Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]1[C:18](=[O:19])[CH2:17][CH:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)C.[BH4-].[Na+].[CH2:26]([OH:28])C>>[OH:19][CH:18]1[CH2:17][CH:16]2[N:7]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]([O:22][CH3:23])[C:13]([O:20][CH3:21])=[CH:14][C:15]=32)[CH2:6][CH:5]1[CH2:4][CH:2]([O:28][CH3:26])[CH3:1]
Reactant: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)C1CC(O)C(CC(C)OC)CN1CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Tetrabenazine (Formula 1; 9.01 mg, 0.0284 mmol) was dissolved in 1 mL of ethanol, the solution was cooled to 0° C., and then NaBH4 (3.22 mg, 0.0851 mmol) was slowly added thereto. The temperature was heated to normal temperature and then the mixture was stirred for 1 hr. The mixture was distilled under reduced pressure, water (3 mL) and CH2Cl2 (3 mL) were added thereto to extract an organic layer, and the organic layer collected was washed with a saturated K2CO3 aqueous solution. Anhydrous magnesium sulfate was used to dry the organic layer, filtration under reduced pressure and evaporation under reduced pressure were performed, and then column chromatography was used to obtain 7.30 mg (yield 80%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[CH:13]=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.CCCCCC.CN(C)[CH:32]=[O:33]>O1CCCC1>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:32]=[O:33])=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)ncn2C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=O)n2C)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
In 16 ml of dry tetrahydrofuran was dissolved 800 mg (3.1 mmol) of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-methyl-1H-imidazole (X=Y=Me) (10). This solution was cooled to -78° C. and 2.2 ml of n-butyllithium-n-hexane (1.66 molar) was added dropwise under nitrogen. After 5 minutes, 680 mg (9.3 mmol) of dry N,N-dimethylformamide was added and the reaction was further conducted at the same temperature for 15 minutes. This reaction mixture was poured in ice-water and extracted with diethyl ether. The organic layer was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:5) to provide 644 mg (yield 73%) of Compound I-6. mp 93 to 94° C.
Reaction SMILES: CI.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:32])[NH:12][C:13]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1.[C:33](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:32])[N:12]([CH3:33])[C:13]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:14][C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(CCCCc2ccccc2)nc(-c2ccncc2)c1-c1ccc(F)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(CCCCc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 1.25 h

Procedure:
Methyl iodide (22 μl, 0.351 mmol) was added to a stirring mixture of 5-(4-fluorophenyl)-2-(4-phenylbutyl)-6-(4-pyridyl)-4(3H)-pyrimidinone (140 mg, 0.351 mmol) and potassium carbonate (49 mg, 0.351 mmol) in N,N-dimethylformamide (5 ml). After 75 min, it was evaporated and the resultant product purified on a silica gel column (hexane-acetone=3:1; 2:1) to provide the title compound. MS (m/z): 414.3 (M+H)+; C26H24FN3O requir. 413.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[Na].[NH2:33][C:34]1[NH:39][C:38]2=[N:40][CH:41]=[C:42]([CH3:43])[C:37]2=[C:36]([Cl:44])[N:35]=1.C(#N)C>C(Cl)Cl>[NH2:33][C:34]1[N:35]=[C:36]([Cl:44])[C:37]2[C:42]([CH3:43])=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:38]=2[N:39]=1
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Reactant: Cc1cnc2[nH]c(N)nc(Cl)c1-2
Agent: Br
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2nc(N)nc(Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product from Step C of Example 62 (1.57 g, 3.16 mmol) in CH2Cl2 (50 mL) was added HBr (5.7 M in acetic acid; 3.3 mL) dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h, concentrated in vacuo and co-evaporated with toluene (2×20 mL). The resulting oil was dissolved in MeCN (20 mL) and added dropwise to a solution of the sodium salt of 2-amino-4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine in acetonitrile [generated in situ from 2-amino-4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see Liebigs Ann. Chem. 1984: 708–721] (1.13 g, 6.2 mmol) in anhydrous acetonitrile (150 mL), and NaH (60% in mineral oil, 248 mg, 6.2 mmol), after 2 h of vigorous stirring at rt]. The combined mixture was stirred at rt for 24 h and then evaporated to dryness. The residue was suspended in water (100 mL) and extracted with EtOAc (300+150 mL). The combined extracts were washed with brine (100 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (5×7 cm) using ethyl acetate/hexane (0 to 30% EtOAc in 5% step gradient) as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (0.96 g) as a colorless foam.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][C@@H:18]([OH:28])[C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5](OC)=[O:6].O>C1COCC1>[OH:26][C@@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:20]([CH2:19][C@@H:18]([OH:28])[C@@H:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:29])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][OH:6])[CH2:25]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A suspension of LiA1H4 (0.15 g, 3 mols. equiv.) in dry THF (25 ml) was stirred under nitrogen whilst standing in an ice/methanol bath. Methyl chenodeoxycholate (5c) (0.5 g, 1.2 mmol) in dry THF (30 ml) was then added dropwise and the resultant mixture stirred at ambient temperature overnight. Water was then introduced carefully to the mixture until all the excess LiA1H4 had been destroyed. The resultant mixture was acidified with 2M HCl and extracted into EtOAc (3×). The combined organic extracts were washed with water (2×), dried and evaporated to give a white foam (0.47 g. 100%). Recrystallisation of 0.27 g from dichloromethane afforded pure 3α,7α,24-trihydroxy-50-cholane (7c)3 (0.16 g, 59%): m.p. 116°-118° C. [Lit. 9a 150° C.; also reported as an amorphous solid9b ]; 1H nmr (90 MHz; CDCl3 /DMSO d 6) δ0.64 (3H, s, 18-CH3), 0.88 (3H, s, 19-CH3), 2.9-3.2 (2H, s (exchanges on adding D2O], OH's, 3.1-3.6 (1H, m, 3β-H), 3.4-3.6 (2H, t[broadened), 24-CH2), 3.6-4.0 (1H, m[exchanges on adding D2O], OH), 3.7-3.9 (1H, m, 7β-H); IR (KBr) 3420 (OH's) cm-1 ; MS: Found m/z 378.3130; C24H42O3 (M) requires m/z 378.3134.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[CH3:21].FC1C=CC([CH:27]=[O:28])=C(C)C=1C>Cl>[F:13][C:14]1[C:15]([CH3:21])=[C:16]([CH3:20])[CH:17]=[CH:18][C:19]=1[CH:27]=[O:28]
Reactant: Cc1cccc(F)c1C
Reactant: Cc1c(F)ccc(C=O)c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(C=O)c(F)c1C
Temperature: 50 °C
Yield: 79.1 %

