=[CH:19]2)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)NCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(ccc(=O)n2CCNC(=O)OCC[Si](C)(C)C)c(-c2ccc(Cl)cc2)c1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-6-(1-tert-butoxy-2-(tert-butyldimethylsilyloxy)ethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one (0.4061 g, 0.812 mmol) in DMF (8.0 mL) was added potassium tert-butoxide (0.137 g, 1.22 mmol) and the mixture stirred for 30 minutes. A solution of 2-(trimethylsilyl)ethyl 2-bromoethylcarbamate (0.327 g, 1.22 mmol) in DMF (1 mL) was added and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was cooled to 0° C., potassium tert-butoxide (0.200 g) was added and the resulting reaction mixture was stirred for 30 minutes. A solution of 2-(trimethylsilyl)ethyl 2-bromoethylcarbamate (0.5 g) in DMF (1 mL) was added and the reaction mixture was warmed to room temperature overnight. Reaction mixture was diluted with ethyl acetate and washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 10 to 50% ethyl acetate/hexanes) to give desired product a yellow foam (0.2725 g). Some O-alkylation side-product was also observed.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[I-].[K+].Cl[CH2:17][C:18]1[N:19]=[C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])[N:23]=[C:22]([S:34][CH2:35][CH3:36])[N:21]2[CH:37]=1>CN(C=O)C>[Cl:33][C:27]1[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:26]=1[C:24]1[N:23]=[C:22]([S:34][CH2:35][CH3:36])[N:21]2[CH:37]=[C:18]([CH2:17][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:19]=[C:20]2[CH:25]=1
Reactant: C1COCCN1
Reactant: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CCl)cn12
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCSc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CN3CCOCC3)cn12
Reaction time: 16 h

Procedure:
102 mg (1.17 mmol) of morpholine are introduced into 7 ml of DMF at 0° C., and 236 mg (0.78 mmol) of triethylamine and a catalytic amount of potassium iodide are added. A solution of 290 mg of 2-(chloromethyl)-7-(2,4-dichlorophenyl)-5-(ethylsulphanyl)imidazo[1,2-c]pyrimidine (Example 91A) in DMF is then slowly added dropwise. The mixture is allowed to reach RT and is stirred at this temperature for a further 16 h. Purification of the crude product by preparative HPLC and drying under high vacuum result in 214 mg (43% of theory) of product.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(=O)([O-])[O-].[Cs+:24].[Cs+].C(=O)=O>O>[C:1]([NH:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O-:18])=[O:17])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cs+:24]
Reactant: O=C(O)CCC(=O)CNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Cs+]
Solvent: O
Product: O=C([O-])CCC(=O)CNC(=O)OCc1ccccc1
Yield: 211.5 %

Procedure:
5-(Cbz-amino)-4-oxopentanoic acid (2.66 g; 10.0 mmol) was added to a stirred solution of caesium carbonate (1.64 g; 5.0 mmol) in de-ionized water (40 mL). After the evolution of CO2 ceased, the mixture was frozen with liquid nitrogen and freeze-dried overnight. 4.2 g (˜100%) product was obtained (pale tan solid). The product was used in 8c without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][CH2:17][S:16](=[O:21])(=[O:20])[CH2:15]1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]=[S:16]1(=[O:21])[CH2:17][CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 100 °C
Yield: 30.9 %

