Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: O=C(O)c1cc2cccc(Br)c2o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1

Procedure:
5.20 g (21.57 mmol) of 7-bromobenzofuran-2-carboxylic acid (Example 29A), 4.3 g (21.57 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 9.84 g (25.89 mmol) of HATU, 13.53 ml (74.68 mmol) of N,N-diisopropylethylamine and 21 ml of DMF are reacted by general method C. The solvent is removed under reduced pressure, and the crude product is taken up in 100 ml of ethyl acetate and washed 15 times with a total of 1.5 1 of 1N sodium hydroxide solution. The organic phase is dried over magnesium sulphate and freed of solvent. 5.2 g (69% of theory) of the title compound are isolated.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[O:12])=[O:10])=[CH:5][CH:4]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[O:12])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 110 °C
Reaction time: 70 h

Procedure:
4,4′-Dimethoxybenzil (5.0 g) was dissolved in acetic acid (95 mL). To the solution, 48 mass % aqueous HBr (31.2 g) was added dropwise at 70° C. over 10 minutes. After addition of HBr, the mixture was stirred at 110° C. for 70 hours. Subsequently, water (150 g) was added to the mixture, to thereby crystallize the product. The crude crystals were recovered through filtration and washed with water (250 g), followed by drying, to thereby yield 4.0 g of 4,4′-dihydroxybenzil as a target product.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]3[CH2:16][CH:15]=[CH:14][S:13][C:12]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:9]2[C:8](=[O:18])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:12]3[S:13][CH:14]=[CH:15][CH2:16][N:11]3[C:10]2=[O:17])=[CH:22][CH:21]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: O=c1[nH]c(=O)n2c(c1-c1ccccc1)SC=CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(=O)c(-c3ccccc3)c3n(c2=O)CC=CS3)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 32.9 %

Procedure:
A mixture of 9-phenyl-4H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (0.26 g), p-methylbenzylchloride (0.21 g) and potassium carbonate (0.28 g) in DMF (5 ml) was stirred at 100° C. for 15 hours. The reaction solution was concentrated to dryness. The resulting residue was dissolved in dichloroethane and was washed with water and dried. m-Chloroperbenzoic acid (0.2 g) was added to the dichloroethane solution little by little under ice cooling, and it was allowed to stand at room temperature for 15 hours. The reaction solution was washed with saturated aq. sodium bicarbonate, and dried, and then trifluoro acetic acid anhydride (0.5 ml) was added thereto and the mixture was refluxed for 15 hours. Oily product obtained by concentration of the resulting solution was dissolved in toluene (20 ml), and a catalytic amount of p-toluene sulfonic acid was added thereto and the mixture was refluxed for 10 hours. The reaction solution was washed with sodium bicarbonate and water, followed by concentration to dryness. The obtained crude crystals were recrystallized from ethyl ether to give colorless crystals (0.12 g, 33%).
