Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([OH:34])[C:12]([C:16]4[CH:17]=[N:18][N:19]([CH:21]5[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]5)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:35])=[O:5])[CH2:3][CH2:2]1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([CH3:44])[CH:38]=1.N1C=CC=CC=1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I.O>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:34][C:37]4[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([CH3:44])[CH:38]=4)[C:12]([C:16]4[CH:17]=[N:18][N:19]([CH:21]5[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23][CH2:22]5)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:35])=[O:5])[CH2:3][CH2:2]1
Reactant: Cc1cc(Br)cc(C)n1
Reactant: C[C@H]1CCc2c(ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c2O)N1C(=O)C1CC1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Oc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)ccc3c2CC[C@H](C)N3C(=O)C2CC2)cc(C)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A mixture of (S)-tert-butyl 4-(4-(1-(cyclopropanecarbonyl)-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.100 g, 0.21 mmol), 4-bromo-2,6-dimethylpyridine (0.077 g, 0.42 mmol), copper (I) iodide (0.004 g, 0.02 mmol), picolinic acid (0.013 g, 0.10 mmol), and potassium phosphate (0.133 g, 0.63 mmol) in DMSO (2 mL) stirred overnight at 90° C. The reaction mixture was cooled to room temperature, poured into water (5 mL), and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1; 2, ethyl acetate/petroleum ether) to afford (S)-tert-butyl 4-(4-(1-(cyclopropanecarbonyl)-5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.030 g, 25%) as yellow oil. MS (ESI, pos. ion) m/z 586 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.CCOCC.C(OC(C)C)(C)C.[C:21]1([CH3:29])[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=1>O1CCCC1.O1CCOCC1>[CH3:29][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:28])[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1ccc(C=O)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C(O)c2ccc(C)cc2)cc1

Procedure:
With reference to FIG. 1, the preferred alcohol is synthesized via a Grignard reaction. First, the magnesium salt of 4-bromotoluene, the Grignard reagent, is prepared in an anhydrous non-nucleophilic ether-based solvent. Examples of suitable solvents include, but are not limited to, diethyl ether, diisopropylether, dioxane and tetrahydrofuran. The preferred solvent is tetrahydrofuran. After preparation of the Grignard reagent, para-tolualdehyde was added to the room temperature solution of the magnesium salt at a rate sufficient to create a reflux. A sufficient time was allowed for the addition of the Grignard reagent to the aldehyde derivative, then the reaction was quenched with a proton source. Following work up of the reaction mixture, 4,4'-dimethylbenzhydrol is isolated (compound I).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C:29](=[O:34])C(C)(C)C)=[C:4]([CH:8](O)[CH:9]([CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)C(OC)=O)[CH:5]=[CH:6][CH:7]=1.O.[ClH:36]>CO>[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:28][C:29](=[O:34])[C:9]([CH:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)=[CH:8]2
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccc(F)c1NC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Reaction time: 2.5 h
Yield: 83 %

Procedure:
tert-Butyl 4-(1-(3-fluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate (7.86 g, 16.4 mmol) was dissolved in methanol (20 mL). Water (45 mL) was added to the mixture followed by concentrated hydrochloric acid (15 mL, 183 mmol). The reaction was heated to reflux and held for 2.5 h. The reaction mixture was concentrated in vacuo, redissolved in ethanol (50 mL), and concentrated in vacuo. The residue was crystallized from ethanol. The resulting solids were filtered, washed with cold ethanol, and dried in vacuo. The title compound was obtained as white solid in 83% yield. 1H NMR (500 MHz, DMSO-d6): δ 11.85 (s, 1H), 8.98 (m, 1H), 8.85 (m, 1H), 7.75 (s, 1H), 7.54 (d, J=7.63, 1H), 7.36 (dd, J=0.22, 8.09, 1H), 7.21-7.11 (m, 1H), 3.41-3.29 (m, 2H), 3.14-2.94 (m, 3H), 2.02 (d, J=13.43, 2H), 1.88-1.71 (m, 2H). Mass spec.: 247.2 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=O.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([NH2:17])=[C:12]([NH2:18])[CH:11]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[NH:18][C:12]2[CH:11]=[C:10]([Cl:9])[C:15]([Cl:16])=[CH:14][C:13]=2[N:17]=1
Reactant: Cn1cccc1C=O
Reactant: Nc1cc(Cl)c(Cl)cc1N
Product: Cn1cccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1

