Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.C(OC(=O)[NH:17][C:18](=S)[NH:19][C:20]1[C:25]([CH3:26])=[N:24][CH:23]=[C:22]([CH3:27])[N:21]=1)C>C(O)C.O>[CH3:27][C:22]1[N:21]2[N:7]=[C:18]([NH2:17])[N:19]=[C:20]2[C:25]([CH3:26])=[N:24][CH:23]=1
Reactant: CCOC(=O)NC(=S)Nc1nc(C)cnc1C
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: Cc1ncc(C)n2nc(N)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.4 %

Procedure:
A mixture of hydroxylamine hydrochloride (13.68 g, 196.85 mmol) and N,N-diisopropylethylamine (20.6 ml, 118.11 mmol) in ethanol (200 ml) was stirred for 10 minutes at 25° C. To this mixture was then added ethyl-N-[(3,6-dimethylpyrazin-2-yl)carbamothioyl]carbamate (10 g, 39.37 mmol), and the resultant mixture was heated under reflux for 16 hours. The resultant mixture was diluted with water (100 ml), stirred for 10 min, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude material thus obtained was triturated with hexane affording 5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine (2.4 g, 71.87%) as a white solid. MS: m/z=164 (M+H+)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.C([Li])(CC)C.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[C:4]=2[O:3][CH2:2]1
Reactant: c1ccc2c(c1)OCO2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cccc3c2OCO3)OC1(C)C
Temperature: -108 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
Benzo[d][1,3]dioxole (3.05 g, 25 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −108° C. utilizing a tetrahydrofuran/liquid nitrogen bath. sec-Butyllithium (1.4 M in cyclohexane; 19.64 mL, 27.5 mmol) was added dropwise, keeping the temperature below −100° C. The reaction mixture was then stirred at temperatures between −100° C. and −108° C. for 2 h to ensure complete deprotonation. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.65 g, 25.00 mmol) was then added to the reaction mixture dropwise, keeping the temperature below −100° C. The reaction mixture was then allowed to warm to room temperature and partitioned between diethyl ether and water. The organic phase was extracted with water once again and the aqueous phases combined and acidified to pH 4 with HCl. The product was extracted with diethyl ether and the organic phase was dried and concentrated under vacuum. The product was purified by flash chromatography (silica gel) to provide the title compound as a white solid (2.14 g, 34.5%): 1H NMR (300 MHz, CDCl3) δ 7.21 (dd, J=7.6, 1.4 Hz, 1H), 6.90 (dd, J=7.7, 1.5 Hz, 1H), 6.82 (t, J=7.6 Hz, 1H), 6.02 (s, 2H), 1.36 (s, 12H); EIMS m/z 248.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH2:30]([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)[CH3:31].O.C([O-])(=O)C.[K+].O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH2:30]([N:32]1[CH:36]=[C:35]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]5)[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:34]=[N:33]1)[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)cn1
Temperature: 150 °C

Procedure:
A mixture of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate (0.5112 mmol; 212.1 mg), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.022 mmol; 227.1 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.05112 mmol; 42.6 mg), potassium acetate hydrate (0.7668 mmol; 0.77 mL) and sodium carbonate decahydrate (0.7668 mmol; 0.77 mL) in Acetonitrile (10 mL) in a pressure tube was heated under microwave at 150° C. for 15 min. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was concentrated. The residue was purified on silica eluted with 0 to 6% MeOH in DCM to afford tert-butyl 4-(6-(6-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate as a dark tan solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([C@H:19]1[CH2:24][CH2:23][C@@H:22]([CH3:25])[CH2:21][CH2:20]1)[C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1>CO.[C].[Pd]>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C@H:19]1[CH2:24][CH2:23][C@@H:22]([CH3:25])[CH2:21][CH2:20]1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1
Reactant: COc1cc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@@H](C)CC2)ccc1O
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N(CCN(C)C)[C@H]2CC[C@@H](C)CC2)ccc1O

