Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Br:15]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(O)(=O)C>[Br:15][C:9]1[C:4]2[N:3]=[N:2][NH:1][C:5]=2[CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=1
Reactant: BrBr
Reactant: CCOC(=O)c1ccc2nn[nH]c2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Br)c2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
A solution of ethyl 1H-1,2,3-benzotriazole-6-carboxylate (5.0 g, 26.2 mmol) in dichloromethane (25.2 mL) was purged with nitrogen and a solution of bromine (1.35 mL, 26.2 mmol) in acetic acid (5.17 mL) was added dropwise. The mixture was stirred at ambient temperature. After 18 h, additional bromine (0.67 mL, 13.1 mmol) was added and the mixture was stirred at ambient temperature. After 18 h, saturated aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.025% trifluoroacetic acid) gave the title compound (0.73 g): LC-MS [M]=270.0.
Reaction SMILES: [C:1]([C:3]1([N:12]([OH:25])[C:13](=[O:24])[CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:8][CH2:7][N:6]([N:9]([CH3:11])[CH3:10])[CH2:5][CH2:4]1)#N.S(=O)(=O)(O)[OH:27].[CH3:31][OH:32]>>[CH3:31][O:32][C:1]([C:3]1([N:12]([OH:25])[C:13](=[O:24])[CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:8][CH2:7][N:6]([N:9]([CH3:11])[CH3:10])[CH2:5][CH2:4]1)=[O:27]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C)c(CC(=O)N(O)C2(C#N)CCN(N(C)C)CC2)c(C)c1
Reactant: CO
Product: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(C)cc2C)CCN(N(C)C)CC1
Temperature: 60 °C

Procedure:
4.5 g N-(4-Cyano-1-dimethylamino-piperidin-4-yl)-N-hydroxy-2-(2,4,6-trimethyl-phenyl)-acetamide (from Step 3) is dissolved in 60 ml methanol. Then, 6.4 g concentrated sulfuric acid is added slowly. The mixture is heated to 60° C. for 2 days, then cooled to ambient temperature, and the solvent evaporated. The residue is partitioned with water and ethyl acetate, the organic layer is separated, washed with brine, dried over sodium sulfate, and the solvent is evaporated. The residue is purified by chromatography on silica gel, with ethyl acetate containing 7.5% triethylamine as a solvent. Thus, 1.35 g 1-Dimethylamino-4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester is obtained. 1H-NMR (CDCl3): 7.90 ppm (s, broad, 1H), 6.84 ppm (s, 2H), 3.86 ppm (s, 2H), 3.71 ppm (s, 3H), 2.80 ppm (m, 2H), 2.70 ppm (m, 2H), 2.53 ppm (m, 2H), 2.40 ppm (s, 6H), 2.23 ppm (s, 3H), 2.22 ppm (s, 6H), 2.15 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](=[S:12])[NH2:11])[CH:3]=1.Cl[CH2:14][C:15]([C:17]([F:20])([F:19])[F:18])=O>C(O)(=O)C>[Cl:9][C:6]1[C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=[C:4]([C:10]2[S:12][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:14][N:11]=2)[N:5]=1
Reactant: NC(=S)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: O=C(CCl)C(F)(F)F
Solvent: CC(=O)O
Product: FC(F)(F)c1cnc(-c2cc(Cl)c(Cl)c(Cl)n2)s1
Yield: 17.8 %

