Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][SiH2]C(C)(C)CCC)[CH:5]=[CH:4][C:3]=1[C:16]#[C:17]I.[Cu](C#N)[C:20]#[N:21].[Br-].[Li+].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:16]#[C:17][C:20]#[N:21]
Reactant: N#C[Cu]C#N
Reactant: CCCC(C)(C)[SiH2]Oc1ccc(C#CI)c(F)c1
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC#Cc1ccc(O)cc1F

Procedure:
To a solution of 25 mmol of 1-(2-fluoro-4-dimethylbutylsilyloxyphenyl)-2-iodoethyne in 50 ml of tetrahydrofuran were added copper cyanide and lithium bromide and the solution was reacted under reflux heating for 3 hours. After completion of the reaction, the solution was poured into a hydrochloric acid solution of ferric chloride and extracted with toluene. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 20 mmol of 2-fluoro-4-hydroxyphenylpropiolonitrile as a colourless solid.
Reaction SMILES: B(F)(F)F.[C:5]([OH:8])(=O)[CH3:6].[C:9]1([CH2:15][C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:9]1([CH:15]([C:5](=[O:8])[CH3:6])[C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: FB(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C(C(C)=O)c1ccccc1
Reaction time: 2.5 h

Procedure:
Boron trifluoride-acetic acid (36%, 34.8 grams) was added with stirring dropwise to a solution of phenylacetone (4.46 grams), acetic anhydride, and para-toluenesulfonic acid (0.6 grams) in a water bath at room temperature. After stirring over night, a solid precipitate formed which was collected and washed with water and then refluxed in 100 ml water and sodium acetate (9.0 grams) for 2-3 hours. The original reaction mixture was also heated with 200 ml water and sodium acetate (13.5 grams) for the same period. Both mixtures were separately extracted with ether and then washed with saturated sodium bicarbonate solution to remove any acid. The ether portions were dried and then evaporated in vacuo leaving an oil which solidified, yield 1.4 grams, m.p. 40°-52° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[NH2:40]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:40][C:33]4[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:32]=4[O:31][CH3:30])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)c(OC)c1
Yield: 53 %

Procedure:
The title compound was prepared in 53% yield from compound (10) and 2,4-dimethoxyphenylamine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.50 (s, 9H), 1.69 (s, 9H), 3.83 (s, 3H), 3.87 (s, 3H), 6.52 (dd, J=2.52, 8.51 Hz, 1H), 6.56 (d, J=0.95 Hz, 1H), 6.57 (d, J=2.52 Hz, 1H), 6.66 (br s, 1H, NH), 7.43 (m, 1H), 7.67 (d, J=8.83 Hz, 1H), 7.82 (m, 1H), 8.20 (d, J=0.95 Hz, 1H), 8.43 (d, J=0.95 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:17][CH:16]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCCN2CCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCN2CCCC2)cc1

Procedure:
A mixture of 1-[2-(4-nitrophenoxy)ethyl]pyrrolidine (from Combi-Blocks, LLC, 5.00 g, 0.0212 mol) in 100 mL of MeOH was hydrogenated in the presence of 0.5 g 10% Pd/C, under balloon pressure of hydrogen, overnight. After filtering off the catalyst, the filtrate was evaporated to dryness and used directly in next step (4.36 g, 99.88%). LCMS (M+H) 207.4.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([OH:15])=O)[C:8]2[C:3]1=[N:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:6][CH:7]=2.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C)C=O>[CH3:1][N:2]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:15])[C:8]2[C:3]1=[N:4][C:5]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[N:6][CH:7]=2
Reactant: Nc1ccccc1
Reactant: Cn1c(=O)n(CC(=O)O)c2cnc(-c3ccccc3)nc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(CC(=O)Nc2ccccc2)c2cnc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A mixture of 8,9-dihydro-9-methyl-8-oxo-2-phenyl-7H-purin-7-acetic acid (3 g) obtained in Example 48-(2), aniline (1.3 g), BOP reagent (5.1 g), triethylamine (1.2 g) and dimethylformamide (20 ml) is stirred at room temperature for two hours. To the reaction mixture is added water, and the precipitates are collected by filtration, and washed with water to give crude 8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide (3.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12].C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)CNc1ccnc(Cl)n1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
2,4-Dichloropyrimidine (25 g, 0.16 moles) and 2,2-dimethyl-propylamine (25 ml, 0.21 moles) are dissolved in 250 ml of THF and K2CO3 (33.1 g, 0.24 mmoles) is added at rt. The mixture is refluxed at rt for 8 h. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesum sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 22 g of desired (2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine in 67% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH:18]=O)[CH3:13].Cl>CO>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:13]
Reactant: O=C1COc2cc(O)ccc21
Reactant: CCOc1ccc(C=O)cc1OCC
Agent: Cl
Solvent: CO
Product: CCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OCC
Temperature: 25 °C