Procedure:
2-(1-Methylpyrrol-2-yl)-5,6-dichlorobenzimidazole was prepared from 1-methyl-2-pyrrolecarboxaldehyde and 4,5-dichloro-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [Na+].[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH-:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][P:27](=[O:28])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOc1ccc(-c2c(Cl)ncn2-c2ccc(S([NH-])(=O)=O)cc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NP(=O)(OCC)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 360 h

Procedure:
To a suspension of 4-[4-chloro-5-(4-ethoxyphenyl)imidazol-1-yl]benzenesulfonamide sodium salt (2.89 mmol) (obtained in the preceding section) in THF (12 mL), diethyl chlorophosphate (0.42 mL, 2.89 mmol) was added under argon atmosphere. The resulting solution was stirred at room temperature for 15 days. It was then concentrated to dryness and the resulting residue was partitioned between H2O and EtOAc, the suspension was filtered and the phases separated. The organic phase was dried and concentrated to afford a solid which was purified by chromatography on silica gel using mixtures hexane/EtOAc and EtOAc/MeOH of increasing polarity as eluent. The product obtained was then recrystallized from ACN to afford the title compound of the example as a yellowish solid (15% yield).
Reaction SMILES: [N:1]([CH2:4][CH:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]([CH3:8])[CH3:7])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>C1COCC1>[NH2:1][CH2:4][CH:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(CN=[N+]=[N-])NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C(CN)NC(=O)OCc1ccccc1
Reaction time: 20 h

Procedure:
To benzyl N-[1-(azidomethyl)-2-methyl-propyl]carbamate 6.9 g (0.0263 mole) in THF (100 mL) was added triphenyl phosphine 7.59 g (1.1 eq). The contents were stirred for 20 hrs. After addition of water (10 mL), and stirring for an additional 6 hrs, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was columned using DCM/MeOH (0-10%) to afford benzyl N-[1-(aminomethyl)-2-methyl-propyl]carbamate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([CH2:25][NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([CH2:25][NH:26][CH2:27][C:28]([F:29])([F:30])[F:31])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: O=C(O)c1ccc(CNCC(F)(F)F)cc1Cl
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNCC(F)(F)F)cc1Cl

Procedure:
To 24.9 g of 2-chloro-4-(methoxycarbonyl)benzoic acid and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at −78° C. until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to −78° C. before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl 4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was cooled to 0° C. in 25 mL of THF before a solution of 19.5 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at ˜50% complete by TLC. The reaction is re-cooled to 0° C. and another 19.5 mL of BH3-THF is added dropwise before the ice bath is removed. Upon completion, the reaction is re-cooled to 0° C. and quenched with 3N HCl dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to 0° C. in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Combi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with 4N HCl in Dioxane at 45° C. and concentrated to give 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide. MS (Q1) 454.6 (M)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20]Br>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][S:15][C:13]1[O:14][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[N:11][N:12]=1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: COc1ccc(CBr)cc1Cl
Product: COc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1Cl
Yield: 87 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-chloro-4-methoxybenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 87%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].CC([N:35]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=1)[C:36](=[O:38])[O-:37])(C)C.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:44]3[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][NH:35][C:36]([O:37][C:16]([CH3:11])([CH3:7])[CH3:15])=[O:38])=[CH:46][CH:45]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: CC(C)(C)N(CCc1ccc(Br)cc1)C(=O)[O-]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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+]
Product: CC(=O)N1c2ccc(-c3ccc(CCNC(=O)OC(C)(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 31 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (125 mg, 0.300 mmol), 1,1-dimethylethyl[2-(4-bromophenyl)ethyl]carbamate (90 mg, 0.300 mmol), potassium carbonate (104 mg, 0.751 mmol) and tetrakis(triphenylphosphine)palladium(0) (17.35 mg, 0.015 mmol) was degassed under house vacuum for 15 min and quenched several times with nitrogen, then was then stirred at 100° C. under nitrogen for 50 min before being cooled to room temperature. Most of the solvent was removed in vacuo and the residue was partitioned between AcOEt (20 mL) and water (15 mL). The layers were separated and the aqueous phase was extracted with AcOEt (15 mL). The combined organic phases were washed with brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 50 to 75% AcOEt in Hexanes) gave 1-methylethyl((2S,4R)-1-acetyl-6-{4-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]phenyl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (50 mg, 0.093 mmol, 31%) as a colourless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]O.Cl.S1C2C=C[N:19]=CC=2C=C1CN>>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH2:19]
Reactant: NCc1cc2cnccc2s1
Reactant: OCc1ccc2ncccc2n1
Agent: Cl
Product: NCc1ccc2ncccc2n1