Reaction SMILES: [CH:1]([CH:4]1[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]([CH3:15])[CH:7]=[CH:6][CH2:5]1)([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.C1CC=CC=C1>C(Cl)(Cl)(Cl)Cl>[CH:1]([CH:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([CH3:15])[CH:7]=[CH:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1C(C)C=CCC1C(C)C
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1=CCCC=C1
Product: CCOC(=O)C1=C(C)C=CCC1C(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 10.5 g (0.05 mol) of ethyl 6-isopropyl-2-methyl-3-cyclohexene-1-carboxylate (mixture of isomers obtained according to Example 1) and 9.8 g (0.055 mol) of N-bromosuccinimide dissolved in 75 ml of CCl4 was stirred for 3 hours under reflux. After cooling the reaction mixture was filtered and the filter cake was washed with some cold CCl4. The filtrate was evaporated down and the evaporation residue dissolved in 50 ml of dimethylformamide. 1.2 g of LiF and 3.4 g of Li2CO3 were added to this solution and the mixture was heated at 120° C. with continuous stirring for 1 hour. After cooling, 150 ml of water were added and the mixture was extracted 3 times with 50 ml of petroleum ether 40`-60. The extract was washed with water, dried and evaporated down, after which the residue was distilled. 8.1 g were obtained of a mixture, 60% of which consisted of the 2,4-cyclohexadiene isomer and the rest of the 1,3- and 2(exocyclic), 3-isomers of said compound. b.p.: 85°-88° C./0.6 kPa; NMR (data of the 2,4-isomer): 0.87 (3H, d, J=7 Hz); 0.90 (3H, d, J=7 Hz); 1.24 (3H, t, J=7 Hz); 1.6 (1H, m); 1.77 (3H, broad s); 2.54 (1H, m); 2.86 (1H, d, J=7 Hz); 4.07 (2H, k, J=7 Hz); 5.3-5.9 (3H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32])([O-:27])=[O:26].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([NH:32][CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN1CCN(c2ccc(Nc3ncc4ccc(NCc5cccc([N+](=O)[O-])c5)n4n3)cc2)CC1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (66.6 mg, 0.000172 mol), 3-nitrobenzylamine (31.42 mg, 0.0002065 mol) Palladium Acetate (4.00 mg, 0.0000178 mol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (30.0 mg, 0.0518 mmol), and Cesium Carbonate (240.0 mg, 0.7366 mmol) were added. The mixture was purged with nitrogen for 15 minutes. 1,4-Dioxane (2.00 mL) was added. The reaction vessel was sealed and heated at 120° C. for 2 hours. The reaction mixture was partitioned with DCM. The solid was filtered through celite and washed with DCM. The filtrate was evaporated to give a semi-solid. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN (0 to 20% ACN). The collected fractions were lyophilized to give N(2)-[4-(4-Methyl-piperazin-1-yl)-phenyl]-N(7)-(3-nitro-benzyl)-pyrrolo[2,1-f][1,2,4]triazine-2,7-diamine a solid (32 mg, 32%). The solid was triturated with Et2O to give a yellow solid. LCMS (E/I+) 459.14 (M+H). NMR 1H (DMSO-d6)-9.75 (bs, 1H), 9.31 (s, 1H), 8.36 9 s, 1H), 8.27 (s, 1H), 8.14 (d, 1H, J=8.20 Hz), 7.86 (d, 1H, J=7.60 Hz), 7.59-7.73 (m, 3H), 7.49 (bs, 1H), 7.09 (bs, 1H), 6.98 (d, 2H, J=8.20 Hz), 6.55 (bs, 1H), 4.76 (s, 2H), 3.75 (d, 2H, J=12.89 Hz), 3.54 (d, 2H, J=11.72 Hz), 3.16 (q, 2H, J=18.79 Hz), 2.79-2.99 (m, 5H).
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([CH2:6][CH:7]=[O:8])=[CH:2]1.[Br:9][C:10]1C=C(C(O)C)C=C[CH:15]=1>C(Cl)Cl.CCOCC>[Br:9][C:10]1[CH:2]=[C:3]([CH2:6][CH:7]=[O:8])[CH:4]=[CH:5][CH:15]=1
Reactant: CC(O)c1cccc(Br)c1
Reactant: O=CCc1ccsc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCc1cccc(Br)c1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 3-thiophenylacetaldehyde but using 3-bromophenyl-ethanol. The title compound: ES-MS: 196.9 [M-2]−; single peak at tR=3.89 min (System 2); Rf=0.66 (CH2Cl2/Et2O, 95/5).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:35])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[N:4][C:5]([Br:35])=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nccnc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Solvent: CC#N
Product: Nc1ncc(Br)nc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-4-(3-aminopyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (389 mg, 1.006 mmol) in acetonitrile (21 mL) was added NBS (171 mg, 0.961 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 20 min. After quenched with sat NaHCO3, and stir for 30 min. The reaction mixture was extracted with EtOAc 3 times, the organic was washed by sat NaHCO3, water and brine, dried, filtered off, and concentrated. The crude material was taken to the next step without further purification. LCMS (m/z): 367 (MH+), 0.88 min.
