Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(O)C>ClCCl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(COC(=O)c2ccc(O)cc2)cc1

Procedure:
4-Hydroxybenzoic acid (1.38 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a. The title compound (2.06 g) was obtained after silica gel column chromatography (0, 1, 2, 3% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.40.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Cc1cccc(OCCCBr)c1
Product: Cc1cccc(OCCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3O)cc2)c1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.742 g of 1-(3-bromopropoxy)-3-methylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.46.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([CH2:16]C(O)=O)#[N:15].C(=O)=O>C(O)(=O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:16][C:14]#[N:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCC(=O)O
Reactant: O=[N+]([O-])c1ccc2c(c1)C=NCC2
Agent: O=C=O
Solvent: CC(=O)O
Product: N#CCC1NCCc2ccc([N+](=O)[O-])cc21
Yield: 76.2 %

Procedure:
A suspension of 7-nitro-3,4-dihydroisoquinoline (13.4 g, 76.1 mmol) and cyanoacetic acid (12.5 g, 150 mmol) in acetic acid (55 ml) was heated at reflux for 0.5 h. After evolution of carbon dioxide had ceased and the reaction mixture had cooled, the solvent was removed on the rotoevaporator. The residue was triturated with isopropanol (100 ml) and the solid was collected. The crude product was partitioned between ethyl acetate and dilute potassium carbonate solution. The dried (MgSO4) organic phase was concentrated to give the title compound as an orange solid (12.6 g, 76%), MS 218 (M+H)+. 1H NMR (CDCl3) 8.03 (dd, 1H), 7.99 (d, 1H), 7.31 (d, 1H), 4.45 (t, 1H, 3.1-3.4 (m, 3H), 2.9-3.0 (m, 3H), 2.07 (broad s, 1H).
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][CH:3]=1.S(O[CH2:13][C:14]([F:17])([F:16])[F:15])(=O)(=O)C>>[I:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH:3]=1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: Cc1ncc(I)[nH]1
Product: Cc1nc(I)cn1CC(F)(F)F

Procedure:
The title compound, MS: m/e=291.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-methyl-1H-imidazole and 2,2,2-trifluoroethyl mesylate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:13])=[CH:5][C:6](=[O:12])[S:7]2.C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][N:26]=[C:27]=[O:28])[CH3:22]>C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][NH:26][C:27]([C:5]1[C:6](=[O:12])[S:7][C:8]2[C:3]([C:4]=1[OH:13])=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)=[O:28])[CH3:22]
Reactant: O=c1cc(O)c2c(F)cccc2s1
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1c(O)c2c(F)cccc2sc1=O
Temperature: 120 °C
Reaction time: 3 h

Procedure:
5-Fluoro-4-hydroxy-thiochromen-2-one (500 mg, 2.55 mmol) was placed in a CEM Microwave vessel and suspended in anhydrous DCM (5 mL.) Triethylamine (710 uL, 5.1 mmol) and isocyanato-acetic acid ethyl ester (572 uL, 5.1 mmol) were added in one portion and the reaction heated to 120° C. in a CEM Discovery Microwave system. After three hours, the reaction was cooled diluted with 10 volumes of dichloromethane, washed with an equal volume of 1N HCl and dried over magnesium sulfate to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Reactant: BrCc1ccco1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccco3)c3ccc(OC)cc23)CC1
Reaction time: 15 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.3 g (1.0 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 2.11 mL (1.3 mmol) of a freshly prepared 0.61 M solution of 2-bromomethylfuran in ethyl ether. After standard work-up, 0.38 g (100% of yield) of 4-(1-furan-2-ylmethyl-5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:32]C)[C:10](=[O:31])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:16](=[O:30])[C:12]3=2)[C:7]1=[O:34].Br>C(O)(=O)C.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:32])[C:10](=[O:31])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:16](=[O:30])[C:12]3=2)[C:7]1=[O:34]
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCN1CCOCC1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=C1c2c(c3n(c(=O)c2O)CCCCN(CCN2CCOCC2)C3=O)CCN1Cc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-morpholin-4-ylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (30 mg, 0.06 mmol) and 33% hydrogen bromide in acetic acid (0.4 mL) in dioxane (2 mL) was stirred at room temperature for 30 minutes. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])=[CH:6][C:5]=1[OH:11]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)c(O)c1

Procedure:
A mixture of 1 g (5.95 mmol) of 2,4-dihydroxybenzoic acid methyl ester, 1.98 g (5.95 mmol) of 1-bromooctadecane and 0.825 g (5.95 mmol) of potassium carbonate was stirred at reflux for 40 hours in 20 ml of acetone and 2 ml of DMF. The usual workup followed by purification by HPLC using 1% ethyl acetate-hexane gave 2-hydroxy -4-(octadecyloxy)benzoic acid methyl ester, mp 61°-64°.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[CH:25][C:24]([C:30]([OH:32])=O)=[N:23]2)=[CH:17][CH:16]=1)(=[O:8])=[O:7])=[O:4].CCN(C(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.[NH2:71][C@H:72]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C@@H:73]([OH:77])[C:74]([OH:76])=[O:75]>>[OH:77][C@H:73]([C@H:72]([NH:71][C:30]([C:24]1[CH:25]=[C:26]([CH2:27][CH2:28][CH3:29])[N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:16][CH:17]=2)[N:23]=1)=[O:32])[CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C:74]([OH:76])=[O:75]
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC)cc1
Reactant: N[C@H](Cc1ccccc1)[C@@H](O)C(=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: CCCc1cc(C(=O)N[C@H](Cc2ccccc2)[C@@H](O)C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC)cc1
Reaction time: 0.02 h
Yield: 17.9 %

Procedure:
A solution of 1-((2′-(N-(methoxycarbonyl)sulfamoyl)biphenyl-4-yl)methyl)-5-propyl-1H-pyrazole-3-carboxylic acid (40.2 mg, 87.8 μmol), DIPEA (91.8 μL, 527 μmol) and HATU (33.4 mg, 87.8 μmol) in DMF (0.4 mL, 4 mmol) was stirred to pre-activate the acid. After 1 minute, (2R,3R)-3-amino-2-hydroxy-4-phenylbutyric acid (17.1 mg, 87.8 μmol) was added, and the mixture was stirred for 10 minutes. The reaction was quenched by adding 1 N HCl and extracted with DCM. The organic layer was added to AcOH (1 mL) and evaporated in vacuo. The material was then purified by preparative HPLC to yield the title compound (10 mg, 95% purity). MS m/z: [M+H]+ calcd for C32H34N4O8S, 635.21; found 635.20.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C:3]=12.C1COCC1.[OH-].[K+:40]>CC(C)=O>[K+:40].[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([O-:33])=[O:32])[C:3]=12
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CC[C@@H]2CC(=O)O)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CC[C@@H]2CC(=O)[O-])cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 24 h

