Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Br.[NH2:28][CH2:29][CH2:30][C:31]1[C:39]2[S:38][C:37](=[O:40])[NH:36][C:35]=2[C:34]([OH:41])=[CH:33][CH:32]=1.[C:42]1([CH2:48][CH2:49][O:50][CH2:51][CH2:52][S:53]([CH2:56][CH2:57][C:58](O)=[O:59])(=[O:55])=[O:54])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.C(O)(=O)C.C(N(CC)CC)C>[OH:41][C:34]1[C:35]2[NH:36][C:37](=[O:40])[S:38][C:39]=2[C:31]([CH2:30][CH2:29][NH:28][C:58](=[O:59])[CH2:57][CH2:56][S:53]([CH2:52][CH2:51][O:50][CH2:49][CH2:48][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)(=[O:54])=[O:55])=[CH:32][CH:33]=1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: O=C(O)CCS(=O)(=O)CCOCCc1ccccc1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCS(=O)(=O)CCOCCc1ccccc1)NCCc1ccc(O)c2[nH]c(=O)sc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
Triethylamine (0.70 ml), 1-hydroxybenzotriazole hydrate (0.98 g) and finally dicyclohexylcarbodiimide (1.49 g) were added to a stirred solution of 7-[2-aminoethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrobromide (1.62 g) and the material from step b) (1.75 g) in DMF (25 ml). The whole was stirred for 16 hours at room temperature. Glacial acetic acid (0.1 ml) was added and stirring continued for 15 min. The DMF was removed under reduced pressure and the residue slurried with ethyl acetate (50 ml). The suspended dicyclohexylurea was removed by filtration. The filtrate was washed with saturated aqueous sodium bicarbonate and dried (MgSO4). The solvent was removed under reduced pressure to yield a residue which was purified by column chromatography over silica using 95:5 dichloromethane:ethanol to give the subtitled compound (1.89 g, 71%).
Reaction SMILES: O1CCCC1.C([O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][C:11]=1CC)C.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)(=O)C>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(CCc2ccco2)cc1CC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(CCc2ccco2)cc1
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To an anhydrous tetrahydrofuran (10 mL) solution of ethyl 4-(2-furan-2-yl-ethyl)-benzoic acid ethyl ester (706 mg, 2.89 mmol) described in Manufacturing Example 80-1-2 was added diisobutyl aluminum hydride (0.97 M toluene solution, 7.45 mL, 7.23 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere. After 30 minutes of stirring, 15% aqueous potassium sodium tartrate solution (40 mL) was added to the reaction solution, and stirred for 30 minutes at room temperature. Ethyl acetate (100 mL) was added, and the organic layer and water layer were separated. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (580 mg, 99%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[N:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH2:24]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[F:8][C:7]1[C:2]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:34][CH:35]=2)=[N:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)[N:6]=1
Reactant: CCCCCCCCOc1ccc(-c2cnc(Br)c(F)n2)cc1
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCCCCCC)cc3)c(F)n2)cc1
Yield: 73.7 %

Procedure:
An analogous reaction to Example 1b of 2.00 g (5.25 mmol) of 2-bromo-3-fluoro-5-(4-octyloxyphenyl)pyrazine (prepared as described in Example 1a-1c) and 1.31 g (5.25 mmol) of 4-octyloxyphenylboronic acid gives 1.96 g of 2-fluoro-3,6-bis (4-octyloxyphenyl)pyrazine. ##STR18## The compound has the following phase sequence:
Reaction SMILES: [N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH:20]=O.[BH4-].[Na+].[OH-].[NH4+]>O.C(O)(=O)C>[CH3:28][O:27][C:23]1[CH:22]=[C:19]([CH2:20][NH:14][C:11]2[CH:12]=[CH:13][C:8]3[S:7][C:6]4=[N:1][CH2:2][CH2:3][CH2:4][N:5]4[C:9]=3[CH:10]=2)[CH:18]=[C:17]([O:16][CH3:15])[C:24]=1[O:25][CH3:26]
Reactant: Nc1ccc2c(c1)N1CCCN=C1S2
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CNc2ccc3c(c2)N2CCCN=C2S3)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 6.2 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine, 7.8 parts of 3,4,5-trimethoxybenzaldehyde and 60 parts of acetic acid are added portionwise 1.2 parts of sodium borohydride at a temperature between 18° and 20° C. Upon completion, stirring is continued for 30 minutes at room temperature. Water is added and the whole is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol, yielding 9.2 parts of 3,4-dihydro-N-(3,4,5-trimethoxyphenylmethyl)-2H-pyrimido[2,1-b]benzothiazol-7-amine; mp. 190.7° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=O.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:1]=[C:20]1[S:16][C:17](=[O:22])[NH:18][C:19]1=[O:21]
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccccc1-c1ccccc1Cl
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccccc2-c2ccccc2Cl)S1

