Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:24][Si](C)(C)C)=[N-].C(O)(=O)C>ClCCl.CO>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:24])=[O:18])=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)O)cc2)CCC1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Yield: 93 %

Procedure:
To a solution of 4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoic acid (15 g, 52 mmol) in dichloromethane (200 mL) and methanol (50 mL), cooled at 0° C., was added in a dropwise manner a 2 M solution of diazomethyl trimethylsilane in hexanes (28 mL, 57 mmol). The reaction mixture was stirred at room temperature for one hour before the addition, at 0° C., of acetic acid (10 mL). The mixture was washed with saturated aqueous sodium bicarbonate solution until the aqueous phase remained basic. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo, yielding the methyl 4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoate as a white crystalline solid (14.8 g, 93%). M.p.=90° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.91 (d, J=7.6 Hz, 2H), 7.74 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 3.84 (s, 3H), 2.38 (br.s, 4H), 2.1-1.9 (m, 1H), 1.85-1.7 (m, 1H), 1.32 (br.s, 9H); LCMS [M-tBu+H]: 250.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13].[OH-].[Na+].O>C(O)C>[CH:14]1([C:12]([CH:11]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(=O)C1CC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C=CC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 39.3 g of 4-cyanobenzaldehyde and 25.2 g of cyclopropyl methyl ketone in 60 ml of aboslute ethanol was added 21 ml of 20% sodium hydroxide solution over a 25 minute period. The mixture was stirred for one hour at room temperature, cooled to 1° C. and 40 ml of cold water added. The solid material was collected by filtration and triturated with 450 ml of methylene dichloride and 150 ml of water at room temperature. The aqueous phase was extracted with methylene dichloride and the combined organic layers dried and concentrated in vacuo. The residue was recrystallized from absolute ethanol to give 45.0 g of 4-cyanophenylvinyl cyclopropyl ketone, m.p. 104° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[S:15][C:14]([N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:13][N:12]=3)=[CH:10][C:4]=2[O:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[O:3][C:4]=3[CH:10]=2)=[N:12][N:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc3[nH]c(=O)oc3c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CNc1nnc(-c2ccc3[nH]c(=O)oc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Yield: 52.7 %

