Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)CCC(C)=[O:20]>ClCCl>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:20]
Reactant: CC(=O)CCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
A solution of dicyclohexylcarbodiimide (0.084 g, 0.216 mmol) in dichloromethane (1 ml) was added to a solution of levulinic acid (0.047 g, 0.406 mmol) in dichloromethane (2 ml). A white crystalline solid of dicyclohexylurea formed immediately. The suspension was allowed to stand at room temperature for 30 min, then chilled in an ice bath for 3 h min, and left to stand at 4° overnight before filtration. The colourless filtrate was concentrated to give a colourless oil with a small amount of suspended white solid of dicyclohexylcarbodiimide (DCC) and dicyclohexylurea (DCU). This was used as crude in the preparation of (3).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCc1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1ccc(OC)cc1OCc1ccccc1
Yield: 102 %

Procedure:
Under a nitrogen atmosphere, 18.30 g (120.2 mmol) of 2-ethyl-5-methoxyphenol (2) was dissolved in 150 ml of acetone. To this solution was added 33.24 g (240.5 mmol) of potassium carbonate followed by 15.02 ml (126.3 mmol) of benzyl bromide. The resultant mixture was heated to reflux for 16 hours. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (300 ml) and water (300 ml). The ethyl acetate layer was separated, washed with 1M NaOH (2×200 mL) and brine (1×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield 29.70 g of crude 3-benzyloxy-4-ethyl-1-methoxybenzene (3). Chromatography of the crude product on 400 g of silica gel 60 (EM Science) using 97:3 hexane: ethyl acetate yielded 12.62 g (43%) of 3-benzyloxy-4-ethyl-1-methoxybenzene (3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)=[C:4]([F:18])[CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)=[C:4]([F:18])[CH:3]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccc(Cl)cc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c[nH]c(-c2ccc(Cl)cc2F)n1
Temperature: 65 °C
Reaction time: 48 h
Yield: 10.6 %

Procedure:
To a solution of ethyl 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylate 41 (175 g, 4.3 mol) in THF (1 L, 6 vol) and H2O (500 mL, 3 vol) was added NaOH (78 g, 1.95 mol, 3.0 eq), and the reaction was stirred at 65° C. for 48 h till it completed (checked by LC-MS). Adjust the mixture with 2 N HCl to pH=5, and product was separated out as a yellow solid, filtered to give 210 g wet cake, the wet cake was washed with H2O (300 mL), DCM (3×300 mL), PE (500 mL), and dried to afford 110 g pure 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylic acid 42 (CAS Reg. No. 1260649-87-3) (Scheme 15). 1H NMR (DMSO d6) δ: 12.8 (br s), 8.0, 7.9 (br s), 7.46, 7.4 (m),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[C:16]([NH:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=3[F:31])=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].C(N(CC)CC)C.ClC1C=CC=C(F)C=1CN1C2C=CC=CC=2S(=O)(=O)N(C2C=CC(=O)N(C)C=2)C1=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[C:32](=[O:33])[N:21]([CH2:22][C:23]3[C:24]([F:31])=[CH:25][C:26]([F:30])=[CH:27][C:28]=3[F:29])[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:12]2(=[O:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NS(=O)(=O)c2cccnc2NCc2c(F)cc(F)cc2F)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cn1cc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)ccc1=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ncccc3S2(=O)=O)cc1OC
Yield: 59.1 %

Procedure:
The title compound (63 mg, 0.13 mmol) was prepared from N-(3,4-dimethoxyphenyl)-2-[(2,4,6-trifluorobenzyl)amino]pyridine-3-sulfonamide (98 mg, 0.22 mmol), 1,1′-carbonyldiimidazole (143 mg, 0.88 mmol) and triethylamine (0.06 mL, 0.44 mmol) using the methods of (132).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[CH:13][C:12]([CH3:23])=[C:11]([CH3:24])[CH:10]=2)=[O:5])[CH3:2].[H-].[Na+].[CH:28](I)([CH3:30])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][CH:28]([CH3:30])[CH3:29])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[CH:13][C:12]([CH3:23])=[C:11]([CH3:24])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(C)c(C)cc2[nH]c1=O
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(OC(C)C)nc2cc(C)c(C)cc2c1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-chlorophenyl)-1,2-dihydro-6,7-dimethyl-2-oxo-3-quinolinecarboxylic acid ethyl ester (2.0 g) in DMF (20 ml) was added sodium hydride (60% in oil) (270 mg), followed by stirring at room temperature for 30 minutes. To this solution was added isopropyl iodide (0.9 ml), followed by stirring at 70° C. for 5 hours. After the mixture was cooled, ethyl acetate was added, and this mixture was washed successively with dilute hydrochloric acid, aqueous potassium carbonate and water and then dried, after which the solvent was distilled off. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1), to yield 4-(2-chlorophenyl)-6,7-dimethyl-2-(1-methylethyloxy)-3-quinolinecarboxylic acid ethyl ester as colorless crystals (1.72 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][N:18]([C:21](OC(C)(C)C)=O)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[N:9][CH:10]=1)=[O:4].[CH3:30][CH:31]1[CH2:35]C[C:33](=O)[CH2:32]1>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][N:18]([CH:21]4[CH2:33][CH2:32][CH:31]([CH3:35])[CH2:30]4)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: CC1CCC(=O)C1
Reactant: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Product: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC(C)C2)CC3)cn1

