Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:27])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cc(OCC(F)(F)F)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Temperature: 95 °C
Yield: 48.7 %

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.1 g), 2,2,2-trifluoroethyl 4-toluenesulphonate (0.071 g), potassium carbonate (0.08 g) and DMF (2 ml) was stirred and heated to 95° C. for 24 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic solution was washed with water and with brine, dried over magnesium sulphate and evaporated The residue was purified by column chromatography on silica using a 45:46:4 mixture of methylene chloride, ethyl acetate and methanol as eluent. There was thus obtained the title compound (0.058 g); NMR Spectrum: (CDCl3) 1.95–2.1 (m, 2H), 2.1–2.3 (m, 2H), 2.32 (s, 3H), 2.3–2.45 (m, 2H), 2.75 (m, 2H), 4.48 (m, 2H), 4.64 (m, 1H), 6.05 (s, 2H), 6.6 (d, 1H), 6.74 (d, 1H), 6.78 (d, 1H), 6.97 (d, 1H), 8.5 (s, 1H), 9.28 (s, 1H); Mass Spectrum: M+H+ 511 and 513.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7]C(N=[N+]=[N-])=O)=[CH:4][CH:3]=1.C([N:19]([CH2:24]CCC)CCCC)CCC.C1([O:34]C2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[CH:7][NH:19][C:24]2=[O:34])=[CH:13][CH:14]=1
Reactant: CCCCN(CCCC)CCCC
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: [N-]=[N+]=NC(=O)C=Cc1ccc(Br)cc1
Product: O=c1[nH]ccc2ccc(Br)cc12
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of compound 4 (121.6 g, 0.48 mol) and tributylamine (177.9 g, 0.96 mol) in diphenylether (1.2 L) was headed to 210° C. for 2 hours under N2. Then the mixture was cooled to room temperature, the precipitate was filtered, washed with hexane, and dried to give 5 (32 g, 30%)
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[N:7]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:20]>>[Cl-:20].[C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([CH2:15][CH2:16][NH+:17]([CH3:19])[CH3:18])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cl
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1CCN(C)C
Product: C[NH+](C)CCn1nc(C(C)(C)C)cc1C(=O)O
Product: [Cl-]
Temperature: 80 °C

Procedure:
Ethyl 3-tert-butyl-1-(2-(dimethylamino)ethyl)-1H-pyrazole-5-carboxylate (98 mg, 0.367 mmol) was dissolved in 6M aqueous HCl (4 mL, 24.00 mmol) and the colorless solution was heated to 80° C. for 72 h. The volatiles were evaporated in vacuo and the resulting white solid was coevaporated with Et2O 10 mL) to give the title compound as a white solid. Yield: 100 mg (99%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[CH:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=[CH:13][C:4]=1[C:1](=[N:15][OH:16])[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1ccc2c(c1)CCCC2
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 6-acetyltetralin (5.0 g, 29 mmol) in methanol (30 mL) under a nitrogen atmosphere was added hydroxylamine hydrochloride (2.18 g, 32 mmol) and sodium acetate (2.59 g, 32 mmol) and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was taken up in diethyl ether and washed with water and then with saturated sodium chloride solution. The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford an oil which solidified. The solid was pulverized and rinsed with hexanes to afford the title compound of Step C (3.85 g) as an off-white solid. 1H NMR (CDCl3): δ 9.1 (br s,1H), 7.33 (m,2H), 7.07 (d,1H), 2.78 (m,4H), 2.27 (s,3H), 1.79 (m,4H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].C(#N)C>CC(C)=O>[Br-:11].[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1)([OH:19])=[O:18]
Reactant: c1ccc2ncccc2c1
Reactant: O=C(O)CCCCCBr
Solvent: CC(C)=O
Solvent: CC#N
Product: O=C(O)CCCCCN1CC=Cc2ccccc21
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Chinolin (5.2 g, 40 mmol) and 6-bromo-hexanicacid (7.8 g, 40 mmol) was added to 30 ml acetonitrile. The mixture was refluxed under nitrogen atmosphere for three hours and then stirred for 15 hours at room temperature. 50 ml acetone was added and the solution was stirred for further 1 hour. The white precipitate was filtered, washed with acetone (2*10 ml) and dried.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][C:14]([C:16]1([NH2:25])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])[CH3:12].CCN(C(C)C)C(C)C.CC(O)C.C(Cl)Cl>C(Cl)Cl>[CH2:11]([O:13][C:14]([C:16]1([NH:25][C:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:10])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1ncccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)C1(NC(=O)c2ncccc2F)Cc2ccccc2C1
Reaction time: 0.03 h