Procedure:
To a solution of 2-formyl-(2′-chloro-1,1′-biphenyl) (0.12 g, 0.55 mmol) and 2,4-thiazolidinedione (0.08 g, 0.65 mmol) in toluene (10 mL) were added piperidine (0.008 mL, 0.073 mMol) and benzoic acid (0.011 mg, 0.08 mmol), and the reaction was refluxed for 4 h with continuous removal of water. The solvent was then distilled off and the oily residue obtained was purified by chromatography on silica-gel using hexane: ethyl acetate (3:1) as the eluent to yield titled product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.O.[OH:27][CH:28]([C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)[CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:39]1[CH2:40][CH2:41][CH2:42][C@H:38]1[CH:28]([OH:27])[CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: OC(COCc1ccccc1)[C@@H]1CCCN1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.9 %

Procedure:
N-(tert-Butoxycarbonyl)-L-proline (2.93 g), HOBt (4.55 g) and water-soluble carbodiimide hydrochloride (2.88 g) were added to a methylene chloride suspension (30 ml) of (S)-2-[1-hydroxy-2(phenylmethyloxy)ethyl]pyrrolidine (3.00 g) obtained in Example 5a), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with 5% citric acid, saturated sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated to give the title compound (4.99 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2n1C1CCN([C@H]2CC[C@@H](O)CC2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dihydro-1-{1-[4-oxocyclohex-1-yl]piperidin-4-yl}-2H-benzimidazol-2-one (100 mg) in dry tetrahydrofuran (25 mL) at -78° C., under nitrogen, was added L-Selectride (0.385 mL of a 1.0M solution in tetrahydrofuran). The reaction mixture was stirred at -78° C. for 30 min, then quenched with water (3 mL). The solution was allowed to warm to room temperature and ethyl acetate (50 mL) was added. The organic layer was washed with saturated sodium carbonate (10 mL), then water (10 mL), then brine (10 mL) and then dried over sodium sulfate. Concentration under reduced pressure yielded cis-1,3-dihydro-1-{1-[4-hydroxycyclohex-1-yl]piperidin-4-yl}-2H-benzimidazol-2-one (43 mg) as a colorless solid: 1H NMR (400 MHz, CD3OD) 7.42 (m, 1H), 7.05 (m, 3H), 4.32 (m, 1H), 3.94 (m, 1H), 3.17 (m, 2H), 2.53 (m, 5H), 1.88-1.71 (m, 8H), 1.59-1.53 (m, 2H). The hydrochloride salt was precipitated from diethyl ether/methylene chloride: analysis calculated for C18H25N3O2.HCl.0.70 H2O C: 59.48, H: 7.32, N: 11.56; found C: 59.46, H: 7.28, N: 11.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:27])[C:24]=1[O:25]C)[C:5]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]=2[S:9](=[O:21])(=[O:20])[CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:27])[C:24]=1[OH:25])[C:5]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]([F:18])([F:19])[F:17])[CH:14]=[CH:15][C:10]=2[S:9](=[O:20])(=[O:21])[CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CS(=O)(=O)c3ccc(C(F)(F)F)cc32)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)c(O)c(Cl)c1)N1CS(=O)(=O)c2ccc(C(F)(F)F)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole (209 mg) was dissolved in N,N-dimethylformamide (2 mL), lithium chloride (106 mg) was added to the solution, and then the mixture was stirred at 120° C. for 2 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (167 mg) as a pale yellow crystal.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[F:5][C:6]([F:22])([F:21])[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][OH:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>C1COCC1>[CH3:3][O:20][CH2:19][C@H:16]1[CH2:15][CH2:14][C@H:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]([F:21])([F:22])[F:5])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1
Reactant: CI
Reactant: OC[C@H]1CC[C@H](c2ccc(C(F)(F)F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1CC[C@H](c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.5 h

Procedure:
60 ml of THF are added under an N2 atmosphere to 100 mmol of NaH in the form of an oil dispersion. The mixture is mixed vigorously and heated to 45°-50° C. 120 mmol of methyl iodide are then added, and 80 mmol of trans-4-(p-trifluoromethylphenyl)cyclohexylmethyl alcohol in 20 ml of THF are subsequently added dropwise over the course of 30 minutes. The reaction mixture is then stirred for 30 minutes at the same temperature, cooled and carefully hydrolysed using aqueous THF. When the vigorous evolution of H2 is complete, customary work-up gives trans-4-methoxymethyl(p-trifluoromethylphenyl)cyclohexane.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[C:10]([F:11])[C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:15]1([C:21](=[N:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:40]=2)[C:34](N(OC)C)=[O:35])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21](=[N:28][C:29]2[CH:40]=[C:33]([C:34]([C:2]3[C:6]4[CH:7]=[N:8][CH:9]=[C:10]([F:11])[C:5]=4[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=3)=[O:35])[CH:32]=[N:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)n1cc(Br)c2cncc(F)c21
Product: CC(C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncc(F)c21