Procedure:
A mixture of 4, 5, 6-trichloropyridine-2-carbothioamide (2.85 g, 11.8 mmol) and 1-chloro-3,3,3-trifluoroacetone (2.59 g, 17.7 mmol) in glacial acetic acid (25 mL) was heated at reflux for 4 hours. Upon cooling, the solids formed were filtered and washed with water (3×100 mL) and sodium bicarbonate (3×50 mL). The solids were then dissolved in dichloromethane and the organic phase was washed with brine (150 mL), and dried (MgSO4). The solvent was removed and the residue purified by preparative liquid chromatography (90% acetonitrile in water) to give 2,3,4-trichloro-6-[5-(trifluoromethyl)-1,3-thiazol-2-yl]pyridine (0.70 g, 2.1 mmol); 1H NMR (CDCl3) δ 7.91 (s, 1H); 8.29 (s, 1H) and give 2,3,4-trichloro-6-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridine (0.20 g, 0.6 mmol); 1H NMR (CDCl3) δ 8.24 (1H, s), 8.39 (1H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:35][C:36]1[C:41]2[N:42]=[C:43](I)[S:44][C:40]=2[CH:39]=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:35][C:36]1[C:41]2[N:42]=[C:43]([C:23]3[C:22]([NH2:34])=[N:21][CH:20]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:18]=4)[CH:24]=3)[S:44][C:40]=2[CH:39]=[C:38]([O:46][C:47]([F:50])([F:49])[F:48])[CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: FC(F)(F)Oc1cc(Br)c2nc(I)sc2c1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(Br)cc(OC(F)(F)F)cc2s1
Temperature: 80 °C

Procedure:
A mixture of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB8) (75 mg, 0.16 mmol), 4-bromo-2-iodo-6-trifluoromethoxy-1,3-benzothiazole (81 mg, 0.19 mmol), potassium carbonate (66 mg, 0.48 mmol), Pd(PPh3)4 (18 mg, 0.016 mmol) in DME (3 mL) and H2O (1 mL) was evacuated and refilled with N2 (3×), then it was heated at 80° C. for 2 h. The mixture was diluted with EtOAc (30 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex.:EtOAc=30:70→15:85) to give the Boc-protected title compound as a yellow solid, MS (ES+): m/z=639/641 (1/1) [MH+]. This material was dissolved in DCM (1 mL) and treated with 1M HCl in diethyl ether (3 mL, 3 mmol). The resulting mixture was stirred at room temperature overnight. The solid that formed was filtered off, washed with DCM, and dried in vacuo to give the title compound as yellow solid. MS (ES+): m/z=538.98/540.96 (1/1) [MH+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[NH:12][C:11]2[C:13]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=3)=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:10]=2[N:9]=1>>[N:1]1([C:8]2[NH:9][C:10]3[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[C:13]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([F:28])=[C:23]([F:29])[CH:22]=4)[C:11]=3[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3nc(Cl)[nH]c23)cc(F)c1F
Product: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(N4CCNCC4)nc23)cc(F)c1F

Procedure:
Piperazine (429 mg, 4.99 mmol, Aldrich) and 2-chloro-5-trifluoromethyl-7-(3,4,5-trifluoro-phenyl)-1H-benzoimidazole (582 mg, 1.66 mmol, Example 51b) reacted under the conditions of Example 100e to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 401 (M+1).
Reaction SMILES: [NH2:1]/[C:2](/[CH:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][N:10]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:29][C:30](=O)[C:31]#[CH:32]>C(O)C>[CH2:7]([O:6][C:4]([C:3]1[C:2]([CH:9]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:12][CH2:11][N:10]2[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[N:1][C:31]([CH3:32])=[CH:30][CH:29]=1)=[O:5])[CH3:8]
Reactant: C#CC(C)=O
Reactant: CCOC(=O)/C=C(\N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Solvent: CCO
Product: CCOC(=O)c1ccc(C)nc1C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Yield: 59.6 %

Procedure:
To a solution of bis(1,1-dimethylethyl) 2-[(1Z)-1-amino-3-(ethyloxy)-3-oxo-1-propen-1-yl]-1,4-piperazinedicarboxylate (may be prepared as described in Intermediate 4; 7.4 g) in ethanol (300 mL), was added 3-butyn-2-one (3.15 g) and the reaction was heated to reflux for 20 hours. The reaction mixture was evaporated and then partitioned between 2× EtOAc and water. The combined organic phases were washed with brine, dried through a hydrophobic frit, and then evaporated to a brown oil (8.54 g), which was purified by silica column (SP4-40M) eluting with 0-40% ethyl acetate in isohexane over 12CV. The clean fractions were combined and evaporated to give the title compound as a yellow oil (4.96 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([O:14]CC)=[O:13].[C:17](=[O:20])([O-])[O-].[Cs+].[Cs+].[CH3:23]C1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C>[Cu]I.C(O)C>[CH2:17]([O:20][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([OH:14])=[O:13])[CH3:23]
Reactant: CCOC(=O)C1OCCc2c(Br)cccc21
Reactant: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Solvent: CCO
Product: CCOc1cccc2c1CCOC2C(=O)O
Temperature: 160 °C

