Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:16]3(C(O)=O)[CH2:18][CH2:17]3)[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1(P([N:36]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:36][C:16]1([C:12]2[CH:11]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)[CH:15]=[N:14][CH:13]=2)[CH2:18][CH2:17]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(-c2cncc(C3(C(=O)O)CC3)c2)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cncc(C3(N)CC3)c2)cc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)cyclopropanecarboxylic acid (900 mg, 3.01 mmol) in toluene (50 mL) was added TEA (0.63 mL, 4.52 mmol) and diphenylphosphoryl azide (0.977 mL, 4.52 mmol), and the mixture was heated to 100° C. for 4 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was re-dissolved in THF (100 mL) and a solution of KOtBu (2.03 g, 18.08 mmol) in THF (40 mL) was added. The mixture was stirred at 0° C. for 1 h. The mixture was then warmed to room temperature overnight. Silica gel (10 g) was added and the mixture was concentrated in vacuo. The residue was purified by silica chromatography eluting with a 0-10% MeOH-DCM gradient to give 4-(5-(1-aminocyclopropyl)pyridin-3-yl)-2-chlorobenzonitrile. m/z 270.0, 272.0 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14](#[N:17])[CH:15]=[CH2:16]>CO>[CH3:1][N:2]([CH2:16][CH2:15][C:14]#[N:17])[CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5]
Reactant: C=CC#N
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Product: CN(CCC#N)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 63 °C

Procedure:
607 g (3.1 mol) of N-methylglucamine (NMG) are suspended in 729 g of methanol in a 2 l four-necked flask with a stirrer, dropping funnel, reflux condenser and thermometer. The reaction mixture is heated to 63° C., while stirring. 163 g (3.1 mol) of acrylonitrile are added dropwise in the course of 30 minutes. When the addition has ended, the clear solution is stirred at 63° C. for a further 3 hours. According to analysis by gas chromatography, the conversion in the reaction is complete, so that the reaction product can be employed directly for the hydrogenation (second process stage).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]4[C:14](=[CH:15][C:16]5[O:22][CH2:21][O:20][C:17]=5[CH:18]=4)[NH:13][C:12](=O)[N:11]=3)=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>CN(C=O)C>[Cl:26][C:12]1[N:11]=[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[C:19]2[C:14](=[CH:15][C:16]3[O:22][CH2:21][O:20][C:17]=3[CH:18]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2[nH]1)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 25 °C
Yield: 111.1 %

Procedure:
4-(3,4-Methylenedioxyphenyl)-6,7-methylenedioxyquinazolin-2(1H)-one (1 g, 3.23 mmol) was treated with DMF (one drop) and phosphorous oxychloride (7 mL, 75 mmol) and the suspension was heated to reflux for 4 h. Upon cooling to rt, the reaction mixture was poured into ice and the pH was adjusted to ˜8 with 3N NaOH solution. The precipitate was vacuum filtered and dried to give the title compound as a brown granular solid (1.18 g). 1H NMR (DMSO-d6) 6.16 (s, 2H), 6.32 (s, 2H), 6.85-7.41 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Brc1ccc(C2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCCC1c1ccc(Br)cc1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A solution of 2-(4-bromophenyl)pyrrolidine (2.26 g, 10 mmol) in dioxane (18 mL) and water (12 mL) was added potassium carbonate (5.52 g, 40 mol) and benzyl chloroformate (1.88 g, 11 mmol) at ambient temperature and stirred overnight. Then the mixture was partitioned between ethyl acetate and brine. The organic phase was concentrated in vacuo and the residue was purified by column chromatography (silica gel, EtOAc:hexane=1:10) to give the title compound (2.95 g, 82%) as a colorless oil. LC-MS (ESI) m/z: 360 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:20]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:20][C:19]2[CH:18]=[C:17]([F:16])[CH:24]=[C:23]([F:25])[CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1cc(F)cc(CBr)c1
Product: N#Cc1ccc(N(Cc2cc(F)cc(F)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 3,5-difluorobenzyl bromide
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[C:11]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH:12]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:18][O:17][C:15]([CH:11]1[CH2:14][CH2:13][CH:12]1[N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])=[O:16]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: COC(=O)C1=CCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C1CCC1n1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 66 h
Yield: 61 %