Procedure:
Prepared according to the method described for Preparation 36 using 3-bromo-7-fluoro-1-isopropyl-1H-pyrrolo[3,2-c]pyridine (Preparation 46) and 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Preparation 52). Taken on directly to the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21]([N:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:25][C:26](O)=[O:27])=[O:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[C:64]([O:68][C:69](=[O:76])[NH:70][CH2:71][CH2:72][CH2:73][CH2:74][NH2:75])([CH3:67])([CH3:66])[CH3:65]>CN(C=O)C.O.C(OCC)(=O)C>[C:64]([O:68][C:69](=[O:76])[NH:70][CH2:71][CH2:72][CH2:73][CH2:74][NH:75][C:26](=[O:27])[CH2:25][CH2:24][N:23]([C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([CH2:10][NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:22])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:67])([CH3:65])[CH3:66]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NCCCCNC(=O)OC(C)(C)C)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the product of 1e (5.23 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 5.23 mmol) and N-methyl-morpholin (5.23 mmol) in 20 mL DMF was stirred at room temperature for 30 minutes. Then (4-amino-butyl)-carbamic acid tert-butyl ester (5.23 mmol) was added and the mixture stirred at room temperature for another 24 hours. The mixture was then diluted with water (100 mL) and the product was isolated through extraction with ethyl acetate.
Reaction SMILES: [CH2:1]([N:3]1[C@@H:8]([CH3:9])[C:7](=[O:10])[NH:6][C:5]2[CH:11]=[C:12]([CH2:15]O)[CH:13]=[N:14][C:4]1=2)[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH2:15][C:12]3[CH:13]=[N:14][C:4]4[N:3]([CH2:1][CH3:2])[C@@H:8]([CH3:9])[C:7](=[O:10])[NH:6][C:5]=4[CH:11]=3)[CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CCN1c2ncc(CO)cc2NC(=O)[C@@H]1C
Product: CCN1c2ncc(CN3CC=C(c4ccc(Cl)cc4)CC3)cc2NC(=O)[C@@H]1C

Procedure:
Compound 63 was prepared using a procedure analogous to that described in connection with compound 1D, except that (S)-4-ethyl-7-(hydroxymethyl)-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one was used instead of (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine was used instead of 1-(4-chlorophenyl)piperazine. 1H NMR (CHLOROFORM-d) δ (ppm): 7.79 (d, J=1.5 Hz, 1H), 7.68 (br. s., 1H), 7.27-7.34 (m, 4H), 7.02 (s, 1H), 6.06 (br. s., 1H), 4.21 (q, J=6.8 Hz, 1H), 3.98-4.12 (m, 1H), 3.44-3.61 (m, 2H), 3.07-3.26 (m, 3H), 2.75 (t, J=5.2 Hz, 2H), 2.55 (br. s., 2H), 1.36 (d, J=6.8 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H); [M+H] calc'd for C22H25ClN4O, 397. found, 397.
Reaction SMILES: C([O-])=O.[K+].C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1>[Ru].CO>[Cl:8][C:9]1[CH:10]=[C:11]([C@H:15]([OH:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: [Ru]
Agent: O=C[O-]
Agent: [K+]
Solvent: O=CO
Solvent: CO
Product: C[C@@H](O)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A ruthenium complex RuCl[(R,R)-Tsdpen] (mesitylene) (2.1 mg, 0.0033 mmol), potassium formate (1.0 g, 12 mmol), formic acid (138 mg, 3 mmol) and 3′-chloroacetophenone (1.55 g, 10 mmol, substrate/catalyst ratio=3000) were set in a 20 mL glass Schlenk-type reaction tube under an argon atmosphere. Methanol (6 mL) was added thereto and stirred at 50° C. for 24 hours to give (R)-1-(3′-chlorophenyl)ethanol at 100% yield and 96.5% ee optical purity.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.C1(C)C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[CH2:35][CH3:36])=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(Br)nc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCc1ccccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To a stirred slurry of 1.75 g (3.35 mmol) of (S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-bromo-pyridin-3-yl)propanoate and 1.005 g (6.70 mmol, 2 eq.) of 2-ethylphenylboronic acid in 50 mL of 1:1 isopropanol/toluene was added 25.0 mL of 2 M aqueous sodium carbonate solution. The reaction mixture was purged twice with argon and evacuated and then 124 mg (0.167 mmol, 0.05 equivalents) of bis(tricyclohexylphosphine)palladium (II) chloride was added and the mixture was again purged with argon and evacuated. The rapidly stirred mixture was heated at 80° C. under argon. After 20 h, the reaction mixture was cooled to room temperature and partially concentrated to remove isopropanol. The residue was partitioned between ethyl acetate and water and the aqueous phase was extracted once more with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated to give a brown oil. Purification by chromatography on silica gel using ethyl acetate/dichloromethane (1:9) as eluant (5×15 cm column), gave the desired compound as a colorless oil, 1.25 g, 77% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].Cl>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccccc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (10.5 g., 0.075 mole) in ethanol (30 ml.) is added to a solution of levo-4-(2-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (14.67 g., 0.045 mole) and sodium hydroxide (2.40 g., 0.06 mole) in water (150 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, acidified with dilute hydrochloric acid (30 ml.), and the solid (yellow) which forms after scratching is filtered and air-dried to yield 24.1 g. of material with m.p. 150°-165°C. (sinters at 140°). Several recrystallizations from n-butyl chloride, followed by several recrystallizations from acetonitrile gives a white solid, m.p. 189°-190°C., [α]D25 = -61.5 (in 1% CHCl3).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]1([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na]>C(Cl)(Cl)Cl>[C:19]1([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([C:34]([NH:12][S:9]([CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:11])=[O:35])[CH2:32][CH2:33]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NS(=O)(=O)C=Cc1ccccc1
Reactant: O=C(Cl)N1CCC(CCCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: O=C(NS(=O)(=O)C=Cc1ccccc1)N1CCC(CCCc2ccccc2)CC1
Reaction time: 1 h
Yield: 41 %

Procedure:
A stirred mixture of 1.83 g. (0.01 mole) of 2-phenylethenesulfonamide, 3.45 g. (0.025 mole) of potassium carbonate and 4.0 g. (0.015 mole) of 4-(3-phenylpropyl)piperidinocarbonyl chloride, in 75 ml. of chloroform is heated under reflux for 22 hours. The solvent is then removed by evaporation in vacuo, and to the residue is added 75 ml of 0.5N sodium hydroxide and 35 ml. of ether. The mixture is stirred for 1 hour, and then the solid which remains undissolved is removed by filtration. This affords 1.84 g. (ca. 41% yield) of the title compound as a mixture of its sodium and potassium salts.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([CH:10]([CH3:37])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])(O)=[O:8]>C(Cl)Cl>[Cl:4][C:7]([CH:10]([CH3:37])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)C(=O)O)ccc21
Solvent: ClCCl
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)C(=O)Cl)ccc21

Procedure:
Oxalyl chloride (1.88 g) was added dropwise to a stirred solution of methyl 4-[5-(2-carboxypro- pyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (4.2 g) (prepared as described in Example 67, part c) in methylene chloride (100 ml) under a nitrogen atmosphere. After 2 hr the solvent was evaporated, the residue dissolved in ethyl acetate (50 ml) and the solvent evaporated. The residue was dissolved in tetrahydrofuran (50 ml) and the solvent again evaporated, and the residue used directly in the next step without characterization.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[N+:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>CN(C)C=O.[Pd]>[OH:1][CH:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:22]([O-:24])=[O:23])[CH:30]=2)=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CC(O)CCc1ccc(I)cc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)CC(O)CCc1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 100 °C
Yield: 31.7 %

Procedure:
3-Hydroxy-5-(4iodo-phenyl)-pentanoic acid (Intermediate 10, 16 mg, 50 μmol), cesium carbonate (40 mg, 125 μmol), 3-nitrophenylboronic acid (10 mg, 60 μmol) and FibreCat™ 1001 (20 mg, 2.7% w/w palladium) were suspended in dimethylformamide (200 μL) and then heated at 100° C. for 1 hour. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The residue was partitioned between 10% methanol/dichloromethane and 2 M HCl then the phases separated. The organic phase was evaporated under reduced pressure and the residue purified via mass directed HPLC to give the title compound (5 mg, 32%) as a white solid. LC/MS: 3.18 min; z/e 314, calcd (M−1) 314. 1H NMR (400 MHz: DMSO-d6): 8.4 (1 H), 8.15 (2 H), 7.7 (3 H), 7.35 (2 H), 3.85 (1 H), 2.7 (2 H), 2.32 (2 H), 1.7 (2 H).