Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([O-:17])=O)=[CH:13][CH:12]=2)=[N:9][CH:10]=1)(=[O:4])[CH3:3].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>ClCCl>[N:44]1([CH2:43][C@@H:39]2[CH2:40][CH2:41][CH2:42][N:38]2[C:15]([C:14]2[CH:13]=[CH:12][C:11]([C:8]3[N:9]=[CH:10][C:5]([C:2](=[O:4])[CH3:3])=[CH:6][CH:7]=3)=[CH:19][CH:18]=2)=[O:17])[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)[O-])cc2)nc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: COc1nc(Cl)nc(OC)n1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)nc1
Reaction time: 0.75 h

Procedure:
Procedure W′: To a stirring solution of 4-(5-acetyl-pyridin-2-yl)-benzoic acid sodium salt (11.0 mmol) and n-methyl morpholine (1.0 mmol) in dichloromethane (0.10M) in a 0° C. ice bath, add 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.0 mmol). Remove the ice bath and stir for 45 minutes. After this time, add (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.0 mmol) and stir at room temperature for three hours. After this time, wash the reaction with saturated aqueous sodium bicarbonate while extracting with 10% isopropanol/dichloromethane (3×). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify the title compound via chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e): 378.3 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH:27]([CH3:29])[CH3:28]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH:27]([CH3:29])[CH3:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cc1ccncc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)Cc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-4-isobutylpyridine (Intermediate 52), the title compound was obtained as a dark orange sticky solid after purification by preparative HPLC.
Reaction SMILES: [CH2:1]([C@H:4]1[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]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>CN(C=O)C>[CH2:1]([C@H:4]1[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:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25][O:26][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)COCC2CC2)C1=O
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a solution of (3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (98 mg, 0.227 mmol) in DMF (1.10 mL) was added 60% sodium hydride in mineral oil (27.2 mg, 0.680 mmol) at 0° C. After being stirred at 0° C. for 2 min, (bromomethyl)cyclopropane (47.3 μL, 0.680 mmol) was added. The mixture was stirred at 0° C. for 2 h and then warmed to rt. Then the reaction was stirred at rt overnight. The reaction was quenched (sat aq. NH4Cl), extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography on silica gel (10% to 20% EtOAc/Hexanes gradient) provided (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one as the less polar isomer and the title compound as the more polar stereoisomer.
Reaction SMILES: [N+:1]([C:4]1[C:9](=O)[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:23])=O>C(OCC)(=O)C>[Cl:23][C:9]1[N:8]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(=O)[nH]c1C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)nc1C(=O)OCC
Temperature: 80 °C
Yield: 73.9 %

Procedure:
Diethyl 1,6-dihydro-5-nitro-6-oxo-2,3-pyridinedicarboxylate (26.23 g, 0.092 mol) is partially dissolved under N2 atmosphere in 250 mL of phosphorous oxychloride and the mixture is heated to 80° C. for 15 hours. The mixture is cooled and concentratrated and the resulting oil dissolved in ethyl acetate and washed with water, 10% K2CO3 and brine. The organic layer is dried over MgSO4, filtered and the solvent removed to yield a solid which is recrystallized from absolute ethanol/water to give 20.65 g of the product as a brown solid in 73.9% yield, having a melting point of 84.5°-86° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CC(C)=O.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)c(-n2cccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1-n1cccc1
Temperature: 60 °C

Procedure:
4-Nitro-2-pyrrol-1-yl-phenol (13.39 g, 0.066 mol), K2CO3 (10.9 g, 0.08 mol), Acetone (400 mL, 5 mol), and Ethyl bromoacetate (8.00 mL, 0.07 mol) were stirred at rt for 5 hours. The reaction mixture was filtered and concentrated to a yellow oil which solidified. The resulting residue was heated to 60° C. under high vacuum rotavap to remove residual ethyl bromo acetate. Recovered 15.36 g (81%) yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[C:11]([CH:13]=1)N.N([O-])=[O:16].[Na+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[C:11]([OH:16])[CH:13]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(Br)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 50.7 %