Procedure:
Adenine (486 mg, 3.6 mmol) was combined with an excess of methyl 1-cyclobutene carboxylate (~25 mmol) from Step B of Example 35 and 53 μL (0.36 mmol) of DBU in 75 mL of acetonitrile and the mixture was stirred at ambient temperature, under a nitrogen atmosphere. After 66 h, a second 53 μL aliquot of DBU was added and stirring continued. After a total of 136 h, the reaction was quenched by the addition of 0.28 mL of glacial acetic acid and concentrated in vacuo. The residue was dissolved in approximately 3 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @5-10 psi with a step-wise solvent gradient of methanol in methylene chloride, starting with 100% methylene chloride and increasing in 2% steps to 8% methanol, each step was 200 mL of solvent. The title compound was obtained in 61% yield (542mg) as a mixture of cis and trans isomers and equilibrated to the desired trans isomer by treating the mixture of isomers with 394 μL of DBU in 35 mL of acetonitrile at 45° C., under nitrogen, for 46 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in approximately 2 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @5 psi with a step-wise solvent gradient of 200 mL of methylene chloride followed by 200 mL of 5% methanol in methylene chloride and 200 mL of 7% methanol in methylene chloride to give 502 mg (57% yield) of the desired trans isomer of the title compound; 1H NMR (CD3OD) δ 2.11 (m, 1H), 2.30 (m, 1H), 2.45 (m, 1H), 2.77 (m, 1H), 3.68 (s, 3H), 4.01 (m, 1H), 5.18 (q, 1H), 8.20 (s, 1H), 8.25 (s, 1H); MS DCI-NH3M/Z: 248 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Br>CC(O)=O>[Br:16][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
To a solution of 2,4-di-t-butylphenol (Aldrich, 2.0 g, 9.7 mmol) in 2 ml of HOAc was added Br2 (0.5 ml, 9.7 mmol). The reaction mixture was stirred at room temperature for 12 hours. Solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate/hexane 1/20) to yield the desired product (2.54 g) as a white solid. 1H NMR δ 7.33 (d, J=2.3 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 1.41 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]2[CH2:36][O:35]2)=[CH:30][N:29]=1>C(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:36][C@@H:34]([C:31]1[CH:30]=[N:29][C:28]([Cl:27])=[CH:33][CH:32]=1)[OH:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCNCc3ccccc3)cc2)cc1
Reactant: Clc1ccc([C@@H]2CO2)cn1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3ccc(Cl)nc3)cc2)cc1
Yield: 70.5 %

Procedure:
A solution of methyl 4′-[2-(benzylamino)ethyl]-1,1′-biphenyl-4-carboxylate (460 mg), and 2-chloro-5-[(2R)-2-oxiranyl]pyridine (207 mg) in ethanol (10 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chlorofor:methanol=100:1) to give methyl 4′-[2-[N-benzyl-N-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate (470 mg) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.N1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[S:32]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10])(=[O:34])=[O:33]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 2-methoxy-4-nitrobenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight or until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with 10% aqueous HCl (20 mL), water (20 mL), and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to yield 353 mg of benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-4-nitrobenzenesulfonylamino)phenyl]-amide. LC: Tr 1.21 min; MS: 520.7.7 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 4.24 (s, 3H), 6.72 (bs, 1H), 6.88 (d, 1H), 7.03 (t, 1H), 7.16 (t, 1H), 7.30 (d, 1H), 7.52 (t, 1H), 7.51 (t, 1H), 7.64 (s, 1H), 7.67-7.88 (m, 5H), 7.92 (s, 1H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>>[F:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1
Reactant: Cc1ccc(F)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)cc1N1CCNCC1
Reaction time: 1 h
Yield: 118.8 %