Procedure:
tert-Butyl (S)-1-(5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (130 mg, 205 μmol) in 10 mL DCM was treated with 10 mL TFA for 60 minutes. After removing the solvent, the remaining residue was dissolved in 100 mL EtOAc. The resulting solution was washed with a mixture of aqueous saturated sodium bicarbonate plus 5% 5N NaOH, then twice with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate. Removal of the solvent gave the title compound 6-(5-((S)-2-amino-3-(4(trifluoromethyl)phenyl)propylamino)-1,3,4-thiadiazol-2-yl)benzo[d]oxazol-2(3H)-one as an off-white amorphous solid (47 mgs, 53%). LCMS (API-ES) m/z (%): 436.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 2.78 (dd, J=13.60, 7.53 Hz, 1H) 2.99 (dd, J=13.60, 5.58 Hz, 1H) 3.35-3.40 (m, 1H) 3.40-3.47 (m, 1H) 3.48-3.55 (m, 1H) 7.13 (d, J=8.22 Hz, 1H) 7.48 (d, J=8.02 Hz, 2H) 7.53 (dd, J=8.12, 1.47 Hz, 1H) 7.62 (d, J=7.24 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([CH:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][O:41]C)[CH2:35][CH2:34]4)=[O:32])[CH:25]=3)=[CH:22][C:15]=2[N:14]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([CH:33]4[CH2:34][CH2:35][N:36]([CH2:39][CH2:40][OH:41])[CH2:37][CH2:38]4)=[O:32])[CH:25]=3)=[CH:22][C:15]=2[N:14]=1
Reactant: COCCN1CCC(C(=O)Nc2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)CC1
Solvent: ClCCl
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)C4CCN(CCO)CC4)c3)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-methoxyethyl)piperidine-4-carboxamide (1 eq) in methylene chloride at −78° C. was added 1M borontribromide in methylene chloride (10 eq) and the resulting mixture and the resulting mixture was stirred at −78° C. for 1 h. It was then brought to ambient temperature and stirred for 2 h. LC/MS showed formation of the product. The reaction was quenched with saturated sodium carbonate solution at 0° C. The mixture was concentrated and then brought to pH=9. It was then extracted with ethyl acetate and the organic layer was dried with sodium sulfate and concentrated and purified on preparative chromatography to yield N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-1-(2-hydroxyethyl)-piperidine-4-carboxamide. MS: MH+=573.6.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:11]=[C:10]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[C:9]=1[C:31]1[O:35][N:34]=[C:33]([C:36]([NH:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]2)=[O:37])[CH:32]=1.[Cl-].[NH4+]>O1CCOCC1.O.C(OCC)(=O)C.[Zn]>[C:48]([O:47][C:45]([N:42]1[CH2:41][CH2:40][CH:39]([NH:38][C:36]([C:33]2[CH:32]=[C:31]([C:9]3[C:10]([O:21][C:22]4[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=4)=[CH:11][C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:13][C:8]=3[O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[O:35][N:34]=2)=[O:37])[CH2:44][CH2:43]1)=[O:46])([CH3:49])([CH3:50])[CH3:51]
Reactant: COCCOCOc1cc(OCOCCOC)c(-c2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)no2)c(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COCCOCOc1cc(OCOCCOC)c(-c2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)no2)c(Oc2ccc(N)cc2)c1
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a stirred solution of tert-butyl 4-{[(5-{2,4-bis[(2-methoxyethoxy)methoxy]-6-(4-nitrophenoxy)phenyl}isoxazol-3-yl)carbonyl]amino}piperidine-1-carboxylate (5.3 g, 7.4 mmol) in a mixture of dioxane (100 mL) and water (20 mL) were added portion wise zinc powder (1 g, 14.8 mmol, 2 eq.) and ammonium chloride (3.9 g, 74 mmol, 10 eq.) at 100° C. After stirring for 30 minutes, the reaction mixture was cooled and diluted with ethyl acetate. After washing with 1 M Na2CO3 solution, the organic phase was dried over Na2SO4 and the solvent removed. The crude product was filtered over a small pad of silica gel eluting with hexane/ethyl acetate 3/1 to provide the title compound (4.38 g, 86% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([CH3:19])[CH:13]=[CH:12][C:11]([S:14]([O:17]C)(=[O:16])=[O:15])=[CH:10][CH:9]=1>CC(C)=O>[C:8]1([CH3:19])[CH:9]=[CH:10][C:11]([S:14]([O-:17])(=[O:15])=[O:16])=[CH:12][CH:13]=1.[NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[CH3:8]
Reactant: Nc1ncccn1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC(C)=O
Product: C[n+]1cccnc1N
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 120 °C

Procedure:
1.8 g of 2-aminopyrimidine and 5.6 g of methyl p-toluenesulfonate were fed into a 200 ml three-necked flask and the mixture was stirred under heating on an oil bath at 120° C. for 3 hours. The reaction mixture was cooled to 60° C., to which 100 ml of acetone was added and the resultant mixture was stirred at room temperature for 1 hour. The crystals thus formed were suction-filtered, washed with acetone and dried at room temperature under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[N:12]O)=[C:4]([F:14])[CH:3]=1.[C:15]1([N:21]2[C:25]3([CH2:30][CH2:29]N[CH2:27][CH2:26]3)[C:24](=[O:31])[NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[N:12]2[CH2:29][CH2:30][C:25]3([N:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:22][NH:23][C:24]3=[O:31])[CH2:26][CH2:27]2)=[C:4]([F:14])[CH:3]=1
Reactant: ON=C1CCCc2c(F)cc(Cl)cc21
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCCc3c(F)cc(Cl)cc31)CC2