Procedure:
67.60 g of aluminum chloride (mol. Wt. 133.34; 507.0 mmol), 450.0 g of 1,2-dichlorobenzene (mol. Wt. 147.00; 3,061 mmol), and about 503.54 g of 3-fluoro-o-xylene (mol. Wt. 124.16; 789.3 mmol) were charged to a 2 liter Parry -brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 50° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 28 hours (the reaction temperature was maintained at 50° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluoro-o-xylene, 1,2-dichlorobenzene, and left about 94.98 g of a benzaldehyde mixture consisting of 4-fluoro-2,3-dimethylbenzaldehyde (89.1 %) and 2-fluoro-3,4-dimethylbenzaldehyde (10.9%) (mol. Wt. 152.17; 624.2 mmol; yield of approximately 79.1%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([CH:23]=[C:24]([CH3:26])[N:25]=4)[CH:22]=3)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:28]>C(Cl)Cl.O1CCOCC1>[ClH:28].[ClH:28].[CH3:26][C:24]1[N:25]=[C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:8]4([NH2:7])[CH2:9][CH2:10]4)=[N:12][CH:13]=3)=[CH:22][N:21]2[CH:23]=1
Reactant: Cc1cn2cc(-c3ccc(C4(NC(=O)OC(C)(C)C)CC4)nc3)ccc2n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cn2cc(-c3ccc(C4(N)CC4)nc3)ccc2n1
Reaction time: 1 h

Procedure:
{1-[5-(2-Methyl-imidazo[1,2-a]pyridin-6-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (21 mg, 0.06 mmol) was dissolved in 0.5 mL of CH2Cl2 and 1 mL of 4M HCl in dioxane was added. The resulting suspension was stirred for 1 h. The mixture was concentrated to yield crude 1-[5-(2-methyl-imidazo[1,2-a]pyridin-6-yl)-pyridin-2-yl]-cyclopropylamine dihydrochloride. The material was used in subsequent reactions without purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:19][CH2:20][CH2:21][CH3:22])=[O:7])=[CH:4][C:3]=1[O:11][CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)c1ccc(Br)c(OCCCC)c1
Reaction time: 8 h
Yield: 66.81 %