Procedure:
A solution of concentrated sulphuric acid (6 mL) in distilled water (75 mL) was added to 5-bromo-2-methylaniline (1 g, 5.38 mmol). The resultant suspension was heated to 90° C. and stirred for 4.5 h. The reaction mixture was then cooled using an ice bath and a solution of sodium nitrite (384 mg, 5.57 mmol) in water (5 mL) was added to the reaction mixture at 0° C. The reaction was then allowed to warm to ambient temperature. The reaction mixture was then added to a solution of concentrated sulphuric acid (6 mL) in water (75 mL) which had been preheated to 90° C. The reaction mixture was stirred for 1 h at 90° C. and allowed to cool, on standing, overnight. A precipitate was observed in the reaction mixture. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to afford 5-bromo-2-methylphenol as a brown solid (510 mg, 2.73 mmol, 51%). M.S. (ESI) (m/z) 185, 187[M−H]−
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1
Reactant: OC(c1ccccc1)c1ccc2cccnc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClC(c1ccccc1)c1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A mixture of 3.2 parts of intermediate 2, namely α-phenyl-7-quinolinemethanol, 8 parts of thionyl chloride and 65 parts of dichloromethane was stirred for 4 hours at room temperature. The reaction mixture was evaporated and the residue was poured into water. The product was extracted with dichloromethane (3×39 parts) and the combined extracts were dried, filtered and evaporated, yielding 3.4 parts (98.5%) of 7-(chlorophenylmethyl)quinoline (interm. 23).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([S:15][C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH3:26])[CH:6]=1)[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[C:7]([S:15][C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C:17]=2[CH3:26])[CH:6]=1)[CH3:2]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)c1cc(Sc2c(C)[nH]c3cc(Cl)ccc23)cc(C(F)(F)F)c1
Product: CCOC(=O)c1cc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-5-trifluoromethyl-benzoic acid ethyl ester and 3-bromopyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][CH:19]([C:32]2[N:37]=[CH:36][C:35](Br)=[CH:34][N:33]=2)[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]#[N:31])[CH:21]=2)[CH2:8][C@H:7]1[CH2:39][CH3:40])=[O:5])[CH3:2].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:68]([N:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1)(=[O:70])[CH3:69]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][CH:19]([C:32]2[N:37]=[CH:36][C:35]([N:74]3[CH2:75][CH2:76][N:71]([C:68](=[O:70])[CH3:69])[CH2:72][CH2:73]3)=[CH:34][N:33]=2)[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]#[N:31])[CH:21]=2)[CH2:8][C@H:7]1[CH2:39][CH3:40])=[O:5])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(c2cc(C#N)cc(C(F)(F)F)c2)c2ncc(Br)cn2)C[C@H]1CC
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(c2cc(C#N)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
(2R,4S)-4-[(5-Bromopyrimidin-2-yl)-(3-cyano-5-trifluoromethyl-benzyl)]amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (300 mg) is dissolved in toluene (4 ml), and thereto are added tris(dibenzylideneacetone)dipalladium (44 mg), sodium tert-butoxide (70 mg), 2-(di-tert-butylphosphino)biphenyl (58 mg) and acetyl piperazine (93 mg). The mixture is stirred at room temperature for 1 hour under nitrogen flow, then heated at 50° C. and stirred for 5.5 hours, and partitioned by adding a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=1:1→0:1) to give (2R,4S)-4-{[5-(4-acetylpiperazin-1-yl)pyrimidin-2-yl]-(3-cyano-5-trifluoromethyl-benzyl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (177 mg). MS (m/z): 667 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:14][C:15]1[C:16]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:17][C:18]2[O:22][C:21]([CH2:24][OH:25])([CH3:23])[CH2:20][C:19]=2[C:26]=1[C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:13])[CH3:12].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[C:11]([O:14][C:15]1[C:16]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:17][C:18]2[O:22][C:21]([CH:24]=[O:25])([CH3:23])[CH2:20][C:19]=2[C:26]=1[C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:13])[CH3:12]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CO)O2
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(C=O)O2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
Under a nitrogen atmosphere, 2.64 ml of oxalyl chloride was added to 40 ml of dichloromethane and the mixture was cooled to -78° C. Then, a solution of 3.62 ml of dimethyl sulfoxide in 10 ml of dichloromethane was added dropwise at -78° C. and the mixture was stirred for 30 minutes. A solution of 5.4 g of 5-acetoxy-4,6-di-t-butyl-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 47 in 15 ml of dichloromethane was added dropwise and the mixture was stirred again at -78° C. for 1 hour. The mixture was combined with 15.3 ml of triethylamine and allowed to warm to room temperature over 1 hour. After reaction, the reaction solution was combined with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 20% ethyl acetate to give 3.95 g of 5-acetoxy-4,6-di-t-butyl-2-formyl-2-methyl-2,3-dihydrobenzofuran (rotamer mixture) as a white crystal (yield 71%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([S:15](=[O:20])(=[O:19])[N:16]([CH3:18])[CH3:17])=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11]C)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21]>C(#N)C.O>[Cl:1][C:2]1[C:14]([S:15](=[O:19])(=[O:20])[N:16]([CH3:17])[CH3:18])=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21]
Reactant: COC(=O)c1cc2cc(S(=O)(=O)N(C)C)c(Cl)c(Cl)c2o1
Solvent: O
Solvent: CC#N
Product: CN(C)S(=O)(=O)c1cc2cc(C(=O)O)oc2c(Cl)c1Cl
Reaction time: 6 h
Yield: 81.9 %