Procedure:
The title compound, m.p.>250° C. and MS: m/e=414.2 (M+H+) was prepared in accordance with the general method of example 11 from 7-chloro-5-fluoro-3,4-dihydro-1(2H)-naphthalenone oxime and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [N:1]#[C:2][NH2:3].[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:19]=[C:20]2[N:24]([CH3:25])[C:23](SC)=[N:22][C:21]2=[O:28])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6].CC(C)([O-])C.[K+].P(=O)(O)(O)O>C(O)C.O>[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:19]=[C:20]2[N:24]([CH3:25])[C:23]([NH:3][C:2]#[N:1])=[N:22][C:21]2=[O:28])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6]
Reactant: N#CN
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1C
Agent: CC(C)(C)[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN1C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N=C1NC#N
Reaction time: 2.5 h
Yield: 50.6 %

Procedure:
Cyanamide (0.2 g, 4.8 mmols) is added to a solution of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-1,5-dihydro-1-methyl-2-(methylthio)-4H-imidazol-4-one (1.5 g, 3.9 mmols) and potassium tert-butoxide (0.5 g, 4.3 mmols) in ethanol (25 mL) and the mixture is stirred under an inert atmosphere and heated to reflux. After 2.5 hours the mixture is allowed to cool, and is then poured into water (200 mL), acidified with phosphoric acid, and stirred. After half an hour the product is filtered off, washed three times with water, and dried. Recrystallization from acetonitrile gave the 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl-cyanamide (0.7 g), mp 257°-259° C. (dec).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[Si](OCC1[C:32](F)=[C:33]([F:41])[C:34]([F:40])=[C:35]([C:37](=[O:39])C)[CH:36]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:40][C:34]1[C:35]([CH2:37][OH:39])=[CH:36][C:1]2[C:2]([CH3:3])=[N:4][O:5][C:32]=2[C:33]=1[F:41]
Reactant: CC(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c(F)c1F
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1noc2c(F)c(F)c(CO)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of propan-2-one oxime (1.73 g, 23.7 mmol) in THF (25 ml) was added potassium t-butoxide (1M solution in THF, 23.8 mL) at 0° C. under nitrogen atmosphere and the mixture was stirred with warming to room temperature for 1 hour. The mixture was cooled to −78° C. and a solution of 1-(5-((tert-butyldiphenylsilyloxy)methyl)-2,3,4-trifluorophenyl)ethanone (Intermediate 332, 3.0 g, 6.8 mmol) in THF (15 mL) was added to the mixture and stirred for 20 minutes at −78° C. then at −20° C. for 2 hours. The reaction was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated to give material that was used for the next step without any further purification. A stirred solution of the material dissolved in ethanol (130 ml) was treated with 5 ml of 5% aqueous HCl at 45° C. for 8 hours. The reaction quenched with 10% aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer washed with water, dried, and concentrated. The residue was purified over a silica gel flash column (elution with 15-20% EtOAc in hexanes) to give title compound as yellow solid. Yield: 600 mg, (46%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=1.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)=[O:30])=[CH:25][CH:24]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:29]([C:26]4[CH:27]=[N:28][C:23]([Cl:22])=[CH:24][CH:25]=4)([C:31]4[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=4)[OH:30])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[C:18]([Cl:20])[CH:17]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Reactant: COc1cc(-c2cc(Cl)cc(Cl)c2)c2cc(Br)ccc2n1
Product: COc1cc(-c2cc(Cl)cc(Cl)c2)c2cc(C(O)(c3ccc(Cl)nc3)c3cncn3C)ccc2n1
Yield: 39.4 %

Procedure:
Following the same procedure as described in example 1E, 6-bromo-4-(3,5-dichloro-phenyl)-2-methoxy-quinoline (1.88 g, 4.91 mmol) and (6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (0.94 g, 4.27 mmol) generated the title compound of 16C as a yellow solid (0.885 g, 39.5% yield).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][C:9]1[C:10]([Cl:16])=[N:11][C:12]([Cl:15])=[N:13][CH:14]=1>C(O)=O>[Cl:15][C:12]1[N:11]=[C:10]([Cl:16])[C:9]([NH:8][CH:5]=[O:7])=[CH:14][N:13]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1cnc(Cl)nc1Cl
Temperature: 20 °C
Reaction time: 4 h