Procedure:
Using a solution of 1 g of N-(2-dimethylaminoethyl)-N-(cis-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 111) in 60 ml of methanol, and 0.05 g of 10% palladium-carbon, a reaction similar to that conducted in Example 76 was carried out. As a result, 0.91 g of N-(2-dimethylaminoethyl)-N-(cis-4-methylcyclohexyl)-3-(4-hydroxy-3-methoxyphenyl)propionamide (a compound of the present invention) was obtained as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[C:5]([Br:17])=[CH:4][N:3]=1.[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]1[CH:41]([NH2:43])[CH3:42])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:30][CH:29]1[CH:41]([NH:43][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[C:5]([Br:17])=[CH:4][N:3]=1)[CH3:42])=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: Clc1ncc(Br)c(-n2cnc3ccccc32)n1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Nc1ncc(Br)c(-n2cnc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reaction time: 14 h

Procedure:
A solution of 2-chloro-4-(benzimidazol-1-yl)-5-bromopyrimidine (100 mg) and 1-benzyloxycarbonyl-2-(1-aminoethyl)-4-tert-butyloxycarbonylpiperazine, diastereomer 1 (EXAMPLE 14 Step D; 115 mg), in 10 mL of toluene was heated to 100° C. and stirred overnight (14 h) at this temperature. The mixture was then cooled and diluted with 20 mL of EtOAc and 30 mL of water. The phases were separated and the aqueous phase was extracted with 2×20 mL of EtOAc. The combined organics were dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluting with 20:1 hexanes-acetone to provide 133 mg of the title compound. Mass spectrum (ESI) 638.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6](C(O)CO)[CH:7]=1.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[OH:24]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[CH:6][CH:7]=1.[CH3:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]=1[OH:24]
Reactant: Nc1ccc(O)c(C(O)CO)c1
Agent: Cc1ccc2ccccc2c1O
Product: Nc1ccc(O)cc1

Procedure:
1-(5-Amino-2-hydroxyphenyl)ethane-1,2-diol (compound 1, DiOHPAP) when coupled with 2-methyl-1-naphthol coupler produces a color which closely matches that obtained from the couple of 4-aminophenol with 2-methyl-1-naphthol. The color on piedmont hair is red, without violet tone, similar to the color derived from p-aminophenol (PAP) with 2-methyl-1-naphthol. The visual observation is also confirmed by CIBL*a*b* values (Table 3) obtained from coupling of 4-aminophenol, 1-(5-amino-2-hydroxyphenyl)ethane-1,2-diol, 2-methyl-4-aminophenol (2-MePAP) and 3-methyl-4-aminophenol (3-MePAP) with 2-methyl-1-naphthol. CIE b* value (which indicates direction of yellow and blue) decreases in order of 4-aminophenol, 1-(5-amino-2-hydroxyphenyl)ethane-1,2-diol, 2-methyl-4-aminophenol and 3-methyl-4-aminophenol. The b* value differences between PAP and compound 1,2-methyl-4-aminophenol and 3-methyl-4-aminophenol, are 3.12, 6.26 and 10.92, respectively. Compound 1 shows the smallest differences among the various PAP derivatives tested. On the other hand, CIE a* values (which indicate red and green directions) undergo little change as compared to the large change in b* value. Hue angle difference (Δh) between PAP and compound 1 is 4.37. 2-MePAP and 3-MePAP show much larger hue angle difference, 11 and 18 respectively. This finding indicates that 1-(5-amino-2-hydroxyphenyl)ethane 1,2-diol 1 is a better alternative to 4-aminophenol than 2- or 3-methyl-4-aminophenol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH:9]([F:27])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].N.CO>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[C@@H:9]([F:27])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(F)C2NC(=O)Nc1cccc2[nH]ncc12
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)C[C@H](F)[C@H]2NC(=O)Nc1cccc2[nH]ncc12

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound N-(5-tert-butyl-2-fluoro-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea (Ex. 39) using a chiral column ChiralCel OD. 1H NMR (300 MHz, d6-DMSO) 13.01 (broad s, 1H), 8.87 (s, 1H), 8.08 (s, 1H), 7.71 (d, 1H), 7.33 (s, 1H), 7.30 (d, 1H), 7.21 (m, 2H), 7.09 (d, 1H), 6.87 (d, 1H), 5.33-5.46 (m, 2H), 3.05-3.27 (m, 2H), 1.27 (s, 9H). MS (DCI/NH3) m/e 367 (M+H)+. [α]D +19.69° (c=0.975, 1:1 MeOH:CH2Cl2). Structure is trans by ROESY NMR, absolute stereochemistry assigned arbitrarily.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH2:3]1.[Cl:17][C:18]1[N:19]=[C:20]([C:25](O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:17][C:18]1[N:19]=[C:20]([C:25]([NH:1][CH:2]2[CH2:5][N:4]([C:6]3[S:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9]([CH2:11][CH3:12])[N:10]=3)[CH2:3]2)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]
Reactant: CCc1nc(N2CC(N)C2)sc1C(=O)OC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCc1nc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)sc1C(=O)OC
Yield: 98.6 %

Procedure:
The same operation as in Example (217c) was performed using methyl 2-(3-aminoazetidin-1-yl)-4-ethyl-1,3-thiazole-5-carboxylate obtained in Example (222b) (94 mg, 0.39 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (68 mg, 0.39 mmol), WSC hydrochloride (224 mg, 1.17 mmol), 1-hydroxybenzotriazole (53 mg, 0.39 mmol) and N-methylmorpholine (0.09 mL, 0.78 mmol), to obtain 153 mg of the title compound as a milk white solid (99%).
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH2:40][CH2:41][O:42][CH3:43])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:44])=[CH:24][N:23]=1>CN(C)C(=O)C>[Cl:44][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35](=[O:36])(=[O:37])[N:38]([CH2:40][CH2:41][O:42][CH3:43])[CH3:39])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COCCN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Solvent: CC(=O)N(C)C
Product: COCCN(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(=O)N(C)C)CC3)ncc1Cl

Procedure:
Following a procedure similar to Example 258c, 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-(2-methoxy-ethyl)-N-methyl-benzenesulfonamide, which was prepared in a manner similar to 1141a-c, were converted to 2-[7-(5-chloro-4-{2-[2-methoxy-ethyl)-methyl-sulfamoyl]-phenylamino}-pyrimidin-2-ylamino)-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-N,N-dimethyl-acetamide (40 mg, 22%) as an off-white solid. MP: 67-76° C.; 1H-NMR (CDCl3) δ 9.22 (s, 1H), 8.47 (d, J=8.8 Hz, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.54 (t, J=8.4 Hz, 1H), 7.52 (s, 1H), 7.22 (t, J=8.4 Hz, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 3.46 (m, 2H), 3.31 (m, 2H), 3.29 (s, 2H), 3.22 (s, 3H), 3.14 (s, 3H), 2.98 (s, 3H), 2.87 (overlapped* s, 3H), 2.87 (overlapped* m, 2H), 2.70 (m, 6H); LC/MS (ESI+): 632.23 (M+H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[CH3:21][Si:22]([C:25]#[C:26][Sn](CCCC)(CCCC)CCCC)([CH3:24])[CH3:23]>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: C[Si](C)(C)C#Cc1cc(-c2ccc(O)c(F)c2)nc2ccc(O)cc12
Yield: 94 %

Procedure:
This compound was prepared from 6b and (trimethylsilylethynyl)tributyltin according to method J. Red powder; Yield: 94%; 1H-NMR (300 MHz, acetone-d6) δ 0.43 (s, 9H), 7.21 (dd, J=8.8, 8.8 Hz, 1H), 7.51 (dd, J=9.1, 2.7 Hz, 1H), 7.68 (d, J=2.7 Hz, 1H), 8.05 (m, 1H), 8.07 (d, J=9.0 Hz, 1H), 8.13 (s, 1H), 8.18 (dd, J=12.8, 2.1 Hz, 1H), 9.05 (s, 1H), 9.26 (s, 1H); MS (ESI) m/z 350 ([M−H]−), 352 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.[CH3:13][CH:14]([CH3:23])[C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:13][CH:14]([CH3:23])[C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:7][CH2:8]2)[CH2:19][CH2:18]1)=[O:16]
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: CC(C)C(=O)N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: COc1ccc2c(c1)C(N1CCN(C(=O)C(C)C)CC1)CC2