Procedure:
The mixture of ethyl 5-bromoisochroman-1-carboxylate (1.0 g, synthesis methods A1 and A2), cesium carbonate (4.57 g), 3,4,7,8-tetramethyl-1,10-phenanthroline (332 mg), copper (I) iodide (134 mg) and ethanol (10 ml) was heated in microwave reactor at 160° C. Methanol was evaporated and the title compound was isolated and purified with separation method B. (Yield 400 mg).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]([NH2:8])=[S:7])=[O:5].[CH2:9]([I:11])[CH3:10]>C(Cl)Cl>[IH:11].[CH2:2]([O:3][C:4]([C:6]([S:7][CH2:9][CH3:10])=[NH:8])=[O:5])[CH3:1]
Reactant: CCI
Reactant: CCOC(=O)C(N)=S
Solvent: ClCCl
Product: CCOC(=O)C(=N)SCC
Product: I
Reaction time: 5 h

Procedure:
4.0 g of ethyl 2-thiooxamate was dissolved in 70 ml of methylene chloride in a nitrogen atmosphere. To this solution, 5.2 g of ethyl iodide was added dropwise at room temperature. After completion of the dropwise addition, the mixture was reacted with stirring for an additional 5 hours to obtain ethyl ethoxycarbonylformthioimidate hydrogen iodide [H5C2O2CC(SC2H5)=NH.HI]. Then, the methylene chloride was evaporated off under reduced pressure, and the residue was mixed with 35 ml of acetic acid, 4.9 g of anhydrous sodium acetate and 5.2 g of phenacylamine hydrochloride (the same as used in Synthesis Example 2), followed by reacting the mixture at 90° to 100° C. for 3 hours.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[NH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.Cl[CH2:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[N:17]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)[N:18]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Reactant: N#Cc1ccc(-c2ccn3c(=O)[nH]nc3c2Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(C#N)cc3)ccn2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a solution of 4-(8-bromo-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile (510 mg, 1.81 mmol) and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (455 mg, 2.17 mmol) in anhydrous DMF (8 mL) was added anhydrous potassium carbonate (499 mg, 3.62 mmol). The resulting suspension was stirred under argon at 80° C. for 2 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional of 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (120 mg, 0.57 mmol) and anhydrous potassium carbonate (200 mg, 2.07 mmol) were added, and the reaction mixture was stirred at 85° C. for 6 h more. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated under reduced pressure to afford a light brown solid. The solid was suspended in EtOAc/hexanes (about 1:1 ratio), then sonicated for 10 min to obtain a fine suspension. After filtration, the collected solid was washed with hexanes and dried in air to afford 500 mg of the title compound as a yellow solid. HPLC/MS: retention time=3.44 min, [M+H]+=489.2.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]1C[CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O>C(Cl)(=O)C=C.C1C=CC=CC=1>[C:15]([O:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:14])[CH:16]=[CH2:17]
Reactant: C1CCOC1
Reactant: O[C@H]1CC[C@H](c2ccccc2)CC1
Agent: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)O[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
First, 2.5 g of trans-4-phenylcyclohexanol, 50 ml of tetrahydrofuran, and 1.8 g of triethylamine were placed in a 100 ml flask. A solution in which 1.7 g of acryloyl chloride was dissolved in 5 ml of benzene was added dropwise to the mixture under ice water cooling. The mixture was allowed to warm to room temperature and stirred for 5 hours. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) and recrystallized from acetone to obtain 1.8 g of trans-4-phenylcyclohexyl acrylate (Y: 55.1%). The compound thus obtained had a purity of 99.7% by GC and 1 spot by TLC. Furthermore, the compound had an m.p. of 67.3° C.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[N:5]=[C:4]2[NH:14][N:15]=[CH:16][C:3]=12.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)=O>CN(C=O)C.CO>[OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:3]=12
Reactant: COC(=O)CBr
Reactant: CC(C)C(=O)Nc1nc(O)c2cn[nH]c2n1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)Cc1n[nH]c2nc(NC(=O)C(C)C)nc(O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 16 (4.42 g; 20 mmole) is suspended in dry DMF (40 ml), sodium hydride (0.5 g; 20.8 mmole) is added in portions, and the mixture is stirred at room temperature for 60 min. Methyl bromoacetate (1.9 ml; 20.6 mmole) is then added at room temperature, by syringe, and stirring is continued at room temperature. At completion of the reaction (monitored by TLC), the reaction mixture is treated with a small amount of carbon dioxide in methanol. The solvent is then evaporated and the residue dissolved in CH2Cl2, washed once with water and then evaporated to dryness. The product is purified by chromatography to yield the desired isomer (17).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[CH2:11][CH:12]=O.O>CC(O)C>[Br:9][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]2[N:3]([CH:11]=[CH:12][N:1]=2)[CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=CCCl
Solvent: CC(C)O
Solvent: O
Product: Nc1cc(Br)cn2ccnc12
Yield: 93.6 %

