Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[F:20])=[C:10]([CH3:21])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=1[CH3:24])=[O:5])[CH3:2].[Br:25]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[F:20])=[C:10]([CH3:21])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=1[CH2:24][Br:25])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1CBr
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a solution of 4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.150 g, 0.451 mmol) in DMF (5 mL) was added N-bromosuccinimide (0.084 g, 0.474 mmol). After stirring for 30 minutes, the reaction mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to yield a yellow residue. Purification by flash column chromatography (methylene chloride) gave 0.122 g (66%) of a yellow residue.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]C)=[O:35])[CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(COc5c(C)cccc5C)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C)c1OCc1noc(C(C)C)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 120 °C
Yield: 62.3 %

Procedure:
To a solution of methyl 6-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (23 mg, 0.043 mmol) in 2:1 tetrahydrofuran:methanol (0.75 mL) was added 1 N sodium hydroxide (0.064 mL, 0.064 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The mixture was concentrated and water was added followed by 1 N hydrochloric acid (0.064 mL, 0.064 mmol). The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine and concentrated to afford of 6-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a yellow solid (14 mg, 62%). 1H-NMR (400 MHz, CDCl3) δ 8.43 (d, J=9 Hz, 1H), 8.29 (d, J=8 Hz, 1H), 8.21 (d, J=9 Hz, 1H), 8.07 (m, 2H), 7.70 (d, J=9 Hz, 2H), 7.10 (d, J=9 Hz, 2H), 7.01-6.62 (m, 3H), 5.06 (s, 2H), 4.97 (s, 2H), 3.30 (septet, J=7 Hz, 1H), 2.23 (s, 6H), 1.39 (d, J=7 Hz, 6H). HRMS (ESI) C32H30N2O5 calculated: 437.2263 (M+H)+, found: 437.2263 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@H:8]([OH:51])[CH2:9][CH2:10][N:11]([C@@H:23]2[C:40]3=[CH:41][C:36](=[CH:37][C:38]([O:42][CH3:43])=[N:39]3)[C:35]3[C:30](=[CH:31][C:32]([NH:44][C:45](=[O:48])[O:46][CH3:47])=[CH:33][CH:34]=3)[NH:29][C:28](=[O:49])[C@H:27]([CH3:50])[CH2:26][CH2:25][CH2:24]2)[C:12](=[O:22])[CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[F:52].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:51])[CH2:9][CH2:10][N:11]([C@@H:23]2[C:40]3=[CH:41][C:36](=[CH:37][C:38]([O:42][CH3:43])=[N:39]3)[C:35]3[C:30](=[CH:31][C:32]([NH:44][C:45](=[O:48])[O:46][CH3:47])=[CH:33][CH:34]=3)[NH:29][C:28](=[O:49])[C@H:27]([CH3:50])[CH2:26][CH2:25][CH2:24]2)[C:12](=[O:22])[CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[F:52]
Reactant: CCOP(=O)(CC(=O)N(CC[C@@H](O)c1nccc(Cl)c1F)[C@H]1CCC[C@@H](C)C(=O)Nc2cc(NC(=O)OC)ccc2-c2cc(OC)nc1c2)OCC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(CC(=O)N(CCC(=O)c1nccc(Cl)c1F)[C@H]1CCC[C@@H](C)C(=O)Nc2cc(NC(=O)OC)ccc2-c2cc(OC)nc1c2)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 5P (15.5 mg, 0.020 mmol) in anhydrous DCM (4 mL) was added Dess-Martin periodinane (11.18 mg, 0.026 mmol). The mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM (3×). The combined organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated to give 5Q (15 mg, 99%). MS (ESI) m/z: 762.0 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14](=[CH:20][C:21]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([OH:29])=O)[C:22]=3[CH3:30])[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][NH2:36])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][NH:36][C:27]([C:23]1[C:22]([CH3:30])=[C:21]([CH:20]=[C:14]2[C:13]3[C:17](=[CH:18][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:11][CH:12]=3)[NH:16][C:15]2=[O:19])[NH:25][C:24]=1[CH3:26])=[O:29])[CH3:32]
Reactant: CCN(CC)CCN
Reactant: Cc1[nH]c(C=C2C(=O)Nc3cc(NC(=O)c4ccccc4)ccc32)c(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(NC(=O)c4ccccc4)ccc32)c1C
Reaction time: 2 h

Procedure:
To a solution of N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-benzamide (80 mg, 0.32 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (53 mg, 0.32 mmol) in ethanol (8 ml) is added 4 drops of piperidine. It is stirred at 80° C. for 20 hours and then cooled to room temperature. The precipitate is collected by vacuum filtration, washed with a small amount of cold ethanol to give crude 5-(6-benzoylamino-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid. This carboxylic acid (20 mg, 0.050 mmol) is then dissolved in DMF (1 ml). To this reaction is also added N, N-diethylethylenediamine (17 mg, 0.15 mmol), N,N-diisopropylethylamine (19 mg, 0.15 mmol) and HATU (23 mg, 0.061 mmol). It is stirred for 2 hours and concentrated. The desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 1.24 (t, 6H, J=7.2 Hz), 2.43 (s, 3H), 2.47 (s, 3H), 3.20-3.24 (m, 6H), 3.57 (q, 2H, J=5.4 Hz), 7.38 (d, 1H, J=6.6 Hz), 7.53 (t, 2H, J=7.2 Hz), 7.56 (s, 1H), 7.58-7.61 (m, 2H), 7.73-7.77 (m, 2H), 7.96 (d, 2H, J=7.8 Hz), 9.32 (s, 1H), 10.27 (s, 1H), 10.97 (s, 1H), 13.60 (s, 1H); LC-MS: 500.2 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:35][CH3:36]>>[NH:2]=[C:1]([N:40]1[CH2:41][CH2:42][N:37]([CH2:34][CH2:35][CH3:36])[CH2:38][CH2:39]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 30 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of n-propylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C@@H:10]([OH:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[CH:27]=[C:28]([CH2:32][O:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[CH:26][CH:27]=3)=[CH:19][CH:18]=2)[C@@H:10]([OH:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCOCc1cccc(Br)c1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 26 h

Procedure:
A solution of 11.8 g (35.0 mmol) of (3R,4R,5S)-5-ethoxy-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butylester in 40 ml of dimethylformamide was treated in succession with 10.3 g (45.0 mmol) of 3-bromo-propoxymethyl-benzene and 8.29 g (60.0 mmol) of potassium carbonate. This mixture was stirred at 120° C. for 26 hours. Subsequently, it was filtered, concentrated to a few milliliters, poured into 300 ml of an ice/water mixture and extracted three times with 100 ml of dichloromethane each time. The combined organic phases were washed once with a small amount of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The resulting crude product was separated on silica gel using a mixture of dichloromethane and methanol as the eluent and yielded (3R,4R,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-hydroxy-piperidine-1-carboxylic acid tert-butylester as colorless oil; MS: 486 (M+H+); 508 (M+Na+).
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])(=O)C.[Na+].C(O)(=O)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:21]([NH:11][NH:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNC(=O)c1ccccc1O
Reactant: O=C(Cl)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(NNC(=O)c1ccccc1O)c1ccccc1

Procedure:
A four neck flask (1 liter) equipped with a thermometer and a stirrer was charged with 60.8 g (0.4 mol) of salicylohydrazide, 49.2 g (0.6 mol) of sodium acetate and 700 ml of acetic acid. Dropwise added thereto was 67.4 g (0.48 mol) of benzoyl chloride in one hour while stirring, and stirring was continued at room temperature (20° C.) for 3 hours. After finishing the reaction, 1.5 liter of deionized water was added and crystal was filtered off. After washing sufficiently the crystal with 500 ml of methanol, it was dried under reduced pressure to obtain slightly brown crystal.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH:34]1[CH:39]2[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]2)[CH2:35]1>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:33][CH:34]2[CH:39]3[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]3)[CH2:35]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:3]=1
Reactant: Nc1cc(OCc2cccc(Cl)c2)c(C(=O)O)cc1Cl
Reactant: NC1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1cc(OCc2cccc(Cl)c2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reaction time: 0.75 h
Yield: 73.3 %