Procedure:
In a 20 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 4-(5-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 16c (203.70 mg, 0.69 mmol) was taken up in clean, dry, reagent grade dichloromethane (5.00 ml, 77.53 mmol). The mixture was stirred until all solids were in solution and the trifluoroacetic acid (0.50 ml, 6.73 mmol) was added in one portion. The reaction stirred at room temperature for 1 h. After 1 h, the volatiles were removed under reduced pressure. The yellow oil was then taken back up in 5 ml of dichloromethane and the volatiles were removed once more under reduced pressure. The resultant yellow oil was further dried under high vacuum. The product, 1-(5-fluoro-2-methyl-phenyl)-piperazine 16d (160.10 mg, 0.82 mmol), was isolated as a yellow oil and was carried on without further purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]3[CH2:15][C:16]4([CH2:19][CH:12]3[C:11]2=[O:20])[CH2:18][O:17]4)=[CH:6][CH:5]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(O)C=CC=CC=1>O>[OH:17][C:16]1([CH2:18][NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH:12]2[C:11](=[O:20])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:22])([F:21])[F:1])=[CH:9][CH:8]=3)[CH2:14][CH:13]2[CH2:15]1
Reactant: O=C1C2CC3(CO3)CC2CN1c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccccc1
Solvent: Oc1ccccc1
Solvent: O
Product: O=C1C2CC(O)(CNc3ccccc3)CC2CN1c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 24 %

Procedure:
rac-(3aR,5S,6aS)-2-[4-(trifluoromethoxy)phenyl]hexahydro-1H-spiro[cyclopenta[c]pyrrole-5,2′-oxiran]-1-one (80 mg, 0.25 mmol), aniline (5 mL) and PhOH (23 mg, 0.24 mmol) were mixed together, and the mixture was stirred for 24 h at 60° C. The solution was then poured into water (25 mL) and extracted with ether (3×20 mL). The combined ether was washed with sodium hydroxide (10%, 3×10 mL), with water (30 mL) and dried over Na2SO4. The solvent was removed and the residue was purified by prep-TLC (petroleum ether:ethyl acetate=1:1) to yield the title compound (25 mg, 24%). 1H NMR (300 MHz, CDCl3): δ 7.57-7.55 (m, 2H), 7.27-7.13 (m, 4H), 7.00-6.93 (m, 3H), 5.26 (bs, 1H), 4.07 (t, 1H, J=9.3 Hz), 3.75-3.73 (m, 1H), 3.34-2.22 (m, 3H), 3.05-2.90 (m, 1H), 2.46-2.42 (m, 1H), 2.02-1.90 (m, 3H); LC-MS: 407.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([OH:34])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:48][CH:49](Br)[CH3:50]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:50][CH2:49][Br:48])=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Br)Br
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCBr)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21

Procedure:
2.22 g of 5-benzyloxy-3-(1-tert-butoxycarbonyl-5-hydroxy-1H-indol-2-yl)-indazole-1-carboxylic acid tert-butyl ester and 7.8 g of cesium carbonate, in 22 ml of dibromoethane, are stirred at 80° C. (temperature of the oil bath) for 48 hours. The reaction mixture is filtered through sintered glass and the solid is rinsed with 20 ml of dichloromethane. The filtrate is concentrated under vacuum. The reaction crude is purified by flash chromatography on 160 g of silica. The eluent is 100% dichloromethane. 2 g of 5-benzyloxy-3-[5-(2-bromo-ethoxy)-1-tert-butoxycarbonyl-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester are isolated.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:17]([OH:19])=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(N1CCCCC1)C.ClC(OCC)=O.[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])[NH2:38].Cl>O1CCCC1>[CH3:34][O:35][C:36](=[O:40])[C@H:37]([CH3:39])[NH:38][C:17](=[O:19])[C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](Cc1ccc(OC(C)=O)cc1)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: CCN1CCCCC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(OC(C)=O)cc1)NC(C)=O
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of N,O-diacetyltyrosine (13.3 g, 50 mmoles) and N-ethylpiperidine (7 ml) in tetrahydrofurane (100 ml) precooled to -15° C. was added ethyl chloroformate (5 ml). After 15 minutes of stirring and cooling (-15° C.) alanine methyl ester liberated from its hydrochloride (7.0 g, 50 mmoles) with N-ethylpiperidine (7 ml) was admixed. After 2 hours of stirring at 0° C. and 12 hours of standing at room temperature, the solution was evaporated, the residue was taken into ethyl acetate and the organic phase was successively washed with 1M hydrochloric acid, water, 5% sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and evaporated. Crystallization from 2-propanol-petroleum ether yielded 10.6 g (60%) of the title product. An analytical sample was recrystallized similarly, m.p. 173° to 176° C. [α]D20 -7.5°.
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[O-:23][CH2:24][CH3:25].[Na+]>CO>[CH2:24]([O:23][CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[CH3:25]
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CI)c2OC1C(F)(F)F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CO
Product: CCOCc1cc(C)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
The ethyl 8-(iodomethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605e, Step 2 (0.2 g, 0.47 mmole) was dissolved in methanol (5 mL) and the solution was cooled to 0° C. (ice bath). Sodium ethoxide (0.10 g, 1.41 mmole) was added dropwise to the above solution, which was stirred for 2 hours at 0° C. The solution was warmed to room temperature and stirred for an additional 2 hours. The reaction was condensed in vacuo to give a yellow oil (0.16 g, 98%). No further purification was performed: GCMS m/z 344.00 (M+).
Reaction SMILES: Cl.C1(C[N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[OH:16])[CH2:11][CH2:10]2)C=CC=CC=1.C(O)C.[H][H]>CO.[Pd]>[F:36][C:33]([F:34])([F:35])[C:30]1[CH:29]=[CH:28][C:27]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)([OH:16])[CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:32][CH:31]=1
Reactant: [H][H]
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
A mixture of 10.0 grams (0.019 mole) of N-phenylmethyl-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine hydrochloride (prepared as in Steps A and B of Example 3) and 3.0 grams of 5% palladium (catalyst) on charcoal in about 200 mL of 1:1 methanol:ethanol was shaken in a Parr hydrogenator for five to six hours at about 85° C., until the theoretical amount of hydrogen gas was taken up. The mixture was cooled to ambient temperature where it stood for about 18 hours. The mixture was filtered and concentrated under reduced pressure to a residue, which was stirred with ethyl acetate and an aqueous solution saturated with sodium bicarbonate until the residue dissolved. The organic layer was separated and passed through phase-separation paper to remove aqueous material. The organic layer was concentrated under reduced pressure, yielding about 7.0 grams of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.Cl.C(OCC)(=O)C>C(OCC)C>[ClH:27].[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1nc2ccccc2o1

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloro-1,3-benzooxazole as starting materials and by operations similar to those of Example 303-3 and 303-4 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C1C(=CC=CC=1)C(O)=[O:22].C(=O)(O)[O-].[Na+]>CO>[O:22]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:4][CH2:3]2)[CH2:1]1
Reactant: C=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 71.9 %

Procedure:
14.7 g of benzyl 4-methylene-1-piperidinecarboxylate was dissolved in 300 ml methanol, 20.4 g of phthalic acid monoperacid magnesium salt and 13.3 g of sodium bicarbonate were added thereto, and the mixture was stirred at room temperature for 7.5 hr. The reaction solution was evaporated. Ethyl acetate was added to the resulting residue which was then washed with water and brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated, and then subjected to silica gel column chromatography to give 11.3 g of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:16][O:17][CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[CH2:32]=O>>[ClH:2].[Cl:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C@H:15]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:16][O:17][CH2:18][CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([CH3:32])[CH2:24][CH2:25]3)=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O=C(N[C@@H](COCCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Reactant: C=O
Agent: Cl
Product: CN1CCC(CCOC[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1
Yield: 137.6 %

Procedure:
Using alkylation method B, 3-chloro-N-[(R)-1-phenyl-2-[2-(piperidin-4-yl)ethoxy]ethyl]-1H-indole-6-carboxamide hydrochloride (300 mg, 0.65 mmol) and paraformaldehyde (195 mg, 6.5 mmol) afforded 213 mg (75%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH2:11])=[N:7]1)[CH3:2].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc(N)n1
Reactant: O=C(O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc(NC(=O)c2ccc(Cl)cc2)n1

Procedure:
59.1 Using general method A, with THF instead of DMF as solvent, (3-amino-pyrazol-1-yl)-acetic acid ethyl ester (example 57.1) was coupled with 4-chlorobenzoic acid to give [3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid ethyl ester. Off-white solid. MS 308.3 ([M+H]+)