Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=3)=[CH:15][CH:14]=1)=[O:11])[CH2:3]2.S(Cl)([Cl:30])=O.[NH3:32]>C1COCC1>[ClH:30].[NH2:32][C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]([C@@H:4]3[CH:5]4[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]4)[CH2:3]3)=[O:11])=[CH:14][CH:15]=2)=[CH:20][CH:21]=1)=[O:26]
Reactant: N
Reactant: O=C(O)c1ccc(-c2ccc(NC(=O)[C@@H]3CN4CCC3CC4)cc2)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
60 mg (0.16 mmol) of 4′-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1′-biphenyl-4-carboxylic acid hydrochloride and 2 ml (27.4 mmol) of thionyl chloride are heated under reflux for 3 h. The excess of thionyl chloride is distilled off. The crude acid chloride prepared in this way is introduced into 1 ml of THF and stirred with 3.1 ml (1.55 mmol) of ammonia (0.5M solution in dioxane) at RT for three days. The solvent is removed under reduced pressure, and the crude product is purified by preparative HPLC. 11 mg (18% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[SH:16][C:17]1[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:19][N:18]=1>>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:16][C:17]2[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:19][N:18]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCSc1nnc(S)s1
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Product: CCCc1c(CSc2nnc(SCCCCCC(=O)OCC)s2)ccc(C(C)=O)c1O
Yield: 92.4 %

Procedure:
Using as starting materials 0.30 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 0.46 g of ethyl 6-[(5-mercapto-1,3,4-thiadiazol-2-yl]thio]hexanate, 0.59 g of oily ethyl 6-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]hexanate was obtained in a manner similar to Example 9.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic ethyl ester (4.7 g, 10 mmol) dissolved in THF:methanol (3:1 150 mL) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3 g (67%); white solid; mp 182° C.; MS: 446 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7].C(N(CC)CC)C.[O:35]=[C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38](=[O:45])[N:37]1[CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][CH2:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:10][CH:9]2[CH3:22])=[O:7])=[C:2]([NH:1][S:48]([CH2:47][CH2:46][N:37]2[C:36](=[O:35])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]2=[O:45])(=[O:49])=[O:50])[CH:26]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a solution of of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone (0.050 g, 0.13 mmol) in methylene chloride (1 mL) at ambient temperature was added triethylamine (0.027 mL, 0.19 mmol) and 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.045 g, 0.17 mmol). The reaction was stirred overnight at ambient temperature. Additional triethylamine ((0.027 mL, 0.19 mmol) and 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.045 g, 0.17 mmol) was added. The reaction was stirred one hour, then additional triethylamine (0.055 mL, 0.34 mmol) was added. The reaction was stirred and hour, then additional 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.090 g, 0.34 mmol) was added. After stirring an additional 1 hour, the reaction was treated with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via radial chromatography (2 mm plate) gave the title compound (0.030 g).
Reaction SMILES: C([O:9][CH2:10][C@H:11]1[O:15][CH:14]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([NH2:29])=[N:20][C:21]=3[NH:25][CH:26]2[CH2:28][CH2:27]2)[CH2:13][O:12]1)(=O)C1C=CC=CC=1.N>CO>[OH:9][CH2:10][C@H:11]1[O:15][CH:14]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([NH2:29])=[N:20][C:21]=3[NH:25][CH:26]2[CH2:28][CH2:27]2)[CH2:13][O:12]1
Reactant: Nc1nc(NC2CC2)c2ncn(C3CO[C@@H](COC(=O)c4ccccc4)O3)c2n1
Agent: N
Solvent: CO
Product: Nc1nc(NC2CC2)c2ncn(C3CO[C@@H](CO)O3)c2n1

