Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][NH2:31])=[CH:28][C:23]=2[O:22][CH2:21]1.CCN(C(C)C)C(C)C>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][NH:31][C:3]3[S:4]/[C:5](=[CH:9]\[C:10]4[CH:11]=[C:12]5[C:17](=[CH:18][CH:19]=4)[N:16]=[CH:15][CH:14]=[CH:13]5)/[C:6](=[O:8])[N:7]=3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2ccc3c(c2)OCO3)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-benzo[1,3]dioxol-5-yl-ethylamine and DIEA to give (2-benzo[1,3]dioxol-5-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 404 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]([O:16][CH3:17])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:19][C@@H:20]([CH3:23])[CH2:21][CH3:22])=[N:11][C:12]=2[NH2:18].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CO>ClCCl>[CH3:17][O:16][C:15]1[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8]2[C:13]([N:14]=1)=[C:12]([NH2:18])[N:11]=[C:10]([O:19][C@@H:20]([CH3:23])[CH2:21][CH3:22])[N:9]=2
Reactant: C1CCNCC1
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Solvent: CO
Solvent: ClCCl
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 9-(5-chloropentyl)-8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-9H-purin-6-amine and piperidine but with purification on silica using a 0-25% methanol in dichloromethane gradient.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:31]([F:34])([F:33])[F:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH2:15][CH:2]([OH:1])[CH:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][C:31]([F:32])([F:34])[F:33])=[CH:7][CH:6]=2)[CH3:14])[CH:18]=1
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(Oc1ccc(-c2ccccc2OC(F)(F)F)cc1)C(O)CCc1cccnc1
Temperature: 80 °C
Yield: 69.7 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 2-bromo(trifluoromethyloxy)benzene (0.26 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium (0) (0.025 g) in ethanol (3 ml). The reaction mixture was heated in a sealed vial at 80° C. for 2 hours. After cooling, the solution was is concentrated under reduced pressure and taken up in acetone and filtered through a small plug of silica. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil (0.145 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:12]Br>C(Cl)Cl>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[N:3][CH:4]=1
Reactant: Oc1nccc2ccccc12
Reactant: BrBr
Solvent: ClCCl
Product: Oc1ncc(Br)c2ccccc12
Reaction time: 4 h
Yield: 63.4 %

Procedure:
To a suspension of 5.0 g (34.5 mmol) of 1-hydroxyisoquinoline in 100 ml of methylene chloride was added 6.0 g (37.7 mmol) of bromine in 20 ml of methylene chloride. The mixture was stirred for four hours, the solid was filtered and washed with methylene chloride. This solid was recrystallized from ethanol to give 4.9 g (63%) of the desired product; mp 245°-250° (dec).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)[C:2]#[CH:3].Br[C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1>C1COCC1.C(NC(C)C)(C)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:3]#[C:2][CH2:1][N:4]2[C:12]3[C:7](=[CH:8][C:9]([CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:10][CH:11]=3)[CH:6]=[CH:5]2)=[N:21][CH:22]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCn1ccc2cc(CN3CCCC3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Brc1ccc(C#CCn2ccc3cc(CN4CCCC4)ccc32)nc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Under an argon atmosphere 5 mg (0.03 mmol) CuI and 18 mg (0.03 mmol) Pd(PPh3)2Cl2 are added to a solution of 337 mg (1.41 mmol) 1-prop-2-ynyl-5-pyrrolidin-1-ylmethyl-1H-indole and 345 mg (1.41 mmol) 2,5-dibromo-pyridine in 50 mL THF and 0.4 mL diisopropylamine and the reaction mixture is stirred for 17 h at RT. The mixture is evaporated down i. vac., the residue is taken up in 30 mL EtOAc, the organic phase is washed with 30 mL water and 30 mL saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([CH3:24])=[C:18]([O:25][CH3:26])[CH:17]=2)[N:3]=1.C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([CH3:24])=[C:18]([O:25][CH3:26])[C:17]=2[Br:34])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(Nc2nc(N)n(-c3ccc(C#N)cc3)n2)cc(OC)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Nc2nc(N)n(-c3ccc(C#N)cc3)n2)c(Br)c(OC)c1C
Yield: 42.4 %