Procedure:
To a flask containing 4-bromo-3-hydroxybenzoic acid (T9.1)(available from Combi-Blocks Inc.)(2.40 g, 11.06 mmol) and Cs2CO3 (8.287 g, 25.44 mmol) in DMF (40 mL), was added 1-bromobutane (2.494 mL, 23.22 mmol), and the mixture was stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by CombiFlash® column chromatography (0 to 20% EtOAc/Hexanes) to provide T9.2 (2.4326 g, 66.81% yield).
Reaction SMILES: CON=[CH:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[O:8][C@@H:7]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:6]1.CC=[O:34]>CO>[CH:4]([C@@H:5]1[C@@H:9]([CH2:10][O:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[O:8][C@@H:7]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:6]1)=[O:34]
Reactant: CC=O
Reactant: CON=C[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CON1C(=O)c2ccccc2C1=O
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](C=O)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O

Procedure:
3'-Deoxy-3'-C-[(methoxyimino)methyl]-5'-O-phthalimidothymidine upon treated with CH3CHO in MeOH regenerated the 3'-C-formyl group. The product on purification by silica gel column chromatography furnished the title compound as homogeneous material in 81% overall yield for 3 steps. 1H NMR (CDCl3) δ 9.95 (s, 1, CH=O); 8.62 (br s, 1, NH); 7.71-7.90 (m, 5, aromatic H, H-6); 6.06 (t, 1, H-1', J1'2' =6.61 Hz, J1'2' =6.6 Hz); 4.36-4.73 (m, 3, H-4', H5',5"); 3.78 (m, 1, H-3'); 2.20-2.90 (m, 2, H-2'2"); 1.98 (s, 3, C5CH3).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18]([CH3:19])=[O:30])[O:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: CSc1nc2ccc(Cn3cnc4cncnc43)cc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cncnc43)cc2o1
Temperature: 0 °C
Reaction time: 6 h
Yield: 33.8 %

Procedure:
A mixture of 6-((9H-purin-9-yl)methyl)-2-(methylthio)benzo[d]oxazole (400 mg, 1.35 mmol) and m-CPBA (289 mg, 1.69 mmol) in DCM (25 mL) was stirred at 0° C. for 6 h. The reaction mixture was washed with aq Na2S2O3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give 6-((9H-purin-9-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole as a light yellow solid (143 mg, 33.89%). 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 9.03 (s, 1H), 8.13 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.44 (d, J=9.9 Hz, 1H), 5.62 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 314 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]2[C:5]([CH2:6][N:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>ClCCl>[Cl:1][C:2]1[N:11]2[C:5]([CH2:6][N:7]([C:16]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=4[CH3:32])=[CH:21][CH:22]=3)=[O:24])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccc(Cl)n3Cc3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccc(Cl)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1 mmol of 3-chloro-10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 2 mmol of triethylamine, and 1.1 mmol of 2-methylbenzoylchloride in 8 ml of dichloromethane is stirred at room temperature overnight. The mixture is washed with water, and 1M NaHCO3 and dried(Na2 SO4). The solvent is removed in vacuo to give a solid which is recrystallized from dichloromethane-hexane to give crystals, 185°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[C:4](C(OC)=O)[CH:3]=1.[NH2:16]N>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[C:4]([NH2:16])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)n1
Reactant: NN
Product: COC(=O)c1cc(Cl)cc(N)n1

Procedure:
4-Chloropyridine-2,6-dicarboxylic acid, dimethyl ester (230 mg, 1 mmol) was converted to the monoacyl hydrazide by adding one-half equivalent of anyhydrous hydrazine. The monohydrazide was converted to the monoacyl azide by the methodology described in step B of Example 35. The title compound was obtained by applying the methodology described in step C of Example 35.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Si:23]([O:40][CH2:41][CH2:42][CH2:43]/[C:44](=[CH:54]\[S:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)/[C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Si:23]([O:40][CH2:41][CH2:42][CH2:43]/[C:44](=[CH:54]\[S:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)/[C:45](=[S:10])[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:36]([CH3:38])([CH3:37])[CH3:39])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)[Si](OCCC/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC/C(=C\Sc1ccccc1)C(=S)Nc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Lawesson reagent was added to tetrahydrofuran solution including 2.81 g of (E)-5-(tert-butyldiphenylsilyloxy)-N-phenyl-2-(phenylthiomethylene)pentanamide. The resulting solution was heated under reflux for one night and cooled to room temperature, followed by adding saturated sodium bicarbonate water to extract. The water layer was extracted with ethyl acetate, and the organic layer was mixed and dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.17 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH:14]=[N:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1)[CH3:13]
Reactant: Nc1cccc(Cl)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1cccc(Cl)c1
Yield: 100.5 %