Procedure:
Example 255 (E255) was prepared from N-methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide (D49) and 3-methyl cyclopentanone using the method described for Example 223; MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=O.C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)(=O)C>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([CH2:3][OH:2])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCc1cnc2ccc(Cl)cc2c1-c1ccccc1
Yield: 83.5 %

Procedure:
While stirring a mixture of 6-chloro-4-phenyl-3-quinolinecarboxylic acid methyl ester (8.0 g) and ethyl ether (100 ml) at 0° C., lithium aluminum hydride (1.0 g) was added, followed by stirring for 30 minutes. After water (5 ml) was added, the mixture was stirred at room temperature for 30 more minutes. After ethyl acetate was added, the insoluble material was altered off. The filtrate was washed by successively with aqueous potassium carbonate and saturated aqueous sodium chloride and then dried, after which the solvent was distilled off, to yield 6-chloro-3-hydroxymethyl-4-phenylquinolin as colorless crystals (6.05 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:2]#[CH:3].N1C=CC=CC=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>CCOCC>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:25]([CH:22]1[CH2:24][CH2:23]1)=[O:26])[C:2]#[CH:3]
Reactant: C#CCOCCCCCCCCCCO
Reactant: O=C(Cl)C1CC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C#CCOCCCCCCCCCCOC(=O)C1CC1

Procedure:
91 g. of 10-(2-propynyloxy)-1-decanol are dissolved in 500 ml. of ether and treated with 37 g. of pyridine. While cooling with ice and stirring, there are added dropwise 49.5 g. of cyclopropane carboxylic acid chloride and 50 ml. of ether thereto. Subsequently, the mixture is stirred at room temperature for 3 hours. The mixture is poured onto ice-water, exhaustively extracted with ether and the extract is washed with 2 N hydrochloric acid, water, 10% potassium bicarbonate solution, semi-saturated and saturated sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (95:5 parts by volume) there is obtained pure cyclopropane carboxylic acid 10-(2-propynyloxy)decyl ester; nD25 =1.4616.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)[CH:9]=2)[CH2:2]1.C(OC1C=C(C2C=CSC=2)C=CC=1)CCC=C.S1C=CC(C2C=C(O)C=CC=2)=C1.BrCCCC=C.ClC1C=CC=C(C(OO)=O)C=1.Cl.[CH2:66]([NH:68][CH2:69]/[CH:70]=[CH:71]/[C:72]#[C:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH3:67]>C1C=CC=CC=1.C(O)C.C(N(CC)CC)C>[CH2:66]([N:68]([CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:9]=1)[CH2:69]/[CH:70]=[CH:71]/[C:72]#[C:73][C:74]([CH3:75])([CH3:77])[CH3:76])[CH3:67]
Reactant: CCNC/C=C/C#CC(C)(C)C
Reactant: c1cc(OCCCC2CO2)cc(-c2ccsc2)c1
Agent: C=CCCCBr
Agent: C=CCCCOc1cccc(-c2ccsc2)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(C/C=C/C#CC(C)(C)C)CC(O)CCCOc1cccc(-c2ccsc2)c1
Yield: 63.9 %

Procedure:
0.22 g of 1,2-epoxy-5-[3-(3-thienyl)phenoxy]pentane [synthesized by the epoxidation reaction of 3-[3-(4-pentenyloxy)phenyl]thiophene, prepared from 3-(3-thienyl)phenol and 5-bromo-1-pentene, with m-chloroperbenzoic acid in benzene] was dissolved in 4 ml of ethanol, and 0.22 g of (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, 0.34 ml of triethylamine were added. The mixture was refluxed for 5 hours, and then the solvent was evaporated. The residue was purified by silica gel column chromatography [chloroform / ethyl acetate=20/1] to give 0.23 g of the captioned compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13]O)[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12.N1C=CC=CC=1.S(Cl)([Cl:23])=O.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][Cl:23])[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12
Reactant: COc1cc(CCO)cc2c1OCO2
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(CCCl)cc2c1OCO2
Temperature: 60 °C
Yield: 94.3 %

Procedure:
3.92 g (20 mmol) of 2-(3-methyoxy-4,5-methylenedioxyphenyl)ethyl alcohol (3) and 1.94 ml (24 mmol) of pyridine were dissolved in 40 ml of toluene, and to this mixture was added portionwise 1.74 ml (24 mmol) of thionyl chloride in 5 ml of toluene under cooling with water. The mixture was heated to 60° C. for 2 hours, then cooled and washed with 30 ml of water, 20 ml of water, 30 ml of a saturated sodium hydrocarbonate aqueous solution and 30 ml of a saturated saline solution successively in this order. This reaction mixture was then dried over anhydrous sodium sulfate and decolored by active carbon. The solvent was distilled off to obtain 4.05 g of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl chloride (5) as a crystal with a yield of 94%, which was recrystallized from n-hexane. Melting point: 67°-68° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH2:24][CH2:23][CH2:22][C:17]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:16]=2)=[C:9]([O:25][C:26](=[O:28])[CH3:27])[CH:8]=1)[CH3:2].C1(SC2C=CC=CC=2)C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH2:24][CH2:23][CH2:22][C:17]3([CH2:18][CH2:19][CH2:20][CH2:21]3)[CH:16]=2)=[C:9]([O:25][C:26](=[O:28])[CH3:27])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(OCC2=CC3(CCCC3)CCC2)c(OC(C)=O)c1
Reactant: [H][H]
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(OCC2=CC3(CCCC3)CCC2)c(OC(C)=O)c1
Yield: 76.8 %

Procedure:
To a solution of (E)-3-[3-acetoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-acrylic acid ethyl ester (0.43 g) obtained in Step 4 in ethyl acetate (8 mL) were added 10% palladium carbon (86 mg) and a 0.1M ethyl acetate solution of diphenyl sulfide (1.08 mL), followed by stirring under increased pressure (0.4 MPa) in an atmosphere of hydrogen at room temperature for 6 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (hexane→ethyl acetate:hexane (volume ratio)=1:19 to 1:9) to give 3-[3-acetoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acid ethyl ester (0.332 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OB(O)O)=[CH:5][CH:4]=1)=[O:2].[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(OB(O)O)cc1
Reactant: COC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1ccc(C=O)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 56.5 %

Procedure:
To a solution of 4-formylphenylboric acid (6.7 g) in N,N-dimethylformamide (100 ml) were added 2-bromobenzoic acid methyl ester (6.5 g), tetrakis(triphenylphosphine)palladium [Pd(PPh3)4] (1.0 g) and tripotassium phosphate (23 g). The reaction mixture was stirred for 5 hours at 75° C. The reaction mixture was filtrated and concentrated. To the residue were added 1N hydrochloric acid and ethyl acetate, and the mixture was concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1) to give the title compound (4.1 g) having the following physical data.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.O1CCCC1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:36]([CH:37]([F:48])[C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)=[C:35]([CH:49]([CH3:51])[CH3:50])[CH:34]=[C:33]3[C:25]=2[C:26](=[O:52])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:36]([C@H:37]([F:48])[C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:46])([F:47])[F:45])=[CH:40][CH:39]=3)=[C:35]([CH:49]([CH3:50])[CH3:51])[CH:34]=[C:33]3[C:25]=2[C@@H:26]([OH:52])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:23]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](F)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 3.1 mg (0.02 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 3 ml of abs. tetrahydrofuran, 0.15 ml (0.84 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 105 mg (0.21 mmol) of 5-(4-fluorophenyl)-6-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 53A), dissolved in 4 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature for 6 h. 3 ml of methanol are added and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane→cyclohexane/ethyl acetate 10:1). This gives 110 mg of a mixture of the two target compounds. Subsequent chromatographic separation on a chiral phase [column: chiral silica gel selector based on poly(N-methacryloyl-L-leucine-tert-butylamide), 670 mm×40 mm; mobile phase: MTBE/isohexane 15:85; flow rate: 80 ml/min; 24° C.; detection: 280 nm] gives 36 mg (36% of theory, 98% ee) of Example 30 and 45 mg (43% of theory, >99% ee) of Example 31.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH3:17])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:19].[Na+].O>O1CCOCC1.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH3:17])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:19])=[CH:4][CH:3]=1
Reactant: C=CCn1c(=O)cc(OC)c2ccc(F)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(=O)n(CC=O)c2cc(F)ccc12
Reaction time: 5 h
Yield: 93.2 %