Procedure:
To a suspension of 4-[5-Amino-3-(3,5-dimethoxy-4-methyl-phenylamino)-[1,2,4]triazol-1-yl]-benzonitrile (155 mg, 0.44 mmol) in CCl4 (10 mL) and benzene (10 mL) was added N-bromosuccimide (100 mg, 0.56 mmol) and benzoyl peroxide (10 mg). The reaction mixture was refluxed for 16 h. Concentration. The residue was purified by HPLC to give the title compound (80 mg). FIA-MS: m/e=429.1 and 431.1 (M+H), 427.1 and 429.1 (M−H). Rt=3.89 min (Method A). 1H-NMR (500 MHz, DMSO(d6)): 7.95 (d, 2H), 7.82 (s, 1H), 7.80 (d, 2H), 7.37 (s, 1H), 6.88 (br. s, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].Cl>[OH-].[Na+].C1(C)C=CC=CC=1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-amino-phenol (60 g, 6.55 mol) in 2 N NaOH (1 l), cooled to 10° C., pivaloyl chloride (68 ml, 0.55 mol) in toluene (200 ml) is added within 1 h. After stirring for 15 h at 25° C., the mixture is cooled to 0° C. and acidified to pH 1 with conc. HCl. Extraction with EtOAc washing with water, 10% NaHCO3, water, and brine, followed by drying (Na2SO4), evaporation of volatiles, and crystallization (EtOAc/hexanes) gives N-(3-hydroxy-phenyl)-2,2-dimethyl-propionamide. N-(3-Hydroxy-phenyl)-2,2-dimethyl-propionamide (49 g, 0.254 mol) in dichloromethane (1 l) is treated with dihydropyrane (66 ml, 0.762 mol) and pyridinium p-toluenesulfonate (957 mg, 3.8 mmol). After stirring for 6 days at 25° C., the solvent is removed and the residue crystallized from EtOAc/hexanes to give 2,2-dimethyl-N-[3-(tetrahydro-pyran-2-yloxy)-phenyl]-propionamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH2:11][CH:10]([CH2:13][O:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][CH:3]=1.[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])([O:20][CH3:21])=[O:19].[OH-].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([C:24](=[O:25])[CH2:23][CH2:22][C:18]([O:20][CH3:21])=[O:19])[CH2:11][CH:10]([CH2:13][O:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:6][CH:7]=1
Reactant: CCCOCC1CNC(c2ccc(Cl)cc2)O1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCOCC1CN(C(=O)CCC(=O)OC)C(c2ccc(Cl)cc2)O1

Procedure:
To 25.6 milliliters of 25 percent w/v, 2-p-chlorophenyl-5-propoxymethyl oxazolidine solution in 50 milliliters of benzene was added 3.8 grams of 3-carbomethoxypropionyl chloride. To this reaction mixture was added 2 grams of 50% sodium hydroxide. Upon completion of the reaction solvent, benzene, was removed in vacuo. There was obtained 6.0 grams of the title compound, nD30 1.4975. Analytical data supports the structure.
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)C.[CH2:14]=[CH:15][CH:16]=[CH2:17]>C1(C)C=CC=CC=1>[CH3:13][C:7]1[C:8](=[O:12])[C:9]([CH3:11])=[CH:10][C:5]2([CH2:17][CH2:16][CH:15]=[CH:14][CH2:4]2)[CH:6]=1
Reactant: Cc1cc(CN(C)C)cc(C)c1O
Reactant: C=CC=C
Solvent: Cc1ccccc1
Product: CC1=CC2(C=C(C)C1=O)CC=CCC2
Yield: 78 %

