Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:29])([F:30])[F:31])=[O:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Yield: 92.7 %

Procedure:
4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (245 mg, 0.475 mmol) from above was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature and the solvents were evaporated. The residue was partitioned between methylene chloride and dilute sodium hydroxide solution. The organic layer was washed with brine and dried over sodium sulfate. Evaporation of solvents gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (183 mg) as a white solid. LC-MS calcd for C22H20F3N3O2 (m/e) 415.41, obsd 416.0. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [H-].[Na+].[O:3]([CH2:10][CH:11]1[O:15][C:14](=[O:16])[NH:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[O:3]([CH2:10][CH:11]1[O:15][C:14](=[O:16])[N:13]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCBr
Reactant: O=C1NCC(COc2ccccc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CC(COc2ccccc2)OC1=O
Yield: 72.6 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 113 mg of sodium hydride (as a 55% by weight dispersion in mineral oil), 10 ml of anhydrous dimethylformamide, 420 mg of 5-phenoxymethyloxazolidin-2-one (prepared as described in Preparation 112) and 471 mg of ethyl 3-bromopropionate were used, to give 463 mg of the title compound having an Rf value of 0.34 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@@H:15]([NH2:17])[CH3:16])[C:6]=2[N:18]=1.C1CCC([N:28]=[C:29]=[N:30]C2CCCCC2)CC1.C(OC(NC(NC(OC(C)(C)C)=O)=S)=O)(C)(C)C.C(O)C(N)(CO)CO>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@@H:15]([NH:17][C:29]([NH2:30])=[NH:28])[CH3:16])[C:6]=2[N:18]=1
Reactant: C[C@H](N)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: C[C@@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=N)N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
To a solution of 2-amino-9-[(2S)-2-aminopropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (30, 100 mg, 0.350 mmol) in methylene chloride (3 mL) was added PL-DCC resin (394 mg, 0.575 mmol) and the mixture was stirred at room temperature for 15 min. N,N′-bis-tert-butoxycarbonylthiourea (112 mg, 0.406 mmol) was added and the reaction mixture was stirred at room temperature overnight. PS-trisamine resin (4.12 g, 3.6 mmol/g, 14.8 mmol) was subsequently added and the resulting mixture was stirred at room temperature overnight. The resins were removed by suction filtration and the filtrate was concentrated under reduced pressure. Purification of the crude material by reverse phase C-18 silica gel chromatography [0-70% acetonitrile in water (containing 0.1% TFA)] afforded 2-amino-9-((2S)-2-{[amino(imino)methyl]amino}propyl)-9H-pyrido[2,3-b]indole-3-carboxamide (71, 48 mg 26%). NH4OAc standard conditions. DAD Retention time=4.98 min. M+H=326.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:14])[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)=[O:4].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][C:11]([CH:8]1[CH2:9][CH2:10][C:5]([CH3:14])([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)=[O:12]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1(C)CCC(C(=O)O)CC1
Solvent: ClCCl
Product: COC(=O)C1(C)CCC(C(=O)Cl)CC1
Temperature: 38 °C

Procedure:
A solution of 4-(methoxycarbonyl)-4-methylcyclohexanecarboxylic acid (6.67 g, 33.3 mmol) in dichloromethane (30 mL) was charged with thionyl chloride (40 mL, 80 mmol) and then heated to 38° C. for 17 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to yield methyl 4-(chlorocarbonyl)-1-methylcyclohexanecarboxylate, which was used without further purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)[CH:13]=2)[CH:8]=1)(=O)=O.CN(C=O)C.[CH3:32][C:33]#[CH:34].Cl>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[F:24][C:19]1[CH:18]=[C:17]([C:12]2[CH:11]=[CH:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:32]#[C:33][CH3:34])[CH:8]=3)[CH:13]=2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: C#CC
Reactant: O=S(=O)(Oc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1)C(F)(F)F
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC#Cc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1
Reaction time: 2 h

Procedure:
11.4 g of 6-(3,4-difluorophenyl)-2-naphthyl trifluoromethanesulfonate and 60 ml of DMF were dissolved in 20 ml of triethylamine. To the solution were then added 0.4 g of tetrakis(triphenylphosphine)palladium (0) and 0.1 g of copper iodide (I). Methyl acetylene was then introduced into the reaction mixture at ordinary temperature and pressure. The reaction mixture was then stirred for 2 hours. The reaction solution was neutralized with a 10% hydrochloric acid, extracted with 100 ml of toluene, and then washed with water and saturated brine. The solvent was then distilled off. The residue was then purified through silica gel column chromatography (hexane) to obtain 7.4 g of 2-(3,4-difluorophenyl)-6-(1-propinyl)naphthalene.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(=[O:4])=[O:3].Br[C:13](C)(C)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:3])=[O:4]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CS(=O)(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1S(C)(=O)=O

Procedure:
To a solution of 2-(methylsulfonyl)phenol (200 mg, 1.16 mmol) in CH3CN (10 mL) was added ethyl 2-bromo-2-methylpropanoate (232 mg, 1.39 mmol) and K2CO3 (690 mg, 5 mmol) at 25° C. The mixture was refluxed for 16 h and then quenched by addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>CS(C)=O>[CH:22]1([NH:25][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 20-mL sealed tube, was placed methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (200 mg, 0.67 mmol, 1.00 equiv), cyclopropanamine (10 mL), DMSO (1 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with H2O. The resulting solids were collected by filtration and applied onto a silica gel column with PE/EA (50:1). This resulted in 182.4 mg (83%) of methyl 3-(cyclopropylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[O:18][N:17]=[C:16]([O:19][CH2:20][CH:21]3[O:23][CH2:22]3)[CH:15]=2)[CH:11]=[CH:12][CH:13]=1.[Cl-].[Na+]>C(#N)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[O:18][N:17]=[C:16]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][OH:2])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Clc1cccc(-c2cc(OCC3CO3)no2)c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: OCC(O)COc1cc(-c2cccc(Cl)c2)on1
Yield: 82.5 %

Procedure:
100 ml (72.3 mmoles) of a 10% w/v aqueous solution of potassium carbonate were added to a solution of 15.0 g (59.6 mmoles) of 5-(m-chlorophenyl)-3-(2,3-epoxypropoxy)isoxazole (prepared as described in Preparation 2) in 50 ml of acetonitrile, and the mixture was heated under reflux for 3 hours. At the end of this time, the reaction mixture was cooled by allowing it to stand, and then 400 ml of a 10% w/v aqueous solution of sodium chloride were added thereto, and the mixture was extracted twice, each time with 400 ml of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was then purified by column chromatography through silica gel, eluted with a 1:2 by volume mixture of benzene and ethyl acetate, to give 13.2 g (yield 82.5%) of the title compound as a colorless amorphous powder, melting at 92°-93° C.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C)C=O>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:13]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)CCl
Reactant: CN(C)CCNc1ccc(-c2n[nH]c3ncccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(-c2ccc(NCCN(C)C)cc2)c2cccnc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 6 g of 3-[4-(2-dimethylaminoethylamino)phenyl]-1H-pyrazolo[3,4-b]pyridine, 5 g of potassium carbonate and 60 ml of dimethylformamide was added dropwise 4.6 g of ethyl chloroacetate. The mixture was stirred at 50° C. for 4 hours. After the solvent was distilled off, the residue was dissolved in ethyl acetate and washed with water. After ethyl acetate was distilled off, the residue was purified by column chromatography to give ethyl 3-[4-(2-dimethylaminoethylamino)phenyl]-1H-pyrazolo[3,4-b]pyridin-1-ylacetate in an oily form.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CO>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:23])[CH2:22][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC1CO1
Solvent: CO
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Yield: 33 %

Procedure:
A solution of methyl 3-[5-acetamido-2-(2,3-epoxypropoxy)benzoyl]propionate (0.52 g, 0.0016 mole), t-butylamine (20 ml) and methanol (10 ml) was heated under reflux for 16 hours. Evaporation of the reaction mixture left an oil which was dissolved in ethanol and treated with ether to give crystalline methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21 g, 33%; m.p. 127°-128°). (Found; M+, 394. C20H30N2O6 requires: M, 394).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C)n(C(C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (2.73 g), (1-bromoethyl)benzene (1.15 mL) and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 19%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:17][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)c(-c2ccccc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CBr)cc1-c1ccccc1
Yield: 99.3 %