Procedure:
A solution of 7-fluoro-4-(methyloxy)-1-(2-propen-1-yl)-2(1H)-quinolinone (0.386 g, 1.66 mmol), sodium periodate (0.83 g, 3.7 mmol) and osmium tetroxide (1.7 ml, 4% in water) in 1,4-dioxane (15 ml) containing water (3 ml) was stirred for 5 h. The mixture was separated between dichloromethane and water. The organics were isolated, dried and concentrated to provide the title compound (0.364 g, 93%).
Reaction SMILES: Br.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:15][C:16](=[O:28])[C:17]2[CH:22]=[C:21]([O:23]C)[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].CCOC(C)=O>CC(O)=O>[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:15][C:16](=[O:28])[C:17]2[CH:22]=[C:21]([OH:23])[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: COc1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ncc1[N+](=O)[O-]
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1cc(O)c([N+](=O)[O-])cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 30% HBr in AcOH (10 mL, Spectrochem, India) was added (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-methoxy-5-nitropicolinamide (1 g, 0.002 mol), and the resulting reaction mixture was stirred for 12 h at 90° C. The reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, the reaction mixture was concentrated and neutralized with sat'd NaHCO3 solution (pH˜7-7.5) and the aqueous solution was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated to afford the title compound as a pale yellow solid. 1H NMR (DMSO-d6) δ: 9.84 (d, J=7.5 Hz, 1H), 8.77 (s, 1H), 8.53 (d, J=4.5 Hz, 1H), 7.83-7.70 (m, 1H), 7.57-7.49 (m, 3H), 7.38-7.31 (m, 2H), 6.56 (d, J=7.5 Hz, 1H). MS (ESI, positive ion) m/z: 471.4 (M+H).
Reaction SMILES: [CH2:1]([O:6][C:7](=[O:22])[C:8]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[CH:11]=[CH:10][C:9]=1[OH:21])[CH2:2][CH2:3][CH2:4][CH3:5].[BH4-].[Na+]>>[CH2:1]([O:6][C:7](=[O:22])[C:8]1[CH:13]=[C:12]([C@H:14]2[CH2:15][CH2:16][C@H:17]([OH:20])[CH2:18][CH2:19]2)[CH:11]=[CH:10][C:9]=1[OH:21])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOC(=O)c1cc(C2CCC(=O)CC2)ccc1O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCOC(=O)c1cc([C@H]2CC[C@H](O)CC2)ccc1O

Procedure:
In an analogous fashion to Example 1b the product was prepared using 6.13 g (20 mmols) of 2-hydroxy-5-(4-oxocyclohexyl)benzoic acid pentyl ester and 0.76 g (200 mmols) NaBH4. Recrystallisation from isopropanol gave the 2-hydroxy-5-(trans-4-hydroxycyclohexyl)benzoic acid pentyl ester product.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2.C(N(CC)CC)C.[N:25]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[C:26]=[O:27]>O1CCCC1>[CH3:2][N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2)[C:26]([NH:25][C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)=[O:27]
Reactant: CNc1cccc2cc(-c3nccs3)[nH]c12
Reactant: O=C=Nc1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)Nc1ccsc1)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
To a solution of N-methyl-2-(1,3-thiazol-2-yl)-1H-indole-7-amine hydrochloride (50 mg) and triethylamine (35 mL) in tetrahydrofuran (3 mL) was added 3-isocyanatothiophene (26 mg). The reaction mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (74 mg, yield 99%) as yellow crystals. melting point 266° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[NH:49][CH2:50][CH2:51][CH2:52]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[NH:49][CH2:50][CH2:51][CH2:52][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Reactant: OCCCNc1cc(F)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCNc4cc(F)ccc4F)cc3)cc21
Reaction time: 3 h

Procedure:
A solution of 0.303 g of benzyl 4-{4-hydroxyphenyl}-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidinecarboxylate, 0.104 g of 3-(2,5-difluorophenylamino)propan-1-ol and 0.176 g of triphenylphosphine in 8 ml of tetrahydrofuran is admixed with 0.136 ml of diisopropyl azodicarboxylate. The reaction solution is left to stand at room temperature over 3 hours and subsequently concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.29 (1:1 EtOAc-heptane); Rt=6.02.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.I[C:11]1[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:18][C:13]1[CH:12]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[N:2]2)[CH:16]=[C:15]([CH3:17])[CH:14]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: Cc1cc(C)cc(I)c1
Product: Cc1cc(C)cc(-n2ncc3ccccc32)c1
Yield: 96 %

Procedure:
Using general procedure A, indazole (148 mg, 1.25 mmol) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 10:1; 10 mL fractions). Fractions 4-10 provided 222 mg (96% yield) of the product as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.20 (d, J=1.0 Hz, 1H), 7.83-7.74 (m, 2H), 7.46-7.40 (m, 1H), 7.36 (s, 2H), 7.25-7.19 (m, 1H), 7.01 (s, 1H), 2.43 (s, 6H).