Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=1>CO>[CH2:1]([N:8]([CH3:17])[C:9]1[CH:10]=[C:11]([NH:16][C:21]2[N:20]=[C:19]([OH:18])[CH:24]=[CH:23][N:22]=2)[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nccc(O)n1
Reactant: Cc1ccc(N)cc1N(C)Cc1ccccc1
Solvent: CO
Product: Cc1ccc(Nc2nccc(O)n2)cc1N(C)Cc1ccccc1
Temperature: 160 °C
Yield: 29.2 %

Procedure:
An intimate mixture of N3-benzyl-N3,4-dimethyl-benzene-1,3-diamine (158 mg, 0.7 mmol) and 4-hydroxy-2-methylthio-pyrimidine (109 mg, 0.77 mmol) is heated in an oil bath of 160° C. After 3 h the melt is cooled to room temperature and treated with MeOH. The remaining solid is collected by filtration, washed with MeOH, and dried, giving 65.5 mg (29%) of N3-benzyl-N1-(4-hydroxy-pyrimidin-2-yl)-N3,4-dimethyl-benzene-1,3-diamine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[CH2:22]([N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1cccc(C(C)c2nccn2Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of the compound of Example 1 (100 mg, 0.50 mmol) and caesium carbonate (407 mg, 1.25 mmol) in acetone (4 ml) was added benzyl bromide (171 mg, 1.00 mmol). The reaction mixture was stirred at room temperature, under nitrogen, for 18 h and then concentrated in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (10 ml) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organic phases were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:14])[CH:11]([CH3:13])[CH3:12].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:15]([O:1][C:2]1[C:7]([I:8])=[C:6]([O:9][CH2:10][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[CH:5]=[CH:4][C:3]=1[C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C(=O)c1ccc(O)c(I)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)c1ccc(OCc2ccccc2)c(I)c1OCc1ccccc1
Reaction time: 1 h
Yield: 158.7 %

Procedure:
Combine 1-(2,4-dihydroxy-3-iodo-phenyl)-2-methyl-propan-1-one (1357 g, 4.43 mol), benzyl bromide (1345 mL, 11.28 mol), and cesium carbonate (2460 g, 7.55 mol) in dimethylformamide (12 L) in a 22-L Morton flask and stir at room temperature overnight. Filter the salts and concentrate the filtrate (8 L of dimethylformamide is evaporated off). Combine residue with the salts, dilute with water (10 L) and extract with 2:1 ethyl acetate/toluene (2×6 L). Wash extracts with water (3×4 L), brine, dry with magnesium sulfate, filter, and evaporate. Stir the resulting solid in 9 L of 10% ethyl acetate in hexane for 1 hr, filter, wash solid with hexanes and air dry to provide the title compound (1710 g, 79% yield) as an off-white solid. HPLC Rt=6.60 min; 1H NMR (DMSO-d6) δ 7.61 (d, J=8.0 Hz, 1H), 7.4 (m, 10H), 6.99 (d, J=8.0 Hz, 1H), 5.27 (s, 2H), 4.84 (s, 2H), 3.43 (hept, J=8.0 Hz, 1H), 0.99 (d, J=8.0 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].Br[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCCN(CCO)CCOc1ccccc1
Yield: 78 %

Procedure:
The reaction mixture of 2-(2-hydroxy-ethylamino)ethanol (32 g, 310 mmol), 1-(2-bromoethoxy)benzene (51 g, 256 mmol), and potassium carbonate (70 g, 512 mmol) in ethanol (200 mL) was refluxed overnight, concentrated, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to afford the title compound (45 g, 78%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([CH:18]1[CH2:25][C:21]2[S:22][CH:23]=[CH:24][C:20]=2[CH2:19]1)[CH3:17]>O>[CH2:16]([CH:18]1[CH2:25][C:21]2[S:22][C:23]([CH:14]=[O:15])=[CH:24][C:20]=2[CH2:19]1)[CH3:17]
Reactant: CCC1Cc2ccsc2C1
Reactant: CN(C=O)c1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC1Cc2cc(C=O)sc2C1
Temperature: 30 °C
Reaction time: 6 h