Procedure:
Intermediate 8 was prepared from (1,5-naphthyridin-2-yl)methanol (8-4) following the procedures similar to the procedure for synthesizing intermediate D from D-3. MS (m/z): 160 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](N(OC)C)=[O:9])[C:5]([CH:14]=[CH2:15])=[C:4]([NH:16][CH3:17])[N:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[C:5]([CH:14]=[CH2:15])=[C:4]([NH:16][CH3:17])[N:3]=1
Reactant: C=Cc1c(NC)nc(Cl)nc1C(=O)N(C)OC
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1c(NC)nc(Cl)nc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-N-methoxy-N-methyl-6-(methylamino)-5-vinylpyrimidine-4-carboxamide (136 mg) in THF (1.8 mL) at 0° C. was added phenylmagnesium bromide (1 M solution in THF, 1.3 mL)) dropwise, and the reaction mixture was stirred at 0° C. for 30 min. The reaction was worked up with EtOAc/sat. NH4Cl, and the crude product was purified by preparative TLC eluting with 40% EtOAc/Hexanes to give the title compound as a colorless oil (87 mg). LC-MS (M+H)+=274.03.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])[CH:6]=[C:5]([N+:17]([O-])=O)[CH:4]=1>CO.[Pd]>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])[CH:8]=1)[NH2:17]
Reactant: O=C(NCC(O)CO)c1cc(CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(CO)cc(C(=O)NCC(O)CO)c1