Procedure:
Following the same general procedure as in Example I, 5 mmols of N,N-dimethyl-4-aminomethyl-2,6-dimethylphenol were reacted with 20 mmols of 1,3-butadiene in 40 g of toluene at 189°-205° C. for six hours. GC analysis showed a 78% yield of 2,4-dimethylspiro[5.5]undeca-1,4,8-trien-3-one.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[N:19]([CH3:20])[C:10]2=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]2[N:8]=1.[Na].[CH2:22]([SH:24])[CH3:23].CN1CCCC1=O.[NH4+]>[Cu](I)I.O>[CH2:22]([S:24][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[N:19]([CH3:20])[C:10]2=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]2[N:8]=1)[CH3:23]
Reactant: CCS
Reactant: Cn1c(-c2ccsc2Br)nc2cc(C(F)(F)F)cnc21
Agent: I[Cu]I
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCSc1sccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
A mixture of 0.72 g of 2-(2-bromothiophen-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine, 0.25 g of ethyl mercaptan sodium salt (80%), 0.08 g of copper iodide and 4 ml of N-methylpyrrolidinone was stirred at 70° C. for 4 hours. Water and aqueous ammonium (28%) were poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.30 g of 2-(2-ethylthiothiophen-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (13)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH3:14]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCN(C)C
Reactant: COc1ccc2c(c1)NC(=O)C2C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)NC(=O)C2(C)C
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−78° C.) of 6-methoxy-3-methyl-1,3-dihydro-indol-2-one (679 mg, 3.83 mmol, example 77) in THF (13 mL) is added TMEDA (1.16 mL, 7.66 mmol) followed by dropwise addition of 2.5M n-BuLi (3.06 mL, 7.66 mmol). The mixture is stirred 15 min then warmed to −25° C. Iodomethane (275 μL, 4.40 mmol) is added dropwise and stirred for 30 min. Reaction is quenched with sat NH4Cl soln, warmed to room temp and diluted with EtOAc. Washed organic layer with sat NH4Cl soln, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 35% ethyl acetate in hexanes) to give the title compound as a white crystalline solid. MS (ESI) 192 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:15](=O)[CH3:16])=[CH:5][C:6]1[C:11]2=[N:12][O:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.[CH:19]([O:22][C:23](=[O:28])/[CH:24]=[C:25](\[NH2:27])/[CH3:26])([CH3:21])[CH3:20]>C(O)C>[CH3:16][C:15]1[NH:27][C:25]([CH3:26])=[C:24]([C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[O:28])[CH:5]([C:6]2[C:11]3=[N:12][O:13][N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)C(=Cc1cccc2nonc12)C(C)=O
Reactant: C/C(N)=C/C(=O)OC(C)C
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc2nonc12

Procedure:
To achieve the afore-mentioned objects, the present invention provides for a process for the manufacture of the Isradipine which, involves two steps. In the first step 2,1,3-benzoxadiazole-4-carboxaldehyde is reacted with methyl acetoacetate in the presence of acetic acid and piperidine in diisopropyl ether. The product 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester is isolated and purified to get substantially high purity product with less than 0.3% 2,1,3-benzoxadiazole-4-carboxaldehyde content present in the purified product. In the second step the purified intermediate 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester is reacted with isopropyl-β-aminocrotonate in ethanol at 25 to 35° C. The crude Isradipine is crystallised from ethanol to get pure Isradipine having substantially higher purity and containing lower amount of the symmetrical ester isomers (III) and (IV).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]3[C:13]([NH2:14])=[N:12][N:11]([CH3:15])[C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[C:16]([NH:14][C:13]1[C:9]2[S:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:10]=2[N:11]([CH3:15])[N:12]=1)=[O:20]
Reactant: Cn1nc(N)c2sc3c(Cl)cccc3c21
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1nn(C)c2c1sc1c(Cl)cccc12

Procedure:
By substituting this amide for the amide employed in Example 1, the corresponding 3,7-dichlorobenzo[b]thiophene-2-carbonitrile, m.p. 124°-128° C., was obtained. Treatment of this nitrile was methylhydrazine in dimethyl sulfoxide gave 5-chloro-1-methyl-1H-(1)-benzothieno[3,2-c]pyrazol-3-amine, m.p. 239°-241° C. Reaction of this amine with isobutyryl chloride followed by work up as described in Example 1 gave 2-methyl-N-(5-chloro-1-methyl-1H-(1)benzothieno[3,2-c]pyrazol-3-yl)-propanamide, m.p. 218°-219° C.
Reaction SMILES: [Mg].[CH:2]1([C:5]([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:4][CH2:3]1.[CH2:11](Br)[C:12]#[CH:13].[Cl-].[NH4+]>CCOCC>[CH:2]1([C:5]([OH:6])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][C:12]#[CH:11])[CH2:4][CH2:3]1
Reactant: CCCCC(=O)C1CC1
Reactant: C#CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCC(O)(CCCC)C1CC1

Procedure:
To a stirred, refluxing suspension of amalgam prepared from 6.2 g of magnesium and 50 mg of mercuric chloride suspended in 60 ml of ether is added a solution of a mixture of 30.4 g of n-butyl cyclopropyl ketone (Example 8) and 29.8 g of propargyl bromide in 65 ml of ether during 60 minutes. After reaction at reflux temperature for an additional 30 minutes, the mixture is cooled to 0° and treated with 35 ml of saturated ammonium chloride. The mixture is diluted with ether and filtered through Celite. The filtrate is washed with brine, dried over potassium carbonate, and concentrated. The residue is distilled to provide a liquid, b.p. 93°-94° C. (12 mm), pmr spectrums (C D Cl3): δ 0.43 (cyclopropyl hydrogens), 2.07 (triplet, HC□C), and 2.44 (doublet, C□CCH2).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:15])[CH3:3].[N-:16]=[N+]=[N-].[Na+].O.C(=O)([O-])[O-].[K+].[K+]>C(O)(C(F)(F)F)=O>[CH3:1][CH:2]([O:4][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:15])[NH:16][C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)Oc1cccc2c1CCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)Oc1cccc2c1CCCC(=O)N2
Yield: 60.9 %

Procedure:
A mixture of 4.39 g of 5-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one and 1.74 g of sodium azide in 70 ml of TFA is refluxed for 2 hours. The reaction medium is poured into 250 ml of water, brought to pH 7 by adding potassium carbonate and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and MeOH (100/0 to 90/10). 2.87 g of 6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are obtained in the form of a beige solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@H:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([NH:23][CH3:24])=[O:22].CO>CCCCCCC>[CH3:24][NH:23][C:21]([CH:20]([NH:19][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CNC(=O)[C@H](N)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCCCCCC
Product: CNC(=O)C(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and (αR)-α-amino-N-methyl-benzeneacetamide hydrochloride (1:1) (CAN 97549-10-5) as starting materials. Racemization occurred during the synthesis and the product was isolated by chiral chromatography on Chiralpak AD using heptane/20% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 380.1968 (M+H)+, αD20 (MeOH)=−6.0°.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:4].[Br:13]N1C(=O)CCC1=O.O.[Cl-].[Na+].O>C(#N)C>[Br:13][C:7]1[CH:6]=[C:5]([C:9]([F:10])([F:11])[F:12])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(F)(F)F)c1N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(Br)cc(C(F)(F)F)c1N
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a room temperature solution of 2-methyl-6-(trifluoromethyl)aniline (3.0 g, 17 mmol) in acetonitrile (85 mL) was added N-bromosuccinimide (3.0 g, 17 mmol) in small portions over 30 minutes. The reaction was allowed to stir for 1 hour. The reaction was poured into a water/brine mixture and was extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-40% ethyl acetate/heptanes) gave the title compound (4.13 g, 95%) as a brown oil. 1H NMR (400 MHz, CDCl3, δ): 7.42 (d, J=2.34 Hz, 1H), 7.31 (s, 1H), 2.17 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][Mg]Br.[Cl-].[NH4+]>CCOCC>[CH2:23]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C@H:10]([OH:11])[CH3:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C[C@@H](O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 66.1 %

Procedure:
Ether (100 mL) was added to a 500 mL round-bottom flask containing (S)-2-(dibenzylamino)-3-(4-(trifluoromethyl)phenyl)propanal (4.51 g, 11.3 mmol). The mixture was cooled to −78° C., and methylmagnesium bromide (3.16 M in ether, 35.9 mL, 113 mmol) was added dropwise over 15 minutes. After 5 hours, ammonium chloride (50 mL) was added dropwise, and the mixture was warmed to room temperature. The mixture was extracted with EtOAc (2×500 mL), washed with brine (250 mL), dried over sodium sulfate, and purified by chromatography through a 300 g column eluting with a gradient of 0% to 70% EtOAc in hexane, to provide (2R,3S)-3-(dibenzylamino)-4-(4-(trifluoromethyl)phenyl)butan-2-ol (3.09 g, 65.9% yield) as a yellow oil. LCMS (ES+) m/z=414.3 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.28 (m, 3H) 2.84-2.94 (m, 2H) 3.08 (dd, J=12.81, 6.36 Hz, 1H) 3.66-3.76 (m, 4H) 4.03 (dt, J=10.66, 6.41 Hz, 1H) 7.15-7.28 (m, 12H) 7.51 (d, J=8.02 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:28][CH2:29][C:30](Cl)=[O:31]>>[Cl:28][CH2:29][C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)CCl)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and chloroacetyl chloride (17 mg, 150 μmol). Yield 22 mg (73%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (4,4-difluoro-1-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=468.1, tR (minutes, Method G)=2.48
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[OH:26][CH2:27][CH2:28][CH:29]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:29][CH2:28][CH2:27][OH:26]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Reactant: O=CCCO
Product: CC1=C(CCON=CCCO)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-hydroxypropanal by the method of Example 1.