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,4-diethoxybenzaldehyde 1.58 ml were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.27 g.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35]>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][NH:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CN(C)CCN
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CNCCN(C)C)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and N1,N1-dimethylethane-1,2-diamine.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OC([C:17]2[CH2:18][CH2:19][O:20][CH2:21][CH:22]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:8][C:3]1[C:2]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC1(C)OC(C2=CCOCC2)OC1(C)C
Reactant: Fc1ncccc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ncccc1C1CCOCC1
Yield: 51.1 %

Procedure:
A mixture of 3-bromo-2-fluoro-pyridine (500 mg, 2.84 mmol), 4-(4,4,5,5-Tetramethyl-[1,3]dioxolan-2-yl)-3,6-dihydro-2H-pyran (656 mg, 3.12 mmol), K3PO4 (1.2 g, 5.68 mmol), and Pd (dppf)Cl2 (208 mg, 0.284 mmol) in 1,4-Dioxane/H2O (5:1) (30 mL) was heated to reflux overnight under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated and purification by prep-TLC to give 2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine (260 mg, 1.45 mmol, 51.2%).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(SC)ccc1C(=O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CSc1ccc(C(=O)O)c(O)c1
Temperature: -65 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
2-Methoxy-4-(methylthio)benzoic acid (1.002 g, 5.05 mmol) was dissolved in dichloromethane (18 mL). The solution was cooled to −65° C. in a dry ice/chloroform bath. A dichloromethane solution of boron tribromide (5.4 mL, 5.4 mmol) was then added slowly. After 3 hours, the reaction was quenched with water (5 mL) and 1 N HCl (10 mL). After stirring for 10 minutes, the reaction was extracted with dichloromethane (100 mL). The organic layer was washed with 1 N HCl (10 mL) and then dried over magnesium sulfate, filtered, and concentrated to give the pure product as a pale yellow solid (866 mg, 4.70 mmol, 93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[CH:14][N:13]=2)=[O:10])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].C([Sn](CCCC)(CCCC)[C:33]1[CH:38]=[CH:37][N:36]=[N:35][CH:34]=1)CCC>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.CN(C=O)C>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:38]=[CH:37][N:36]=[N:35][CH:34]=3)=[C:3]([C:24]([F:27])([F:26])[F:25])[CH:4]=2)=[N:13][CH:14]=1
Reactant: O=C(Cc1ccc(Br)c(C(F)(F)F)c1)Nc1ccc(-c2cnccn2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccnnc2)c(C(F)(F)F)c1)Nc1ccc(-c2cnccn2)cn1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a reaction tube containing 2-(4-bromo-3-(trifluoromethyl)phenyl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 118-1 (53 mg, 0.12 mmol), 4-(tributylstannyl) pyridazine (54 mg, 0.14 mmol) and Pd(PPh3)4 (14 mg, 0.012 mmol) under argon was added DMF (0.6 mL). The mixture was stirred at 120° C. for 10 hours. The crude product, which was a solution, was subjected directly for reverse phase HPLC to give N-(5-(pyrazin-2-yl)pyridin-2-yl)-2-(4-(pyridazin-4-yl)-3-(trifluoromethyl)phenyl)acetamide 118 as white solid. MS m/z 437.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.14 (s, 1H), 9.35 (dd, 2H), 9.31 (d, 1H), 9.27 (s, 1H), 9.12 (d, 1H), 8.72 (dd, 1H), 8.62 (d, 1H), 8.52 (dd, 1H), 8.23 (d, 1H), 7.95 (s, 1H), 7.82-7.75 (m, 2H), 7.52 (d, 1H), 4.00 (s, 2H).
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]2[CH:8]=[C:9]([N:13]3[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]4[C:22]5[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=5[CH:28]=[CH:29][C:14]3=4)[CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1.[CH3:30]N1C(C2C=C(N3C(=O)CC(=O)NC4C5CCCCC=5C=CC3=4)C=CC=2)=NN=N1>>[CH3:30][N:4]1[N:3]=[N:2][C:6]([C:7]2[CH:8]=[C:9]([N:13]3[C:19](=[O:20])[CH2:18][C:17](=[O:21])[NH:16][C:15]4[C:22]5[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=5[CH:28]=[CH:29][C:14]3=4)[CH:10]=[CH:11][CH:12]=2)=[N:5]1
Reactant: Cn1nnnc1-c1cccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)c1
Reactant: O=C1CC(=O)N(c2cccc(-c3nnn[nH]3)c2)c2ccc3c(c2N1)CCCC3
Agent: [Na]
Product: Cn1nnc(-c2cccc(N3C(=O)CC(=O)Nc4c3ccc3c4CCCC3)c2)n1

Procedure:
5-[3-(1H-Tetrazol-5-yl)phenyl]-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione sodium salt (40 mg, 0.10 mmol) obtained in Example 2 was used in a process similar to Example 6 to give 5-[3-(2-methyl-2H-tetrazol-5-yl)phenyl]-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione as slightly brown crystal (18 mg, yield 46%) and 5-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione as slightly brown crystal (3 mg, yield 8%).
Reaction SMILES: [C:1](=[N:14][OH:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:26]=[C:27]([C:32]3([O:38][CH3:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:28]=[C:29]([F:31])[CH:30]=2)=[CH:20][CH:19]=1>>[F:31][C:29]1[CH:28]=[C:27]([C:32]2([O:38][CH3:39])[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH:26]=[C:25]([S:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][O:15][N:14]=[C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:19][CH:20]=2)[CH:30]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(CCl)cc3)c2)CCOCC1
Reactant: ON=C(c1ccccc1)c1ccccc1
Product: COC1(c2cc(F)cc(Sc3ccc(CON=C(c4ccccc4)c4ccccc4)cc3)c2)CCOCC1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 1, benzophenone oxime was reacted with 4-[3-(4-chloromethylphenylthio)-5fluorophenyl]-4-methoxytetrahydropyran to give benzophenone O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzyl}oxime as an oil in 44% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6](O)=[O:7])[CH3:2].S(Cl)([Cl:18])=O>>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]([Cl:18])=[O:7])[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(C(=O)O)C1CCCCC1
Product: CCOC(=O)C(C(=O)Cl)C1CCCCC1

Procedure:
A solution of 2-cyclohexyl-malonic acid monoethyl ester (2.9 g, 14 mmol; CAS Reg. No. 147596-63-2) in thionyl chloride (29 ml) was heated under reflux conditions for 2 h. The solvent was removed under reduced pressure to give chlorocarbonyl-cyclohexyl-acetic acid ethyl ester. 1,2,3-Benzotriazole (1.47 g, 12 mmol) was dissolved at ambient temperature under an argon atmosphere in CH2Cl2 (45 ml). Et3N (1.86 ml, 13 mmol) and a solution of chlorocarbonyl-cyclohexyl-acetic acid ethyl ester in CH2Cl2 (4 ml) was added. The reaction mixture was stirred at ambient temperature for 14 h, quenched with ice cold aqueous 2 N HCl and extracted two times with iPrOAc. The combined extracts were washed with ice water/1 N aqueous HCl solution, ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (1.05 g, 3.3 mmol; 25%) as yellow oil. MS: m/e=316.2 [M+H+].
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>O>[Cl:11][C:8]1[CH:9]=[N:10][C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: O
Product: COc1ccc(CNc2ncc(Cl)cc2C(=O)O)cc1
Temperature: 150 °C