Procedure:
To a hot solution of 582 mg (1.653 mmol) of methyl ester obtained in Example 1 in 15 ml of acetonitrile is added 1.7 ml (1.7 mmol) of aqueous N-NaOH solution and the mixture is stirred for 6 hours. Another 1.7 ml (1.7 mmol) of aqueous N-NaOH solution is added thereto and the reaction mixture is further stirred at room temperature for 24 hours. The precipitated crystals are collected by filtration and washed with a small amount of acetonitrile. The filtrates and washings are gathered and evaporated under reduced pressure to give a residue, which is dissolved in water and washed with methylene chloride. The previously obtained crystals are suspended in the aqueous layer, acidified with dil. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to leave a residue, which is recrystallized from ethyl acetate/hexane to give 458 mg (Yield 82.0%) of the objective compound (A'-1a), m.p. 242°-245° C.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8](OCC)=O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Cl-].[NH4+:14].C[Al](C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]12[CH2:7][C:4]([CH2:8][NH2:14])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: CCOC(=O)C12CCN(CC1)C2
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Al+3]
Agent: [Cl-]
Product: NCC12CCN(CC1)C2

Procedure:
1-Azabicyclo[2.2.1]heptan-4-ylmethanamine was prepared by treatment of ethyl 1-azabicyclo[2.2.1]heptane-4-carboxylate with ammonium chloride and trimethylaluminum and reducing the resulting amide with lithium aluminum hydride.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]([OH:29])[CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[OH-].[Na+].Cl>O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CCOCC.O1CCCC1>[ClH:2].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]([O:29][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: ClCc1ccc2ccccc2n1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Clc1ccc(C(Cn2ccnc2)OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
3.2 g of 2-Chloromethylquinoline hydrochloride (0.015 mol) (commercially available), 3.85 g of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (0.015 mol), 14.8 g sodium hydroxide (0.37 mol) in 25 ml of water, 0.25 g of benzyltrimethylammonium chloride and 40 ml of tetrahydrofuran are reacted in a manner as described in Example 1. After work up, the oily product (6.4 g) is dissolved in 150 ml of ether, charcoaled and then etheral hydrochloric acid is added to the clear solution while stirring. The precipitated hydrochloride (5.8 g) is filtered off, washed with ether and hexane and recrystallized from acetonitrile; m.p. 148°-149° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.[CH2:32]([NH:34][CH3:35])[CH3:33].Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:32]([N:34]([CH3:35])[C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3([C:10]4[N:6]5[CH2:7][CH2:8][S:9][C:3]([CH2:2][OH:1])([CH3:31])[CH2:4][C:5]5=[N:12][N:11]=4)[CH2:14][CH2:15]3)=[CH:21][CH:20]=2)=[N:23][CH:24]=1)[CH3:33]
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)O)cn5)cc4)CC3)n2CCS1
Reactant: CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)nc1
Yield: 8.2 %

