Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([CH2:8][C:9](=[O:25])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=O)C>CO.[OH-].[Na+]>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([CH2:8][C:9](=[O:25])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@]12CC[C@H](O)CC1CC(=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of 3β-acetoxyandrostane-7,17-dione in MeOH (156 mL), 5N NaOH (54 mL) was added. After stirring at room temperature for 10 min the solution was evaporated and the residue extracted with CH2Cl2 (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give 3β-hydroxyandrostane-7,17-dione (1.70 g, 95%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.56 (1H, d), 3.35 (1H, m), 2.66-0.87 (20H, m), 1.02 (3H, s), 0.76 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:12]1(=[O:16])[O:15][CH2:14][CH2:13]1>[OH-].[Na+].CCOCC>[Cl:10][C:9]1[C:2]([Cl:1])=[C:3]([CH:4]=[O:5])[CH:6]=[CH:7][C:8]=1[O:11][CH2:14][CH2:13][C:12]([OH:16])=[O:15]
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Reactant: O=C1CCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=Cc1ccc(OCCC(=O)O)c(Cl)c1Cl

Procedure:
2,3-dichloro-4-hydroxybenzaldehyde (38.2 g., 0.2 mole) is dissolved in a 10% sodium hydroxide solution (200 ml.). The solution is heated to boiling and β-propiolactone (144 g., 2.0 moles) is added dropwise at such a rate as to keep the solution boiling. During the addition 10% sodium hydroxide solution is added in portions to maintain an alkaline mixture. Then the solution is cooled and acidified. The precipitated material is dissolved in ether and the product is extracted into a 5% sodium bicarbonate solution. Acidification of the aqueous solution precipitates 3-(2,3-dichloro-4-formylphenoxy)propionic acid, which is purified by recrystallization from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([NH:19][CH3:20])[CH:11]=1>[Pd].CO.O1CCCC1>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=2[O:2][CH3:1])=[O:21])=[CH:11][C:12]=1[NH:19][CH3:20]
Reactant: CNc1cc(C(=O)NCCOc2ccccc2OC)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(C(=O)NCCOc2ccccc2OC)ccc1N
Reaction time: 2.5 h
Yield: 103.7 %

Procedure:
A mixture comprising N-[2-(2-methoxyphenoxy)ethyl]-3-methylamino-4-nitrobenzamide (3.56 g, 10.3 mmol), suspended palladium on carbon (10%, 0.5 g) in methanol (100 mL) and tetrahydrofuran (50 mL) was stirred under a hydrogen atmosphere at ambient pressure for 2.5 hours. The mixture was filtered and the solution concentrated in vacuo to provide 4-amino-N-[2-(2-methoxyphenoxy)ethyl]-3-methylaminobenzamide (3.37 g, 100% yield) as a green foam; MS (PB-PCI) C17H21N3O3 m/e calc 315.37; found 316 (MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][C:24]([S:30](Cl)(=[O:32])=[O:31])=[CH:25][CH:26]=2)[N:21]=1.C(Cl)Cl>CO.C(Cl)Cl>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:24]2[CH:23]=[C:22]3[C:27]([CH:28]=[CH:29][C:20]([O:19][CH3:18])=[N:21]3)=[CH:26][CH:25]=2)(=[O:31])=[O:32])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2n1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.305, 1.2 mmol) as in EXAMPLE 24, Part B using 2-methoxyquinoline-7-sulfonyl chloride (0.30 g, 1.16 mmol) in place of 6-methoxynaphthalene-2-sulfonyl chloride. 2-Methoxy-quinoline-7-sulfonic acid {1-[3-cyanobenzyl]-2-oxopyrrolidin-3-(S)-yl}amide is obtained as a solid (0.27 g, 0.62 mmol) upon chromatography (CH2Cl2 to 3% MeOH/CH2Cl2).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:12][CH:13]=2)=[O:7])[CH2:2]1.Cl[C:22]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:23]=1[C:24]#[N:25].C(O)CCC.O>C(OCC)(=O)C.[Cl-].[Na+].O>[C:24]([C:23]1[C:22]([N:1]2[CH2:4][CH:3]([NH:5][C:6]([C:8]3[CH:13]=[N:12][C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)=[N:10][CH:9]=3)=[O:7])[CH2:2]2)=[N:29][C:28]([CH3:30])=[CH:27][C:26]=1[CH3:31])#[N:25]
Reactant: O=C(NC1CNC1)c1cnc(-c2cccc(F)c2)nc1
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C#N)c(N2CC(NC(=O)c3cnc(-c4cccc(F)c4)nc3)C2)n1
Temperature: 90 °C
Yield: 99.4 %