Procedure:
The starting material (Compound 24: 3.3 g) was stirred with ammonia in MeOH (80 mL; 2M) for 20 hrs. Nitrogen was bubbled through the reaction mixture to remove the excess ammonia. Then, the solution was concentrated to yield the crude as a β/α mixture (β/α=2.3:1). The β/α isomers were separated by chromatography on silica gel using DCM/MeOH as eluent to yield 1.18 g (70% β isomer).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]([O:36]CC1C=CC(OC)=CC=1)=[O:35])=[O:27])[NH:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]([OH:36])=[O:35])=[O:27])[NH:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)[C@@H]2CCC[C@@H]2NC(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)c2cc(C)nn2C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)O)n(C)n1
Reaction time: 1 h
Yield: 9.2 %

Procedure:
To a mixture of 4-methoxybenzyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1,3-dimethyl-1H-pyrazole-5-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.50 g) and methylene chloride (5.0 ml) was added trifluoroacetic acid (5.0 ml) under ice-cooling, followed by stirring for 1 hour under ice-cooling. The reaction mixture was concentrated under reduced pressure, and diethyl ether and a saturated sodium bicarbonate solution were added to the residue. The organic layer was separated, the aqueous layer was then washed with diethyl ether, and citric acid was added thereto under ice-cooling. The solid precipitated was collected by filtration, washed with water, then purified by silica gel column chromatography (5% methanol/chloroform), solidified with a 50% aqueous ethanol solution, and washed to obtain (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1,3-dimethyl-1H-pyrazole-5-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylic acid (37 mg).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]([Cl:12])[C:6]([CH3:11])([CH3:10])[C:7](=[O:9])[CH3:8])[CH3:3].[Br:13]Br>C(Cl)(Cl)Cl.Cl>[CH3:3][C:2](=[CH:4][CH:5]([Cl:12])[C:6]([CH3:11])([CH3:10])[C:7](=[O:9])[CH2:8][Br:13])[CH3:1]
Reactant: CC(=O)C(C)(C)C(Cl)C=C(C)C
Reactant: BrBr
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)=CC(Cl)C(C)(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
6.03 g (0.032 mol) of 2,5,5-trimethyl-4-chloro-2-hepten-6-one are dissolved in 75 ml of chloroform, 2 drops of an ethereal hydrogen chloride solution are added, and 5.12 g (0.032 mol) of bromine are then added in one portion at 25° C. The mixture is stirred for 2.5 hours at room temperature, and hydrogen bromide and solvent are distilled off in vacuo; the final residues are removed in a high vacuum. 8.7 g are obtained of crude, 2,5,5-trimethyl-4-chloro-7-bromo-2-hepten-6-one, the structure of which is confirmed by the 1H-NMR spectrum. It is used directly in the next stage:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.[OH-].[Na+]>C(Cl)Cl>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:15][CH:16]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc(N4CCOCC4)cc3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: c1cc(N2CCOCC2)ccc1-c1ccc(C2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
5-(4-Morpholin-4-ylphenyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.37 g, 0.874 mmol) was dissolved in DCM (12 mL), TFA (4 mL) was added and the reaction mixture was stirred at RT for 1 hour, until all starting material had disappeared. Water and 1 N NaOH was added until pH=12. After extraction with DCM (4×40 mL) the DCM phase was dried with Na2CO3, filtered and evaporated to give 280 mg (100%) white crystals.
Reaction SMILES: CCCCCCCCCCCCCCCCCCN[C:20]([CH2:22][CH2:23][C:24]1[CH:29]=[C:28](C(C)(C)C)[C:27](O)=[C:26](C(C)(C)C)[CH:25]=1)=O.[O-:39][Mn](=O)(=O)=O.[K+].[C:45]([O-])([O-:47])=[O:46].[Na+].[Na+]>CC(O)=O.O>[CH3:20][CH:22]1[O:47][C:45](=[O:46])[C:29]2[C:28]([OH:39])=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23]1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1Cc2cccc(O)c2C(=O)O1
Reaction time: 0.5 h