Procedure:
A solution of 4-amino-5-chloro-2-[(3-chlorophenyl)methoxy]benzoic acid (3.13 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 11.5 mmol), stirred for 45 minutes, and degassed over 15 minutes under a stream of nitrogen. A solution of 3-aminoquinuclidine (1.85 g, 14.7 mmol) in anhydrous tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and partitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (50 mL) containing some 2-propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo, and rinsed with water in order to remove the remaining imidazole by-product. The residue was dried azeotropically with toluene, then taken up in tetrahydrofuran and filtered through a short column of alumina (eluted with 10% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated from cold ether/petroleum ethers (30°-60° C.), and recrystallized from acetonitrile (2 crops) to afford 3.08 g (73%) of pale yellow solid; mp 168°-169° C.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32]O[CH2:30][CH2:29]1)[CH:19]=2)=[O:15])=[O:6])#[N:2].[N:34]1(CCO)CCOC[CH2:35]1>>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:34]([CH3:35])[CH2:30][CH2:29]1)[CH:19]=2)=[O:15])=[O:6])#[N:2]
Reactant: OCCN1CCOCC1
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccc(OCCN3CCOCC3)cc2[nH]1
Product: CN1CCN(CCOc2ccc3cc(C(=O)N[C@H]4CCCC[C@H]4C(=O)NCC#N)[nH]c3c2)CC1

Procedure:
N-((1S,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexyl)-6-(2-morpholin-4-ylethoxy)-1H-indole-2-carboxamide using Mitsunobu coupling with 2-morpholin-4-yl-ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[CH3:2].[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:21].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([CH2:20][CH3:21])=[CH:23][CH:24]=2)[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: CCOc1cc(CN2CCC(=O)CC2)ccc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(Nc3ccc(CC)cc3)CC2)ccc1OC
Temperature: 85 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
A solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-one (94.8 mg, 0.36 mmol, 1.2 equiv; intermediate C1) and 4-ethyl-phenylamine (36.4 mg, 0.30 mmol, 1.0 equiv; commercially available) in ethanol (2 mL) and acetic acid (0.38 mL) was heated to 85° C. After 2 h, sodium cyanoborohydride (22.6 mg, 0.36 mmol, 1.2 equiv), dissolved in ethanol (1 mL), was added and the mixture stirred at 85° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 17.2 mg (16%) of the title compound. MS (ISP): 369.4 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][N:20](C(=O)C(F)(F)F)[CH2:19][CH2:18]4)[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:13]3[CH2:16][CH:15]([N:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)[CH2:14]3)=[O:12])=[CH:29][CH:30]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(c1ccc(C2CCCCC2)cc1)N1CC(N2CCNCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 1i (0.95 g, 2.24 mmol) in CH3OH (16 mL) and H2O (4 mL) was added K2CO3 (0.8 g, 5.79 mmol). The mixture was stirred at room temperature for 1 h. After filtration, the solvent was removed by evaporation. The crude compound 1j was used in the next reaction without further purification. MS m/z (M+H+) 328.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[CH:29](=O)[CH3:30]>>[CH2:29]([NH:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1)[CH3:30]
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CC=O
Product: CCNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid and acetaldehyde following the procedure described in Example 71. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 418 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[CH:19]=[CH:18][N:17]=[N:16]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:16]2[N:17]=[CH:18][CH:19]=[N:15]2)[CH3:13])[CH2:11][O:10]1
Reactant: c1c[nH]nn1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1nccn1)[C@@]1(c2ccc(F)cc2F)CO1