Procedure:
A 40 mL reaction vial which contains a stirring bar is charged with 3-Fluoropyridine-2-carboxylic acid (997 mg, 7.07 mmol) and dry DCM (15 mL). Stirring is initiated. After 2 min, the HTBU (2.7 g, 7.07 mmol) is added. After 5 min, 2-Amino-indan-2-carboxylic acid ethyl ester (1.45 g, 7.07 mmol) is added followed by DIPEA (2.50 mL, 14.5 mmol). The reaction is allowed to stir for 18 h. Analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (50 mL). This is washed consecutively with water (3%, 25 mL), saturated aqueous NaHCO3 (2×25 mL) and brine (25 mL), and then dried over MgSO4, filtered and evaporated in vacuo to provide 4.15 g of light orange solid. This material is dissolved in 20 mL of DCM. This material is purified utilizing an ISCO Companion with an 80 g cartridge of silica. The gradient is 5% EtOAc in heptanes for 4 column volumes followed by a linear gradient to 60% EtOAc in heptanes over 10 column volumes. 14 mL fractions of UV active elutant are collected. Fractions 6 through 14 are combined and evaporated in vacuo. This yields 2.04 g white solid (2.04 g, 88%).
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23])=O)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[NH2:11][C@H:12]1[C@@H:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][C:13]1=[O:23]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Oc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@@H]1C(=O)N[C@@H]1Oc1ccccc1
Yield: 77 %

Procedure:
(3S, 4R)-3-benzyloxycarbonylamino-4-phenoxy-azetidin-2-one (1.85 g. 5.9 mmole) is hydrogenated with 2 g of 10% palladium on activated carbon in THF (30 ml) and ethyl acetate (30 ml) at 50 psi hydrogen pressure at room temperature for 2 hours. After removal of catalyst by filtration, 810 mg of deprotected (3S, 4R)-3-amino-4-phenoxy-azetidin-2-one is obtained.
Reaction SMILES: C(O[C:4](=[O:14])[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH:6]O)C.[NH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1)[NH2:16]>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[C:4](=[O:14])[N:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=3)[NH:16][CH:6]=2)[CH:9]=1
Reactant: CCOC(=O)C(=CO)c1cccnc1
Reactant: NNc1ccc(C(F)(F)F)cn1
Product: O=c1c(-c2cccnc2)c[nH]n1-c1ccc(C(F)(F)F)cn1