Procedure:
To a stirred solution of AO-1 (16.5 g, 83.0 mmol) in AcOH (150 mL) kept below 10° C. is added a solution of KMnO4 (14.5 g, 92.0 mmol) in H2O (150 mL) dropwise. The reaction mixture is stirred for 30 min. The mixture is diluted with water, basified by addition of saturated aq Na2CO3 and extracted with EtOAc. The solution is concentrated and the residue is purified by SFC to yield AO-2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]1=[C:25]3[N:26]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1.Br[CH2:28][C:29]([OH:31])=[O:30].[OH-].[Na+]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][N:18]([CH2:28][C:29]([OH:31])=[O:30])[CH2:17][C:16]1=[C:25]3[N:26]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCO2
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)CN1CCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Reaction time: 24 h
Yield: 53.8 %

Procedure:
An IPA (0.1 mL) solution of (6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaene (Example 21, 5 mg, 0.014 mmol), 2-bromoacetic acid (2.9 mg, 0.021 mmol) and NaOH (1 N, 42 μL, 0.042 mmol) was heated at 60° C. in a sealed vessel overnight, then at 120° C. for 24 hours. After cooling, the reaction mixture was directly purified by reverse-phase column chromatography eluting with 0-50% acetonitrile/H2O to afford the title product (3.1 mg, 53% yield). MS (apci) m/z=412.2 (M+H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].C[O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([O:21][CH3:22])=O>CCCCCCC>[CH3:22][O:21][CH2:19][CH2:18][O:17][CH2:16][C:15]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:14]
Reactant: COCCOCC(=O)OC
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: CCCCCCC
Product: COCCOCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1

Procedure:
34.4 grams of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 29.6 grams of methyl 2-methoxyethoxyacetate and 300 mL of heptane are transferred to a 500 mL 3-necked, round-bottomed flask equipped with a mechanical stirrer, Dean-Stark trap and condenser. Trace amounts of water are removed by azeotropic distillation. 0.25 mL of tetraisopropyl orthotitanate is added to the reaction mixture. The reaction mixture is refluxed for six hours and the liberated methanol is collected in the Dean-Stark trap. The reaction mixture is allowed to cool and is then partitioned between 300 mL of ethyl acetate and 300 mL of water. The phases are separated and the organic phase is washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent leaves the title compound as a red oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][O:28][CH2:29][CH:30]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].I[CH3:32]>CN(C=O)C.O>[O:28]1[CH2:27][CH:26]=[C:25]([C:24]2[C:19]([O:18][C:15]3[CH:14]=[CH:13][C:12]([C:10]([C:2]4[N:3]([CH3:32])[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)=[O:11])=[CH:17][CH:16]=3)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2[nH]1
Reactant: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(=O)c2ccc(Oc3ncccc3C3=CCOCC3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone (0.350 g, 0.881 mmol) in DMF (5 mL) was treated with iodomethane (0.083 mL, 1.321 mmol). The mixture was stirred at RT and after 4 hours, it was diluted with water and extracted (2×) with DCM. The organic portions were combined and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate, reduced and purified by column chromatography on silica gel using a gradient of 30 to 80% EtOAc in hexanes to afford (4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone as white solid. MS (ESI, pos. ion) m/z: 411.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CN[C:56]2[N:64]=[C:63](NCCN3CCCCC3)N=[C:61]3[C:57]=2N=C[N:60]3[C@@H:74]2[CH2:78][C@H:77](N3C=C(CO)C=N3)[C@@H:76](O)[C@H]2O)C=CC=CC=1.N1([C@@H]2CCNC2)CCCC1>>[ClH:1].[N:60]1([C@@H:61]2[CH2:57][CH2:56][N:64]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[CH:7][N:8]4[C@@H:11]4[CH2:15][C@H:14]([N:16]5[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]5)[C@@H:13]([OH:23])[C@H:12]4[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:3]=3)[CH2:63]2)[CH2:74][CH2:78][CH2:77][CH2:76]1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Agent: C1CCN([C@@H]2CCNC2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N6CCCC6)C5)nc43)[C@H](O)[C@@H]2O)n1
Product: Cl

