Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH3:14].CN([CH:18]=[O:19])C.O=P(Cl)(Cl)Cl>C1C(Cl)=CC=C(Cl)C=1>[CH3:14][O:13][C:4]1[CH:5]=[C:6]([CH:18]=[O:19])[C:7]2[C:12]([C:3]=1[O:2][CH3:1])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COc1ccc2ccccc2c1OC
Reactant: CN(C)C=O
Solvent: Clc1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C=O)c2ccccc2c1OC
Temperature: 0 °C
Yield: 68.9 %

Procedure:
A mixture of 1,2-dimethoxynaphthalene (0.74 g, 4 mmol) and DMF (0.8 mL, 10 mmol) in dichlorobenzene (0.8 mL) was stirred with POCl3 at 100° C. for 2h. The reaction mixture was cooled to 0° C, quenched with a cold aqueous solution of NaOAc, diluted with H2O and extracted with benzene. The extracts were dried (MgSO4), concentrated and in vacuo and dichlorobenzene was removed by kugelrohr distillation at 110° C./0.5 mm Hg. Column chromatography (20%EtOAc in hexane) gave the product 518 (596 mg, 68%), which was used in the following step without further purification. 1H NMR (CDCl3) 10.42 (s, 1H), 9.00-9.15 (m, 1H), 8.15-8.30 (m, 1H), 7.61 (s, 1H), 7.50-7.65 (m, 2H), 4.12 (s, 3H), 4.07 (s, 3H).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCc1ccc(Cl)cc1
Solvent: CO
Product: N#CNC(=NCc1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 4-chlorobenzylamine (0.41 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.65 g, 2.4 mmol, yield: 91%) as colorless powder.
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1[CH:16]=[CH:15][CH:14]=CC=1.C1([ClH]C(Cl)=O)CC1>ClCCl>[CH3:2][O:9][C:7](=[O:8])[CH2:6][C:4]([CH:14]1[CH2:15][CH2:16]1)=[O:5]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC(=O)C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
48.6 g of meldrum's acid (337.4 mmol) were dissolved in 200 ml of dichloromethane at room temperature and the solution was cooled to 0° C. 40 g of pyridine (506.1 mmol) were added to said solution. 35.3 g of cyclopropyl carbonic acid chloride (337.4 mmol) were then added at 0° C. within 1 h. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCl and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and stirred under reflux for 2 h. The reaction mixture was concentrated to dryness and the oily residue was purified by destillation at 90° C. bath temperature to yield 42.7 g (71.1%) of the title compound.
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:17])=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:7]=1[OH:17])=[O:34])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=Nc1ccccc1OCc1ccccc1
Agent: NC(N)=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2OCc2ccccc2)c1O
Yield: 26.3 %

Procedure:
Following the general procedure for urea formation outlined in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (52 mg, 0.23 mmol) and 2-benzyloxyphenylisocyanate (40 mg, 0.17 mmol) were coupled to form the desired urea (20 mg, 26%). EI-MS (m/z) 446.2, 448.3, 450.2 (M−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:10]1[C:11]2[C:6](=[CH:5][C:4]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:3][C:2]=2[F:1])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1
Yield: 83.9 %

Procedure:
A solution of 8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.17 g, 0.63 mmol) and NCS (0.10 g, 0.76 mmol) in THF (20 mL) were stirred under nitrogen at room temperature overnight according to Method C. The solution was concentrated onto Florosil and purified on a silica column (20% ethyl acetate—hexanes) to yield 0.16 g (84%) of the title compound as a yellow solid. An analytical sample was further prepared by preparative reverse phase HPLC to yield a light yellow solid: mp 120-124° C.; 1H NMR (DMSO-d6): δ 3.82 (3H, s), 7.06 (2H, d, J=8.80 Hz), 7.34 (1H, d, J=8.91 Hz), 7.67 (1H, dd, J=1.69 Hz, J=15.48 Hz), 7.78 (2H, d, J=8.78 Hz), 8.01 (1H, d, J=1.54 Hz), 10.62 (1H, s); MS (ESI) m/z 301/303 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:15][CH:16]=1)(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: C=C(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc(CP(=O)(OCC)OCC)cc1
Yield: 92 %

Procedure:
By the same procedure as described in example 1, diethyl 4-(amino)benzylphosphonate (1.94 g; 8 mmoles), triethylamine (0.87 g; 8.6 mmoles), and methacryloyl chloride (0.9 g; 8.6 mmoles) in toluene (9 ml) afford diethyl 4-(methacrylamido)benzylphosphonate as a slight yellow solid (2.3 g; yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]([C@H:23]3[CH2:26][C@H:25]([C:27](OCC)=[O:28])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[N:6]([C@H:23]3[CH2:24][C@H:25]([CH2:27][OH:28])[CH2:26]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)[C@H]1C[C@H](n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@H]2C[C@H](CO)C2)c2cnccc12
Temperature: 60 °C

