Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[OH-].[Na+].Cl[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]>C(Cl)Cl>[CH2:1]([NH:3][C:7](=[O:8])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCNC(=O)Oc1ccccc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
An aqueous solution of ethylamine (2.58g of 70% solution, 0.04 mole) and an aqueous sodium hydroxide solution (1.44g in 8 ml solution, 0.036 mole) were added dropwise simultaneously over a period of 15 minutes to a cool solution of phenyl chloroformate (6.0g, 0.038 mole) in methylene chloride (35 ml). The reaction mixture was stirred for one hour, then separated. The organic layer was dried over anhydrous magnesium sulfate, then filtered and stripped of solvent on a Rotovap. White crystals of phenyl N-ethylcarbamate weighing 6.27g were obtained having a melting point of 49°-50° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=1[CH:18]1[NH:22]C(=O)N[C:19]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[Na+].Cl>>[NH2:22][CH:18]([C:10]1[CH:11]=[CH:12][C:13]([C:15]([OH:17])=[O:16])=[CH:14][C:9]=1[S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:19]([OH:24])=[O:25]
Reactant: O=C1NC(=O)C(c2ccc(C(=O)O)cc2SCc2ccccc2)N1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: NC(C(=O)O)c1ccc(C(=O)O)cc1SCc1ccccc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A solution of 5-(2-benzylthio-4-carboxyphenyl)hydantoin (0.375 g, 0.12 mmol) in 2N sodium hydroxide (6 ml, 12 mmol) was heated with stirring in a sealed reaction vessel for 20 hours at 120° C. The cooled solution was acidified wih 2N hydrochloric acid (1 ml) to pH~4 and chromatographed on ion exchange (Dowex 50×8-100). The column was eluted sequentially with water, tetrahydrofuran-water (1:1), water, then 10% pyridine in water. Fractions collected after pyridine water were combined, evaporated to dryness, redissolved in water, then freeze-dried to give the title product as an off-white solid, m.p. ~226° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:17]([O-:19])=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH2:25][CH3:26])=[O:6]
Reactant: O=C(O)c1cc(O)c(-c2ccccc2)c([N+](=O)[O-])c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(O)c(-c2ccccc2)c([N+](=O)[O-])c1

Procedure:
A mixture of 3-hydroxy-5-nitro-4-phenylbenzoic acid (22 g; prepared as in Example 2, step B), conc. sulfuric acid (10 ml) and ethanol (400 ml) is refluxed for 20 hours. The resulting solution is concentrated in vacuo to about 100 ml and is then diluted with water (about 300 ml). The separated ethyl 3-hydroxy-5-nitro-4-phenylbenzoate is collected by filtration, washed with water and dried. After recrystallization from carbon tetrachloride, the ester is obtained with a melting point of 128°-130° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1>>[Cl:38][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][O:29][CH2:28][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOCc1cccc(Cl)c1

Procedure:
Prepared according to the procedure described in Example 14, Step 4, using 1-{4′-[4-(2-Hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-bromomethyl-3-chloro-benzene.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:4]1=2.[CH3:14][C:15]([CH3:17])=[O:16]>O>[S:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:12]=[CH:14][C:15](=[O:16])[CH3:17])[CH:10]=[CH:11][C:4]1=2
Reactant: CC(C)=O
Reactant: O=Cc1ccc2sccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc2sccc2c1

Procedure:
An aqueous solution of 10% sodium hydroxide (1 ml) was added dropwise to a solution of benzo[b]thiophene-5-carboxaldehyde (7.0 g) in acetone (15 ml) and water (5 ml), the temperature of the reaction mixture being maintained below 30° C. during the addition. On completion of the reaction (ca 3 hrs) the mixture was poured into water. The dried (MgSO4) dichloromethane extract was evaporated to give 1-(benzo[b]thien-5-yl)but-1-en-3-one as a yellow solid, mp 75° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][N:23]=[CH:24]2)=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH:24]1[C:25]2[C:20](=[CH:19][CH:18]=[C:17]([N:6]3[C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=4[C:4]4[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]3=4)[CH:26]=2)[CH:21]=[CH:22][N:23]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1ccc2ccncc2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ccncc3c2)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.499 mmol), 7-bromoisoquinoline (155 mg, 0.748 mmol), K3PO4 (317 mg, 1.495 mmol), CuI (9 mg, 0.047 mmol) and L-Proline (11 mg, 0.095 mmol) in dry DMF (2 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(isoquinolin-7-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a yellow solid. 1H NMR (TFA salt, CD3OD) d (ppm): 9.57 (s, 1H), 8.6 (d, 1H), 8.37 (m, 2H), 8.2 (d, 1H), 8.0 (d, 1H), 7.4 (s, 1H), 7.21 (d, 1H), 7.1 (d, 1H), 4.76 (m, 1H), 4.42 (m, 1H), 3.82 (m, 1H), 3.61 (m, 1H), 3.21 (s, 3H), 3.1 (m, 2H), 2.42 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])=[CH:21][CH:20]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[CH3:35][NH:36][CH3:37]>CN(C=O)C>[CH3:35][N:36]([CH3:37])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])=[CH:21][CH:20]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(CCNc2ncnc3cc(OCCCCl)ccc23)cc1
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc2c(NCCc3ccc(NC(=O)Nc4ccccc4)cc3)ncnc2c1
Yield: 49.1 %

