Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4C=CC=C[CH:32]=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[C:39](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)(C)(C)[CH3:40].CCC(=O)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH:30]([CH2:31][CH3:32])[CH2:39][CH3:40])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCC(=O)CC
Product: CCC(CC)Nc1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Yield: 24 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, intermediate 1j (100 mg, 0.234 mmol), 3-pentanone (33.8 mg, 0.469 mmol) and NaBH(OAc)3 (139.1 mg, 0.657 mmol) yielded 27.8 mg (24%) of intermediate 11a. MS (ESI) 497.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][C:14]1[C:15]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=3)[CH2:23][CH2:24]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Agent: Cl
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Yield: 59.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-fluorobenzoyl chloride (5 g) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride (5 g) described in Preparation Example 52, the title compound (5 g) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]1[N:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:32]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=[CH:40][N:41]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: COC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 44.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) in DMF (4 mL) were added potassium carbonate (110 mg) and methyl 2-chloronicotinate (137 mg) at room temperature, and the mixture was stirred at 100° C. for 48 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][N:7]=1.[Mn]([O-])(=O)(=O)=[O:20].[K+]>CC(C)=O>[C:2]([C:3]1[N:4]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][N:7]=1)([OH:20])=[O:1]
Reactant: O=CN1CCC(CCCn2ccnc2CO)CC1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=CN1CCC(CCCn2ccnc2C(=O)O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
The solution of 4-[3-(2-hydroxymethyl-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde in acetone (63 ml) was cooled to 0° C. and potassium permanganate (5.5 g, 0.035 M) was added portionwise. After complete addition, the reaction was stirred at 0° C. for 2 hrs. The acetone solution was separated by filtration, and the residue was stirred twice with water (50 ml). The aqueous solution was freeze dried to yield 4-[3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde (5.5 g, 83% yield). This product (7.1 g, 0.027 M) in water (26 ml) and 1 N NaOH (26 ml) was heated at 100° C. for 5 hrs. The reaction was adjusted pH 6 and purified on ion-exchange column (Bio-Rex 70) eluted with 0.01 N, 0.02 N, 0.04 N, 0.08 N and 0.1 N HCl solution successively to give 1-[3-(4-piperidinyl)propyl]-1H-imidazole-2-carboxylic acid 1.75 molar hydrochloride 0.65 molar hydrate (4.6 g, 73% yield).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]1=[O:19])=O)C.[BH4-].[Na+]>C1COCC1.CO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH:7]([OH:19])[CH2:8]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CO)C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a stirred solution of 3-Oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (10 g) in a mixture of THF (100 mL) and MeOH (50 mL) was added NaBH4 in 10 lots over 1 h period. At the end of 1 h, TLC analysis (eluant: EtOAC) showed complete consumption of starting material. Removed solvent under reduced pressure, to the residue was added saturated NH4Cl solution (200 mL) and stirred for 1 h at rt. The aqueous layer was extracted with DCM (4×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated the filtrate. The product was purified by silica gel column chromatography (Eluant 8:2 EtOAc/Hexanes) to give 3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (6.6 g, cis/trans mixture). The cis/trans mixture (5 g) was separated on ISCO (Combiflash instrument) on a silica gel column (300 g) by eluting with ethyl acetate in hexanes to get (±)-trans-3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, HRf) and (±)-cis-3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, LRf).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[CH3:13].[H-].[Na+].[C:16]([NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)(OCC)=[O:17].C(O)C>N1C=CC=CC=1>[CH3:13][C:12]1[NH:11][CH:10]=[N:9][C:8]=1[CH2:7][S:6][CH2:5][CH2:4][NH:3][C:16]([NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)=[O:17]
Reactant: CCOC(=O)Nc1nc(C)cs1
Reactant: Cc1[nH]cnc1CSCCN
