Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[C:9]#[N:10])=[CH:3][CH:2]=1.[CH3:26][O-].[Na+].CI.[Cl-].[NH4+]>CO>[C:1]1([CH3:25])[CH:2]=[CH:3][C:4]([S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)([CH3:26])[C:9]#[N:10])=[CH:5][CH:6]=1
Reactant: C[O-]
Reactant: Cc1ccc(SC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: Cc1ccc(SC(C)(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Yield: 92 %

Procedure:
Anhydrous methanol (2 ml) was added to 439 mg of alpha-(p-tolylthio)(m-benzoylphenyl)acetonitrile, and the mixture was stirred under ice cooling. Then, 0.55 ml of a 2.5 M methanol solution of sodium methoxide was added, and 0.12 ml of methyl iodide was added dropwise. The mixture was further stirred for 30 minutes at room temperature. An aqueous solution of ammonium chloride (0.5 g/20 ml) was added, and the mixture was extracted with 15 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford an oily residue. The residue was purified by column chromatography (silica gel; benzene) to afford 422 mg (yield 92%) of alpha-(p-tolylthio)-alpha-(m-benzoylphenyl)propionitrile as a colorless oil.
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].S(Cl)(C)(=O)=O.[I-:22].[Na+]>C(#N)C.C(N(CC)CC)C>[C:1]([C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][I:22])#[N:2]
Reactant: [I-]
Reactant: CC(C)C(C#N)(CCCO)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)C(C#N)(CCCI)c1ccccc1
Reaction time: 0.42 h

Procedure:
5.00 g 23.0 mmol of 4-Cyano-5-methyl-4-phenylhexanol disclosed in Example 2 or 3 of JP 11-70613-A was added to and dissolved in acetonitrile 150 ml and triethylamine 3.53 ml. Mesyl chloride, 1.96 ml 25.3 mmol, was added thereto. After 25 minutes, sodium iodide 20.7 g was added thereto. The reaction mixture was partitioned by adding brine and ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate and then with brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound, 5. 89 g 18.0 mmol, 78.2%, was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=1)[CH:23]=O)[CH3:18]>>[CH2:29]([O:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH2:17][CH3:18])[CH:27]=1)[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:30]
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)cc(OCC)c1
Yield: 33 %

Procedure:
The title compound (13 mg, 33%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3,5-diethoxybenzaldehyde. MS: 398.5 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][CH:8]=1)[CH3:2].[Sn].Cl.C(Cl)Cl>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([SH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Sn]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(S)cc1

Procedure:
To a mixture of (4-chlorosulfonyl-phenoxy)-acetic acid ethyl ester (0.98 g, 3.5 mmol) and tin powder (2.1 g) in ehtanol (4.4 mL) is added HCl in dioxane (1.0 M, 4.4 mL) under nitrogen. The mixture is heated to reflux for 2 hrs, it is poured into ice and methylene chloride and filtered. The layers are separated and extracted with methylene chloride, dried and concentrated. The crude product is used for next step without purification.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CCO>[CH:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[CH:18]([OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCCc2cc(OCC3CCCCC3)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCCCc2cc(OCC3CCCCC3)ccc21
Temperature: 40 °C

Procedure:
To a suspension of 2-cyclohexylmethoxy-6,7,8,9-tetrahydro-benzocyclohepten-5-one (14.5 g, 53.23 mmol) in EtOH (150 mL) was added NaBH4 (1.96 g, 53.23 mmol) portionwise over 10 min. The mixture was heated to 40° C. for 1 h, cooled to 0° C., then made acidic with the addition of 1 N HCl. The white precipated solids were filtered, washed with water, and dried in vacuuo (14.25 g, 97%). m.p. 102-103° C.
Reaction SMILES: [CH:1]([N:3]1[C:8]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12]CC)=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1)=[O:2].[OH-].[K+]>C(O)C>[CH:1]([N:3]1[C:8]([C:9](=[N:15][O:16][CH3:17])[C:10]([OH:12])=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1)=[O:2]
Reactant: CCOC(=O)C(=NOC)C1=CSCCN1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)C1=CSCCN1C=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 82 %