Procedure:
A solution of 1-(4-{2-[7-(3-chloro-propoxy)-quinazolin-4-ylamino]-ethyl}-phenyl)-3-phenyl-urea (20 mg, 0.042 mmol) and dimethylamine (94.7 mg, 0.840 mmol) in DMF (1 mL) was heated at 150° C. in CEM microwave for 10 min. The reaction mixture was purified using silica gel preparative thin layer chromatography to provide the title compound (10 mg, 49%). 1H-NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 8.19 (t, 1H, NH), 8.10-8.12 (m, 1H), 7.43-7.45 (m, 2H), 7.36-7.38 (m, 2H), 7.26 (t, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.08-7.11 (m, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.95 (t, 1H), 4.13 (t, 2H), 3.69 (q, 2H), 2.89 (t, 2H), 2.44 (t, 2H), 2.20 (s, 6H), 1.89-1.93 (m, 2H). LC-MS (ESI) m/z 485.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(Br)c(C(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(O)ccc1Br
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1-bromo-2-isopropyl-4-methoxy-benzene (Intermediate 143, 2.20 g, 9.60 mmols) in 50 mL CH2Cl2 at −78° C. was added BBr3 (4.81 g, 19.2 mmols; 19.2 mL of a 1 M solution in CH2Cl2). After stirring for 3 hours at −78° C. the solution was warmed to 0° C. for 3 hours and then at 25° C. for 1 hour before being quenched with H2O. The mixture was diluted with Et2O and washed with H2O and saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (2.5-10% EtOAc-hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13](=O)[C:12]=2[CH:20]=1)#[N:7]>CN(C)C=O>[Cl:3][C:13]1[C:12]2[CH:20]=[C:8]([C:6]#[N:7])[CH:9]=[CH:10][C:11]=2[O:16][C:15]([CH3:18])([CH3:17])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)NC(=O)c2cc(C#N)ccc2O1
Solvent: CN(C)C=O
Product: CC1(C)N=C(Cl)c2cc(C#N)ccc2O1
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (0.5 ml) was added with ice-cooling to dimethylformamide (10 ml) and the mixture was stirred for 10 minutes. To the mixture was added 6-cyano-2,2-dimethyl-3,4-dihydro-2H-1,3-benzoxazin-4-one (1.0 g), and the mixture was stirred with ice-cooling for 1 hour and then at room temperature for 2 hours. The mixture was extracted with addition of ethyl acetate and ice water. The ethyl acetate layer was successively washed with an aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Hexane was added to the residue and 4-chloro-6-cyano-2,2-dimethyl-2H-1,3-benzoxazine (0.41 g, mp. 124°-126° C.) was obtained by crystallization therefrom.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[S:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22]1.[BH3-]C#N.[Na+].CC(O)=O>CO>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:26][C:23]1[CH:24]=[CH:25][S:21][CH:22]=1
Reactant: O=Cc1ccsc1
Reactant: COc1ccc(NCc2c(Cl)cncc2Cl)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(N(Cc2ccsc2)Cc2c(Cl)cncc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate B1 (200 mg, 0.64 mmoles) was dissolved in MeOH (10 mL). Molecular sieves (4A, 200 mg) were added, and then thiophen-3-carbaldehyde (0.056 mL, 0.64 mmoles) was added. The mixture was stirred at room temperature for 2 hours, then NaBH3CN (121 mg, 1.9 mmoles) was added. AcOH was added dropwise to pH=5. After 48 hours, molecular sieves were removed by filtration, and water was added (20 mL). The mixture was extracted with AcOEt (3×50 mL), and the organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The crude material was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 9/1 to 7/3) to yield the title compound in amount of 173 mg.
Reaction SMILES: C([N:8]1[C:20]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:19]2[C:10]([C:11]([NH2:25])=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=32)=[N:9]1)C1C=CC=CC=1>Br>[CH3:23][CH:22]([CH3:24])[CH2:21][C:20]1[NH:8][N:9]=[C:10]2[C:19]=1[C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:12]=[C:11]2[NH2:25]
Reactant: CC(C)Cc1c2c(nn1Cc1ccccc1)c(N)nc1ccccc12
Agent: Br
Product: CC(C)Cc1[nH]nc2c(N)nc3ccccc3c12
Temperature: 150 °C
Yield: 25.5 %