Reaction SMILES: O.O.O.O.[N+]([O-])([O-])=[O:6].[Ca+2:9].[N+]([O-])([O-])=O.[O:14]=[P:15]12[O:26]P3(OP(OP(O3)([O:22]1)=O)(=O)[O:16]2)=O.O>C(O)C>[P:15]([O-:26])([O-:22])([O-:16])=[O:14].[Ca+2:9].[Ca+2:9].[Ca+2:9].[P:15]([O-:26])([O-:22])([O-:16])=[O:14].[O-2:6].[Ca+2:9]
Reactant: O=[N+]([O-])[O-]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [O-2]

Procedure:
117.56 g of Calcium Nitrate tetra hydrate was dissolved in 250 ml of ethanol similarly 21.28 g of phosphorous pentoxide was dissolved in 250 ml of ethanol. The resulting solutions were mixed on complete dissolution of the salts and fed to an oil burner for combustion. The flue gases were directed into a stainless steel vessel containing water. After burning a powdered material was recovered form the water dried overnight at 100° C. and submitted for XRD (X-Ray Diffraction) analysis. The resulting XRD pattern is given in FIG. 3 and can be compared with that of the NIST standard HAP shown in FIG. 2. As indicated the burning of the ethanol solution having a molar Calcium to Phosphorous ratio of 1.67 resulted in the formation of HAP without further high temperature processing but peaks characteristic of TriCalcium Phosphate (TCP) and Calcium Oxide (CaO) are observed in the diffraction pattern.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14]1([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C-:26]#[N:27].C([Al+]CC)C>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:26]([C:2]1([N:23]2[CH2:22][CH2:21][CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:25][CH2:24]2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)#[N:27]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: [C-]#N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Al+]CC
Product: CC(C)(C)OC(=O)N1CCC(C#N)(N2CCC(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (0.91 g, 4.9 mmol), 4-phenylpiperidine (0.792 g, 4.91 mmol) and titanium (IV) isopropoxide (1.39 g, 4.91 mmol) was stirred at room temperature for about 16 h. Diethylaluminum cyanide solution (1M in DCE, 9.82 mL) was added and the reaction mixture was stirred for about 4 hours then quenched by the dropwise addition of saturated aqueous sodium bicarbonate solution. The reaction mixture was filtered and the layers separated. The organic phase was washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure to yield tert-butyl 3-cyano-3-(4-phenylpiperidin-1-yl)pyrrolidine-1-carboxylate (1.2 g, 3.38 mmol) as a yellow oil. HPLC (Table 1, Method f) Rt 6.03 min; m/z: (M+H)+ 356.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]3)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1.[OH:28]O>CO.O.Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([N:19]3[CH2:20][CH2:21][CH:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]3)[CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:6]=[CH:7][CH:8]=1)=[O:28]
Reactant: CSc1cccc(-c2nc(N3CCC(C(=O)O)CC3)cc3cccnc23)c1
Reactant: OO
Agent: Cl
Solvent: CO
Solvent: O
Product: CS(=O)c1cccc(-c2nc(N3CCC(C(=O)O)CC3)cc3cccnc23)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Example 41 (1-[8-(3-Methylsulfanyl-phenyl)-[1,7]naphthyridin-6-yl]-piperidine-4-carboxylic acid) (30 mg, 0.07 mmol) is dissolved in methanol (200 μl), and hydrogen peroxide (11.1 μl) is added at room temperature. After 3 hours a further amount of hydrogen peroxide (15 μl) is added and the reaction mixture stirred at 45° C. overnight. The mixture is then cooled to room temperature, diluted with water and acidified with 7 M HCl (1 drop). The reaction mixture is extracted into ethyl acetate, which is washed with water and brine. The organic layer is then dried over magnesium sulfate and concentrated to give the product as an amorphous solid. MS (ES+) 396.1308
Reaction SMILES: [OH-].[Na+].N1C=[CH:6][N:5]=[N:4]1.[C:8]([C:12]1([C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH2:14][O:13]1)([CH3:11])([CH3:10])[CH3:9].O.[CH3:27][N:28]1CCCC1=O>>[C:8]([C:12]([C@@H:15]1[CH2:17][C@H:16]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])([OH:13])[CH2:14][N:5]1[CH:6]=[N:28][CH:27]=[N:4]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C1([C@@H]2C[C@H]2c2ccc(Cl)cc2Cl)CO1
Reactant: CN1CCCC1=O