Procedure:
5-Bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-1H-indole-7-carboxamide (0.050 g, 0.134 mmol) and (4-fluorophenyl)boronic acid (0.024 g, 0.174 mmol) was dissolved in a 6:1 solution of 1,4 dioxane (3 mL)/water (0.5 mL) in a 20 mL microwave reaction vessel. Potassium carbonate (0.093 g, 0.670 mmol) was added and the solution was degassed with Nitrogen. PdCl2(dppf)2 (0.017 g, 0.023 mmol) was added and the reaction was heated in a microwave at 100° C. for 20 min. The solution was passed through a StratoSphere SPE PL-Thiol MP SPE column to remove palladium and purified on Gilson preparative HPLC using Acetonitrile/Water with 0.1% TFA. The desired fractions were concentrated, giving 0.016 g (30%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2)#N.P([O-])([O-])(O)=[O:13]>O.C(O)(=O)C.N1C=CC=CC=1.[Ni].O>[NH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:1]=[O:13])=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: O=P([O-])([O-])O
Agent: [Ni]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: O=Cc1ccc2[nH]ncc2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
5-Cyanoindazole (2.32 g) [Hailey etc Synthetic communications, (1997), 27 (7), 1199-1207] was dissolved in a mixture of water (16.7 ml ), glacial acetic acid (16.7 ml ) and pyridine (33.4 ml) under a atmosphere of nitrogen. Sodiun hydrogen phosphate (4.64 g) was added to the mixture followed by raney nickel/ water (2 g/ml). The reaction mixture was heated to 50° C. for 5 hrs and then allowed to cool to room temperature and stirred for 18 hrs. The catalyst was then filtered off and washed with pyridine and water. The pH of the solution was adjusted to 9.0 with sodium carbonate and the product extracted with ethyl acetate (×2). The organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude solid was purified by washing with toluene to afford the title compound as a beige solid (2.36 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: C[C@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Agent: [Na]
Product: COc1cccc(N2CCN(c3ccc(S(=O)(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)c1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-propionic acid, sodium salt and 4-(3-methoxy-phenyl)-piperazine were condensed to give the title compound as a pale red-brown solid, mp=137-139° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)[C:32]([OH:34])=O.[F:50][C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=1[CH:58]([NH2:60])[CH3:59]>CN(C=O)C.C(OCC)(=O)C.O.C(Cl)CCl>[F:50][C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=1[CH:58]([NH:60][C:32](=[O:34])[C:31](=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)[CH2:30][CH2:29][CH2:28][Cl:27])[CH3:59]
Reactant: COc1cc(C=C(CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Reactant: CC(N)c1cc(F)ccc1F
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C=C(CCCCl)C(=O)NC(C)c2cc(F)ccc2F)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
IPEA (1 mL), EDC (320 mg) and HOBT (226 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (250 mg) and 1-(2,5-difluorophenyl)ethylamine (175 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system→ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,5-difluorophenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 30 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,5-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system→ethyl acetate-methanol system) to obtain 140 mg of the title compound as a racemate. The compound (15 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: hexane:ethanol=3:7) to obtain the title optically active substance with a retention time of 25 minutes (6.2 mg; >99% ee) and the title optically active substance with a retention time of 39 minutes (5.8 mg; >99% ee). The physical properties of the compounds are as follows.
Reaction SMILES: O(CC(Cl)=O)C1C=CC=CC=1.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]([O:24][C:25]1[CH:30]=[CH:29][C:28](Cl)=[CH:27][CH:26]=1)=[C:16]2[C:32]([F:35])([F:34])[F:33]>>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:16]2[C:32]([F:34])([F:33])[F:35]
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Agent: O=C(Cl)COc1ccccc1
Product: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccccc1

Procedure:
The title compound was prepared using commercially available 2-phenoxyacetyl chloride in place of 2-(4-chlorophenoxy)acetyl chloride according to the procedure described in Intermediate 7, step c.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:15]([O:17][CH:18]=[CH:19][C:20](Cl)=[O:21])[CH3:16]>C(Cl)Cl>[CH2:15]([O:17][CH:18]=[CH:19][C:20]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[O:21])[CH3:16]
Reactant: CCOC=CC(=O)Cl
Reactant: Nc1ccc(I)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC=CC(=O)Nc1ccc(I)cc1
Reaction time: 5 h
Yield: 55.8 %

Procedure:
To the mixture of 4-iodoaniline (14 g, 64 mmol) and pyridine (10.5 mL, 128 mmol) in methylene chloride (85 mL) was added 3-ethoxy-acryloyl chloride (10 g, 75 mmol). After stirring for 5 hrs, more 3-ethoxy-acryloyl chloride (5 g, 38 mmol) and pyridine (10.5 mL, 64 mmol) was added. After stirring for 2 days, the reaction mixture was washed with water 3×100 mL), dried over MgSO4 and concentrated to give 3-ethoxy-N-(4-iodo-phenyl)-acrylamide as black oil (11.32 g, 56%). LC-MS m/e 318 (MH+).