Procedure:
Hydrogen bromide (10 mL of 30% by weight in acetic acid) and 2-benzyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (0.75 g, 2.27 mmol) were combined in a TEFLON-lined Parr vessel and heated at 150° C. for 24 hours and then allowed to cool to ambient temperature over five hours. The reaction was filtered to remove a solid, and the filtrate was adjusted to pH 7 with the addition of 50% sodium hydroxide and 2M aqueous sodium carbonate. A precipitate formed and was isolated by filtration, washed with water, and air-dried. The solid was purified by chromatography on a HORIZON HPFC system (25+M cartridge, eluting with chloroform/CMA in a gradient from 80:20 to 40:60) followed by recrystallization from acetonitrile (19 mL/g) and a small amount of methanol. The crystals were isolated by filtration, washed with acetonitrile, and dried for 36 hours in a vacuum oven at 65° C. to provide 139 mg of 1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine as small, pale orange needles, mp 248-249° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C[O-].[Na+].[O:15]([CH2:22][CH2:23][N:24]1[CH:28]=[C:27]([CH:29]=O)[CH:26]=[N:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[O:15]([CH2:22][CH2:23][N:24]1[CH:28]=[C:27](/[CH:29]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])[CH:26]=[N:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cnn(CCOc2ccccc2)c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnn(CCOc2ccccc2)c1
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
Trimethyl phosphonoacetate (20.6 g, 112 mmol) was dissolved in 350 mL THF. A 25% w/w NaOMe solution (25 mL) was then added at room temperature and the resulting mixture was stirred for 30 min. 1-(2-Phenoxyethyl)-1H-pyrazole-4-carbaldehyde (24 g, 111 mmol) dissolved in 150 mL THF was added and the reaction mixture was stirred for 5 h before being quenched with aqueous ammonium chloride and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography using a gradient of hexane/EtOAc (30:1 to 1:2) to yield (E)-methyl 3-(1-(2-phenoxyethyl)-1H-pyrazol-4-yl)acrylate (22 g, 72.7%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:36])[NH:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH2:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([NH:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH2:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)=[O:36]
Reactant: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1
Temperature: 25 °C