Procedure:
1-Hydroxymethyl-3-nitro-5-(2,3-dihydroxypropylaminocarbonyl)benzene (12.0 g, 44.4 mmol) was hydrogenated in methanol (150 ml) at 60 psi H2 using Pd/C (10%, 100 mg) as the catalyst. The catalyst was removed by filtration and the residue was evaporated. Addition of methanol (10 ml) precipitated the product as a white solid which was filtered off and dried. Yield: 6.6 g (62%).
Reaction SMILES: [Br-].[C:2]([O:6][C:7]([N:9]1[C:17]2[CH:16]=[CH:15][N+:14]([CH:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:13][C:12]=2[CH:11]=[CH:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[BH4-].[Na+]>CCO>[C:2]([O:6][C:7]([N:9]1[C:17]2[CH2:16][CH2:15][N:14]([CH:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:7]([O:6][CH2:2][CH3:3])=[O:8])([CH3:24])[CH3:25])[CH2:13][C:12]=2[CH:11]=[CH:10]1)=[O:8])([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)CCCCC(c1ccccc1Cl)[n+]1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2c(ccn2C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h
Yield: 140.2 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-5-[1-(2-chlorophenyl)-6-methylheptyl]-1H-pyrrolo[3,2-c]pyridin-5-ium bromide (2.4 g, 4.0 mmol) in 70% EtOH (60 mL) was added (at room temperature, with vigorous stirring, and in portions) sodium borohydride (0.30 g, 8.0 mmol). When the sodium borohydride was completely added, the stirring was terminated and mixture was stirred for 0.5 hours. The solvent was evaporated under reduced pressure and water (60 mL) was added. The product was extracted with dichloromethane (3×150 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, ethyl acetate/heptane=1/10 to 1/3) to yield 5-[1-(2-chlorophenyl)-6-ethoxycarbonyl-6-methylheptyl]-4,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (1.45 g, 60.9% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.50 (dd, 1H, J=7.5, 1.2 Hz), 7.37 (d, 1H, J=8.1, 1.5 Hz), 7.27-7.10 (m, 3H), 5.94 (d, 1H, J=3.3 Hz), 4.16-4.13 (m, 1H), 4.09 (q, 2H, J=6.9 Hz), 3.62 (d, 1H, J=14.1 Hz), 3.28 (d, 1H, J=13.5 Hz), 2.85-2.60 (m, 4H), 1.98-1.76 (m, 2H), 1.55 (s, 9H), 1.42 (t, 2H, J=6.9 Hz), 1.28-1.16 (m, 4H), 1.21 (t, 3H, J=7.2 Hz), 1.11 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.98, 149.49, 139.66, 134.90, 129.44, 129.15, 127.93, 127.60, 126.84, 120.92, 119.77, 109.20, 83.26, 63.76, 60.33, 48.81, 48.19, 42.30, 40.80, 33.23, 32.13, 28.31, 26.07, 25.35, 22.96, 14.52. HRMS (DART-TOF): Calculated for C20H41ClN2O2 (M+H)+: 517.2828. found 517.2833.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:24][CH3:25])=[N:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>CO.CC(=O)OCC>[CH:19]1([N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([NH:9][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:18]=3)[C:14]([CH2:24][CH3:25])=[N:15]2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCc1nn(C2CCCC2)c2cc(N)ccc12
Reactant: O=Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCc1nn(C2CCCC2)c2cc(NCc3cccnc3)ccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-pyridinecarboxaldehyde (106 mg, 1.0 mol) in methanol (5.0 mL) was added 6-amino-1-cyclopentyl-3-ethyl-1H-indazole (240 mg, 1.05 mmol) and p-toluenesulfonic acid monohydrate (2.0 mg). The reaction mixture was stirred for 4 h. The flask was then cooled to 0° C. and sodium borohydride (0.09 g, 2.3 mmol) was added portion-wise over 4 h. The reaction mixture was allowed to warm to room temperature over 16h with stirring. TLC indicated the reaction was complete (1:3 hex:EA). The solvent was evaporated and diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, and concentrated to yield the desired product. 1H NMR (300 MHz) δ 8.64 (s,1H), 8.51 (m,1H), 7.70 (m, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.25 (m, 1H), 6.50 (m,1H), 6.33 (s,1H), 4.68 (p,J=7.8 Hz, 1H), 4.55 (br,1H), 4.40 (s,1H), 2.90 (q,J=7.7 Hz,2H), 2.1–1.8 (m,6H), 1.8–1.6 (m,2H), 1.34 (t,J=7.7 Hz,3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:16]([CH3:30])[CH2:15]1)=[O:13].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:16]([CH3:30])[CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CC1CN(C(=O)c2cc(S(C)(=O)=O)ccc2I)CCN1c1ccc(C(F)(F)F)cc1
Reactant: C1COCCN1
Product: CC1CN(C(=O)c2cc(S(C)(=O)=O)ccc2N2CCOCC2)CCN1c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
(2-Iodo-5-methanesulfonyl-phenyl)-[3-methyl-4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg, 0.09 mmol) was poured into morpholine (2.0 ml) and the reaction mixture was stirred for 24 h at 100° C. before being concentrated in vacuo. The residue was then purified by column chromatography (SiO2, 20 g, Heptane/EtOAc 0-100%) to give the title compound as a light brown solid (43.5 mg, 94%). MS (m/e): 512.3 (M+H+).
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:12]([CH2:13][F:14])[C@H:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][CH2:29][CH3:30])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[OH:10]
Reactant: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNCc1ccc(-c2ccc([C@H](O)[C@H](N)CF)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.7 %

Procedure:
To a stirred solution of (4S,5R)-5-[4-(6-Ethylaminomethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.05 g, 0.112 mmol) in CH2Cl2 (0.2 mL) is added trifluoroacetic acid (0.2 mL) at 0° C. Reaction mixture allowed to warm to room temperature and stirred for 2 hours. The volatiles were removed under reduced pressure to obtain crude material purified by column chromatography eluting in 10% methanol in CH2Cl2 to afford crude title compound (0.04 g, crude). LC-MS (m/z): [M+H]=304.2.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH2:28].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH:28][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NCCc1cccs1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2cccs2)nc1
Yield: 51.7 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 268 mg, 1.00 mmol), 2-thiopheneethylamine (152 mg, 1.20 mmol), Ti(iPrO)4 (568 mg, 2.00 mmol), TiCl4 (1.0M/DCM, 2.00 ml, 2.00 mmol), and NaBH3CN (125 mg, 2.00 mmol) gives the title compound (196 mg) as a white solid. Mass spectrum (ion spray): m/z=380 (M+1); 1HNMR (CDCl3): 8.58 (s, 1H), 8.15 (d, 1H), 7.35 (d, 1H), 7.16 (d, 1H); 6.99 (s, 1H), 6.96-6.93 (m, 3H), 6.86 (d, 1H), 5.81 (br. s, 2H), 4.28 (t, 1H), 3.11-2.96 (m, 5H), 2.83 (m, 1H), 2.46 (m, 1H), 1.87 (m, 1H).