Procedure:
The compound is prepared analogously to Example 2 from 580 mg (3.00 mmol) of the compound from Example 2A and 558 mg (3.00 mmol) 2-hydrazino-5-(trifluoromethyl)pyridine.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[NH2:14])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:23][C:24]([F:57])([F:56])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([O:43][C:44]4[N:49]=[CH:48][N:47]=[C:46](COS(C)(=O)=O)[CH:45]=4)=[CH:40][CH:41]=3)[CH:36]=[CH:35]2)=[O:33])[CH:28]=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:56][C:24]([F:23])([F:57])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([O:43][C:44]4[CH:45]=[C:46]([CH2:6][N:8]5[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[NH2:14])[CH2:9]5)[N:47]=[CH:48][N:49]=4)=[CH:40][CH:41]=3)[CH:36]=[CH:35]2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)C1
Reactant: CS(=O)(=O)OCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1CCN(Cc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Carbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, 1.03 mmol) is dissolved in DCM (5 mL). TFA (2 mL, 26.0 mmol) is added and the reaction is allowed to stir at rt overnight. The solvent is removed in vacuo and THF (5.0 mL) is added followed by methanesulfonic acid 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl ester (0.347 g, 0.685 mmol) and DIEA (0.60 mL, 3.42 mmol). The reaction is heated at 60° C. for 19 h. The solvent is removed in vacuo and the residue separated by FCC (0-15%, 10% NH3MeOH/DCM) to provide (±)-5-[6-(3-carbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 524.9 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (s, 1H), 8.72 (s, 1H), 8.30 (d, J=8.84 Hz, 1H), 8.14 (d, J=3.79 Hz, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.65 (t, J=8.08 Hz, 1H), 7.51 (d, J=2.53 Hz, 2H), 7.16 (dd, J=8.84, 2.27 Hz, 1H), 7.12 (s, 1H), 6.81 (d, J=3.54 Hz, 1H), 3.63 (br. S., 1H), 3.14 (d, J=7.33 Hz, 1H), 2.94 (br. S., 1H), 1.99 (br. S., 1H), 1.25 (d, J=6.06 Hz, 6H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]2[C:22](=[C:23]3[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]3)[C:21]1[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=1[C:19]1[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=1.[Br:33]Br>C(O)(=O)C>[Br:33][C:31]1[CH:30]=[CH:29][C:21]2[C:22]3[C:13]([C:14]4[C:19]([C:20]=2[CH:32]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:12][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[C:28]1[C:23]=3[CH:24]=[CH:25][CH:26]=[CH:27]1
Reactant: c1ccc2cc(-c3cc4c5ccccc5c5ccccc5c4c4ccccc34)ccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)c1ccccc1c1cc(-c3ccc4ccccc4c3)c3ccccc3c21
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
4.05 g of 10-(2-naphthyl)benzo[g]chrysene and 400 mL of acetic acid were placed in a flask. 1.92 g of bromine was added, and the resultant was heated with stirring at 100° C. for 8 hours. After cooling to room temperature, the reaction solution was poured to 1 L of ice water. Deposited solids were separated by filtration, and washed with water and then with methanol, and dried. The thus obtained solids were purified by means of silica gel column chromatography, whereby 4.35 g (yield: 90%) of 3-bromo-10-(2-naphthyl)benzo[g]chrysene was obtained.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([F:17])[C:6]([F:18])=[C:5]([F:19])[C:4]=1[F:20].[Cl:21]C1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[F:17][C:7]1[C:8]([S:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:26])=[C:3]([F:2])[C:4]([F:20])=[C:5]([F:19])[C:6]=1[F:18].[ClH:21]
Reactant: Fc1c(F)c(F)c(SCc2ccccn2)c(F)c1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of 2-(((pentafluorophenyl)thio)methyl)pyridine, hydrochloride (2.0 g) in methylene chloride (50 ml) at 0° C. was treated portionwise with m-chloroperoxybenzoic acid (1.41 g) over 1/2 hour. The mixture was allowed to warm to ambient temperature, sufficient methylene chloride was added to form a solution, and the mixture was stirred a further 1/2 hour. The solution was washed with saturated Na2CO3 solution and water, dried (MgSO4) and evaporated. The residue was converted into the hydrochloride in acetone with ethereal HCl solution to give the title compound, hydrochloride (1.3 g) mp 154°-6° C. (Found: C,41.6; H,2.15; N,3.8 C12H6F5NOS.HCl requires C41.9; H,2.05; N,4.1%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][N:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][N:3]=1)#[N:14]
Reactant: Brc1ccc(C2OCCO2)cn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C2OCCO2)cn1
Temperature: 80 °C
Yield: 74 %

Procedure:
2-Bromo-5-(1,3-dioxolan-2-yl)pyridine (895 mg, 3.89 mmol), zinc cyanide (1.14 g, 5.83 mmol) and tetrakis(triphenylphosphine)palladium (899 mg, 0.778 mmol) were dissolved in N,N-dimethylformaldehyde (30 ml) and the mixture was heated to reflux at 80° C. under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated, water was added thereto, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by column chromatography (hexane/ethyl acetate=7/3) to give 2-cyano-5-(1,3-dioxolan-2-yl)pyridine (506 mg, yield: 74%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=1.CN(C=O)C.[CH2:21]([O:23][C:24](=[O:41])[CH2:25][CH:26]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH3:22]>C(OCC)(=O)C>[I:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH:26]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:41])=[CH:28][CH:29]=1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: BrCc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1ccc(F)cc1)c1ccc(OCc2cccc(I)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cs2CO3 (4.89 g 15 mmol) and 1-(bromomethyl)-3-iodobenzene (4.45 g, 15 mmol) were added successively to a dry DMF (20 mL) solution of 45.2 (2.88 g, 10 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (200 mL), washed with water (100 mL×2) and brine (100 mL), and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography to give compound 47.1 as a colorless oil. MS ESI (pos.) m/e: 505.0 (1+H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:41])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21](OCCCC)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].[NH2:44][C:45]1[NH:49][N:48]=[N:47][N:46]=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:41])[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([NH:44][C:45]4[NH:49][N:48]=[N:47][N:46]=4)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)Cc1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Reactant: Nc1nnn[nH]1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Cc2ccc(OC(F)(F)F)cc2)C2CCc3cc(C(=O)Nc4nnn[nH]4)ccc32)CC1

Procedure:
Butyl 1-((trans-4-tert-butylcyclohexyl){[4-(trifluoromethoxy)phenyl]acetyl}amino)indane-5-carboxylate, enantiomer A (55 mg) or enantiomer B (45 mg), was saponified with aqueous LiOH and then coupled to 5-amino tetrazole following the procedure described (Step D., Example 1/2) to give 1-((trans-4-tert-butylcyclohexyl){[4-(trifluoromethoxy)phenyl]acetyl}amino)-N-1H-tetrazol-5-ylindane-5-carboxamide. Enantiomer A: HPLC/MS: m/z=585.2 (M+1), Rt=2.75 min. 1H NMR (DMSO-d6): δ 12.30 (1H, br s), 7.90 (1H, s), 7.85 (1H, d, J=8.0 Hz), 7.31 (4H, s), 7.04 (1H, d, J=8.0 Hz), 4.83 (1H, m), 3.77 (2H, m), 3.37 (1H, m), 2.96 (1H, m), 3.08-3.00 (1H, m), 2.91-2.84 (1H, m), 2.41-2.31 (1H, m), 2.24-2.19 (1H, m), 1.78 (2H, m), 1.61 (2H, m), 1.18-0.95 (4H, m), 0.85 (9H, s). Enantiomer B: HPLC/MS and 1H NMR (DMSO-d6) are identical to those of enantiomer A.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15]>CN(C=O)C.[Cu-]=O>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: COc1ccccc1I
Reactant: C#CC(=O)OC
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: COC(=O)C#Cc1ccccc1OC
Temperature: 110 °C
Yield: 49.2 %

Procedure:
To a suspension of methyl propiolate (2, 1.314 ml, 15.41 mmol) and copper(I) oxide (1.086 g, 7.59 mmol) in DMF (20 ml) was added 1-iodo-2-methoxybenzene (1, 1.262 ml, 9.48 mmol). The resulting mixture was heated in a Microwave reactor to 110° C. for 2 hrs. The reaction mixture was filtered through a short pad of silica gel and washed w/EtOAc. The organic layer was washed w/1M HCl, brine and sat'd NaHCO3, dried (Na2SO4) and concentrated to leave an oil as crude product, which was purified by flash chromatography (SiO2, EtOAc/Hexane, 1:2) to afford methyl 3-(2-methoxyphenyl)propiolate 3 (932 mg, 4.66 mmol, 49.1% yield). 1H-NMR (500 MHz, CDCl3), δ: 7.54 (1H, dd), 7.44 (1H, td), 6.98-6.92 (m, 2H), 3.92 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][NH:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][N:13]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3CCNC3C2)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC2CN(Cc3ccccc3)CC21