Procedure:
2,3-diamino-5-bromopyridine (10.0 g, 45.86 mmol) was dissolved in 80 ml of IPA and then 50% wt chloroacetaldehyde/H2O (6.51 ml, 50.45 mmol) was added. The resulting mixture was heated at reflux for 24 hrs. The mixture was cooled down and then filtered. The cake was dried to afford 9.10 g of product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22]([NH:39][CH2:38][C:37]([F:41])([F:40])[F:36])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(F)(F)F
Reactant: C[C@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@](F)(C(=O)NCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Yield: 58 %

Procedure:
Using (R)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 2,2,2-trifluoro-ethylamine, the title compound was prepared in the same manner as described for example 1c. Final chromatography on silica (heptane/ethyl acetate gradient from 5 to 100%) afforded the title compound as white solid (58%). MS: m/e=558(M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:11])=[CH:7]2.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[CH3:11][C:8]1[CH2:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1=Cc2cccc(Cl)c2C1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CC1=Cc2cccc(-c3ccccc3)c2C1
Temperature: 1 °C

Procedure:
A 5L round bottom flask was equipped with mechanical stirring, a reflux condenser and ice bath. 488.2 g distilled 7-chloro-2-methylindene (2.97 mol) was added, dissolved in 2L ether and 32.2 g Ni(dpp) (0.059 mol, 2 mol %) slurried in the solution, and stirred to cool to 0-2° C. 1.05L of 3.1M phenylmagnesium bromide in ether (3.25 mol, 10% excess) was added slowly from an addition funnel so that the temperature remained below 5° C. Once complete, the ice bath was removed, and the reaction stirred up to room temperature. The reaction was refluxed for 8 hours, and checked for completion by GC. The reaction flask was cooled with an ice bath, and 250 mL water added, then 1L 10% HCl. The aqueous and organic layers are separated, and the organic layer dried over anhydrous Na2SO4. Ether was distilled, and the residual oil placed on a column of 100 g silica gel. Elution with hexane was performed, the hexane distilled under reduced pressure to a temperature of 90° C. 2-methyl-7-phenylindene (Spaleck compound 13a) was obtained by distillation at <1 mm Hg with a 36 cm Vigreux column at 125° C. A fore-cut containing biphenyl was obtained at 70-90° C. and discarded. Yield was 507.8 g (2.47 mol) equal to 80%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)[CH:8]=[O:9].[CH2:11]([N:13]1[C:17](O)=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[N:14]1)[CH3:12]>O>[Cl:3][C:17]1[N:13]([CH2:11][CH3:12])[N:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:16]=1[CH:8]=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nc(C(F)(F)F)cc1O
Reactant: CN(C)C=O
Solvent: O
Product: CCn1nc(C(F)(F)F)c(C=O)c1Cl