Procedure:
115 cm3 of phosphorus oxychloride and 155 cm3 of N-methylformanilide are stirred for 30 minutes at ambient temperature. 228 g of 5-ethyl-4,5-dihydro-6H-cyclopenta[b]thiophene, prepared as in Example 5, are added dropwise to this complex whilst the temperature is maintained at 30° C., if necessary by cooling with iced water. After the end of the addition, the reaction mixture is stirred for a further 6 hours at ambient temperature and is then poured carefully on to a mixture of water and ice. The organic products are extracted with ether. The extract is washed with water until neutral and then dried over sodium sulphate. The ether is evaporated and the residue obtained (290 g) is distilled in vacuo. This gives 205 g of 5-ethyl-4,5-dihydro-6H-cyclopenta[b]thiophene-2-carboxaldehyde as a liquid, b.p. 112°-115° C./0.6 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[CH3:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)[C:13](=[O:15])[CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOc1ccccc1C1CCC(=O)N1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CCOc1ccccc1C1CCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2-ethoxyphenyl)pyrrolidin-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.08 min.; [M+H]+: 379.99 g/mol.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:7]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=1[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]([C:6]1[N:7]=[C:3]([CH2:2][O:12][C:13]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=2[CH:15]=[O:16])[S:4][CH:5]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CC(C)(C)c1csc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCc2nc(C(C)(C)C)cs2)c(C=O)c1
Yield: 72.8 %

Procedure:
A mixture of 2-bromomethyl-4-tert-butylthiazole (3.4 g), 2-hydroxy-5-methoxybenzaldehyde (2.21 g) and potassium carbonate (2.0 g) in acetone (25 ml) was stirred under reflux for 7 hours. After being filtered, the filtrate was concentrated under reduced pressure to give a crude residue. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give a syrup. The syrup was crystallized from n-hexane and filtered to give 4-tert-butyl-2-(2-formyl-4-methoxyphenoxymethyl)thiazole (3.23 g).
Reaction SMILES: S1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:3][CH2:2]1.O[O:17][S:18]([O-:20])=O.[K+]>CO.O>[O:17]=[S:18]1(=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:3][CH2:2]1
Reactant: O=S([O-])OO
Reactant: c1ccc2c(c1)SCCC2n1ccnc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=S1(=O)CCC(n2ccnc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-thiochroman-4-yl-1H-imidazole, which can be prepared as described in Example 16, (130 mg, 0.60 mmol) in methanol (3 mL) at 0° C. is added dropwise a solution of Oxone® (excess) in water (3 mL). The reaction mixture is stirred overnight at room temperature. The reaction is then concentrated an the resulting residue is purified by silica gel flash chromatography (0:1 to 1:19 methanol-dichloromethane), to afford 1-(1,1-dioxo-thiochroman-4-yl)-1H-imidazole; MS: (ESI) m/z 249.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 2.83-3.13 (m, 2 H), 3.42-3.65 (m, 1 H), 3.64-3.82 (m, 1 H), 6.18 (t, J=7.1 Hz, 1 H), 7.14 (d, J=7.6 Hz, 1 H), 7.49-7.78 (m, 4 H), 8.02 (d, J=8.0 Hz, 1 H), 9.06 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Li])CCC.[CH2:14]1[O:24][C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15]1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:20]1([OH:23])[CH2:21][CH2:22][C:17]2([O:24][CH2:14][CH2:15][O:16]2)[CH2:18][CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccccc1I
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2F)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
To a solution of 2-fluoro-1-Iodobenzene (11.1 g, 50.0 mmol) in 50 mL THF, cooled to -78° C. under argon, was added n-butyllithium (20.0 mL 2.5M in hexane, 50.0 mmol). The solution was stirred 10 min. at -78° C., and a solution of 1,4-cyclohexanedione mono-ethylene ketal (7.81 g, 50.0 mmol) in 50 mL THF was added slowly. The solution was warmed to r.t. and stirred for 60 min., then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude solid was crystallized from dichloromethane/hexane to give 8-(2-Fluoro-phenyl)-1,4-dioxa-spiro-[4.5]decan-8-ol (3.8 g, 30%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:10]1[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C>ClCCl>[Cl:3][C:14]1[CH:15]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=[C:12]([CH3:17])[N:13]=1
Reactant: Cc1cc(C(C)(C)C)cc[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C(C)(C)C)cc(Cl)n1
Temperature: 100 °C

Procedure:
Add phosphorus oxychloride (15 mL) to 4-tert-butyl-2-methyl-pyridine 1-oxide (2.00 g, 12.10 mmol) and heat to 100° C. for 36 hours. Evaporate off the excess phosphorus oxychloride. Treat the oil cautiously with ice and water with stirring and make basic by treatment with aqueous bicarbonate solution. Extract with dichloromethane (3×75 mL) and pool, desiccate, filter, and concentrated. Chromatograph the crude product on silica using a gradient of (0→5→8%) ethyl acetate in dichloromethane to afford the title compound (0.82 g, 4.46 mmol). MS (ESI), m/z 184 (M+1).
Reaction SMILES: Br.[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12]C)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O)CO.O.[NH2:19]N>O>[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][NH2:19])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: NN
Reactant: CNc1nc2c(C)cccc2s1
Agent: Br
Solvent: O
Solvent: OCCO
Product: Cc1cccc2sc(NN)nc12
Yield: 90 %