Procedure:
The title compound was prepared by the above procedure using 6-methoxy-1-indanone (3.2 g, 20 mmol), 1-(2-methylpropionyl)piperazine (3.0 g, 20 mmol), titanium(IV) isopropoxide (8 mL, 24 mmol) and sodium borohydride (2.7 g, 67 mmol) to give 2.2 g of product as the fumarate salt.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[CH2:12][C@H:13]([OH:15])[CH3:14]>ClCCl>[OH:15][C@H:13]([CH3:14])[CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=2)[NH:8][N:7]=1
Reactant: COc1ccc2[nH]nc(C[C@@H](C)O)c2c1
Solvent: ClCCl
Product: C[C@@H](O)Cc1n[nH]c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of (R)-1-(5-Methoxy-1H-indazol-3-yl)-propan-2-ol (2.31 g, 11.2 mmol) in anhydrous dichloromethane (50 mL) cooled at −78° C. was added a 1 N borontribromide solution in dichloromethane (33.6 mL, 33.6 mmol). After the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 2 hours. The mixture was cooled (ice bath) and quenched with 20 mL of water. Dichloromethane was evaporated and the residue was mixed with ethyl acetate (100 mL). To this solution potassium carbonate was added in small portions until gas evolution ceased and the pH was about 8. The mixture was extracted with ethyl acetate (3×100 mL) and the combined extracts were dried and evaporated to dryness. Chromatography on silica (gradient, 50% to 90% ethyl acetate in hexane) gave an oil (1.50 g, 70%): LC/MS (+APCI) m/z 193 (M+H).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:9]=1
Reactant: O=C1CCCN1
Reactant: N#Cc1ccc(F)cc1Br
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1ccc(F)cc1N1CCCC1=O
Temperature: 105 °C
Yield: 86.9 %

Procedure:
A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-pyrrolidinone (0.46 mL, 6.00 mmol), Cs2CO3 (2.28 g, 7.0 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos) (0.231 g, 0.40 mmol) in dioxane (6 mL) was degassed with argon for 15 min. Pd2 dba3 was introduced and the reaction mixture heated at 105° C. for 48 h. The mixture was cooled, diluted with ethyl acetate or dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes:ethyl acetate (3:7) gradient as the eluent to afford the title compound as a white solid (0.887 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.69 (1H, dd, J=5.8, 8.6 Hz), 7.22 (1H, dd, J=2.5, 9.6 Hz), 7.07 (1H, ddd, J 2.5, 7.6, 8.6 Hz), 3.96 (2H, t, J=7.0 Hz), 2.62 (2H, t, J=8.1 Hz), 2.30–2.22 (2H, m); LCMS (+ESI, M+H+) m/z 205.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[CH2:17]([S:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([Cl:27])[C:21]=1[Cl:28])[CH3:18].C1(C2C=CC=C(C3C=CC=CC=3)N=2)C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[Cl:27][C:22]1[C:21]([Cl:28])=[C:20]([S:19][CH2:17][CH3:18])[CH:26]=[CH:25][C:23]=1[NH:24][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: CCSc1ccc(N)c(Cl)c1Cl
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: c1ccc(-c2cccc(-c3ccccc3)n2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
Oxalyl chloride (0.75 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 25) (1.37 g) in DCM (10 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 18 hours and was then added to a solution of 4-ethylsulphanyl-2,3-dichloroaniline (Method 7) (1.92 g) and 2,6-diphenylpyridine (2.0 g) in DCM (50 ml). The mixture was stirred for 3 hours at room temperature, volatile material was removed by evaporation and the residue was purified by chromatography eluting with 0-20% EtOAc/isohexane to give the title compound (2.12 g) as a solid. NMR (CDCl3) 1.35 (t, 3H), 1.76 (s, 3H), 2.97 (q, 2H), 3.61 (s, 1H), 7.22 (d, 1H), 8.27 (d, 1H), 8.91 (s, 1H); m/z: 360.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[S:26](Cl)(=[O:28])=[O:27].[H-].[Na+]>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][S:26]([C:19]3[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=3[O:17][CH3:16])(=[O:28])=[O:27])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2csc(N)n2)cc1
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c(S(=O)(=O)Nc2nc(-c3ccc(C(C)C)cc3)cs2)c1