Procedure:
To a vial was added N-azetidin-3-yl-2-(3-fluorophenyl)pyrimidine-5-carboxamide (0.04 g, 0.13 mmol), 2-chloro-4,6-dimethylnicotinonitrile (32.5 mg, 0.19 mmol), and 0.3 mL each of n-butanol, TEA and water. The mixture was heated to 90° C. for 12 hrs and then diluted with ethyl acetate and brine. The layers were separated and the organic layer dried (Na2SO4) and the solvent removed to give a solid, which was purified by chromatography (silica, DCM to 1-5% MeOH/DCM) to give the product, N-[1-(3-cyano-4,6-dimethylpyridin-2-yl)azetidin-3-yl]-2-(3-fluorophenyl)pyrimidine-5-carboxamide (52 mg, 76%). HRMS (M+H)=403.1682 expected, 403.1750 observed.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[CH3:8][C:9]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:37][C:36]3[CH:35]=[N:34][N:33]([CH3:38])[C:32]=3[NH:31][C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]2=3)=[O:27])[CH:23]=[CH:22][C:10]=1[CH2:11][NH:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][N:18]1[CH2:17][CH2:16][CH:15]([CH2:14][C:13]([NH:12][CH2:11][C:10]2[CH:22]=[CH:23][C:24]([C:26]([N:28]3[CH2:37][C:36]4[CH:35]=[N:34][N:33]([CH3:38])[C:32]=4[NH:31][C:30]4[CH:39]=[CH:40][CH:41]=[CH:42][C:29]3=4)=[O:27])=[CH:25][C:9]=2[CH3:8])=[O:21])[CH2:20][CH2:19]1
Reactant: CC(C)(C)CC=O
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CNC(=O)CC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CNC(=O)CC1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
3,3-Dimethylbutyraldehyde (0.048 ml, 0.38 mmol) was added to a solution of N-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-2-piperidin-4-yl-acetamide from Example E91 (130 mg, 0.25 mmol) in methanol/acetic acid (49:1, v/v, 2.5 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (24 mg, 0.38 mmol) was added, and the mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was dissolved in dichloromethane, washed with saturated Na—HCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 1.5% 35% ammonia:15% methanol:83.5% dichloromethane) to give a white solid identified as the title compound (107 mg, 75%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:9]=2[N:10]=1.[CH:32]1[CH:37]=[CH:36][C:35]([O:38][C:39](OC2C=CC=CC=2)=[N:40][C:41]#[N:42])=[CH:34][CH:33]=1>C(O)(C)C>[C:41]([NH:40][C:39](=[N:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=3[F:22])[C:9]=2[N:10]=1)[O:38][C:35]1[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=1)#[N:42]
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: Cc1cc(F)ccc1-c1nc(NCCN=C(NC#N)Oc2ccccc2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.5 h

Procedure:
The title compound from Example 8 [8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[(2-aminoethyl)amino]-8H-pyrido[2,3-d]pyrimidin-7-one](0.382 g, 0.0009 mol) was treated with stirring with diphenylcyanocarbonimidate (0.214 g, 0.0009 mol) in isopropanol (5 mL). Stirred at 23° for 0.5 hours. LC/MS showed a new major peak corresponding to the desired product and no starting material in the solution. LC MS (m/e)=570(MH+). Rt=2.24 min.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([O:27][CH3:28])=[N:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[CH:15][C:14]=3[N+:29]([O-])=O)=[C:11]([C:32](OCC)=[O:33])[CH:10]=[N:9]2)[CH2:5][O:4][CH2:3][CH2:2]1.O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[O:1]1[CH2:7][CH:6]([N:8]2[C:12]3[C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:20]([O:27][CH3:28])=[N:21][C:22]([CH3:26])=[CH:23][C:24]=5[CH3:25])=[CH:15][C:14]=4[NH:29][C:32](=[O:33])[C:11]=3[CH:10]=[N:9]2)[CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(-c2c(C)cc(C)nc2OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nc(C)cc(C)c1-c1ccc2c(c1)[nH]c(=O)c1cnn(C3COCCOC3)c12
Temperature: 80 °C
Reaction time: 4.25 h
Yield: 11.8 %

Procedure:
Iron powder (17 mg) was added to a solution of ethyl 1-(1,4-dioxepan-6-yl)-5-{4-(2-methoxy-4,6-dimethylpyridin-3-yl)-2-nitrophenyl}-1H-pyrazole-4-carboxylate (15 mg) in acetic acid (1 mL)-water (0.05 mL), and the mixture was stirred at 80° C. for 4.25 hours in a nitrogen atmosphere. The reaction mixture was returned to room temperature, and ethyl acetate (5 mL) was added to the reaction mixture. The insoluble matter was removed by filtration through Celite™. The filtrate was concentrated under reduced pressure. A solution of the residue in ethyl acetate was sequentially washed with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by preparative thin-layer chromatography (silica gel, ethyl acetate/n-heptane, 66%) to give the title compound (1.5 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:47][C@H:48]1[CH2:53][CH2:52][N:51]([C:54]([C:56]2[CH:61]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:59]=[C:58]([C:66]([F:69])([F:68])[F:67])[CH:57]=2)=[O:55])[C@H:50]([CH2:70][C:71]2[CH:76]=[CH:75][C:74]([Cl:77])=[CH:73][CH:72]=2)[CH2:49]1>C(Cl)Cl.C1COCC1>[F:69][C:66]([F:67])([F:68])[C:58]1[CH:57]=[C:56]([CH:61]=[C:60]([C:62]([F:63])([F:64])[F:65])[CH:59]=1)[C:54]([N:51]1[CH2:52][CH2:53][C@H:48]([NH:47][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([OH:1])[CH:11]=2)=[O:14])[CH2:49][C@H:50]1[CH2:70][C:71]1[CH:72]=[CH:73][C:74]([Cl:77])=[CH:75][CH:76]=1)=[O:55]
Reactant: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(Cl)cc2)C1
Reactant: O=C(O)c1cc(O)nc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(Cl)cc2)C1)c1cc(O)nc2ccccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 2.52 g (13.32 mMol) 2-hydroxyquinoline-4-carboxylic acid, 2.7 g (15.98 mMol) HOBt (80%), 3.7 ml (26.64 mMol) triethylamine and 3.8 g (18.64 mMol) DCC in 50 ml of CH2Cl2 were added at room temperature 12.3 g (13.32 mMol) [(2R,4S)-4-Amino-2-(4-chloro-benzyl)-piperidin-1-yl]-(3,5-bis-trifluoromethyl-phenyl)-methanone (synthesis described in EP 707006A). After 18 h the reaction mixture was diluted with 500 ml THF and filtered through a fritted glass funnel with suction. The filtrate was further diluted with ethyl acetate and washed three times with brine. The organic phase was dried with Na2SO4 and concentrated in vacuo. The product was purified by chromatography on silica gel using successively EtOAc/CH2Cl2 (2:1), EtOAc and EtOAc/THF (3:1) as eluents. The product was suspended in hexane and stirred at 60° C. overnight. The mixture was filtered and dried and a yield of 6.2 g of white crystals. M.p.222-224° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][CH:6]([F:18])[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1>ClCCCl>[F:5][CH:6]([F:18])[O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:12][C:13]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: FC(F)Oc1ccc(OC(F)F)cc1
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(OC(F)F)ccc1OC(F)F
Temperature: 5 °C