Procedure:
Acetic anhydride (12 ml) was added to a mixture of 5-amino-2,4-dichloropyrimidine (2.34 g, 14.4 mmol) and formic acid (30 ml) at 0° C. The mixture was stirred at 20° C. for 4 hours, evaporated to dryness and co-evaporated with toluene. The crystalline product was homogeneous on t.l.c. (chloroform-methanol, 15.1) and used without further purification. (2.74 g, 100%). IR: υmax (KBr) 3445, 3350, 3240, 1635, 1570, 1515, 1415 cm-1. 1H NMR δH [(CD3)2SO] 8.45 (1H,s,H.2), 9.40 (1H,s,CH), 10.40 (1H,br.s, NH).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1.[CH2:13]=O.[BH3-][C:16]#[N:17].[Na+]>CO.CC(O)=O>[CH3:13][N:17]([CH3:16])[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(N)cn1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1ccc(N(C)C)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of methyl 2-(5-aminopyridin-2-yl)acetate (800 mg, 4.8 mmol) and paraformaldehyde (578.3 mg, 19.3 mmol) in methanol (20 mL) was added NaBH3CN (1.2 g, 19.26 mmol) and AcOH (1 drop, cat.). The mixture was stirred at room temperature for 12 h. Then, the reaction was quenched with aqueous ammonium chloride and extracted with DCM. The organic layer was with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to get desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][Si:11]([CH2:14][CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(OCC)(=O)C.O.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:8][C:5]1[N:4]=[CH:3][C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:7][N:6]=1
Reactant: COc1ncc(Br)cn1
Reactant: CC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ncc(C#C[Si](C)(C)C)cn1
Temperature: 60 °C
Yield: 98.2 %

Procedure:
To a solution of 5-bromo-2-methoxypyrimidine (500 mg, 2.7 mmol) in ethyl acetate (2 mL) and water (0.2 mL) was added trimethylsilylethane (0.41 mL, 3 mmol), triethylamine (0.75 mL, 5.4 mmol), copper iodide (25 mg, 0.13 mmol) and bis(triphenylphosphine)palladium(II) dichloride (47 mg, 0.067 mmol). The solution was heated to 60° C. for 16 h. Ethyl acetate (100 mL) was added and the solution was washed with water (3×10 mL), dried over MgSO4 and treated with decolorizing charcoal. Ethyl acetate was removed in vacuo to give the title compound as a clear oil (547 mg, 97%). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 2H), 4.01 (s, 3H), 0.24 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]2[C:14]3[C:9](=[C:10]([CH3:18])[C:11]([CH3:17])=[C:12]([O:15][CH3:16])[CH:13]=3)[CH:8]([OH:19])[CH2:7]2)[N:3]=[CH:2]1.[CH2:20](O)[CH3:21]>Cl>[CH2:20]([O:19][CH:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH3:17])[C:10]=2[CH3:18])[CH:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)[CH2:7]1)[CH3:21]
Reactant: COc1cc2c(c(C)c1C)C(O)CC2c1c[nH]cn1
Reactant: CCO
Agent: Cl
Product: CCOC1CC(c2c[nH]cn2)c2cc(OC)c(C)c(C)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1H-imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-ol (cis-isomer, 0.1 g) is dissolved in the mixture of ethanol (20 ml) and concentrated hydrochloric acid (2 ml). The solution is stirred at 25° C. for one hour. Work-up of the reaction mixture gives the crude product, which is purified by flash chromatography using methylene chloride-methanol as eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:37])([F:36])[C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.F[C:39](F)(F)[C:40]1C=C(S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)C=CC=1>>[CH3:12][N:8]([C@@H:9]([CH2:10][CH2:11][CH2:39][CH3:40])[C:13](=[O:15])[NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:36])[F:37])[CH:19]=3)(=[O:25])=[O:26])[CH2:31]2)[CH2:34][CH2:33]1)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Product: CCCC[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norleucine for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step D of Example 252 for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 266: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.44 (d, J=6.9 Hz, 1H), 8.36-8.38 (bs, 1H), 8.19 (d, J=7.9 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 5.0 (m, 0.7H), 4.6 (m, 0.3H), 4.18-4.24 (m, 1H), 3.83-3.86 (m, 1H), 3.13-3.19 (m, 1H), 3.08-3.13 (m, 1H), 2.97-3.10 (bs, 3H), 2.91 (dd, J=9.4, 7.4 Hz, 1H), 2.44-2.59 (m, 2H), 1.98-2.19 (m, 1H), 1.84-1.98 (m, 1H), 1.72-1.85 (m, 2H), 1.47-1.60 (m, 1H), 1.44-1.46 (m, 9H), 1.22-1.34 (m, 1H), 1.15-1.34 (m, 4H), 0.76-0.81 (m, 3H); MS (ESI+) m/z 562 (M+H)+, 579 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH3:20][N:21]([CH2:23][CH2:24][CH2:25]Cl)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:8]([C:7]1[C:2](=[O:1])[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]([CH2:25][CH2:24][CH2:23][N:21]([CH3:22])[CH3:20])[CH:6]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1cc2c(O)c(C(=O)c3ccccc3)cnc2n1
Reactant: CN(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1cc(C(=O)c2ccccc2)c(=O)c2cn(C)nc21

Procedure:
5.1 g. of (4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenylmethanone (0.02 mol.), 4.8 g. of dimethylaminopropyl chloride (0.04 mol.) and 5.6 g. of potassium carbonate (0.04 mol.) are heated in 50 ml. of dimethylformamide at 80° for 12 hours with stirring. The mixture is filtered hot, evaporated to dryness and the residue is recrystallized from ethyl acetate to obtain 5-benzoyl-7-[3-(dimethylamino)Propyl]-2,7-dihydro-2-methyl-4H-pyrazolo[3,4-b]pyridin-4-one, yield 4.6 g. (68%); m.p. 186°-188°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:47]=[CH:46][C:20]([C:21]([N:23]([CH3:45])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)=[O:37])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:56])C=1.C(OCC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:47]=[CH:46][C:20]([C:21]([N:23]([CH3:45])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[S:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:38]4[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]4)=[O:37])=[O:56])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3SCCCCCC(=O)N3CCN(C)CC3)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3S(=O)CCCCCC(=O)N3CCN(C)CC3)cc2)cc1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-ylthio]phenyl]benzamide (500 mg) and m-chloroperbenzoic acid (133 mg) in dichloromethane (20 ml) was stirred in an ice bath for 2 hours and the solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a syrup. The crude product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-ylsulfinyl]phenyl]benzamide (423 mg) as a white powder.
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21](O)=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:25][CH2:26][C:27]#[N:28].C(P(=O)([O-])OCC)#N>ClCCl.C(N(CC)CC)C>[C:26]([CH2:27][NH:28][C:21]([C:20]1[N:19]=[CH:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:9][C:10]=12)=[O:22])#[N:25]
Reactant: N#CCN
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Agent: CCOP(=O)([O-])C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCNC(=O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reaction time: 1.17 h

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 323, 0.203 g), 0.060 g of aminoacetonitrile hydrochloride, and 3 ml of dichloromethane are added 0.23 ml of triethylamine and 0.15 ml of ethyl cyanophosphonate. A slight exotherm ensued. After about 45 min a precipitate formed and an additional 5 ml of dichloromethane are added. When the reaction had stirred for a total of 70 min it is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel (125 ml) eluting with methanol/methylene chloride (2/98), the appropriate fractions are pooled and concentrated to give the title compound, mp 241°-242.5°; MS (m/z) at 350; IR (mineral off) 1641, 1506, 1658, 1409, 1417, 2237 (weak) cm-1 ; NMR (CDCl3) 1.83, 3.31, 4.36, 5.06, 7.12-7.30, 7.40, 7.49, 7.94 δ.