Procedure:
N-[4-(4-Isopropyl-phenyl)-thiazol-2-yl]-2,5-dimethoxy-benzenesulfonamide was prepared (62 mg) following general procedure C (method 1) using 4-(4-isopropyl-phenyl)-thiazol-2-yl amine (50 mg, 0.23 mmol), 2,5-dimethoxybenzenesulfonyl chloride (59 mg, 0.25 mmol), NaH (14 mg, 60%, 0.34 mmol) and THF (1 mL). LCMS m/z: 419 (M+1)+; 1H NMR (CDCl3, 400 MHz): δ 1.27 (d, 6H); 2.95 (m, 1H), 3.75 (s, 3H), 3.81 (3, 3H), 6.52 (s, 1H), 6.9 (d, 1H), 7.0 (dd, 1H), 7.31 (m, 2H), 7.44 (m, 2H), 7.6 (d, 1H), 10.2 (brs, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:13][C:12]([CH3:14])=[C:11]2[C:7]=1[CH2:8][C@H:9]1[C:15]([CH3:17])([CH3:16])[C@H:10]12)=[O:5].[CH2:19]([Mg]Cl)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH2:20][CH2:19][C:4]([C:6]2[S:13][C:12]([CH3:14])=[C:11]3[C:7]=2[CH2:8][C@H:9]2[C:15]([CH3:17])([CH3:16])[C@H:10]23)=[O:5])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CON(C)C(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reactant: Cl[Mg]CCc1ccccc1
Product: Cc1sc(C(=O)CCc2ccccc2)c2c1[C@H]1[C@@H](C2)C1(C)C

Procedure:
3-Phenyl-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]-pentalen-4-yl)-propan-1-one is prepared by reacting (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]penta-lene-4-carboxylic acid methoxy-methyl-amide with phenethyl magnesium chloride in analogy to Example 48; LC-MS: tR=1.15, [m+1]+=311.00.
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.Cl.[C:31]([C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)#[CH:32]>>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([C:32]3[N:35]4[CH2:34][C:33]([OH:39])([CH2:38][CH2:37][CH2:36]4)[CH:31]=3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Reactant: C#CC1(O)CCCNC1
Agent: Cl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5=CC6(O)CCCN5C6)ccc43)cc2OC)cn1

Procedure:
7-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1-azabicyclo[3.2.1]oct-6-en-5-ol was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole and 3-ethynylpiperidin-3-ol hydrochloride using the procedure outlined for the synthesis of Example 3-30: 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=2.5 Hz, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.69 (dd, J=8.5, 2.5 Hz, 1H), 7.59 (dd, J=8.5, 1.0 Hz, 1H), 7.29-7.26 (m, 1H, partially obscured by CHCl3), 6.89 (d, J=9.0 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.75-6.73 (m, 2H), 6.09 (s, 1H), 5.29 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.41-3.39 (m, 1H), 2.92-2.83 (m, 3H), 1.89-1.81 (m, 3H), 1.71-1.67 (m, 1H) ppm; (M+1)=499.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[C:22]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].[K]>>[C:22]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])([O:30][CH2:31][CH3:32])=[O:29]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: [K]
Product: CCOC(=O)C(C(=O)OCC)c1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with potassium diethyl malonate to obtain 4-(bis(carboethoxy)methyl)-7-nitro-2,5-bis(trifluoromethyl)-benzimidazole; this intermediate is deesterified and decarboxylated to yield 4-methyl-7-nitro-2,5-bis(trifluoromethyl)-benzimidazole, m.w., 313.2. In like procedures, the following are prepared: