Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[N:28]=[C:27]([CH:29](Cl)[C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])[CH:26]=[CH:25][CH:24]=1>C1COCC1>[Br:22][C:23]1[N:28]=[C:27]([CH:29]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1cccc(C(Cl)c2cccc(Br)n2)c1
Reactant: c1cncc(Cc2cccnc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(C(c2cccc(Br)n2)C(c2cccnc2)c2cccnc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(pyridine-3-ylmethyl)pyridine (0.700 g, 4.11 mmol) in anhydrous THF (20 mL) @ −78° C. under N2 was added LDA (3.43 mL, 1.8 M) dropwise. The mixture was stirred for 1 hr @ −78° C., and 3-[(6-bromopyridin-2-yl)(chloro)methyl]benzonitrile was added. The reaction was warmed to 0° C., and stirred for 2 hr. The resulting mixture was quenched with saturated aqueous NH4Cl, and extracted 3× with EtOAc. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (1-4% MeOH in CH2Cl2) to give racemic 3-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]benzonitrile. LRMS m/z (M+H) Calcd.: 441.0, found: 441.0. The racemic mixture was separated by ChiralPak AD (40% iPrOH in Hexanes+1 mL/L DEA to 80% iPrOH in Hexanes+1 mL/L DEA over 45 min). The first peak was enantiomer A of 3-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]benzonitrile, and the second peak was enantiomer B of 3-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](Cl)=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:12][C:13]1[C:14]([NH:20][CH2:21][CH3:22])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1.C([O-])(O)=O.[Na+].O>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:12][C:13]2[C:14]([NH:20][CH2:21][CH3:22])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Reactant: CCNc1nc(Cl)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCNc1nc(Cl)ccc1NC(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 5-bromo-2-chloro-3-pyridinecarbonyl chloride (30.0 g, 97.0 mmol) in MeCN (100 mL) was added via cannula to a solution of 3-amino-6-chloro-2-(ethylamino)pyridine (16.6 g, 97.0 mmol) in MeCN (180 mL) containing solid NaHCO3 (14.2 g, 169 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. Water (200 mL) was added and the mixture was stirred for 10 min. The resulting suspension was filtered. The solid was washed with Et2O (50 mL) and concentrated from pyridine solution (3×50 mL) to give the title compound (28.4 g, 75% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][N+:6]([O-:8])=[O:7])[CH3:2].[CH3:10][Si:11](C)([CH3:15])[CH2:12]CO.O>C1C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[N+:6]([CH2:5][C:4]([O:3][CH2:1][CH2:2][Si:11]([CH3:15])([CH3:12])[CH3:10])=[O:9])([O-:8])=[O:7]
Reactant: C[Si](C)(C)CCO
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: c1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOC(=O)C[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a stirred solution of nitroacetic acid ethyl ester (5.0 g, 37.6 mmol) and 2-(trimethylsily)ethanol (7.27 g, 61 mmol) in dry benzene (100 mL) is added titanium tetraisopropoxide (1.05 q, 3.69 mmol) and the mixture is heated at reflux for 1 hour. The solution is cooled to 40° C. and water (2 mL) is added and stirring is continued for 10 minutes at room temperature. The solvents are evaporated and the residue is taken up in dichloromethane and dried over anhydrous magnesium sulfate. The mixture is filtered through a small pad of Celite and the solvent is evaporated. The residue is purified by distillation to give nitroacetic acid, 2-(trimethylsily)ethyl ester (6.10 g, 79%) as a colorless liquid. B.pt. 90°-95° C./0.3 mmHg.
Reaction SMILES: S(O[CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])(C1C=CC(C)=CC=1)(=O)=O.[C:23](=[NH:34])([O-:33])[C:24]1[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:26](=N)[O-:27].[K+].[K+]>CN(C)C=O>[CH2:19]([Si:16]([CH2:17][CH3:18])([CH2:21][CH3:22])[C:15]#[C:14][CH2:13][CH2:12][N:34]1[C:23](=[O:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26]1=[O:27])[CH3:20]
Reactant: CC[Si](C#CCCOS(=O)(=O)c1ccc(C)cc1)(CC)CC
Reactant: N=C([O-])c1ccccc1C(=N)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[Si](C#CCCN1C(=O)c2ccccc2C1=O)(CC)CC

Procedure:
108 g of (4-triethylsilanylbut-3-yn-1-ol) tosylate in 50 ml of dimethylformamide are added to a suspension of 72.3 g of potassium phthalimidate in 450 ml of dimethylformamide.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(O)(C)C.[OH-].[NH4+:51]>C(Cl)Cl>[NH2:51][CH2:45][C@@H:43]([OH:44])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:39])[CH3:37])[NH:13]2)=[O:11])=[N:5]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H](O)CN)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 26 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (43.6 mg, 0.066 mmol), isopropyl alcohol (2 mL), and ammonium hydroxide (1 mL) was microwaved at 130° C. for 15 min. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((R)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (11.4 mg, 26%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H40Cl2F2N6O3+H [(M+H)+]: 677.2580. found: 677.2576.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:27]([O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OC(=O)c1ccccc1
Yield: 97.2 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.2 ml (1.45 mmol) dry triethylamine and 0.175 ml (1.50 mmol) benzoyl chloride. The mixture was refluxed for 30 min., and then evaporated in vacuo. The residue was stirred with water to give 0.54 g (98%) of 1-benzoyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 186° C. 1H-NMR (DMSO-d6): 8.47 (1H, s), 8.2 (2H, m), 7.8 (4H, m).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][CH3:20])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.C=O.[C:23]([BH3-])#N.[Na+]>C(O)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][N:19]([CH3:23])[CH3:20])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: [BH3-]C#N
Reactant: CNC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 1-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N-methylmethanamine (0.148 mmol, 50 mg) and a 37% aqueous formaldehyde solution (0.445 mmol, 33.4 μL) was added sodium cyanoborohydride (0.163 mmol, 10.25 mg). After stirring for 30 minutes, acetic acid was added to adjust the pH of the reaction mixture to neutral. Stirring was continued for an additional hour during which time the pH was maintained neutral by addition of acetic acid. The reaction mixture was concentrated in vacuo. To the residue dichloromethane and 2N sodium hydroxide (aq) solution were added and the organic layer was separated. The aqueous layer was washed twice with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give 1-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N,N-dimethylmethanamine (57 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:14]([O:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:15]
Reactant: CCI
Reactant: O=Cc1ccc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)ccc1C=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
0.80 g of 2-hydroxy-4-(trifluoromethyl)benzaldehyde was dissolved in 8 ml dimethylformamide, and 0.78 g of ethyl iodide and 0.69 g of potassium carbonate were added, and the mixture was stirred at 70° C. for 2 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), 0.60 g of 2-ethoxy-4-(trifluoromethyl)benzaldehyde was obtained.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:21])([F:20])[C:8]([NH:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:9]>>[F:6][C:7]([F:20])([F:21])[C:8]([NH:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:17]=2)[CH2:12]1)=[O:9]
Reactant: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(NC1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Temperature: 25 °C
Yield: 71 %

Procedure:
After cooling chlorosulfonic acid (3.0 ml) to −78° C. under nitrogen, 2,2,2-trifluoro-N-(2,3-dihydro-1H-inden-2-yl)acetamide (500.0 mg, 2.2 mmol) was added and then allowed to warm up to rt. The solution was poured into an ice-water mixture (100.0 ml), followed by an extraction with EtOAc. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was triturated with Et2O to obtain the product as a white solid (510.0 mg, 71% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.93-7.91 (m, 2H), 7.51-7.49 (m, 1H), 6.50 (s, 1H), 4.91-4.83 (m, 1H), 3.52 (dd, J=16.8, 7.3 Hz, 2H), 3.05 (dd, J=17.0, 4.8 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[Se:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:14]([C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[Se:11][S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Sc1ccccc1
Reactant: O=c1c2ccccc2[se]n1-c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1[Se]Sc1ccccc1

Procedure:
Prepared similar to example 1 from 5 g (15,7 mmol) of 2-(4-nitrophenyl)-1,2-benzisoselenazole-3(2H)-one and 1,75 g (15,9 mmol) thiophenol.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH:4]([OH:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:3].CCOCC.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:2]([CH3:3])([C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:1]
Reactant: CCCCCCC(O)C(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCC(=O)C(C)(C)C
Yield: 67 %

Procedure:
2,2-dimethyl-nonan-3-ol, available as a concentrated solution in ether (ca. 0.23 moles, cf. previous procedure), was dissolved in ca. 350 mL CH2Cl2 in a 500 mL round bottom flask. With vigorous stirring and external cooling, pyridinium chlorochromate (PCC, 76.6 g, 0.355 mol) was added slowly. The reaction mixture turned black and began to warm. The reaction was stirred overnight at mom temperature, and the supernatant was decanted from a black sludge which had formed. The sludge was extracted with ca. 40 mL of hexane, which was combined with the CH2Cl2 solution. This mixture was applied directly to a 100 g silica gel column, and eluted first with CH2Cl2/hexane and then with 10% ethyl acetate in hexane to yield 35.8 g crude, green-colored product. This material was rechromatographed; elution with hexane and careful evaporation at 25° C. on a rotary evaporator yielded 26.1 g 2,2-dimethyl-nonan-3-one (67% yield). 1H NMR (500 MHz, CDCl3), δ (ppm): 2.47 (t, 2H), 1.28 (br, 8H), 0.89 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:22]1[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cc1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Product: Brc1ccc(-n2ccc3cc(OCc4ccccc4)ccc32)cc1

Procedure:
In analogy to example 4.6, 5-benzyloxy-indole and and 1-bromo-4-fluoro-benzene were converted to yield 5-Benzyloxy-1-(4-bromo-phenyl)-1H-indole as light brown solid, mp 118° C., MS: 377 (M, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Si:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C.N#N>CN(C=O)C.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.[Cu]I>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:34]#[C:33][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 59.5 %

Procedure:
A solution of (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (5.00 g, 11.1 mmol), TMS-acetylene (7.90 mL, 55.5 mmol) and triethylamine (4.64 mL, 33.3 mmol) in DMF (56 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (1.28 g, 1.11 mmol) and CuI (106 mg, 0.56 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back-extracted two times then the organic phases were combined and dried over Na2SO4. After concentration, the crude material was purified by silica gel chromatography (10-80% EtOAc-hexanes gradient) to afford (2-methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (3.08 g, 6.60 mmol, 59% yield). LCMS-ESI+: calc'd for C25H35N4O3Si: 467.3 (M+H+). Found: 467.1 (M+H+).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[CH2:6]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:19]([OH:25])[C:20](=[NH:24])[O:21]CC)[CH3:7].O1CCCC1>C1(C)C=CC=CC=1>[CH2:6]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:19]1[O:25][C:1](=[O:2])[NH:21][C:20]1=[O:24])[CH3:7]
Reactant: CCOC(=N)C(O)c1c(OCC)ccc2ccccc12
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc2ccccc2c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 3, using a reaction time of 64 hours at room temperature following the cold phosgene perfusion, ethyl 1-(2-ethoxy-1-naphthyl)-1-hydroxymethanecarboximidate hydrochloride (5.0 g., 16.1 mmoles) in 200 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-ethoxy-1-naphthyl)oxazolidine-2,4-dione (0.57 g., m.p. 221°-224° C., m/e 271).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[OH-].[K+].[CH3:14][C:15]([CH3:17])=O>>[CH3:17][C:15]1[CH:14]=[CH:8][C:7]2[CH:6]=[N:5][C:4]([S:10][CH3:11])=[N:3][C:2]=2[N:1]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Product: CSc1ncc2ccc(C)nc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Treat a solution of 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (10 g, 59.1 mmol) in acetone (100 mL) with KOH (3.32 g, 59.1 mmol), stir at RT for 10 min, then concentrate to dryness. Treat the residue with EtOAc, wash with saturated. aqueous NaHCO3, then brine, dry over Na2SO4 and concentrate to obtain 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine. MS (m/z): 192.1 (M+1). Add a solution of methylamine in ethanol (33%, 80 mL) and heat at 110° C. overnight in a pressure tube. Remove the solvent under reduced pressure and purify the crude product by silica gel chromatography (50-100% EtOAc/Hexanes) to obtain the title compound (6.73 g, 65%, over two steps). MS (m/z): 175.1 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:77][N:78]([CH3:82])[CH2:79][CH2:80][NH2:81]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:81][CH2:80][CH2:79][N:78]([CH3:82])[CH3:77])=[O:28])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCN
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
To a mixture of 0.0604 g (0.131 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0172 g (0.197 mmole) of N,N-dimethylethylenediamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0631 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-ethoxy-benzamide (I-219) as a white solid.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36](Cl)(=[O:38])=[O:37])[CH:35]=1>N.CO>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:38])=[O:37])[CH:35]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(F)cc1S(=O)(=O)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 5-Fluoro-2-methylbenzenesulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (2.7 mg). MS m/z 361 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][N:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1)=[O:4].[N:29]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C@H:30]1[C:39](O)=[O:40].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:19][N:18]([CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:39]([C@@H:30]2[CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:38][N:29]2[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:40])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)[CH3:20]
Reactant: CN(C)Cc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)Cc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 57 %

Procedure:
tert-Butyl 3-{N-[(1R)-2-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared according to the procedure described in Preparation V, (2R)-2-amino-1-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-3-(4-chlorophenyl)propan-1-one (0.34 g, 0.85 mmol), Boc-L-Tic-OH (Peptech Corp.) (0.26 g, 0.93 mmol), EDC (0.2 g, 1.0 mmol), HOBT (used in place of HOAT) (Bachem) (0.14 g, 0.93 mmol) and CH2Cl2 (4 mL). The crude compound was purified on a Biotage 40S column (CH2Cl2/MeOH 95:5) to give tert-butyl 3-{N-[(1R)-2-(4-{2-[(dimethylamino)methyl]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate as a white foam (0.32 g). MS m/z: 660 (M+H). Calc'd for C37H46ClN5O4: 660.25.