Procedure:
To a solution of ethyl trans-3-(5-chloro-2-{[3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl]methyl}-1H-benzimidazol-1-yl)cyclobutanecarboxylate (80 mg, 0.16 mmol) in EtOH was added NaBH4 (80 mg, 2.1 mmol) in portions at RT. The mixture was then heated at 60° C. for 1 hour. The reaction was completed as indicated by LC/MS. The mixture was quenched with 1N HCl to pH7. After the solvent was removed by concentration, the residue was purified by preparative-HPLC to afford 15.1 mg of [trans-3-(5-chloro-2-{[3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl]methyl}-1H-benzimidazol-1-yl)cyclobutyl]methanol as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2)[CH3:2].[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[C:7]([N+:17]([O-:19])=[O:18])=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2)[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)Nc1ccc2c(c1)CCC2=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCC2=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(1-Oxo-indan-5-yl)-carbamic acid ethyl ester (0.94 g, 4.3 mmol) was dissolved in 20 ml of concentrated sulphuric acid and cooled to 0° C. using an ice-bath. Potassium nitrate (477 mg, 4.7 mmol) was added in small portions. After complete addition, the mixture was stirred for 3 hours at 0° C. and then poured onto crushed ice. The yellow precipitate was filtered off, washed thoroughly with water and dried in vacuo to give a yellow solid product (0.85, 75%).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:9]([O-])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.O.O.[SH-].[Na+]>CO.CCO>[NH2:9][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [Na+]
Agent: [SH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: Cc1ccc(O)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
7.00 g of 3-hydroxy-6-methyl-2-nitropyridine (Aldrich, 0.045 mol) was dissolved in 250 mL of MeOH and 20 mL of H2O along with 15 g of sodium hydrosulfide hydrate (6 eq, 0.27 mol). The reaction mixture was stirred under reflux for 5 hours. The reaction mixture was cooled to room temperature and diluted with 300 mL of absolute EtOH and concentrated to dryness. The resulting residue was dissolved in 300 mL of CH2Cl2 and 10 mL of MeOH. The mixture was sonicated for 10 min and allowed to stand at room temperature for 3 hours. The resulting salts that precipitated out at this point were removed by filtration. The filtrate was concentrated to afford the crude amine. This was purified by passing through a short plug of silica gel and eluting with 95% CH2Cl2, 4% MeOH and 1% Et3N. A total of 5.0 g of the desired amine was obtained (89% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:29](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:29])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-(3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)propanoyl)pyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=446.03 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([CH3:10])[N:3]=1.[OH-].[K+].[Cl:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>O.CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:18]2[C:17]([N+:24]([O-:26])=[O:25])=[CH:16][C:15]([C:27]([F:28])([F:29])[F:30])=[C:14]([Cl:13])[C:19]=2[N+:20]([O-:22])=[O:21])=[N:3][C:4]([CH3:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: Cc1nc(N)c(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Nc2c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c2[N+](=O)[O-])c(Cl)cc1Cl
Reaction time: 3 h

Procedure:
In 30 ml. of dimethylformamide, 1.8 g. of 2-amino-3,5-dichloro-6-methylpyridine was dissolved in 0.67 g. of powdery potassium hydroxide was gradually added with stirring. After the addition, a solution of 3.07 g. of 2,4-dichloro-3,5-dinitrobenzotrifluoride in 10 ml. of dimethylformamide was added dropwise at room temperature and the reaction was continued for about 3 hours. The reaction mixture was acidified with conc. HCl and was poured into water. The precipitate was filtered and recrystallized from methanol to obtain 2.96 g. of the object compound having a melting point of 128° to 130° C.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11][CH2:10][N:5]12.C([N:19](CC)CC)C.ClC(OCC)=O.N>O.CC(C)=O>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH:12]([C:14]([NH2:19])=[O:16])[CH2:11][CH2:10][N:5]12
Reactant: CCN(CC)CC
Reactant: O=C(O)C1CCn2c(cc3ccccc32)C1
Agent: CCOC(=O)Cl
Agent: N
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)C1CCn2c(cc3ccccc32)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A stirred suspension of 27 g (126 mmol) of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylic acid in 30 ml of water and 450 ml of acetone was cooled to 0° C. and treated in succession with 14.7 g (145 mmol) of triethylamine and 17.3 g (159 mmol) of ethyl chloroformate. After 0.5 hour, 6.3 ml of 0.880 ammonia was added and stirring was continued for 1 hour. The solvent was removed under reduced pressure and the residue was triturated with aqueous ethanol. The product was filtered off and dried to give 13 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxamide, as a white solid of melting point 165°-168° C.
Reaction SMILES: [OH2:1].[C:2]([C:24](F)=[O:25])([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([F:23])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3]>>[C:2]([C:24]([OH:25])=[O:1])([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([F:22])([F:21])[F:23])([F:19])[F:18])([F:15])[F:16])([F:12])[F:13])([F:10])[F:9])([F:6])[F:7])([F:3])[F:4]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O
Product: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A 250 ml PFA vessel equipped with a stirrer was used. Water (100 g, 5.6 mol) was temperature conditioned to 60° C. within the vessel, following which C7F15COF (50 g, 0.120 mol; prepared by the method described in JP-A 8-231462) having a purity of 99.9 wt % was added dropwise under stirring in an attempt to form C7F15COOH by a hydrolysis reaction. However, a gel formed, which made stirring impossible.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1.[C:13]([O-])(=O)[C@H:14]([CH3:16])[OH:15].[Na+].[OH-].[NH4+]>Cl>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:13]([CH:14]([OH:15])[CH3:16])=[N:12][C:7]=2[CH:6]=1
Reactant: C[C@H](O)C(=O)[O-]
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Product: COc1ccc2[nH]c(C(C)O)nc2c1
Temperature: 70 °C
Yield: 56.4 %