Procedure:
A mixture of 4-methyl-2-phenylbenzoic acid (1.66 g, 7.82 mmol), prepared as in Example 227B, N-bromosuccinimide (1.40 g, 8.21 mmol) and 2,2′-azobisisobutyronitrile (25 mg) in carbon tetrachloride (30 mL) was stirred at reflux for 1 hour. The reaction mixture was poured into ethyl acetate and extracted with water (3×) and brine, dried, filtered, and concentrated in vacuo to give 4-bromomethyl-2-phenylbenzoic acid (2.26 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
2.5 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine were dissolved in 50 ml of pyridine and treated at room temperature with a solution of 1.7 g of benzoyl chloride in 20 ml of tetrahydrofuran. After stirring at room temperature for two hours the reaction mixture was poured on to ice-water and, after acidification with 3N hydrochloric acid, extracted with ethyl acetate. The oil obtained after drying and evaporating the organic phase was crystallized from hexane/ethyl acetate and gave 3 g of N-(5,6,7,8-tetrahydro-5,5,8.8-tetramethyl-2-naphthyl)benzamide in white crystals, m.p. 146° C.-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.O[Li].O.OO>O1CCCC1>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[O:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:13][CH:12]=1
Reactant: Cc1cccc(N)c1O
Reactant: S=C=Nc1ccc(Br)cc1
Agent: OO
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2nc(Nc3ccc(Br)cc3)oc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient solution of 2-amino-6-methylphenol (0.74 g, 6.0 mmol) and 4-bromophenyl isothiocyanate (1.28 g, 6.0 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the dropwise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 303 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:28](O)(=[O:32])[CH2:29][CH:30]=[CH2:31].N(C(OCC)=O)=NC([O-])=O>CCOCC>[C:28]([O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:32])[CH2:29][CH:30]=[CH2:31]
Reactant: OCc1ccccc1
Reactant: C=CCC(=O)O
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: C=CCC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
138 g (535 mmol) Triphenylphosphine and 84 ml (812 mmol) benzyl alcohol were added dropwise to 46 g (535 mmol) 3-butenoic acid dissolved in 500 ml ether and 87 ml (535 mmol) ethyl azodicarboxylate and the mixture stirred for 7 hours and allowed to stand overnight. After evaporation of the solvent, the residue was purified by column chromotography (silica gel, hexane/ethyl acetate=95:5) and a sample analysed by thin layer chromatography (hexane:ethyl acetate=1:1) (Rf=0.61).
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[NH:19][CH:18]=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CO.O.[OH-].[Li+].OP(O)(O)=O>O>[CH:1]1([C:5]2[C:14]([C:15]3[NH:19][CH:18]=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(-c2nnc[nH]2)c(C2CCC2)cc1C
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C2CCC2)c(-c2nnc[nH]2)cc1C(=O)O
Temperature: 40 °C
Reaction time: 42 h
Yield: 98.8 %

Procedure:
To crude methyl 4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoate (compound 202.2, 0.24 mmol, 1.0 equiv) from the previous step in a 4-mL vial was added methanol (1.5 mL) and water (0.5 mL) and lithium hydroxide monohydrate (20 mg, 0.48 mmol, 2.0 equiv), The resulting mixture was stirred at 40° C. for 42 hours. The reaction mixture was diluted into water (5 mL), acidified to pH 3 with 1M H3PO4 and extracted with DCM (3×5 mL). The organics were dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a white solid (61 mg, 98% over 2 steps). m/z (ES+) 258 (M+H)+.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[NH:19][C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[CH:10]=1)([CH3:8])[CH3:7].CN([CH:23]=[O:24])C>>[CH:6]([C:9]1[NH:19][C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]=1[CH:23]=[O:24])([CH3:8])[CH3:7]
Reactant: COc1cc2cc(C(C)C)[nH]c2cn1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(C=O)c(C(C)C)[nH]c2cn1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
POCl3 (1.1 ml, 12.5 mmol) was added to anhydrous DMF (10 ml) at 0° C. slowly and stirred for 0.5 h. This was added to a solution of 2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine (Compound 5, 468 mg, 2.5 mmol) in anhydrous DMF (15 ml) at room temperature. The mixture was then heated to 90° C. for 2 h and cooled to room temperature, quenched cautiously with aqueous Na2CO3, extracted with EtOAc (×4). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][C:43]1[NH:47][N:46]=[N:45][N:44]=1>CS(C)=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:42][C:43]3[NH:47][N:46]=[N:45][N:44]=3)[CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8]
Reactant: ClCc1nnn[nH]1
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCc3nnn[nH]3)ccc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 585 from (2S,4R)-1-[2-(3-acetyl-6-hydroxy-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 583 (60.0 mg, 0.122 mmol), cesium carbonate (120 mg, 0.367 mmol) and 5-(chloromethyl)-1H-tetrazole (44.0 mg, 0.366 mmol) in DMSO (2.5 mL). Solid. MS (LC/MS): 572 [M+H]+; tR (HPLC conditions k): 3.23 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[O:16])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CC1
Yield: 81.3 %

Procedure:
In the same manner as in Reference Example 2, N-tert-butoxycarbonyl-L-asparagine (5.0 g) and 1-methylpiperazine (2.2 g) were condensed to obtain colorless crystal 1-(N-tert-butoxycarbonyl-L-asparaginyl)-4-methylpiperazine (5.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.I[C:30]1[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:30]2[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: Cn1cc(I)cn1
Product: Cn1cc(C#Cc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)cn1

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and 4-iodo-1-methyl-1H-pyrazole.