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Intermediate BA6) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) by replacing 1-(2-amino-ethyl)piperidine with (R)-[1,3′]bipyrrolidinyl (intermediate EB). MS (ES+) m/e 650.42 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:29])[C:13]([CH2:15][O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
(5)In 25 ml of dry N,N-dimethylformamide was dissolved 11.0 g (25.1 mmol)of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (16b), followed by addition of 5.2 g (38 mmol)of potassium carbonate powder. Then, 3.90 g (27.7 mmol)of methyl iodide was further added and the mixture was stirred at room temperature for 8 hours. This reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with diethyl ether. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:9). From the first fraction, 1.7 g (yield 15%)of the objective position isomer (17b')was obtained as oil. From the subsequent fraction, 9.14 g (yield 80%)of the objective 5-(3,5-dichlorophenylthio)-1-methyl-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17b)was obtained. mp 79-80° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4]Cl.[I-].[Na+].[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4][N:28]1[CH2:29][CH2:30][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1CCc2cc(C(O)CCCl)ccc2N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(C(O)CCN3CCC(c4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2.6 Grams of 6-(1-hydroxy-3-chloropropyl)-3,4-dihydrocarbostyril and 1.8 g of sodium iodide were mixed in 60 ml of dimethylformamide and the mixture was stirred at a room temperature for 7 hours. Then 2.0 g of triethylamine and 2.5 g of 4-phenyl-piperidine were added to the mixture and stirred at a room temperature for 24 hours. The reaction mixture was poured into 200 ml of 1%-sodium hydrogen-carbonate aqueous solution and was extracted with chloroform. The chloroform layer was washed with water and dried, chloroform was removed by distillation. The residue thus obtained was recrystallized from ethanol to obtain 2.5 g of 6-[1-hydroxy-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydro-carbostyril in colorless plate-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:3]=2[O:2][CH3:1])=[O:7])[CH2:18][CH2:17]1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CN1CCNCC1
Product: COc1cc([N+](=O)[O-])ccc1C(=O)N1CCN(C)CC1

Procedure:
Prepared from 2-methoxy-4-nitrobenzoic acid and 1-methyl-piperazine (TPTU, CH2Cl2/CH3CN, Et3N): MS: [M+1]+=280; Anal.: CHN.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:10](=[O:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: COC(CN)OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cccc(CC(=O)NCC(OC)OC)c1

Procedure:
A mixture of 3-methoxyphenylacetic acid (47.7 g, 0.287 m), thionyl chloride (50 ml) and N,N-dimethylformamide (6 drops) in toluene (500 ml) was stirred for 16 hours at 25° and concentrated in vacuo to afford 3-methoxyphenylacetyl chloride. The acetyl chloride was dissolved in chloroform (100 ml) and added to a solution of aminoacetaldehyde dimethyl acetal (32.1 g, 0.306 m) and triethylamine (32.4 g, 0.320 m) in chloroform (500 ml) stirred at 5°. The mixture was stirred at 25° for 16 hours, washed with water, 1.5 N hydrochloric acid and water, dried with magnesium sulfate and concentrated in vacuo to give N-(2,2-dimethoxyethyl)-3-methoxybenzeneacetamide.
Reaction SMILES: C([O:8][C:9](=[O:31])[CH:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:11]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:23]([O:22][C:20]([CH2:19][N:11]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH:10]([C:9]([OH:31])=[O:8])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)CC(C(=O)OCc1ccccc1)N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(C(=O)O)N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 102.4 %

Procedure:
N-(t-butyloxycarbonyl)methyl-N-t-butyloxycarbonyl-D,L-leucine benzyl ester (1.7 g) was dissolved in methanol (25 ml), and 10% palladium-carbon (200 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (1.38 g, 100%), which was directly used for the next reaction.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23](O)=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[CH3:27]>>[CH2:26]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=1)[C:23](=[O:24])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH3:27]
Reactant: CCNCc1cccc(C)n1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccc(C(C)C)cn1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine