Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[C:11](#[N:14])[CH:12]=C.C(N(C)C)C1C=CC=CC=1>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[CH:12][C:11]#[N:14])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: N#CC=Cc1ccc(Br)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
54.88 g (0.25 mol) of 4-bromobenzoyl chloride, 20.81 ml (0.31 mol) of acrylonitrile and 37.65 ml (0.25 mol) of N-benzyldimethylamine are added to 0.561 g (2.5 millimols) of palladium acetate in 500 ml of p-xylene. The mixture is stirred for 1.5 hours at 120° C. The crude product is distilled and recrystallised from cyclohexanone. 35 g (67% of theory) of 4-bromocinnamonitrile are obtained in the form of white flakes; melting point 105.7° C. Analysis for C9H4NBr: calculated C 51.96%, H 2.91%, N 6.73%, Br 38.40%; found C 51.93%, H 3.01%, N 6.69%, Br 38.35%.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=1)[CH:5]([CH3:7])[CH3:6].Cl>C1COCC1.O>[CH2:4]([C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: CCOC(=O)c1csc(CC(C)C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1nc(C(=O)O)cs1
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (4.1 g) was added to a solution of ethyl 2-isobutylthiazole-4-carboxylate (example 72, step c) (5.2 g) in a mixture of THF (80 mL) and water (20 mL). The resulting mixture was stirred overnight. The reaction was carefully acidified with concentrated hydrochloric acid (10 mL) and the volatiles evaporated. The resulting aqueous mixture was poured into brine (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic solutions were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 3.8 g.
Reaction SMILES: C(O)C.[OH-].[Na+].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH:26]=[C:25]([C:27]([O:29]CC)=[O:28])[CH:24]=[N:23]3)[CH:19]=[C:18]([NH:32][C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)[N:17]=2)[CH3:14])=[CH:9][CH:8]=1>O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH:26]=[C:25]([C:27]([OH:29])=[O:28])[CH:24]=[N:23]3)[CH:19]=[C:18]([NH:32][C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)[N:17]=2)[CH3:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cnn(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-n2cc(C(=O)O)cn2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.7 %

Procedure:
2 ml of ethanol, 1 ml of tetrahydrofuran and 80 μl of 12% sodium hydroxide aqueous solution were added to 35 mg of ethyl (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1H-pyrazole-4-carboxylate, and the mixture was stirred at room temperature for 18 hours. 160 μl of 12% sodium hydroxide aqueous solution was added thereto, and the mixture was further stirred for 3 hours. Ethanol was distilled off. The obtained residue was diluted with ethanol, and diluted with water, and the pH of the mixture was adjusted to 7 by using 10% hydrochloric acid, the mixture was subjected to extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 14 mg of the objective compound as white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]3[C:16]4[C:17]([NH:25]CC5C=CC(OC)=CC=5)=[N:18][CH:19]=[C:20]([C:23]#[N:24])[C:21]=4[S:22][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.[O:35]([Si](C)(C)C)[K]>C1(C)C=CC=CC=1>[NH2:25][C:17]1[C:16]2[C:13]3[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:11][C:12]=3[S:22][C:21]=2[C:20]([C:23]([NH2:24])=[O:35])=[CH:19][N:18]=1
Reactant: C[Si](C)(C)O[K]
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(/C=C/c5ccc(F)cc5)ccc4c23)cc1
Solvent: Cc1ccccc1
Product: NC(=O)c1cnc(N)c2c1sc1cc(/C=C/c3ccc(F)cc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the product of Step 1 in toluene (0.022 M) was added KOSiMe3 (5 equiv). The mixture was brought to reflux for 30 min, and was then stirred at room temperature overnight. Following removal of solvent under vacuum, the residue was partitioned between EtOAc/THF and H2O. The resulting emulsion was filtered, and the organic layer was dried (MgSO4), filtered, and evaporated. The crude was dissolved in TFA (0.022 M), and the resulting solution was stirred at 45° C. for 1.5 h. After removal of the TFA under vacuum, the crude material was purified by flash chromatography, eluting 1:1 EtOAc:hexanes, EtOAc, and 1:30 MeOH:EtOAc. The product was stirred with 1:10 EtOAc:hexanes containing trace acetone to give the title compound, after filtration, as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:23])=[C:17]3[O:22][CH2:21][CH2:20][C:18]3=2)[NH:13][C:12]=1[C:24]([OH:26])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:32]([NH:34]CCC1C2C(Cl)=C3OCCC3=CC=2NC=1C(O)=O)=O)(C)(C)C.C(N(C(C)C)CC)(C)C.Cl.CN.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.CN(C)C=O>[Cl:23][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[C:12]([C:24](=[O:26])[NH:34][CH3:32])[NH:13]2)=[C:18]2[CH2:20][CH2:21][O:22][C:17]=12
Reactant: CC(C)(C)OC(=O)NCCc1c(C(=O)O)[nH]c2cc(Cl)c3c(c12)CCO3
Reactant: CC(C)(C)OC(=O)NCCc1c(C(=O)O)[nH]c2cc3c(c(Cl)c12)OCC3
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)c1[nH]c2cc(Cl)c3c(c2c1CCNC(=O)OC(C)(C)C)CCO3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of a mixture (1.85 g) of 8-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-chloro-1,6-dihydro-2H-furo[3,2-e]indole-7-carboxylic acid and 7-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-chloro-3,5-dihydro-2H-furo[2,3-f]indole-6-carboxylic acid, and diisopropylethylamine (4.16 mL), methylamine hydrochloride (988 mg), and N,N-dimethyl formamide (37.0 mL) was added 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.77 g), followed by stirring at room temperature overnight. To the mixture was added water under ice-cooling, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain a yellowish brown solid. This was purified by silica gel column chromatography (toluene:chloroform:methanol=5:4:0 to toluene:chloroform:methanol=50:40:6) to obtain tert-butyl {2-[4-chloro-7-(methylcarbamoyl)-1,6-dihydro-2H-furo[3,2-e]indol-8-yl]ethyl}carbamate (213 mg) of a high-polarity fraction as a compound of Preparation Example 26. Further, the low-polarity fraction was concentrated under reduced pressure and the obtained residue was solidified with ethanol to obtain a yellow solid of tert-butyl {2-[8-chloro-6-(methylcarbamoyl)-3,5-dihydro-2H-furo[2,3-f]indol-7-yl]ethyl}carbamate (750 mg) as a compound of Preparation Example 66 as shown in the table below.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]=[C:5]1Cl)=[O:3].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]#[CH:22])=[CH:14][C:13]=1[NH:23][NH:24]C=O.C(N(CC)CC)C.O>C(#N)C>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]#[CH:22])=[CH:14][C:13]=1[N:23]1[C:2](=[O:3])[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=[N:24]1
Reactant: O=C(Cl)N1CCCC=C1Cl
Reactant: C#CCOc1cc(NNC=O)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: C#CCOc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Reaction time: 1 h

Procedure:
N-Chlorocarbonyl-2-chloro-1,4,5,6-tetrahydro-pyridine (4.32 g, 0.024 mol) dissolved in 20 ml acetonitrile are added to a stirred suspension of formic acid N'-(2,4-dichloro-5-(2-propinyloxy)-phenyl) hydrazide (5.18 g, 0.02 mol) in 250 ml acetonitrile at 0°-10° C. for 20 minutes. This is then reacted at the same temperature with triethylamine (4.04 g, 0.04 mol) and dissolved in 20 ml acetonitrile. This is stirred for one hour at 5°-10° C. and a colourless precipitate precipitates out. This is heated for 4 hours to 50°-55° C. and then stirred for one night at room temperature. The batch is reacted with 30 ml 6N hydrochloric acid and stirred for 1 hour at 50° C. The solvent is drawn off under reduced pressure and the residue digested with iced water. The resultant pale grey precipitate is separated by filtration, washed with water and dried at 50°-60° C. Yield: 6.6 g (=97.6%) Melting point: 160°-162° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:34]=1[NH2:35]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:33]=3[F:32])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1ccc(F)c(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 88 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.070 g, 0.160 mmol) obtained in step 2 and 2-fluoro-5-methylaniline (0.030 g, 0.240 mmol), the title compound (0.074 g, 87%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Cc1cc2c(cc1-c1ccc(N)nc1)CCO2
Reactant: O=C(Cl)c1ccccc1F
Product: Cc1cc2c(cc1-c1ccc(NC(=O)c3ccccc3F)nc1)CCO2
Yield: 74.2 %

Procedure:
Similarly, (2-fluorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (163) (15.5 mg, yield: 74.2%, purity>95%) was prepared from 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (161) (13 mg, 0.06 mmol) and 2-fluorobenzoyl chloride (21 μl).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>COC(C)(C)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a stirred solution of (S)-1-benzyl-3-pyrrolidinol (44.3 g, 0.25 mol) and 1,4-diazabicyclo[2.2.2]octane (33.7 g, 0.3 mol) in 250 mL of tert-butyl methyl ether under an atmosphere of nitrogen at 0° C., was added p-toluenesulfonyl chloride (52.4 g, 0.275 mol) portionwise over 20 min. The reaction mixture was stirred at 0° C. for 1 h. The ice bath was then removed and the mixture was stirred at ambient temperature overnight (20±5 h). Ethyl acetate (100 mL) was then added, followed by saturated aqueous sodium bicarbonate solution (250 mL). The resulting mixture was stirred at ambient temperature for 1 h. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (250 mL); saturated aqueous ammonium chloride solution (250 mL); saturated aqueous sodium chloride solution (250 mL); and then dried over sodium sulfate (80 g). The sodium sulfate was filtered off and washed with ethyl acetate (20 mL) and the solvent was removed in vacuo to give 78.2 g of the title intermediate (94% yield; 95% purity by HPLC Method A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:26])[C:5]([CH:8]([N+:23]([O-])=[O:24])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1.CN(C)C=O.O.N([O-])=O.[Na+].[Cl-].[NH4+]>O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:26])[C:5]([C:8](=[N:23][OH:24])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:20])([F:19])[F:21])=[N:6][CH:7]=1
Reactant: O=C(NCC(c1ncc(Br)cc1Cl)[N+](=O)[O-])c1ccccc1C(F)(F)F
Agent: O=N[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=NO)c1ncc(Br)cc1Cl)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
To 6.0 g of N-[2-(5-bromo-3-chloropyridin-2-yl)-2-nitroethyl]-2-(trifluoromethyl)benzamide in 65 ml of a mixture of N,N-dimethylformamide-water (7:1), 6.4 g of sodium nitrite was added, and the mixture was stirred at 60° C. for 18 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, poured into 100 ml of water, mixed with 20 ml of saturated aqueous ammonium chloride and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 6:4) as the eluent to obtain 3.1 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH3:26])[CH3:16]>C(Cl)CCl>[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:8]([C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:11]([OH:10])=[O:12])=[O:9])=[C:18]1[CH3:26])[CH3:16]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCn1c(C)cc2ccccc21
Solvent: ClCCCl
Product: CCn1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2C(=O)O)c2ccccc21
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A solution of 67.2 g (0.4 mole) of 4-nitrophthalic anhydride and 63.0 g (0.32 mole) of 80.6 percent active 1-ethyl-2-methylindole in 50 ml of ethylene dichloride was heated at reflux for two hours. The reaction mixture was then allowed to cool to room temperature. The yellow precipitate which separated was collected by filtration, washed with fresh ethylene dichloride and dried to obtain 64.5 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-5-nitrobenzoic acid (Formula VIII: R0 =R2 =R3 =Y1 =H; R1 =NO2 ; R5 =CH3 ; R6 =CH2CH3) having a melting point of 203°-204° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([CH2:34][CH3:35])([C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH3:29])/[C:9]1=[O:36])=O)(C)(C)C.[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:53])=[C:42]([CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47])[CH:43]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:36])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([CH2:28][CH3:29])([C:30]([O:32][CH3:33])=[O:31])[CH2:34][CH3:35])[CH2:47][C:46](=[O:48])[NH:45][CH:44]3[C:42]3[CH:43]=[C:38]([Cl:37])[CH:39]=[CH:40][C:41]=3[CH3:53])[C:11]2=[CH:12][CH:13]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)C(=O)OC
Reactant: C=C(N=Cc1cc(Cl)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OC
Yield: 19.4 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-3-[5-chloro-2-(1-methoxycarbonyl-1-ethyl-propoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (2.63 g, 4.9 mmol) prepared in Example 62f was reacted with 1-(5-chloro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (20 mmol) prepared in Example 13b in toluene (20 mL) to give the title compound as a white solid (600 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>O1CCCC1>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(CN)CO
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCC(C)(C)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 32.2 g (0.31 mol) of 3-amino-2,2-dimethyl-propan-1-ol in 60 ml tetrahydrofuran was added dropwise to a solution of 25 g of diketene (0.30 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 150 ml of ethyl acetate. This gave 40.6 g (0.21 mol, 73% yield) of a colorless solid.
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[C:11]([OH:13])=O.[C:14]1([CH2:20][O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][C@H:28]([C:30]([OH:32])=[O:31])[NH2:29])=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:29][C@@H:28]([C:30]([OH:32])=[O:31])[CH2:27][CH2:26][CH2:25][NH:24][C:22]([O:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:23])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Product: O=C(NCCC[C@@H](NC(=O)c1ccc2ccccc2c1)C(=O)O)OCc1ccccc1
Yield: 73 %

Procedure:
Prepared analogously to Example 4a) from 2-naphthalene carboxylic acid and (R)-N5 -(phenylmethoxycarbonyl)-ornithine in a yield of 73% of theory. Colourless crystals, Mp. 155-157° C.