Procedure:
To a suspension of thus obtained ethyl 2-(4-formyl-2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer, 4.8 g.) in ethanol (48 ml.) was added 1 N aqueous solution of potassium hydroxide (22.3 ml.), and the mixture was stirred at room temperature for 1.25 hours. After removing ethanol from the resultant solution under reduced pressure, water was added to the residue to a total volume of 100 ml., and washed with diethyl ether. The solution was adjusted to pH 1 with 10% hydrochloric acid, and salted out. After the solution was extracted with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether (15 ml.) and the crystals were collected by filtration and washed with diethyl ether to give 2-(4-formyl-2,3-dihydro-4H-1,4-thiazin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 3.51 g.).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)=[O:9].[C:19](Cl)(=[O:21])[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-].[Na+].[Cl-]>ClCCl.[Cl-].[Cl-].[Zn+2].O1CCCC1.C(OCC)(=O)C>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C:19](=[O:21])[CH3:20])=[O:9]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]cc(C(C)=O)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a three-neck flask, 4.20 ml (9.25 mmol) of a 2.2 M ZnCl2 solution in 20 ml absolute dichloromethane is charged under nitrogen and the solution is cooled to 0° C. using an ice bath. Thereafter, 5.62 ml (8.99 mmol) of a 1.6 M n-butyllithium solution are slowly added drop-wise. The reaction mixture is heated to room temperature, stirred for 1 hour, then admixed with the solution of 1.50 g (8.56 mmol) methylindole-5-carboxylate in 20 ml absolute dichloromethane and stirred again at room temperature for one hour. Thereafter, the batch is cooled to 0° C. and 1.28 ml (18.1 mmol) acetylchloride is carefully added so as to form an orange suspension. The latter is stirred at room temperature for 1 hour. Then, 0.93 g (7.02 mmol) aluminum chloride is added. After another hour of stirring at room temperature, hydrolysis with semi-saturated NaCl solution is carried out and 100 ml ethyl acetate and 20 ml tetrahydrofurane are added. Three extractions are carried out using ethyl acetate, the combined organic phases are washed with saturated NaCl solution and the organic phase is dried on sodium sulfate. The solvent is distilled off. Chromatographic purification of the residue on silica gel (flow agent: hexane/ethyl acetate 3:2) yields the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][CH:7]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[C:8](O)=[O:9])=[CH:4][C:3]=1[Cl:38].C1N=CN(C(N2C=NC=C2)=O)C=1.[BH4-].[Na+].Cl>C1COCC1.O>[NH2:1][C:2]1[C:33]([C:34]([F:35])([F:36])[F:37])=[CH:32][C:5]([CH2:6][CH:7]([CH2:8][OH:9])[CH2:11][C:12]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)=[O:31])=[CH:4][C:3]=1[Cl:38]
Reactant: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(CC(CO)CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.00 g (5.425 mmol) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyric acid (Intermediate product 68) in 100 mL THF was added 1.054 g (6.500 mmol) CDI and the mixture was stirred for 2 hours at RT. This solution was added dropwise under a nitrogen atmosphere over 5 minutes to an ice-cooled solution of 0.728 g (19.250 mmol) sodium borohydride in 50 mL water and the mixture was stirred for 16 hours at RT. The reaction mixture was acid ified with 1 N aqueous HCl to pH 2 and exhaustively extracted with EtOAc. The combined org. phases were washed with sat. aqueous NaCl solution, dried over sodium sulphate and evaporated i. vac.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([N:5]1[C:9]([S:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:8][C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6]1)=[O:4].Cl>C1COCC1>[CH3:1][N:2]([CH3:21])[C:3]([N:5]1[C:9]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[N:8][C:7]([C:17]([CH3:19])([CH3:18])[CH3:20])=[N:6]1)=[O:4]
Reactant: CCOC(=O)CSc1nc(C(C)(C)C)nn1C(=O)N(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCC(=O)O
Temperature: 200 °C
Reaction time: 48 h

Procedure:
To 1.2 g of 1-dimethylcarbamoyl-3-t-butyl-5-carboethoxymethylthio-1H-1,2,4-triazole (the compound of Example 2) in 20 ml of THF was added 4 ml of 12M HCl. After stirring for 48 h at 200° C. the reaction mixture was partitioned between ether and water, the ether layer was extracted with dilute NaOH and the resulting aqueous layer was acidified and extracted with fresh ether. The resulting ether layer was dried over magnesium sulfate, filtered and evaporated under vacuum to yield 1-dimethylcarbamoyl-3t-butyl-5-carboxymethylthio-1H-1,2,4-triazole as an oil.
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:41]=[CH:40][C:20]([C:21]([N:23]([CH3:39])[C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=4[O:31]CC4C=CC=CC=4)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:41]=[CH:40][C:20]([C:21]([N:23]([CH3:39])[C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=4[OH:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccc(C)cc3OCc3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccc(C)cc3O)cc2)cc1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-benzyloxy-4-methylphenyl)benzamide (2.2 g), 10% palladium hydroxide (220 mg) in methanol (50 ml) was stirred under atmospheric pressure of hydrogen at ambient temperature. After 5 hours, the reaction mixture was filtered through a bed of Celite, and then concentrated to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-hydroxy-4-methylphenyl]benzamide (1.71 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:15]([CH:10]1[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:16]
Reactant: CCC1CN(Cc2ccccc2)CCC1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1CNCCC1O

Procedure:
A mixture of 1-benzyl-3-ethyl-4-hydroxypiperidine (5.0 g, 22.0 mmole) and palladium hydroxide (1.5 g) in methanol (100 ml) was stirred at 5.0 g, 22.0 mmole) and palladium hydroxide (1.5 g) in methanol (100 ml) was stirred at 50-55° C. in hydrogen atmosphere (1 atm.) for 20 hr. The catalyst was filtered off, washed with methanol, and filtrate was concentrated to dryness to give 3-ethyl-4-hydroxypiperidine as oil. Yield 2.9 g (94%), C7H15NO, m/z 130 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1N1CCCCC1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Piperidine (320 μl, 3.23 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1,4-difluoro-2-nitrobenzene (225 mg, 1.41 mmol, commercially available product). The resulting mixture was stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=12/1). Thus, 1-(4-fluoro-2-nitrophenyl)piperidine (298 mg, 94.2%) was yielded as an orange-colored oily material.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]1[N:25]=[C:24]([NH2:26])[CH:23]=[C:22]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:26][C:24]3[CH:23]=[C:22]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:21]=[C:20]([CH3:19])[N:25]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Cc1nc(N)cc(N2CCOCC2)n1
Reactant: Fc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc(Nc2nccc3nc(-c4c(F)cccc4Cl)sc23)cc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a microwave tube was added 4-bromo-2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridine (0.050 g, 1.5 mmol), 2-methyl-6-morpholinopyrimidin-4-amine (0.043 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (2.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature, the solid was removed via filtration and the filtrate was concentrated under reduced pressure. The residue was purified with reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a yellow solid (0.016 g, 24% yield). 1H NMR (500 MHz, DMSO-d6): δ 10.22 (s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.75 (d, J=5.5 Hz, 1H), 7.73-7.68 (m, 1H), 7.62-7.60 (m, 1H), 7.54-7.50 (m, 1H), 6.75 (s, 1H), 3.69-3.67 (m, 4H), 3.52-3.50 (m, 4H), 2.33 (s, 3H). LCMS (Method A): RT=6.16 min, m/z: 457.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].CC1C=C(C=C(C)C=1[N+]([O-])=O)C(O)=O.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[CH3:29])=[O:6]
Reactant: Cc1cc(C(=O)Cl)cc(C)c1[N+](=O)[O-]
Reactant: Cc1ccccc1CN
Agent: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1CNC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dimethyl-4-nitrobenzoyl chloride in tetrahyrofuran, generated from 7.0 g of 3,5-dimethyl-4-nitrobenzoic acid by standard procedures, was added to 4.3 g of 2-methylbenzyl amine and 5.0 ml of triethylamine in tetrahydrofuran. The reaction was stirred at ambient temperature overnight, chilled, and filtered. The filtrate was evaporated in vacuo and the residue therefrom was dissolved in chloroform, washed sequentially with 1N hydrochloric acid, 1N sodium hydroxide, water, and a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated in vacuo. Crystallization from methanol/water provided 4.7 g of the desired title product, m.p. 202°-203° C.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[O:14][C:13]=1[CH:23](O)[CH3:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:5]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[O:14][C:13]=1[CH:23]([Br:2])[CH3:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: CC(O)c1oc(=O)c2ccccc2c1Cc1ccccc1
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1Cc1ccccc1
Yield: 2.9 %

Procedure:
1 M PBr3 in DCM (0.105 mL, 1.105 mmol) was added to 4-benzyl-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate B14, 625 mg, 2.230 mmol) in DCM (2 ml) at RT. Reaction mixture was straightforward purified on Biotage SNAP 25 g silica cartridge with a gradient of hexane and EtOAc to give the title compound (22 mg, 2.9%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=O)=[CH:6][CH:5]=1.CSC.B>C1COCC1>[F:1][C:2]([F:14])([F:15])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:13])=[CH:8][CH:9]=1
Reactant: NC(=O)Cc1ccc(OC(F)(F)F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: NCCc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
2-[4-(Trifluoromethoxy)phenyl]acetamide (1.13 g, 5.156 mmol) was dissolved in THF (20 ml) and the reaction mixture was cooled in an ice-bath. Borane dimethyl sulfide complex (6.4 ml, 2M in THF) was added dropwise. After the addition, the cooling-bath was removed and the mixture was heated to reflux for 5 h and cooled down to rt. HCl (10%, 4 ml) was added, the mixture was stirred at rt overnight and then evaporated to remove THF. Water (15 ml) and diethyl ether (15 ml) were added into the residue. The two phases were separated and NaHCO3 (sat.) was added into the water phase. It was then extracted with EtOAc (20 ml×3). The extracts were combined and washed with brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (ISOLUTE SI, 20 g/70 ml), eluting with MeOH/DCM (1:99, 2:98, 5:95 then 10:90), to give 0.2 g desired product and 0.46 g mixture. The mixture was further purified by re-chromatography (ISOLUTE SI, 20 g/70 ml), eluting with MeOH/EtOAc (2:98, 5:95, 10:90), to give 0.107 g more of the desired product. In total (0.307 g, 29%) of the title compound was obtained. Mass Spectrum: M+H+ 206. 1H NMR (400 MHz, CD3OD): δ 2.95 (t, 2H), 3.12 (t, 2H), 7.23 (d, 2H), 7.38 (d, 2H). 13C NMR (100 MHz, CD3OD): 35.3, 42.5, 122.2 (q, J=250 Hz), 122.6, 131.7, 136.2, 149.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][CH2:6][CH:7](O)[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25]1(=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[NH:26]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][CH2:6][CH:7]([N:26]1[C:27](=[O:34])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]1=[O:35])[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(NCC(O)COc1ccc(F)c(F)c1)OCc1ccccc1
Product: O=C(NCC(COc1ccc(F)c(F)c1)N1C(=O)c2ccccc2C1=O)OCc1ccccc1

Procedure:
2.2 g of rac-benzyl [3-(3,4-difluorophenoxy)-2-hydroxypropyl]carbamate (Example 135A, 6.5 mmol, 1 equivalent) were reacted with 1.2 g of 1H-isoindole-1,3(2H)-dione (phthalimide, 7.8 mmol, 1.2 equivalents) and worked up analogously to Example 137A. This gave 1.78 g (54% of theory; purity 93%) of the title compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C@:11]([F:15])([CH:13]=[CH2:14])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[C:31]([O:32][CH3:33])=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([F:34])[CH:24]=4)=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:6]2[CH2:12][C@:11]([F:15])([CH:13]=[CH2:14])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[C:31]([O:32][CH3:33])=[CH:30][C:26]([C:27]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:28])=[C:25]([F:34])[CH:24]=4)=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid as described in the general procedure for amide bond synthesis using HATU and 4-amino 1-methylpiperidine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19-1.90 (m, 8H) 2.05 (dd, J=4.29, 1.52 Hz, 4H) 2.16-2.28 (m, 2H) 2.34 (s, 3H) 2.83 (br. s., 2H) 3.39 (s, 3H) 3.69-3.89 (m, 2H) 3.96 (s, 3H) 4.00-4.10 (m, 1H) 4.97 (quin, J=8.46 Hz, 1H) 5.37 (d, J=11.12 Hz, 1H) 5.50 (dd, J=17.30, 1.89 Hz, 1H) 6.02 (ddd, J=17.30, 14.53, 10.86 Hz, 1H) 6.67 (d, J=7.07 Hz, 1H) 7.56 (d, J=7.07 Hz, 1H) 7.76 (s, 1H) 7.96 (s, 1H) 8.37 (d, J=15.16 Hz, 1H), [M+H] calc'd for C29H37F2N7O3 570. found 570.
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([O:16][CH3:17])=[N:7]1)=O)C.O.[Li+].[OH-]>C1COCC1>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8]([O:16][CH3:17])=[N:7][NH:6]2
Reactant: CCOC(=O)n1nc(OC)c2c(Br)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1n[nH]c2cccc(Br)c12
Reaction time: 15 h

Procedure:
To a stirring solution of 4-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CLXXXV (1.27 g, 4.14 mmol) in THF (28 ml) and H2O (9 ml) was added LiOH (397 mg, 16.6 mmol). The reaction mixture was stirred at reflux for 2 hours then at room temperature for 15 hours. The mixture was concentrated. The residue was diluted with EtOAc (50 ml), washed with HCl (IM) and brine, dried over MgSO4, filtered and concentrated affording 4-Bromo-3-methoxy-1H-indazole CLXXXVI as an off-white solid (98% yield), which was used without further purification in the next step.