Procedure:
To a solution of 2-{[6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-ylcarbamoyl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (2 mL) was added TFA (2 mL). The mixture was stirred at RT, concentrated in vacuo. The crude was neutralized with 10% Na2CO3 until the aqueous phase is basic, extracted with CH2Cl2three times. The organic solution was dried over Na2SO4 filtered and concentrated in vacuo to provide the title compound. MS (ESI): 396 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[C:5]([C:10]([F:13])([F:12])[F:11])[C:4]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:3]1.CN(C)C=O.C(Cl)(=O)C([Cl:29])=O>ClCCl>[CH3:1][N:2]1[C:6]([C:7]([Cl:29])=[O:8])=[C:5]([C:10]([F:13])([F:12])[F:11])[C:4]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[N:3]1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.0 g (12.8 mmol) of 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid are suspended in 50 ml of dichloromethane. 0.02 ml of N,N-dimethylformamide and 3.54 ml (38.4 mmol) of oxalyl chloride are then added in succession. The reaction mixture is then stirred first at room temperature for 30 minutes and then under reflux for 30 minutes. The solvent is removed under reduced pressure on a rotary evaporator. The 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride formed is used for the subsequent synthesis step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[H-].[Na+].[CH3:23]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:23])[C:7](=[O:20])[C:8]([F:18])([F:19])[CH2:9][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:11]=2[N:12]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (550 mg, 1.82 mmol) was dissolved in DMA (10 mL) and cooled in an ice bath. Sodium hydride (80 mg of 60% in mineral oil, 2 mmol) was added slowly and left to stir for 10 minutes. Methyl iodide (0.125 mL, 2 mmol) was then added and the reaction mixture was warmed up to room temperature. After 30 minutes the reaction was deemed complete by LCMS, poured into ice water, the solution extracted with EtOAc. The organic layer washed with brine and water, dried over MgSO4, and concentrated to give 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one as a brown residue which was used directly for next step. [M+H] calc'd for C13H15ClF2N4O, 317; found 317.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][CH:23]=[C:22]([C:25]([OH:27])=O)[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:34]([C@H:36]1[CH2:41][CH2:40][C@H:39]([NH2:42])[CH2:38][CH2:37]1)=[O:35]>>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:34]([C@H:36]1[CH2:37][CH2:38][C@H:39]([NH:42][C:25]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)[C:17]=3[NH:24][CH:23]=2)=[O:27])[CH2:40][CH2:41]1)=[O:35]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Reactant: COCCNC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COCCNC(=O)[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A68) and trans-4-amino-cyclohexanecarboxylic acid (2-methoxy-ethyl)-amide hydrochloride (A196) the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][C@@H:28]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=4)[C:29]([O:31]C)=[O:30])=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][C@@H:28]([CH2:33][C:34]4[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=4)[C:29]([OH:31])=[O:30])=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a solution of methyl (S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionate (87 mg, 0.16 mmol) in tetrahydrofuran (2 ml) and methanol (1 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 12 hr. The mixture was adjusted to pH 6.5 with 1N hydrochloric acid (4 ml) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration. The solid was washed with diethyl ether to give (S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionic acid (61 mg, yield 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]2[O:9][C:8]([N:13]3[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:11]=1
Reactant: C1CNCCNC1
Reactant: Cc1cc(Cl)cc2nc(S)oc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)cc2nc(N3CCCNCC3)oc12
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, a suspension of 5-chloro-2-mercapto-7-methylbenzoxazole (70 g, 35 mol) in toluene (1.4 L) was added with homopiperazine (70 g, 0.35 mol) with stirring, and then the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, and poured into a mixture of ethyl acetate (0.7 L) and water (0.7 L). The mixture was added dropwise with 6 N hydrochloric acid (55 mL) with stirring to adjust its pH to 7.5. The separated organic layer was washed with water (1.2 L). The remaining organic layer was added with water (1.2 L), and then added dropwise with 6 N hydrochloric acid with stirring to adjust its pH to 1–1.5. The separated aqueous layer was added with ethyl acetate (1.4 L), and then added with 5 N aqueous sodium hydroxide (180 mL) with stirring to adjust its pH to 8.0. The separated organic layer was washed with water (1.4 L), and dried anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound as a crude product (59 g). A solution of the crude product in ethyl acetate (1.2 L) was added with activated carbon (1.5 g), and the mixture was stirred for 30 minutes at room temperature. Then, the activated carbon was removed by filtration, and the solvent was evaporated under reduced pressure. The resultant solid was added with acetonitrile (177 mL), and was dissolved by warming the mixture to 60 C.° with stirring. The resultant uniform solution was left stand for cooling to room temperature over 1 hour, and then further cooled to 5 C.° The deposited crystals were collected by filtration, and dried under reduced pressure at 40 C.° for 4 hours to obtain the title compound (34 g).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([Cl:15])=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:15][C:12]1[C:13](=[O:14])[NH:8][N:9]=[CH:10][C:11]=1[C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1
Reactant: O=c1c(Cl)c(-c2ccc(Cl)cc2)cnn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1[nH]ncc(-c2ccc(Cl)cc2)c1Cl
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 100.2 %

Procedure:
2-Benzyl-4-Chloro-5-(4-chloro-phenyl)-2H-pyridazin-3-one (3.19 g, 9.65 mmol) was dissolved in toluene (50 mL). Aluminum chloride (AlCl3, 3.22 g, 24.1 mmol) was then added and the reaction mixture was heated at 50° C. After 20 min, the reaction mixture was cooled to RT and then poured into ice-water (200 mL). The resultant solution was extracted with EtOAc (3×200 mL). The combined organic layers were washed with water (500 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using EtOAc to give the title compound, 4-chloro-5-(4-chlorophenyl)-2H-pyridazin-3-one (2.33 g) as a white solid. HPLC: 2.74 min.