Reaction SMILES: C1COCC1.B.C1COCC1.[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH2:31][CH2:32][CH3:33])=[CH:27][CH:28]=4)[C:23](=[O:34])[CH:22]=3)=[CH:20][C:15]=2[O:14][CH2:13]1.CCN(CC)CC>CO>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C@H:21]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH2:31][CH2:32][CH3:33])=[CH:27][CH:28]=4)[C:23](=[O:34])[CH2:22]3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CCCOc1ccc2c(c1)C(=O)C=C2c1ccc2c(c1)OCO2
Agent: B
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCOc1ccc2c(c1)C(=O)C[C@H]2c1ccc2c(c1)OCO2
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A 250 mL three-necked flask equipped with air driven stirrer and 250 mL addition funnel was charged with anhydrous THF (50 mL) and (R)-MeCBS (1.6 mL, 1 M, 1.6 mmol). The solution was cooled to −15° C. and BH3-THF (32.4 mL, 1 M, 32.4 mmol) added in a steady stream. Charge the 250 mL addition funnel with 3-(1,3-Benzodioxol-5-yl)-6-propoxy-1H-inden-1-one (10 g, 32.4 mmol) and anhydrous THF (50 mL) and add the solution dropwise over 1.5 h period while maintaining the internal reaction temperature between −10 to −15° C. Upon complete addition, stir the reaction mixture for 0.5 h at −15° C., cool the solution to −25° C. and add CH3OH (20 mL) dropwise over 20 minutes while maintaining the internal reaction temperature below −15° C. Warm the solution to 20° C. over 0.5 h and stir the solution for an additional 0.5 h at ambient temperature. Cool the solution to 0° C. and add Et3N (1 mL, 81 mmol) to the reaction mixture dropwise over 15 minutes while maintaining the internal reaction temperature below 5° C. Add 1,1-bis(triphenylphosphine) nickel(II) chloride (211 mg, 3.24 mmol) and warm the reaction mixture to 60° C. for 4 h. Concentrate the solution to 1/4 volume, cool to room temperature, add Celite (12 g) and then hexanes (85 ml). Stir the mixture vigorously for 10 min and filter through a SiO2 (10 g) and Celite (10 g) pad. Wash the filter pad with THF/hexane (45 mL/120 mL), combine the filtrates, and transfer to a 500 mL round-bottomed flask. Concentrate the solution in vacuo until a precipitate forms, add hexane (40 mL) and cool the solution to −15 CC for 8 h. Filter the precipitate, wash the filter cake with cold (0° C.) hexane solution and dry under vacuum to afford (S)-3-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-inden-1-one as a light yellow solid (8.1 g, 81%, 88% e.e.): mp 68.0-69.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.COCCOC>[Cl:33][C:34]1[N:39]=[CH:38][C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Brc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2ccccn2)cn1
Yield: 87 %

Procedure:
2-bromopyridine (7.0 g, 44.0 mmol), palladium acetate (0.5 g, 2.2 mmol), triphenylphosphine (2.5 g, 9.5 mmol), potassium carbonate (37.0 g, 267.0 mmol), 1,2-dimethoxyethane (60 g) and water (80 g) were added to the resultant 6-chloro-3-pyridyl boronic acid (6.9 g, 44.0 mmol), and the reaction mixture was stirred, and then refluxed with heating for 6.0 hours. Reaction solution was cooled, and then ethyl acetate (50 g) was added, the reaction solution was stirred for 1.0 hour, and was left to stand to separate organic layer. Organic layer was washed with 10% by weight of aqueous solution of ammonium chloride (20 g), 10% aqueous solution of ammonia (20 g), 10% aqueous solution of sodium chloride (20 g), and then condensed under reduced pressure to obtain 6-chloro-3,2′-bipyridine (7.0 g, 38.3 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([C:19]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]4[C:20]=3[CH:21]=[CH:22][N:23]4S(C3C=CC(C)=CC=3)(=O)=O)[N:11](C)[C:12](=O)C(F)(F)F)=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(C)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)N(C)C(=O)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#N>>[CH3:28][C:27]1[C:19]([CH:10]([NH:11][CH3:12])[C:8]2[NH:7][C:6]3[CH:48]=[CH:49][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)=[C:20]2[C:24](=[C:25]([CH3:29])[CH:26]=1)[NH:23][CH:22]=[CH:21]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)N(C)C(=O)C(F)(F)F)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)N(C)C(=O)C(F)(F)F)c(C)cc(C)c32)cc1
Product: CNC(c1nc2cc(C#N)ccc2[nH]1)c1c(C)cc(C)c2[nH]ccc12

Procedure:
The title compound was synthesized from a mixture of (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoro-N-methylacetamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoro-N-methylacetamide as described in Example 64-B and 64-C. 1H NMR (TFA salt, 400 MHz, ACETONITRILE-d3) δ ppm 9.52 (br. s, 1H) 8.00 (s, 1H) 7.54-7.62 (m, 2H) 7.16 (s, 1H) 6.98 (s, 1H) 6.33 (s, 1H) 6.06 (s, 1H) 2.68 (s, 3H) 2.55 (s, 3H) 2.49 (s, 3H). HRMS calcd. for C20H19N5 (M+H)+ 330.1713. found 330.1716.