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (202 mg) and 1H-1,2,3-triazole (0.17 ml), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(2H-1,2,3-triazol-2-yl)ethyl]oxirane (172 mg) was obtained by the same way as in Reference Example 10.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:24])([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[NH2:18]>>[CH3:16][C:17]([NH:18][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH3:24]
Reactant: CC(C)(N)c1nccs1
Reactant: Cc1ccc(C(=O)O)nc1OCC1CC1
Product: Cc1ccc(C(=O)NC(C)(C)c2nccs2)nc1OCC1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36 d) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=332.2 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][C:8]([C:25]3[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:9][CH:10]=2)[N:5]=1.[O:35]([CH:37]([CH3:39])[CH3:38])[Na]>C(O)(C)C>[CH:37]([O:35][CH2:3][C:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:11]2[C:6](=[CH:7][C:8]([C:25]3[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:9][CH:10]=2)[N:5]=1)([CH3:39])[CH3:38]
Reactant: CC(C)O[Na]
Reactant: FC(F)(F)c1ccc(Nc2nc(CCl)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)OCc1nc(Nc2ccc(C(F)(F)F)cc2)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a suspension of [2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine hydrochloride (1.9 g, 0.0037 mol) in dry isopropanol (100 mL), add 20 equivalents of NaO-iPr (prepared from Na and isopropanol). Stir the pale yellow mixture at 60° C. for 5 hours, cool and evaporate the solvent under reduced pressure. Partition the residue between ethyl acetate and water and wash the organic layer with water (1×). Dry the organic layer (Na2SO4) and concentrate to give [2-isopropoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine as a foam. IC50 in standard assay of capsaicin receptor activity is less than 10 nanomolar.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl.C(Cl)Cl>O1CCCC1>[O:6]1[CH2:7][CH2:8][N:3]([CH2:9][CH:11]2[O:13][CH2:12]2)[CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C1CN(CC2CO2)CCO1
Reaction time: 48 h
Yield: 18.5 %

Procedure:
0.87 g (20 mmole) of sodium hydride (as a 55% w/w suspension in mineral oil) were suspended in 20 ml of tetrahydrofuran. 1.74 g (20 mmole) of morpholine and subsequently 1.85 g (20 mmole) of epichlorohydrin were then added, whilst ice-cooling, to this suspension, and the reaction mixture was allowed to stand at room temperature for 48 hours. At the end of this time, methylene chloride was added to the reaction mixture, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride), to give 530 mg of 1-morpholino-2,3-epoxypropane.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:21]2([CH3:22])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[C:18](=[O:20])[CH3:19])[C@H:13]2[C@@H:4]([C@:5]3([CH3:24])[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:23])[CH:7]=[CH:6]3)[CH2:3]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>N1C=CC=CC=1>[S:26]([O:1][C@@H:2]1[C@@:21]2([CH3:22])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[C:18](=[O:20])[CH3:19])[C@H:13]2[C@@H:4]([C@:5]3([CH3:24])[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:23])[CH:7]=[CH:6]3)[CH2:3]1)([CH3:25])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C[C@H](OS(C)(=O)=O)[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
12α-Hydroxypregna-1,4-diene-3,20-dione (3.3 g) was dissolved in 17 mlof pyridine. To the solution was added 3.4 g of methanesulfonyl chloride, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was then poured into 300 ml of diluted hydrochloric acid, and the resulting mixture was extracted with three 300 ml portions of benzene. Theextracts were combined and washed in sequence with diluted hydrochloric acid, aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. Low-boiling fractions were distilled off under reduced pressure from the extract to give 3.8 g of crude 12α-mesyloxypregna-1,4-diene-3,20-dione, which was recrystallized from ethyl acetate. The physical properties for the thus-purified product were as follows:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH:18]=3)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2cnco2)cc1
Yield: 23 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 4-(1,3-oxazol-5-yl)benzenesulfonyl chloride (17.2 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 23% yield (4.2 mg). MS (ESI+) calcd mass for C16H12N6O3S 368.069159, found 368.069509.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:16](OC1C=CC(CO)=CC=1)[CH2:17][CH2:18][CH2:19]CC>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH2:2][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCOc1ccc(CO)cc1
Reactant: CCOc1ccc(CCl)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCOc1ccc(CCl)cc1

Procedure:
This molecule was synthesized following the same general procedure as that for the preparation of 4-ethoxybenzyl chloride; thionyl chloride (7.17 g, 60.3 mmol), 4-hexyloxybenzyl alcohol (11.3 g, 54.3 mmol), CH2Cl2 (150 mL).