Procedure:
7-Benzyl-2,7-diazabicyclo[3.3.0]octane (Example Jc) is reacted with ethyl chloroformate analogously to Example Oa) to give ethyl 7-benzyl-2,7-diazabicyclo[3.3.0]octane-2-carboxylate, and this is then debenzylated hydrogenolytically analogously to Example Jd). A colorless oil of boiling point 90° C./0.1 mbar is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C@@H:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37](=[O:51])[NH:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]=[CH2:50])=[CH:43][CH:42]=1)([CH3:35])([CH3:34])[CH3:33].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH3:19].[C:32]([O:36][C:37](=[O:51])[NH:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48]/[CH:49]=[CH:50]/[C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([C@@H:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][CH2:18][N:19]([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:24])[CH3:25])[CH:11]=2)=[CH:43][CH:42]=1)([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Reactant: C=CCOc1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(/C=C/COc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1OCc1ccccc1)C(C)C
Product: N
Temperature: 25 °C

Procedure:
(3R)-3-[2-(benzyloxy)-5-bromophenyl]-N,N-diisopropyl-3-phenylpropan-1-amine (Prepared according to WO1994/11337, 800 mg, 1.66 mmol), tert-Butyl{2-[4-(allyloxy)phenyl]ethyl}carbamate (Preparation 5, 924 mg, 3.33 mmol), palladium acetate (37 mg, 0.16 mmol), tri(o-tolyl)phosphine (101 mg, 0.33 mmol), and diisopropylethylamine (435 ul, 2.50 mmol) were heated at 90° C. in acetonitrile (10 ml) under a nitrogen atmosphere for 12 hours. The reaction was cooled to room temperature and poured onto ethyl acetate (30 ml) and water (20 ml). The organics were separated, washed with saturated aqueous sodium hydrogen carbonate (20 ml), water (20 ml), brine (20 ml), dried (magnesium sulphate) and the solvent removed in vacuo, the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (90/10/1.0 by volume) to furnish the title compound as a glass, 475 mg.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@:11]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[O:32])([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[C:8]([F:10])[CH:9]=1)(=[O:3])[CH3:2].[CH3:39][Li]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@@:11]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:38])([F:36])[F:37])=[O:32])([C:6]2[CH:5]=[C:4]([C:1]([OH:3])([CH3:39])[CH3:2])[CH:9]=[C:8]([F:10])[CH:7]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:20][C:21]=1[C:26]([F:27])([F:28])[F:29]
Reactant: [Li]C
Reactant: CC(=O)c1cc(F)cc([C@](Cc2ccccc2)(NC(=O)NCC(F)(F)F)c2ccc(F)c(C(F)(F)F)c2)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)cc([C@](Cc2ccccc2)(NC(=O)NCC(F)(F)F)c2ccc(F)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of (R)-1-(1-(3-acetyl-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 257, mg, 0.037 mmol) in THF (1 mL) at 0° C. under argon was added dropwise CH3Li (1.4 M in Et2O, 0.04 mL, 0.056 mmoL). The reaction mixture was stirred at room temperature for 2 h, then quenched with sat. NH4Cl and 0.5 N HCl and the aqueous layer was extracted with EtOAc. The combined organic portions were washed with H2O, sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(2-hydroxypropan-2-yl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 258, 8 mg, yield 39%). LCMS: RT=3.89 min [M+H] 559.4 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4Cl; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) ppm 7.51-7.45 (m, 2H), 7.21-6.96 (m, 6H), 6.68 (d, J=6.8 Hz, 2H), 6.61 (d, J=9.9 Hz, 1H), 5.43 (s, br, 1H), 5.17 (m, 1H), 4.01 (d, J=13.2 Hz, 1H), 3.85-3.62 (m, 3H), 1.46 (s, 3H), 1.44 (s, 3H).