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1csc(NC(=O)NCCSCc2nc[nH]c2C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To 3.40 g (13.9 mmole) of 4-[(2-aminoethyl)thiomethyl]-5-methylimidazole dihydrochloride stirred under flowing nitrogen in 100 ml of dry pyridine is added 1.27 g (ca. 27.9 mmole) of a 50 percent dispersion in oil of sodium hydride. After approximately 90 min. 24.3 g (13.1 mmole) of 2-carbethoxyamino-4-methylthiazole is added, and the resultant mixture is heated at reflux for 1 day. After cooling to room temperature, the mixture is filtered to remove insolubles, and the filtrate is concentrated at reduced pressure. The resultant gum is repeatedly dissolved in aqueous ethanol and dried in vacuo, triturated with pentane to remove mineral oil, and purified by column chromotography* on silica gel. Fractions containing the product are combined, partially concentrated, filtered and finally dried by concentration in vacuo, giving 2.40 g (7.2 mmole) of the desired product as an ethanol solvate. Structure assignment and solvation by one-half mole of ethanol per mole of product are supported by nmr.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH:18]=[C:19]2[S:23][C:22](=[S:24])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]2=[O:29])[N:17]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:9][C:10](=[S:11])[NH:12][C:13]1[S:14][CH:15]=[C:16]([CH:18]=[C:19]2[S:23][C:22](=[S:24])[N:21]([CH2:25][C:26]([OH:28])=[O:27])[C:20]2=[O:29])[N:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CN1C(=O)C(=Cc2csc(NC(=S)NC(=O)c3ccccc3)n2)SC1=S
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.6 g of benzoyl isothiocyanate were added dropwise, at room temperature, to a solution of 4 g of 5-(2-aminothiazol-4-ylmethylene)rhodanine-3-acetic acid in 70 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 6 hours. then ethyl acetate was added and precipitated solids were filtered off. The ethyl acetate solution was washed with water and concentrated under reduced pressure, and the crystalline solid thus obtained was separated by filtration and recrystallized from acetic acid, giving the title compound as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[C:4]([F:13])[CH:3]=1.[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:12])[CH2:9][OH:10])=[C:4]([F:13])[CH:3]=1
Reactant: CC(C)(C=O)c1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(CO)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of 2-(4-Bromo-2-fluoro-phenyl)-2-methyl-propionaldehyde (1.37 g, 5.58 mmol) in MeOH (18 ml) at 0° C. was added NaBH4 (0.21 g, 5.58 mmol). After being stirred for 2 hours at 0° C., the mixture was allowed to warm to room temperature. The reaction mixture was diluted with water (20 ml) and extracted with ether (3×75 ml). The combined organic layers were dried over MgSO4. The solvent was removed, and the residue was purified by flash column chromatography (15–35% EtOAc in Hexane) to give the product (1.10 g, 80.0% yield). 1H NMR (CDCl3) δ: 1.23 (s, 1 H) 1.35 (s, 3 H) 1.35 (s, 3 H) 3.75 (d, J=1.26 Hz, 2 H) 7.17 (d, J=2.27 Hz, 1 H) 7.20 (d, J=3.03 Hz, 1 H) 7.22 (m, 1 H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][CH:17]([CH2:19][S:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]([CH2:40][OH:41])[CH2:15]1)(=[O:13])=[O:12].[H-].[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.O>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][CH:17]([CH2:19][S:20][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:16]([CH2:40][O:41][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:15]1)(=[O:13])=[O:12]
Reactant: BrCc1ccccc1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CC(CO)C(CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc2ccccc2c1)N1CC(COCc2ccccc2)C(CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 0.17 h
Yield: 60.6 %

Procedure:
To a solution of (3RS,4RS)-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanylmethyl-pyrrolidin-3-yl]-methanol (200 mg, 0.345 mmol) in DMF (2 ml) was added 60% NaH (15.2 mg, 0.379 mmol) at 0° C. and stirred for 10 min. Benzyl bromide (45 μl, 0.379 mmol) was added and stirred for 30 min at 0° C. and for 1 h at room temperature. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried, filtered and evaporated. Flash chromatography (hexane/EtOAc 4:1=>1:1) gave 140 mg (61%) of (3RS,4RS)-1-(naphthalene-2-sulfonyl)-3-benzyloxymethyl-4-tritylsulfanylmethyl-pyrrolidine as a colorless foam, MS: 692 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[N:9]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])[C:8](=[O:22])[CH:7]=1.[Cl:28]N1C(=O)CCC1=O>C(#N)C>[Cl:28][C:7]1[C:8](=[O:22])[N:9]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])[C:10]([CH2:12][OH:13])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc(CO)n1-c1c(F)cccc1F
Solvent: CC#N
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)cc(CO)n1-c1c(F)cccc1F
Reaction time: 1 h

Procedure:
The title compound was prepared by taking 4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2(1H)-one (1.5 g, 3.9 mmol) in acetonitrile (15 mL) and adding to that N-chlorosuccinimide (580 mg, 4.3 mmol). The reaction was stirred at rt for 3 h afterwhich a small amount of additional N-chlorosuccinimide (50 mg, 0.4 mmol) was added to the reaction. Stirring was continued for 1 h. The reaction mixture was filtered through a fritted funnel to obtain the crude material. 1H NMR (400 MHz, DMSO-d6) δ 7.69-7.61 (m, 2H), 7.37-7.31 (m, 3H), 7.17 (dt, J=8.8, 2.0 Hz, 1H), 6.80 (s, 1H), 5.70 (t, J=6.0 Hz, 1H), 5.38 (s, 2H), 4.01 (d, J=6.0 Hz, 2H); ES-HRMS m/z 414.0515 (M+H calcd for C19H13ClF4NO3, requires 414.0520).