Procedure:
A mixture of 3-chloroaniline (63.8 g, 0.50 mol) and dimethylformamide dimethyl acetal (106 ml, 0.75 mol) was heated at 100° for 2 h and evaporated at 60° at 0.5 mm Hg to give 91.8 g amber oil; ms 183.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[OH:12][CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][CH2:16][S:17]([NH2:20])(=[O:19])=[O:18]>>[CH3:21][C:14]([CH3:22])([CH2:15][CH2:16][S:17](=[O:19])(=[O:18])[NH2:20])[CH2:13][O:12][C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(C)(CO)CCS(N)(=O)=O
Reactant: Cc1cc2nccn2nc1Cl
Product: Cc1cc2nccn2nc1OCC(C)(C)CCS(N)(=O)=O
Yield: 26.2 %

Procedure:
Using 0.84 g of 6-chloro-7-methylimidazo[1,2-b]pyridazine and 0.91 g of 4-hydroxy-3,3-dimethyl-1-butanesulfonamide, 0.41 g of title compound was obtained in the same manner as in Example 3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:31])[CH:11]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH:28]3[CH2:30][CH2:29]3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:7][CH:8]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>CN(C=O)C.O>[CH:28]1([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH:11]([O:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]4[N:32]=[N:33][NH:34][N:2]=4)=[CH:8][N:7]=3)=[O:31])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:30][CH2:29]1
Reactant: N#Cc1ccc(NC(=O)C(OC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(-c2nn[nH]n2)cn1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 110 °C

Procedure:
The mixture of N-(5-cyano-2-pyridyl)-2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetamide (0.1 g, 0.22 mmol), sodium azide (0.03 g, 0.453 mmol) and ammonium chloride (0.024 g, 0.453 mmol) in DMF (8 mL) was heated at 110° C. for 16 h. After completion, reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (2×50 mL), combined organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Crude compound was purified by LCMS purification to afford title compound. (0.020 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[O:22]=[C:11]1[N:10]([CH2:9][CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]2)[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: N#Cc1ccc2c(c1)N(CC[C@H]1CC[C@H](N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc2c(c1)N(CC[C@H]1CC[C@H](NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2

Procedure:
4-[2-(Trans-4-aminocyclohexyl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 77), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (1.73 mmol) and sodium cyanoborohydride were reacted following the procedure described for Example 21 to give the product in 7% yield, as an off-white solid.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](NCCN3CCCC3)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([N:31](CC)CC)C.C(Cl)(=O)C>C(#N)C>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:31]
Reactant: Cc1[nH]c2ccc(NCCN3CCCC3)cc2c1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Nc1cc2ccccc2[nH]1
Yield: 33 %

Procedure:
To a stirred solution of the 2-methyl-5-(2-pyrrolidine-1-yl-ethylamino)-1H-indole-3-carboxylic acid benzyl ester (147 mg, 0.39 mmol, 1.0 eq) and triethylamine (47.6 mg, 0.47 mmol, 1.2 eq) in acetonitrile in an ice-water bath was added dropwise a solution of acetyl chloride in acetonitrile. After the ice-water bath was removed, the reaction mixture was heated to reflux for overnight. After the mixture was concentrated, the residue was purified by preparative HPLC (reverse-phase, 10-100 CH3CN:H2O, 0.1% TFA) to yield the desire indole amine in 33.0% yield. Elemental Analysis: C25H29N3O3.2HCl.0.3H2O Calcd: C: 60.31; H: 6.40; N: 8.44. Found: C: 60.63; H: 6.40; N: 8.04. ESI-MS: m/z 420.78 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:14](=O)[C:15]([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound is synthesized by reductive amination of 1-Boc-piperazine and Pivalaldehyde analogously to the preparation of Example 233 as a colorless oil; ES-MS: M+H=257.3; TLC: Rf=0.82 (DCM/EtOAc=4:1).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][Si](C)(C)C)=[N:30][CH:31]=2)=[CH:22][CH:21]=1.O>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C[Si](C)(C)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reaction time: 3 h

Procedure:
Under an argon atmosphere 6.6 g (21.0 mmol) TBAF are added to a solution of 5.8 g (20.3 mmol) 5-(4-chloro-phenyl)-2-trimethylsilanylethynyl-pyridine in 200 mL DCM at 0° C. The reaction solution is stirred for 3 h, while the reaction temperature slowly rises to RT. It is added to 50 mL water and the organic phase is extracted four times with 50 mL water, dried over MgSO4 and filtered over activated charcoal. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (PE/EtOAc 1:1).