Reactant: c1c[nH]nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(O)(Cn1cncn1)[C@@H]1C[C@H]1c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
5.6 g of sodium hydroxide (50% by weight) are added to a solution of 5.1 g of triazole in 50 ml of N-methylpyrrolidone, and the mixture is heated at 50° C. for 30 minutes. Then, at room temperature, 10 g of trans-1-(2-tert-butyl-2-oxiranyl)-2-(2,4-dichlorophenyl)cyclopropane which is dissolved in 50 ml of N-methylpyrrolidone are slowly added dropwise. The reaction mixture is stirred at room temperature for 18 hours and then 100 ml of water are added to the solution and the mixture is extracted several times with methyl tert-butyl ether. The isolated organic phase is washed twice with water and then dried over sodium sulfate and concentrated. The remaining residue is purified by flash chromatography on silica gel (9:1 ethyl acetate/n-hexane), resulting in separation of the diastereomers. 7.4 g (60% overall yield) of trans-1-[1-tert-butyl-1-hydroxy-2-(1,2,4-triazol-1-yl)ethyl]-2-(2,4-dichlorophenyl)cyclopropane are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[CH:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]3([O:20][CH3:21])N)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:23][C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])[C:6]=2[CH:33]=1.[C:34]1([CH3:42])[C:35]([CH:40]=O)=[CH:36][CH:37]=[CH:38][CH:39]=1.C(O)(=O)C.C([BH3-])#[N:48].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:22])[C:13]3[CH:18]=[CH:17][C:16]([NH:48][CH2:40][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[CH3:42])=[CH:15][C:14]=3[O:20][CH3:21])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:23][C:24]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[O:25])[C:6]=2[CH:33]=1
Reactant: COC1(N)C=CC=CC1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Reactant: Cc1ccccc1C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(NCc2ccccc2C)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
To a solution of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-(2-methoxy-2-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.8 g) in methanol (30 ml) are added o-tolualdehyde (0.35 ml) and acetic acid (1 ml), and the mixture is stirred at 50-60° C. for 2-3 hours. To the mixture is added sodium cyanoborohydride (0.11 g) at room temperature, and the mixture is stirred for two hours. The mixture is evaporated to remove the solvent, and to the residue is added water. The mixture is extracted with ethyl acetate, and the extract is dried, and evaporated. The residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1→25:1), and recrystallized from acetone/diethyl ether to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-[2-methoxy-4-(2-methylbenzylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.71 g) as white powder.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:14][CH2:15][CH2:16][CH2:17]Br>CC(C)=O>[Br:14][CH2:15][CH2:16][CH2:17][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCOc1ccccc1
Yield: 89.9 %

Procedure:
Phenol (1.0 g, 10.6 mmol) was dissolved in acetone (20 mL). Anhydrous potassium carbonate (7.34 g, 53.1 mmol) and 1,3-dibromopropane (8.58 g, 42.5 mmol) was added to the solution. The reaction mixture was refluxed in an oil bath for 12 h. After the reaction, the potassium carbonate was removed by suction filtration and solvent was removed under reduced pressure to give the crude product which was then purified by column chromatography using ethyl acetate:hexane (3:7) to give product 26 (2.05 g, 90%). 1H NMR (400 MHz, CDCl3) δ 2.24 (m, 2H), 3.54 (t, J=6.4 Hz, 2H), 4.03 (t, J=5.8 Hz, 2H), 6.86 (m, 3H), 7.21 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.[F:12][C:13]([F:24])([F:23])[CH:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1>>[F:23][C:13]([F:12])([F:24])[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:9][C:6]2[C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: Oc1noc2cc(Cl)ccc12
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Product: O=C(Oc1noc2cc(Cl)ccc12)N1CCC(C(F)(F)F)CC1

Procedure:
In analogy to example 1,200 mg (1.18 mmol) of 6-chlorobenzo[d]isoxazol-3-ol were reacted with 305 mg (1.41 mmol) of 4-trifluoromethylpiperidine-1-carbonyl chloride. Yield: 229 mg (56%), M+H+: 349.05.
Reaction SMILES: C(O[CH2:4][CH:5]=[C:6]([C:9]#[N:10])[C:7]#[N:8])C.[CH3:11][NH2:12]>>[CH3:11][NH:12][CH2:4][CH:5]=[C:6]([C:9]#[N:10])[C:7]#[N:8]
Reactant: CCOCC=C(C#N)C#N
Reactant: CN
Product: CNCC=C(C#N)C#N

Procedure:
[(Methylamino)ethylidene)methane-1,1-dicarbonitrile was synthesized in the same manner using (ethoxyethylidene)methane-1,1-dicarbonitrile and methylamine. The NMR data for this compound are shown below.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].II.[Cl-].[Zn+2:12].[Cl-]>C1COCC1>[Zn:12]([CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: [Zn+2]
Reactant: FC(F)(F)CCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(F)(F)CC[Zn]CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
To magnesium (1.373 g, 56 5 mmol) in a 500 mL tear-shaped flask applied vacuum then nitrogen, added 50 mL THF, added 3-bromo-1,1,1-trifluoropropane (6.02 mL, 56.5 mmol), and then 1 crystal of iodine. Within 1 minute the mixture became warm and by 5 minutes was refluxing. The mixture was cooled for 2 minutes with an ice bath to control the exothermic reaction then allowed to warm back up to rt. By 65 minutes, nearly all of the Mg had dissolved. Added zinc(II) chloride (3.85 g, 28 3 mmol) which caused a small amount of heat to be generated. Nearly all was dissolved within 10 minutes to provide ˜1.1 M of Zn(CH2CH2CF3)2 in THF. To 5-bromo-2-chloropyrimidine (7.72 g, 39.9 mmol) and bis(tri-t-butylphosphine)palladium(0) (404 mg, 0.791 mmol) applied vacuum then placed under an atmosphere of nitrogen, added 80 mL THF, and then added over ˜2 minutes 60 mL of the ˜1.1 M of Zn(CH2CH2CF3)2 in THF. The reaction was quenched after 23 hour)s with 300 mL saturated NH4Cl+300 mL EtOAc, the organic layer was then washed with 300 mL saturated NaHCO3 then 300 mL water, dried with MgSO4, filtered, then concentrated to 7.6 g brown oily solids. This material was purified by flash chromatography (0-10% EtOAc/hexanes) to yield product (3.86 g, 18.4 mmol, 46% yield) as a pale yellow solid. MS (ESI) 211.1 (M+1).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH:29](F)[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[C:27]([CH:42]([CH3:44])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:47])[CH2:22][C:23]([CH3:46])([CH3:45])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:32][CH:31]=3)=[C:27]([CH:42]([CH3:43])[CH3:44])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:47])[CH2:22][C:23]([CH3:45])([CH3:46])[O:24]3)=[CH:17][CH:18]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1Cc1ccc(OC(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
230 μl (1.29 mmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 7.23 mg (50 μmol) of (1R,2S)-1-aminoindan-2-ol in 8 ml of tetrahydrofuran, and the mixture is stirred for 30 min. A solution of 163 mg (320 μmol) of rac-5-(4-fluorophenyl)-6-{fluoro[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 25A) in 8 ml of tetrahydrofuran is then slowly added dropwise. The mixture is stirred at room temperature overnight, methanol is then added and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) gives the target product.