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:12]C1C=CC=C(C(OO)=O)C=1.C(Cl)(=O)C(Cl)=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[C:9]([OH:11])[N:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1[nH]ccc2cccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Oc1nccc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In accordance with Scheme 3, the compound of formula X, 1-oxy-7H-[1,7]naphthyridin-8-one can be prepared as follows: The compound of formula IX, 7H-[1,7]naphthyridin-8-one (which can be prepared from commercially available starting product in accordance with literature Chemical & Pharmaceutical Bullentin (1985), 33(2), 626-33) was stirred for about 70 hours at room temperature in chloroform with 3-chloroperbenzoic acid to obtain the compound of formula X. To a suspension of 1-oxy-7H-[1,7]naphthyridin-8-one in dry N,N-dimethylformamide was added drop wise oxalyl chloride at 0° C. After completed addition, the mixture was allowed to warm to room temperature and stirred for about 30 minutes to obtain the compound of formula XI, 2-chloro-[1,7]naphthyridin-8-ol. To a solution of 2-chloro-[1,7]naphthyridin-8-ol in pyridine was added trifluoromethanesulfonic anhydride at about −10° C. The reaction mixture was allowed to warm to room temperature and stirred for about 1 hour to obtain the compound of formula XII, trifluoro-methanesulfonic acid 2-chloro-[1,7]naphthyridin-8-yl ester. Furthermore, the compound of formula XII and a compound of formula R2NH2, for example 2-amnio-4-methylthiazole are dissolved in dry dioxane. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, cesium carbonate and tri(dibenzylideneacetone)dipalladium chloroform complex are added and the reaction mixture is stirred for about 20 hrs at about 130° C. to obtain a compound of formula XIII. The desired compound of formula I can be prepared as follows: To a compound of formula XIII in dry tetrahydrofuran were added tetrakis(triphenylphosphine)palladium and a about 1.0 M solution of diethylzinc in n-hexane. The reaction mixture was heated at reflux for about 1 hour to obtain a compound of formula I.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[CH3:24][S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:24][S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: CSc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccccc2SC)n1
Temperature: 150 °C
Yield: 29.9 %

Procedure:
A solution was prepared using 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol), 2-(methylthio)benzoic acid (0.076 g, 0.463 mmol), HATU (0.176 g, 0.463 mmol), triethylamine (1.0 mL, 13.6 mmol) and anhydrous DMF (10 mL). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.042 g (30% yield) of pure product: MS (ES) m/z 456 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[OH:23])(=[O:4])[CH2:2][CH3:3].[CH3:24][C:25](C)([O-:27])C.[K+].BrCCO>COCCOCCOC>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][OH:27])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: CC(C)(C)[O-]
Agent: OCCBr
Agent: [K+]
Solvent: COCCOCCOC
Product: CCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccccc1C
Reaction time: 2 h
Yield: 13.7 %

Procedure:
A solution of 3-propanoyl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.06 g, 10 mmol) and potassium t-butoxide (1.68 g, 15 mmol) in diglyme (50 ml) was heated to 150°, a solution of 2-bromoethanol (0.85 ml, 12 mmol) in diglyme (25 ml) added dropwise, then the mixture raised to reflux temperature with vigorous stirring. After 1 hour a further portion of 2-bromoethanol (0.85 ml) was added, and reflux continued for 2 hours. The diglyme was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/2-5% methanol) and recrystallisation from aqueous isobutyl alcohol gave 3-propanoyl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline (0.48 g), m.p. 174°-176°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[CH:64]=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[C:62](Br)=[CH:61][C:60]=3[Cl:71])=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[C:60]([Cl:71])=[CH:61][C:62]([C:25]4[CH:26]=[CH:27][C:22]([C:20]5[N:21]=[C:17]([C@@H:12]6[CH2:13][C@H:14]([CH3:16])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:37])[CH:6]([CH3:8])[CH3:7])[NH:18][CH:19]=5)=[CH:23][CH:24]=4)=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[CH:64]=3)=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
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: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
To a solution of [(S)-2-methyl-1-((2S,4S)-4-methyl-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (155 mg, 0.30 mmol) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (180 mg, 0.30 mmol, Preparation 1) dissolved in toluene (1.9 mL) and water (0.33 mL) was added potassium carbonate (210 mg, 1.52 mmol). The reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.036 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce the title intermediate as a brownish solid. (m/z): [M+H]+ calcd for C44H52ClF3N8O, 897.36. found 897.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].I[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH3:11]
Reactant: CCI
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccccc1Br
Yield: 95.2 %

Procedure:
Into a 500-mL round-bottom flask was placed CH3COCH3 (200 mL), 2-bromophenol (10.38 g, 60.00 mmol, 1.00 equiv), iodoethane (28.08 g, 180.04 mmol, 3.00 equiv) and potassium carbonate (33.12 g, 239.64 mmol, 3.99 equiv). The resulting solution was heated to reflux overnight in an oil bath. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). Purification afforded 11.48 g (95%) of 1-bromo-2-ethoxybenzene as a colorless oil.
Reaction SMILES: C(OCCCC)(=O)C=C.[C:10]([O:15][CH3:16])(=O)[C:11](C)=C.[C:17]([O:21][CH2:22][CH2:23][OH:24])(=O)C=C.C(O)(=O)C=C.C(OOC(C)(C)C)(C)(C)C>C(OCCO)CCC>[CH2:10]([O:15][CH2:16][CH2:17][O:21][CH2:22][CH2:23][OH:24])[CH3:11]
Reactant: C=C(C)C(=O)OC
Reactant: C=CC(=O)OCCO
Agent: C=CC(=O)O
Agent: C=CC(=O)OCCCC
Agent: CC(C)(C)OOC(C)(C)C
Solvent: CCCCOCCO
Product: CCOCCOCCO
Yield: 3.7 %

Procedure:
120 g of ethylene glycol monobutyl ether, 120 g of diethylene glycol monoethyl ether, 180 g of the polyether A1) described in example 2 and 100 g of another polyether A1) (i.e., propoxylated trimethylol-propane having an OH number of 56, a viscosity at 25° C. of 500 mPa -s, a molecular weight of 3005 and a functionality of 3) were weighed into a 6 liter reaction vessel equipped with stirring, cooling and heating devices and heated to 155° C. A mixture of 600 g of butyl acrylate, 125 g of hydroxyethyl acrylate and 700 g of methyl methacrylate was then added over a period of 2 hours, while simultaneously adding 42.8 g of di-tert.-butyl peroxide dissolved in 11 g of ethylene glycol monobutyl ether and 11 g of diethylene glycol monoethyl ether to form copolymer A2). Immediately thereafter, a mixture of 256 g of butyl acrylate, 275 g of methyl methacrylate, 162 g of hydroxyethyl acrylate and 56 g of acrylic acid was added over a period of 1 hour, while simultaneously adding 32.2 g of di-tert.-butyl peroxide dissolved in 7 g of ethylene glycol monobutyl ether and 7 g of diethylene glycol monoethyl ether over a period of 1.5 hours to form copolymer A3). After stirring for a further 2 hours at 150° to 155° C., the temperature was reduced to 100° C. and 84 g of dimethylethanolamine and 2700 g of distilled water were added. The resulting aqueous binder dispersion A) had a solids content of 44.5%, an organic solvent content of 4.9%, an acid number of 22 and an OH number of 97.