Procedure:
10 ml of nitric acid (100%) are added dropwise at a temperature of -5° to 0° C. within 5 minutes to a solution of 13.9 g of 1.4-bis(difluoromethoxy)benzene in 33 ml of 1.2-dichloroethane. The reaction mixture is stirred for a further hour at a temperature of 5° C. and allowed to warm to 15° C. within 1/2 hour. The mixture is then poured into icewater. The organic phase is separated, washed with 10% aqueous sodium hydroxide solution, dried over sodium sulfate and evaporated to dreyness, yielding 12.6 g of crude 2.5-bis(difluoromethoxy)-nitrobenzene in form of a yellowish oil.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40].C(Cl)Cl.CCOC(C)=O>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:45]4[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCN(S(C)(=O)=O)CC3)CC2)n1
Yield: 84.8 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (from Example 3) (0.20 g, 0.37 mmol) and 1-(methylsulfonyl)piperazine (0.31 g, 1.9 mmol) in THF (100 mL) was refluxed for 2 days. The solvent was then removed under vacuum, and the residue was diluted with water to give a white solid, which was collected and dried. Chromatography on alumina eluting with CH2Cl2/EtOAc (9:1) gave 0.22 g (84% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[4-({2-[4-(methylsulfonyl)-1-piperazinyl]ethyl}sulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: 1H NMR (CDCl3) δ 7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 4.01 (m, 4H), 3.88 (m, 4H), 3.79 (m, 4H), 3.38 (m, 4H) 3.23 (m, 4H), 3.11 (dd, J=8.5, 6.0 Hz, 2H), 2.92 (dd, J=8.4, 6.0 Hz, 2H), 2.75 (s, 3H), 2.60 (m, 4H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][C@@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17]>>[O:3]1[C:4]2[CH:9]=[C:8]([C:10]([NH:13][C@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:19]([OH:21])=[O:20])=[O:11])[CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CC(C)C[C@@H](N)C(=O)O
Product: CC(C)C[C@@H](NC(=O)c1ccc2c(c1)OCO2)C(=O)O
Yield: 55 %

Procedure:
Prepared in a similar manner to example 1 using benzo[d][1,3]dioxole-5-carbonyl chloride and D-Leucine. Yield: 55%. MS (M+H, 280.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[O:18]1CC[O:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[C:11]3=[O:18])[CH:5]=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[C:11]23[O:21][CH2:20][CH2:19][O:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: O=C1Cc2cc(-c3cccc(Cl)c3)ccc2N1
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C12OCCO2
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C1=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one (10.0 g, 41 mmol) in dioxane (200 cm3) and SeO2 (22.8 g, 205 mmol) was brought to reflux for 2 h then cooled to RT and concentrated onto Florisil. The Florisil washed (acetone:CHCl3 1:9) and the combined organic extracts were evaporated. The residue was purified by column chromatography (SiO2, acetone:CHCl3 1:8) to afford the subtitled compound (8 g, 31 mmol, 76%) as a tan solid: m.p. 256-258° C., 1H NMR (THF-d8) δ 6.96 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.4 (dd, J=7.7, 7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.68 (dd, J=1.84, 1.84 Hz, 1H), 7.83-7.86 (m, 2H), 10.05 (br s, 1H); 13C NMR (DMSO-d6) δ 113.30 (d), 119.08 (s), 123.44, 125.57, 126.65, 127.92, 131.41 (d), 133.88, 134.47 (s), 137.25 (d), 141.51, 150.99, 160.15, 184.83 (s); MS (EI) m/z 256 (M−H)+; Anal. (C14H8ClNO20.1H2O) C, H, N.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C1COCC1>[OH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:15][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:18][CH:17]=3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(-c3ccc(O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.1 %