Procedure:
4-Methyl-2-methylaminobenzothiazole hydrobromide (443 g.; 1.71 mole) was added with stirring to 1.7 liter of ethylene glycol. 85% Hydrazine hydrate (400 grams; 6.75 mole) was added in several portions. The reaction mixture was heated to 130°-135°C. under N2 atmosphere and maintained for about four hours, then cooled slowly with stirring. The product was isolated by addition of water and separated by filtration. It was then dried overnight in a vacuum oven, yielding 275.5 g. (90% yield) of 4-methyl-2-hydrazinobenzothiazole. The nmr spectrum agreed with a reference spectrum and showed no evidence of starting material or other impurity. Non-aqueous titration showed the product to be 97.5% pure.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[F:9][C:10]1[CH:11]=[C:12](B(O)O)[C:13]([O:16][CH3:17])=[CH:14][CH:15]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH2:8])[CH:11]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Nc1cnccc1I
Product: COc1ccc(F)cc1-c1ccncc1N

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-pyridin-3-ylamine (CAS RN 105752-11-2) and 3-fluoro-6-methoxy-phenylboronic acid (CAS RN 179897-94-0) after a reaction time of 18 hours at reflux. The compound was purified by column chromatography eluting with a gradient of n-hexane:EtOAc (40:60 to 20:80). Yellow solid (84%). MS (ESI): m/z=219.6 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:13]=[C:12](Cl)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.Cl.[CH3:16][N:17]([CH3:25])[CH:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:13]=[C:12]([NH:24][CH:21]2[CH2:22][CH2:23][CH:18]([N:17]([CH3:25])[CH3:16])[CH2:19][CH2:20]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCC3
Reactant: CN(C)C1CCC(N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A solution of 10,12-dichloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (264 mg, 1.08 mmol, 1.00 equiv) in DMF (15 mL) was added 1-N,1-N-dimethylcyclohexane-1,4-diamine hydrochloride (270 mg, 1.51 mmol, 1.40 equiv) and potassium carbonate (450 mg, 3.26 mmol, 3.00 equiv) was stirred overnight at 80° C. in an oil bath under nitrogen. The resulting solution was diluted with of EtOAc and washed with of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to provide the resulted 4-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (300 mg, 79%) as a yellow solid. LC-MS: (ES, m/z) 252 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20](Cl)=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1.[CH3:24][NH:25][CH3:26]>C(O)C>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([N:25]([CH3:26])[CH3:24])=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][NH:3]1
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1Cl)=NC2
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ccc2c(n1)C(c1ccccc1Cl)=NCc1n[nH]c(=O)n1-2

Procedure:
A mixture of 19 grams of 1-keto-6-(o-chlorophenyl)-8-chloro-1,2-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine, 80 grams of dimethylamine and 500 ml. of ethanol were heated in the autoclave for 8 hours at 100°-110° C. The solution was evaporated to dryness, the residue stirred with water, filtered off with suction and washed several times with water. Then it was recrystallized from methanol. Yield 8 grams; M.P. 244°-246° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[C:18]([F:34])[CH:17]=2)[C:12](O)=[O:13])=[CH:5][CH:4]=1)#[N:2].[Cl-].[NH4+]>C1COCC1>[F:34][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([F:22])[C:19]=1[O:23][Si:24]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:31]([CH3:32])[CH3:33])[CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1
Reactant: CC(C)[Si](Oc1c(F)cc(CC(CCc2ccc(C#N)cc2)C(=O)O)cc1F)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1c(F)cc(CC(CO)CCc2ccc(C#N)cc2)cc1F)(C(C)C)C(C)C
Temperature: -10 °C

Procedure:
4879 mg (10 mmol) of 4-(4-cyanophenyl)-2-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)butanoic acid are dissolved in 244 ml of THF and cooled to −10° C. under argon. Then 20.01 ml (20.01 mmol) of a 1 M borane-THF complex solution are added dropwise, and the mixture is stirred at 0° C. until reaction is complete. The mixture is hydrolyzed with saturated ammonium chloride solution and extracted with diethyl ether, and the combined organic phases are concentrated. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1→4:1→2:1→1:1). 2705 mg (57% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:2].O=[C:16]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:17]([OH:19])=[O:18]>C1C=CC=CC=1.O1CCOCC1>[C:17]([C:16]1([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:7]2[NH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH2:5][CH2:4][N:3]1[CH2:1][CH3:2])([OH:19])=[O:18]
Reactant: CCNCCc1c[nH]c2ccccc12
Reactant: O=C(O)CCCC(=O)C(=O)O
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCN1CCc2c([nH]c3ccccc23)C1(CCCC(=O)O)C(=O)O
Yield: 40 %