Procedure:
91.1 g (591.2 mmoles) of phosphorus oxychloride was added to 18.0 g (246.3 mmoles) of N,N-dimethylformamide with ice-cooling. Thereto was added, at room temperature, 35.5 g (197.1 mmoles) of 1-ethyl-3-trifluoromethyl-1H-pyrazol-5-ol. The mixture was heated and refluxed for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water with ice-cooling, and extraction with chloroform was conducted. The resulting organic layer was washed with an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain a crude product of 5-chloro-1-ethyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[CH3:32][NH:33][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:15]=2[O:14]1
Reactant: CN
Reactant: COc1ccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c(OC)c1
Product: CNCC1Cc2cccc(-c3ccc(OC)cc3OC)c2O1

Procedure:
The title compound was prepared (0.272 g, 82%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.435 g, 0.987 mmol) and methylamine (0.306 g, 9.87 mmol). mp 185-188° C.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)(C)(C)C.[C:16]([Li])(C)([CH3:18])[CH3:17].CCO/C=C(/C=O)\C.FC(F)(F)C(O)=O.[OH-].[Na+]>>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:16]([CH3:18])=[CH:17]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1
Reactant: [Li]C(C)(C)C
Agent: CCO/C=C(\C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc2ccc(F)cc2c1
Temperature: -20 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
(4-Fluoro-phenyl)-carbamic acid tert-butyl ester (2.11 g, 10.0 mmol, ABCR, Karlsruhe, Germany) was added to a round bottom and purged with nitrogen. Anhydrous tetrahydrofuran (200 mL) was added to dissolve the solids and the flask placed in a dry ice/acetone bath (internal temperature −74° C. uncorrected). tert-Butyl lithium (1.7 M in pentane, 14.2 mL, 24.0 mmol) was added over 5 min causing a yellow color to develop. After the addition was complete the reaction was stirred in a −20° C. bath for 1 h. At this point, 3-ethoxymethacrolein (1.43 mL, 12.0 mmol) was added dropwise over 5 min, keeping the temperature below −19° C. The reaction was stirred at −20° C. for 2 h before slowly adding trifluoroacetic acid (14 mL) over 5 min. The red solution was stirred at room temperature for 16 h before bring to pH 12 with 1 N NaOH. This was extracted twice with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptanes) gave impure desired material. This was extracted into three portions of 1 N HCl, the combined aqueous layers were brought to pH 12 with 6 N NaOH, and then extracted into two portions of ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo to give 6-fluoro-3-methyl-quinoline (48.0 mg) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H) 8.07 (dd, J=9.1, 5.4 Hz, 1H) 7.88 (s, 1H) 7.33-7.46 (m, 2H) 2.53 (s, 3H); MS (M+1): 162.1.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@@H:11]1[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@@H:14]([OH:15])[CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@@H:11]1[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@@H]1COCc1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O[C@@H]1[C@@H](COCc2ccccc2)N(C(=O)OCc2ccccc2)C[C@@H]1O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
The compound (183 mg, 0.40 mmol) synthesized in Example 9 (9a) was dissolved in methylene chloride (4 mL) and pyridine (96 μL, 1.20 mmol) and trifluoromethanesulfonic acid anhydride (0.10 mL, 0.60 mmol) were added thereto, followed by stirring of the mixture at 0° C. for 20 minutes. After water (10 mL) was added thereto at 0° C. and the mixture was extracted with methylene chloride, the organic layer was washed with saturated brine (10 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 2:1, V/V) to obtain the desired title compound (92 mg, yield 50%) as a pale yellow oil.