Procedure:
A solution of the compound (200 mg, 0.458 mmol) obtained in Example 66, ethylmethylamine (197 μL, 2.29 mmol), N,N-dimethylaminopyridine (6 mg, 46 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (264 mg, 1.37 mmol) in N,N-dimethylformamide (4.00 mL) was stirred at room temperature for 14 h. Saturated aqueous sodium hydrogencarbonate (100 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with water and dried with anhydrous sodium sulfate. Then the solvent was distilled off under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=9:1) to obtain the title compound (18 mg, 8%) as a brown solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:16][CH3:17])=[N:12][NH:13]2)=[CH:9][CH:8]=1)=[O:6].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.O>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:16][CH3:17])=[N:12][N:13]2[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
1.17 g (29.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, was added in one portion to a room temperature solution of 5.7 g (27.9 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester in 125 mL anhydrous DMF. After 20 minutes, 3.89 mL (36.6 mmol, 1.3 equiv) cyclopentyl bromide were added dropwise, and the reaction was mixture allowed to stir overnight at room temperature. The mixture was then poured into 1 L H2O and extracted 3×450 mL ethyl acetate. The organic extracts were combined, washed 3×400 mL H2O, 1×200 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave an amber oil, which was purified on a silica gel column (10% ethyl acetate/hexanes, gravity) to give 5.48 g (72%) of a clear oil: 1H NMR (300 MHz, CDCl3) d 8.16 (d, 1H, J=1.0 Hz), 7.7 (m, 2H), 5.00 (quintet, 1H, J=7.5 Hz), 3.97 (s, 3H), 3.01 (q, 2H, J=7.6 Hz), 2.2 (m, 4H), 2.0 (m, 2H), 1.8 (m, 2H), 1.39 (t, 3H, J=7.6 Hz); HRMS calcd for C16H20N2O2; 272.1526. Found: 272.15078.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:3].[OH-].[Na+:32]>C1CCCCC1.CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:32]
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21

Procedure:
In another preferred process, a lower alkyl ester of fluvastatin is suspended in cyclohexane. Then, about one molar equivalent of sodium hydroxide dissolved in a minimum of protic solvent like methanol, is added to the suspension. The addition should cause the suspension to clarify. Upon standing, fluvastatin sodium may precipitate from the solution in amorphous form. Otherwise, additional cyclohexane can be added to induce precipitation.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:17])(=[O:3])[CH3:2].[C:18](OC)(OC)([O:21][CH3:22])[CH2:19][CH3:20]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:10][CH:11]=2)[C:6](=[C:18]([O:21][CH3:22])[CH2:19][CH3:20])[C:5]1=[O:17])(=[O:3])[CH3:2]
Reactant: CCC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: CCC(OC)(OC)OC
Product: CCC(=O)c1ccc2c(c1)C(=C(CC)OC)C(=O)N2C(C)=O

Procedure:
Prepared from 1-acetyl-5-propionyl-2-indolinone and trimethyl orthopropionate
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:14]([C:16]([O:20]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C[C@@H](N)CC1SC=CC=1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([C:16]([NH2:14])=[O:20])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C[C@@H](N)Cc1cccs1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 45 %

Procedure:
Biphenyl acid 10 (40 mg, 0.064 mmol, 1 eq) and HBTU (49 mg, 0.13 mmol, 2 eq) were dissolved in DMF (1 mL) followed by the addition of (S)-N1,N1-dimethyl-3-(thiophen-2-yl)propane-1,2-diamine (23 mg, 0.13 mmol, 2 eq). The reaction mixture was stirred for 2 h, diluted with EtOAc and quenched with a saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford an oil. The crude oil was purified by silica gel chromatography (2-5% MeOH/DCM, 0.1% Et3N) to afford 23 mg of biphenyl amide 251. Yield 45%.
Reaction SMILES: [C:1]1([C@@H:7](NC[C@@H](CCC)CC(O)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:22][CH2:23][CH3:24])(=O)C.Cl>CO>[CH:1]1[CH:6]=[C:5]2[CH:4]=[CH:24][C:23]([OH:22])=[C:7]([C:1]3[C:2]4[C:3](=[CH:8][CH:7]=[CH:23][CH:24]=4)[CH:4]=[CH:5][C:6]=3[OH:22])[C:8]2=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CCC[C@H](CN[C@@H](C)c1ccccc1)CC(=O)O
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(S,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in methanol (20 mL) and (RS)-1,1′-bi-2-naphthol (5.75 g) is added to it at room temperature. The mixture is stirred at 50° C. for 1 hour, during which time solid precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered under reduced pressure to obtain 3.5 g of solid complex. Complex is suspended in the biphasic mixture of ethyl acetate (20 ml) and 1N hydrochloric acid (20 ml) and stirred for 30 to 45 min to decompose the complex. Aqueous phase is washed with 10 mL ethyl acetate. Organic phases are mixed together and washed with brine, followed by drying over sodium sulfate. Solvent is evaporated under vacuum to obtain optically pure (5)-1,1′-bi-2-naphthol (1.5 g) having 99% ee.