Procedure:
5 g of N-ethyl-tryptamine (i.e., 3-(2-ethylaminoethyl)-indole) were dissolved in 100 ml of absolute benzene, and a solution of 4.70 g of α-keto-adipic acid in 50 ml of absolute dioxane was added thereto at room temperature. The mixture was refluxed for 20 hours. After the reaction was completed, the mixture was evaporated to remove solvent. The residue thus obtained was recrystallized from ethanol, whereby 3.51 g of 1,2,3,4-tetrahydro-1-carboxy-1-(3-carboxypropyl)-2-ethyl-β-carboline were obtained. Yield: 38.0%
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([Cl:19])[C:16](Cl)=[C:15]([Cl:21])[CH:14]=1>O.CS(C)=O>[Cl:19][C:17]1[CH:18]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=[C:15]([Cl:21])[C:16]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1
Reaction time: 2 h

Procedure:
32.5 g of potassium hydroxide flakes in 30 ml of water were added to 54.5 g (0.5 mole) of 4-aminophenol dissolved in 350 ml of dimethylsulfoxide, and 150 ml of a water/dimethylsulfoxide mixture were distilled off in vacuo at 15-20 mm Hg. 125 g (0.5 mole) of 1-trifluoromethyl-3,4,5-trichlorobenzene [nD20 : 1.5008 67- 68% of theory, compare J. Am. Chem. Soc. 57, 2066-2068 (1935) and U.S. Pat. No. 2,654,789] were then added to the reaction mixture at about 70°-80° C and the mixture was stirred for a further 2 hours at 120°-130° C. The substance was precipitated with water, filtered off, washed with water and recrystallized moist from an ethanol/water mixture, thus giving 40-50% of theory of 4-(2,6-dichloro-4-trifluoromethylphenoxy)-aniline of melting point 128°-130° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:36][CH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:35])=[O:34]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:28]([S:33]([NH:36][CH2:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Reactant: CC(C)(CO)CNS(=O)(=O)c1ccccc1Br
Product: CC(C)(CO)CNS(=O)(=O)c1ccccc1-c1ccc(-c2ncc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-bromo-N-(3-hydroxy-2,2-dimethylpropyl)benzenesulfonamide. MS (ESI): mass calcd. for C22H22FN5OS, 455.14; m/z found, 456.0 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.26 (s, 1H), 7.93 (dd, J=7.8, 1.5, 1H), 7.72-7.60 (m, 3H), 7.47 (dd, J=7.4, 1.5, 1H), 7.43-7.34 (m, 5H), 4.49 (t, J=5.4, 1H), 3.08 (d, J=5.4, 2H), 2.62 (d, J=6.5, 2H), 0.73 (s, 6H).
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Cl[C:50]1[N:55]=[CH:54][C:53]([O:56][CH2:57][C:58]2([CH3:66])[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]2)=[CH:52][N:51]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[F:48][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:51]=[CH:52][C:53]([O:56][CH2:57][C:58]5([CH3:66])[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]5)=[CH:54][N:55]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=2)[CH2:4][CH2:3]1
Reactant: CC1(COc2cnc(Cl)nc2)COC(C)(C)OC1
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCNCC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(OCC6(C)COC(C)(C)OC6)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 120 °C
Reaction time: 26 h
Yield: 92.1 %

Procedure:
To 377 mg (0.559 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 127 mg (0.466 mmol) of 2-chloro-5-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine, which was prepared by a method similar to that of Reference Example 17, and 154 mg (1.11 mmol) of potassium carbonate, 1 ml of 1,4-dioxane was added, and the reaction mixture was stirred at 120° C. for 26 hours. After completion of the reaction, water was added to the reaction solution and the reaction solution was extracted with ethyl acetate twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=89/11-68/32 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 391 mg of the title compound as a foam (yield: 92%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2.[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])=[C:19]([CH:23]=1)[C:20](O)=[O:21])(=[O:14])=[O:13]>>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:20]([C:19]1[CH:23]=[C:15]([S:12]([CH3:11])(=[O:13])=[O:14])[CH:16]=[CH:17][C:18]=1[O:24][C@@H:25]([CH3:30])[C:26]([F:28])([F:29])[F:27])=[O:21])[CH2:6]2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: Ic1cccc2c1CNC2
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cccc(I)c2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example 1 from 4-Iodo-2,3-dihydro-1H-isoindole and 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example B3). Off white solid. MS (m/e): 540.0 (MH+, 100%).