Procedure:
4.5 g (0.018 mol) of 4-Octyloxy-benzoic acid, 7.0 g (0.038 mol) of 4,4′-Dihydroxy biphenyl and 0.46 g (3.7 mmol) of DMAP are dissolved in 65 mL of dry THF and 4.4 g (0.021 mol) of DCC is added. After stirring for 18 h at room temperature, the suspension is filtered. The residue is dissolved in a hot solution of hexane:CHCl3:THF=2:2:1 and after cooling to room temperature, the precipitate is filtered off. The recrystallisation is repeated until the TLC indicates pure white product (3.7 g, 49% yield).
Reaction SMILES: FC1C=CC(C(C)(C)CC(Cl)=O)=CC=1.ClC1C=CC(C(C)(C)CC(Cl)=O)=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:47])([CH3:46])[CH:37]=[C:38]=[C:39]([CH3:45])[C:40]([O:42]CC)=[O:41])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([CH3:47])([CH3:46])[CH:37]=[C:38]=[C:39]([CH3:45])[C:40]([OH:42])=[O:41])=[CH:34][CH:35]=1
Reactant: CCOC(=O)C(C)=C=CC(C)(C)c1ccc(Cl)cc1
Agent: CC(C)(CC(=O)Cl)c1ccc(Cl)cc1
Agent: CC(C)(CC(=O)Cl)c1ccc(F)cc1
Product: CC(=C=CC(C)(C)c1ccc(Cl)cc1)C(=O)O

Procedure:
Repeating the procedure of Example 7, but replacing the 3-(p-fluorophenyl)-3-methyl-butyryl chloride used therein with an approximately equivalent amount of 3-(p-chlorophenyl)-3-methyl-butyryl chloride, there is accordingly obtained ethyl 5-(p-chlorophenyl)-2,5-dimethyl-hexa-2,3-dienoate from which is obtained 5-(p-chlorophenyl)-2,5-dimethyl-hexa-2,3-dienoic acid (m.p. 106° - 107.5°).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH3:35])[CH:27]=4)[CH2:23][CH2:22][C:21]([C:36]([O:38]C)=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH3:35])[CH:27]=4)[CH2:23][CH2:22][C:21]([C:36]([OH:38])=[O:37])=[CH:20][C:19]=3[CH:40]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cccc(OCCC)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccc(OCCC)c2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 76.7 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (412 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 4 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (308 mg) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][CH2:19][C:20]#N.[BH4-].[Na+].O.CC([O:30]C)(C)C>CO>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14]/[CH:15]=[C:16](\[CH3:22])/[CH2:17][CH2:18][CH2:19][CH2:20][OH:30]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCC#N)c1C
Reactant: COC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCO)c1C
Reaction time: 12 h

Procedure:
Crude (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile in MeOH (3 mL) was cooled to 0° C. and treated with NaBH4 (64.3 mg, 1.74 mmol), which gave immediate effervescence. After 12 h, H2O (10 mL) was added (caution: copious gas evolution), MTBE (10 mL) was added, separated and the aqueous phase extracted with MTBE (3×10 mL). The combined organics were washed with H2O (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to give (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-en-1-ol as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=[O:27])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][Mg]I.C(OCC)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]([OH:27])[CH3:29])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: C[Mg]I
Reactant: Cc1noc(C)c1-c1cc(C=O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1noc(C)c1-c1cc(C(C)O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde (1.30 g, 3.45 mmol) (single enantiomer from Example 137, step 3) in tetrahydrofuran (30.0 mL) was treated with 3.0 M methylmagnesium iodide in diethyl ether (4.03 mL, 12.1 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product as a mixture of diastereoisomers. The diastereoisomers were separated by chiral HPLC (Chiracel AD-H column, 20×250 mm, 5 micron particle size, eluting with 50% ethanol in hexanes at 12 mL/min, 45 mg per injection) to give Peak 1 (Diastereoisomer 1, RT=10.2 min) and Peak 2 (Diastereoisomer 2, RT=12.6 min).