Procedure:
A mixture of 4-methoxy-phenylenediamine dihydrochloride (10 g), sodium L-lactate (10 g) and hydrochloric acid (60 mL, 4M) was heated at 70° C. for 48 hours. The reaction mixture was cooled to room temperature, then treated with ammonium hydroxide. The resulting precipitate was filtered and dried to give 1-(5-methoxy-1H-benzoimidazol-2-yl)-ethanol (5.14 g). (b) 1-(5-Methoxy-1-benzoimidazole)-1-propanol
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[O:30]=[C:31]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([C:41](O)=[O:42])[C:35]=2[CH2:34][CH2:33][N:32]1[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)C.O>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:41]([C:36]1[C:35]2[CH2:34][CH2:33][N:32]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:31](=[O:30])[C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:42])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: CCCCCN1CCc2c(C(=O)O)cccc2C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Yield: 81.2 %

Procedure:
326 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 180 mg of 1-oxo-2-pentyl-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 14 mg of hydroxybenzotriazole, 165 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.47 cm3 of N,N-diisopropylethylamine in 18 cm3 of dichloromethane are stirred for 20 h at a temperature close to 20° C. 10 cm3 of water and dichloromethane are added to the reaction medium. The suspension is filtered, washed successively with water and dichloromethane. The solid obtained is taken up in ethyl ether, filtered, washed with ethyl ether and dried under vacuum at 20° C. 360 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-1-oxo-2-pentyl-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white solid.
Reaction SMILES: [O:1]1CCCC1.O1CCOCC1.CC(C)=[CH:14][CH:15]1[CH:17]([C:18]([O:20][CH2:21][C:22]2[C:27]([F:28])=[C:26]([F:29])[C:25]([CH2:30][O:31][CH3:32])=[C:24]([F:33])[C:23]=2[F:34])=[O:19])[C:16]1([CH3:36])[CH3:35].I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH:14]([CH:15]1[CH:17]([C:18]([O:20][CH2:21][C:22]2[C:23]([F:34])=[C:24]([F:33])[C:25]([CH2:30][O:31][CH3:32])=[C:26]([F:29])[C:27]=2[F:28])=[O:19])[C:16]1([CH3:36])[CH3:35])=[O:1]
Reactant: C1CCOC1
Reactant: COCc1c(F)c(F)c(COC(=O)C2C(C=C(C)C)C2(C)C)c(F)c1F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COCc1c(F)c(F)c(COC(=O)C2C(C=O)C2(C)C)c(F)c1F

Procedure:
To a mixture of 25 ml of tetrahydrofuran and 150 ml of 1,4-dioxane, 15.4 g of 4-methoxymethy-2,3,5,6-tetrafluorobenzyl 3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (prepared by the method described above) were dissolved and 1.0 g of osmium tetraoxide was added thereto at room temperature. Further, 50 ml of water containing 24.0 g of sodium metaperiodate were added thereto and refluxed for 2 hours under heating. After that, the reaction mixture was poured into about 200 ml of water and extracted with 200 ml of ethyl acetate twice. The combined organic layer was washed with 1% aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, subsequently, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give 10.4 g of 4-methoxymethy-2,3,5,6-tetrafluorobenzyl 3-formyl-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)=[O:2].[CH2:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21][CH2:22][C:23]#[CH:24]>CCCCCCC.C(Cl)Cl>[C:25]1([CH2:20][CH2:21][CH2:22][C:23]#[C:24][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=Cc1ccc(C#CCCCc2ccccc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-formyl-phenyl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/DCM 1:1; yield (100 mg, 58%); 1H NMR δ (CDCl3): 9.98 (s, 1H), 8.02 (d, J=8.61 Hz, 2H), 7.81 (d, J=8.63 Hz, 2H), 7.57-7.47 (m, 4H), 2.79 (t, J=7.18 Hz, 2H), 2.48 (t, J=7.17 Hz, 2H), 1.93 (p, J=7.23 Hz, 2H); LCMS m/z: 248.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:18])[CH2:8][CH2:7][CH:6]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][CH2:4]1.[OH-].[K+].[C:21](Cl)(Cl)=[O:22]>C1(C)C=CC=CC=1.O>[CH2:11]([O:10][CH2:9][CH:6]1[CH2:5][CH2:4][C:3]2([O:18][C:21](=[O:22])[NH:1][CH2:2]2)[CH2:8][CH2:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)Cl
Reactant: NCC1(O)CCC(COCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NCC2(CCC(COCc3ccccc3)CC2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of EXAMPLE 385A (475 mg) and potassium hydroxide (641 mg) in toluene (10 mL) and water (25 mL) was cooled in an ice bath and phosgene (20% in toluene, 2.178 mL) was added dropwise maintaining the temperature below 3° C. The reaction was stirred rapidly at ambient temperature for 3 hours while warming to ambient temperature. The reaction mixture was partitioned between brine (100 mL) and ethyl acetate (100 mL). The organics were dried over sodium sulfate, filtered, and concentrated to provide the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([C:15]([CH3:17])=O)[C:10](OCC)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]([NH2:21])=[S:20].[O-]CC.[Na+].[Na]>C(O)C>[C:1]1([CH2:7][CH2:8][C:9]2[C:10](=[O:11])[NH:18][C:19](=[S:20])[NH:21][C:15]=2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1[nH]c(=S)[nH]c(=O)c1CCc1ccccc1

Procedure:
Ethyl α-(phenylethyl)acetoacetate (23.4 g) and thiourea (10.65 g) were added to a solution of sodium ethoxide in ethanol (100 ml) prepared from sodium (4.6 g). The mixture was refluxed for 51/2 hours and evaporated to dryness. The solid residue was dissolved in water and acetic acid was added to pH 4. The white precipitate was filtered off and recrystallised from ethanol to give 5-(2-phenylethyl)-6-methyl-2-thiouracil m.p. 210°-214°.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH:17][OH:18].C1(N=C=NC2CCCCC2)CCCCC1>C(O)C.C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][N:17]([OH:18])[C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][OH:1]
Reactant: CC(C)(CO)C(=O)O
Reactant: ONCc1ccccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)(CO)C(=O)N(O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 7.9 %

Procedure:
To a stirred solution of 3.0 grams (0.025 mole) of 3-hydroxy-2,2-dimethylpropionic acid (Example 12, Step A) and 3.9 grams (0.025 mole) of N-(2-chlorophenyl)methyl hydroxylamine (Example 1, Step A-2) in 65 ml of ethanol was added dropwise a solution of 5.2 grams (0.025 mole) of dicyclohexylcarbodiimide in 25 ml of chloroform. Upon completion of addition the reaction mixture was stirred at ambient temperature for 60 hours. The reaction mixture was concentrated under reduced pressure to give a residual solid. The solid was recrystallized from ethanol, then from ethanol-water to give a solid; mp 229°-230°. The filtrates from the recrystallizations were combined and concentrated under high vacuum to give a residual oil. The residual oil was subjected to column chromatography. Elution was accomplished using 4:1--cyclohexane:ethyl acetate. The appropriate fraction was concentrated under reduced pressure to give a solid. The solid was recrystallized from ethyl acetatehexane to give 0.51 gram of N-[(2-chlorophenyl)methyl]-N,3-dihydroxy-2,2-dimethylpropanamide; mp 130°-132°. The solid was recrystallized a second time from ethyl acetate-cyclohexane to raise the mp to 131°-132°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([O:6][CH:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH3:8])[CH2:2]1.O.[OH-].[Li+].Cl>CO.O>[O:1]1[CH2:5][CH2:4][CH:3]([O:6][CH:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH3:8])[CH2:2]1
Reactant: COC(=O)c1ccc(C(C)OC2CCOC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(OC1CCOC1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
To the solution of methyl 4-(1-(tetrahydrofuran-3-yloxy)ethyl)benzoate (371 mg, 1.48 mmol) in methanol (15 mL) and water (5 mL) was added lithium hydroxide hydrate (100 mg, 2.4 mmol) were add ed. The mixture was stirred at room temperature for 12 hours. Then the reaction mixture was acidified by hydrochloric acid aqueous solution (1 N) to adjust pH=6 and extracted with dichloro methane (10 mL×3). The organic layers were combined and concentrated to give 4-(1-(tetrahydrofuran-3-yloxy)ethyl)benzoic acid (311 mg, 89%)