Procedure:
A mixture of 2,5-dichloronicotinic acid (30.0 g) and 4-methoxybenzylamine (41.0 ml) was heated at 150° C. under nitrogen for 2 hours. The mixture was cooled to ambient temperature, dissolved in boiling water, acidified to pH 6 and filtered. The collected solid was dried, boiled up with IMS, then filtered to give 5-chloro-2-(4-methoxybenzylamino)nicotinic acid, m.p. 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:33][O:34]CC[Si](C)(C)C)[C:9](=[O:32])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C@H:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12](=[O:27])[N:11]3[CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:5]2=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:33][OH:34])[C:9](=[O:32])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C@H:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12](=[O:27])[N:11]3[CH2:28][CH:29]3[CH2:30][CH2:31]3)[C:5]2=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(c3ccc(Cl)cc31)[C@@H](c1cccc(Cl)c1)C[C@H](CC(=O)O)C(=O)N2CC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)N(CO)c3cc(Cl)ccc32)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of (rac) 2-((2′S,3′R,5′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-2,6′-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-5′-yl)acetic acid (Example 62, Step K) (47 mg, 0.078 mmol) in DCM (0.8 mL) at room temperature was added 0.2 mL TFA. The reaction mixture was stirred at room temperature for 19 h before concentrating under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 50 to 100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:3]12.[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.Cl>CN(C)C=O.O1CCOCC1>[CH:28]1([CH2:27][N:8]2[CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]3[CH2:13][CH2:14][NH:15][CH2:16][CH:3]3[C:2]2=[O:1])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3CNC(=O)C2C1
Reactant: BrCC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C1C2CNCCN2c2ccccc2CN1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate (100 mg, 0.315 mmol, Example 1) in anhydrous N,N-dimethylformamide (2 mL) was added sodium hydride (13.86 mg, 0.347 mmol). After stirring for 1 hour at room temperature, (bromomethyl)cyclopropane (102 mg, 0.756 mmol) was added to the reaction mixture. The reaction was stirred for 20 hours. The reaction was then quenched carefully with water and extracted with ethyl acetate. The organic layer was separated, dried with MgSO4, and concentrated. The residue was purified via flash chromatography (0-40% ethyl acetate/hexanes). The material obtained was dissolved in 1,4-dioxane (0.8 mL) and 4 M HCl in 1,4-dioxane (0.8 mL). The mixture was stirred for 20 hours. at room temperature. The title compound was collected by filtration as the hydrochloric acid salt. 1H NMR (500 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.19 (s, 1H), 7.07-6.94 (m, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.70 (t, J=7.2 Hz, 1H), 4.73 (d, J=16.0 Hz, 1H), 4.43 (s, 1H), 4.17 (d, J=16.1 Hz, 1H), 3.51-2.79 (m, 8H), 0.66 (m, 1H), 0.15-0.05 (m, 1H), 0.05-−0.08 (m, J=4.1 Hz, 1H); MS (DCI) m/z 221.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:11][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]1(=[O:18])[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1>C(O)C.N1C=CC=CC=1>[C:15]1(=[O:17])[N:16]([CH2:11][CH:2]([OH:1])[CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:12](=[O:18])[CH2:13][CH2:14]1
Reactant: O=C1CCC(=O)N1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1CCC(=O)N1CC(O)COc1ccccc1
Reaction time: 24 h
Yield: 72.2 %

Procedure:
A mixture of 15 gm (0.1 mole) of 2,3-epoxypropoxybenzene (prepared as described in Example I) and 9.9 gm (0.1 mole) of succinimide in 100 mL ethanol having 10 drops of pyridine was heated to reflux for 4 hours. After standing 24 hours at room temperature a white crystalline product separated. This material was collected, air-dried and recrystallized from 700 mL ethyl acetate:hexane (6:1) to give 18 gm (72%) of white crystals: mp 130°. The NMR spectrum and the elemental analyses were consistent with the assigned structure.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:24][CH3:25])=[C:6]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:7]([C:11]#[N:12])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]>O1CCCC1>[Cl:10][C:8]1[C:7]([C:11]#[N:12])=[C:6]([CH:13]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:16]2)[C:5]([O:24][CH3:25])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: COc1c(C(C)O)cc(Cl)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
A solution of (34-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (4.3 g, 16 mmol) in tetrahydrofuran (46 mL) was treated with 1.0 M borane-THF complex in tetrahydrofuran (19 mL, 19 mmol) and stirred at 20° C. for 15 min. The reaction mixture was cooled to −30° C. and treated with a solution of tert-butyl 3-(3-acetyl-5-chloro-6-cyano-2-methoxyphenyl)azetidine-1-carboxylate (5.7 g, 16 mmol) in tetrahydrofuran (49 mL) slowly. The flask containing the starting material ketone was rinsed with additional tetrahydrofuran (9 mL) and added to the reaction mixture. The temperature of the reaction was −20° C. after the addition was complete. The reaction mixture was warmed to −5° C. over a period of 30 min. The reaction mixture was quenched with water at 0° C., poured into saturated sodium bicarbonate solution, and extracted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-100%) to give the desired product (5.5 g, 97%) as a beige foam as a 97:3 mixture of enantiomers (Retention times=12.19 min and 13.18 min; Phenomenex Lux Cellulose C-2 column, 4.6×150 mm, 5 micron particle size, eluting with 8% ethanol in hexanes at 1 ml/min). 1H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 5.48 (d, J=4.6 Hz, 1H), 5.00-4.90 (m, 1H), 4.43-4.31 (m, 1H), 4.30-4.10 (m, 4H), 3.66 (s, 3H), 1.38 (s, 9H), 1.29 (d, J=6.4 Hz, 3H). LCMS for C14H16ClN2O4 ([M-(t-Bu)+H]+H)+: m/z=311.1; Found: 311.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[Cl:35])=[O:29])C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[Cl:35])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1sccc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1sccc1Cl
Yield: 60.2 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (360 mg, 1.2 mmol) and 3-(3-chloro-thiophen-2-yl)-3-oxo-propionic acid ethyl ester (Example H16) (350 mg, 1.5 mmol) according to the general procedure K. Obtained as a white-yellow solid (353 mg).