Procedure:
(R)-2-(9-Chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (15 mg, 0.031 mmol) was dissolved in a suitable solvent (THF or acetone, 0.5 mL) and heated to 60° C. 2.08 M aqueous KOH (15 mL, 0.031 mmol) was added and the reaction mixture was cooled to 35° C. and stirred for 24 h. No solid product was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)[CH:2]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH2:27]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][N:12]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2cccnc2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone (6.55 g) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (4.8 g) was heated at 130°-135° for 7 hours. The cool mixture was triturated with hot water to give 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone and this product was treated with dilute ethanolic HCl to give the title compound m.p. 237°-241° (ethanol-water)
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][CH2:6][N:7]([CH3:28])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=2[F:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].O1CCCC1>CO.[C].[Pd]>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:28])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[F:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:30]
Reactant: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methylurea (503 mg, 1.20 mmol) in methanol (40 ml)-tetrahydrofuran (20 ml) was added 10% palladium carbon (200 mg), followed by stirring under a hydrogen atmosphere at room temperature for 12 hrs. The catalyst was filtered and washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=10:1) to provide the titled compound (467 mg, 85.6%) as a yellow oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[C:24]([C:28]1[CH:29]=[CH:30][C:31]([O:48][CH3:49])=[C:32]([CH:47]=1)[CH2:33][N:34]1[C:42]2[C:37](=[CH:38][C:39]([Cl:43])=[CH:40][CH:41]=2)[CH:36]=[C:35]1[C:44](O)=[O:45])([CH3:27])([CH3:26])[CH3:25].[NH2:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][OH:54]>C(Cl)Cl.O>[OH:54][CH2:53][C:52]([CH3:56])([CH3:55])[CH2:51][NH:50][C:44]([C:35]1[N:34]([CH2:33][C:32]2[CH:47]=[C:28]([C:24]([CH3:27])([CH3:25])[CH3:26])[CH:29]=[CH:30][C:31]=2[O:48][CH3:49])[C:42]2[C:37]([CH:36]=1)=[CH:38][C:39]([Cl:43])=[CH:40][CH:41]=2)=[O:45]
Reactant: CC(C)(CN)CO
Reactant: COc1ccc(C(C)(C)C)cc1Cn1c(C(=O)O)cc2cc(Cl)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(C)(C)C)cc1Cn1c(C(=O)NCC(C)(C)CO)cc2cc(Cl)ccc21
Reaction time: 0.17 h
Yield: 36.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.57 mmol) followed by 1-hydroxybenzotriazole hydrate (0.08 g, 0.59 mmol) were added to a solution of 1-(5-tert-butyl-2-methoxybenzyl)-5-chloro-1H-indole-2-carboxylic acid (0.20 g, 0.54 mmol) in DCM (10.0 ml) and after stirring for 10 min, 3-amino-2,2-dimethylpropan-1-ol (67 mg, 0.65 mmol) was added. After stirring for 17.5 h, water (10 ml) was added, the layers separated, the organic washed with water (3×15 ml) and dried with magnesium sulfate. Purification was achieved by chromatography on silica using DCM:methanol (3:1) as eluent. Crystallisation of the crude afforded the title compound as a white solid (90 mg, 36%).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]2[CH2:32][CH2:31][CH2:30][S:27]2(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)CCCCl)C1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCCS2(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-3-chloropropane-1-sulfonamide prepared above in Step A (36.1 mg, 0.062 mmol) in DMF (1.2 mL) was added DBU (46.4 μL, 0.308 mmol) at rt. After being stirred at rt overnight, the reaction was quenched (10% citric acid), extracted (3×EtOAc), and washed (saturated aq. NaHCO3 and sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a pale brown film.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1.[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([CH3:19])[CH3:18].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=2)=[O:26])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Reactant: CCN(CC)CCSc1nnc(N)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1nnc(NC(=O)c2ccc(OC(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole (2.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Isopropyloxybenzoic acid (1.8 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.4 g of the aimed compound.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[CH:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10][C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=2[N:7]=1.C(O)=O>ClCCl>[CH:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=3[CH2:10][CH2:11][C@@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]2=[N:5][CH:4]=1
Reactant: COC(CNC1=Nc2ccccc2CCC1NC(=O)OCc1ccccc1)OC
Solvent: ClCCl
Solvent: O=CO
Product: O=C(N[C@@H]1CCc2ccccc2-n2ccnc21)OCc1ccccc1
Reaction time: 0.01 h
Yield: 45 %

Procedure:
Heat a mixture of benzyl N-[2-(2,2-dimethoxyethylamino)-4,5-dihydro-3H-1-benzazepin-3-yl]carbamate (1.80 kg, 4.1 mol) and formic acid (6.4 L) at 95° C. for 80 minutes. Concentrate the mixture under reduced pressure to give a black oil and partition it between dichloromethane (7.0 L) and water (5 L). Add sodium carbonate until the pH of the aqueous layer is 7. Remove the organic layer and wash with water (3×). Extract the aqueous layers with dichloromethane. Combine the organic layers and concentrate under reduced pressure to give a black oil. Divide the 2.297 kg of the black oil into approximately 250 g sections and dissolve each section in dichloromethane (250 mL). Add to 3.5 kg Merck 9385, 60 A, 230-400 mesh silica. Elute target compound with 75:25 ethyl acetate/heptane beginning with six column volumes (faster eluting impurities elute first). Follow with 5:95 methanol/ethyl acetate to remove remaining product (1082 g recovered). Assay product mixture using chiral HPLC conditions as follows: 4.6×150 mm Chiralpak AD-H column, 15:85:0.2 acetonitrile/3A grade ethanol/dimethylethylamine mobile phase, 0.6 mL/min flow rate, 250 nm UV detection. Observe isomer ratio 3:2 desired/undesired under these conditions. Dissolve isomer mixture at 30 mg/mL 20:80 acetonitrile/3A ethanol. Purify isomers using prep chiral HPLC conditions as follows: 8×40.5 cm Chiralpak AD (20 micron) column, 20:80:0.2 acetonitrile/3A ethanol/N,N-dimethylethylamine (DMEA) mobile phase, 490 mL/min flow rate, 250 nm UV detection, 1.5 g (50 mL) injections, 4.6 minute cycle time/injection using Steady State Recycle (SSR) technology (J. H. Kennedy, M. D. Belvo, V. S. Sharp, J. D. Williams, Comparison of separation efficiency of early phase active pharmaceutical intermediates by steady state recycle and batch chromatographic techniques, Journal of Chromatography A, 1046 p 55-60 (2004)). The collection of isomer 1 is from 0.4-0.9 min and collection of isomer 2 is from 2.4-4.2 min. The desired isomer (Isomer 2; R isomer) is the second eluter: benzyl N-[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamate. Concentrate the product containing fractions under reduced pressure to give the title compound (615 g, 73%) as a white solid: MS (m/z): 334 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C([O-])([O-])=O.[K+].[K+].[C:18]([O:21][CH2:22][CH2:23]Br)(=[O:20])[CH3:19]>CC(C)=O.C(OCC)C>[C:18]([O:21][CH2:22][CH2:23][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:20])[CH3:19]
Reactant: CC(=O)OCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCCOC(C)=O
Yield: 75.2 %

Procedure:
A mixture of 4-hydroxy-3-methoxy-benzaldehyde (2.5 g, 16.4 mmol), K2CO3 (6.81 g, 49.3 mmol) and 2-bromoethyl acetate (5.49 g, 32.9 mmol) in acetone (50 mL) is refluxed for 48 h before it is diluted with diethyl ether (250 mL) and washed with water (2×200 mL). The washings are extracted with diethyl ether (200 mL). The combined organic extracts are dried over MgSO4 and concentrated. The remaining residue is purified by column chromatography on silica gel eluting with heptane/EA 1:1 to afford the title compound (2.94 g) as colourless solid. 1H NMR (CDCl3): δ 9.85 (s, 1H), 7.45-7.41 (m, 2H), 6.99 (d, J=7.6 Hz, 1H), 4.51-4.47 (m, 2H), 4.34-4.30 (m, 2H), 3.94 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:31])([F:30])[CH2:28]O>>[F:26][C:27]([F:31])([F:30])[CH2:28][O:13][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1
Reactant: OCC(F)(F)F
Reactant: CC(C)Cc1ccc(CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)Cc1ccc(CC(=O)OCC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A mixture of 1.9 g of p-isobutylphenylacetic acid, 10 ml of 2,2,2-trifluoroethanol and 1 ml of concentrated sulfuric acid was refluxed for 5 hours. After the reaction was complete, the mixture was poured into ice-water. The resulting mixture was neutralized with adding 5% sodium carbonate solution, and then extracted with ether. The ether layer separated was dehydrated and concentrated to leave an oily residue. The residue was distilled in vacuo to yield 2.3 g of p-isobutylphenylacetic acid-2,2,2-trifluoroethyl ester as a colorless liquid, boiling at 78°-79° C./1 mmHg. Analysis-Calculated for C14H17F3O2 : C, 61.30; H, 6.25. Found: C, 61.01; H, 6.15. Mass spectrum: parent ion 274 m/e.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].O[NH:13][C:14](=[NH:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][N:23]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:13]=1
Reactant: COc1ccccc1C(=N)NO
Reactant: COC(=O)CCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCCCc1nc(-c2ccccc2OC)no1
Yield: 62.1 %

Procedure:
Add 5-chlorocarbonylpentanoic acid methyl ester (15.30 g, 86 mmol) to a solution of N-hydroxy-2-methoxybenzamidine (12.0 g, 71 mmol) in pyridine (40 mL) and under nitrogen at a rate to keep the mixture at a gentle reflux. Then, heat the mixture at reflux for 4 hours. Dilute the mixture with water (300 mL) and extract with methylene chloride (3×200 mL). Wash the combined organic extracts with brine (100 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:19), to afford 5-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]pentanoic acid methyl ester (12.8 g, 55%).