Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:12][N:13]1[C:21]2[N:20]=[C:19]([CH:22]([CH3:24])[CH3:23])[NH:18][C:17]=2[C:16](=O)[N:15]=[CH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:33])=O.[NH3:36].Cl>CO>[ClH:33].[NH2:36][C:16]1[N:15]=[CH:14][N:13]([CH2:12][C:11]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[C:21]2[C:17]=1[N:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[N:20]=2
Reactant: N
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2cnc(=O)c3[nH]c(C(C)C)nc32)cc1OCc1ccccc1
Agent: Cl
Solvent: CO
Product: COc1ccc(Cn2cnc(N)c3nc(C(C)C)nc2-3)cc1OCc1ccccc1
Temperature: 60 °C
Yield: 91.8 %

Procedure:
3-(3-Benzyloxy-4-methoxy-benzyl)-8-isopropyl-hypoxanthine (Example 6C) (4.04 g, 10 mmole) and phosphorus oxychloride (40 ml) were heated to 70° C. for 35 minutes. The reaction mixture was evaporated to dryness in vacuo and, after the addition of toluene, evaporation repeated twice. The crude chloropurine was dissolved in THF (40 ml) and added slowly with cooling to 32% aqueous ammonia (12 ml, 200 mmole) in a 450 ml pressure reactor. After the addition of liquid ammonia (50 g) at −30° C. the mixture was heated to 60° C. (340 psi) for 3 hours. The solid was filtered off and the solution evaporated to dryness in vacuo. The residue was suspended in water (100 ml) and the mixture filtered to give the crude product (4.09 g) as a crystalline solid. This was dissolved in methanol (60 ml), treated with 1M methanolic HCl solution (10 ml), evaporated to dryness in vacuo, suspended in acetone and filtered to give 6-amino-3-(3-benzyloxy-4-methoxy-benzyl)-8-isopropyl-3H-purine hydrochloride (4.04 g, 91.8%), as a crystalline solid mp 200° C., (sublimation)/240-243° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:35])[NH:17][CH:18]([C:22](=[O:34])[NH:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])[CH:28]=1)[CH2:19][CH2:20][CH3:21])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16](=[O:35])[NH:17][CH:18]([C:22](=[O:34])[NH:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([CH3:33])([CH3:32])[CH:30]=[O:31])[CH:28]=1)[CH2:19][CH2:20][CH3:21])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cn(C(C)(C)CO)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cn(C(C)(C)C=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 108.2 %

Procedure:
To a solution of oxalyl chloride (1.2 mL, 14.1 mmol) in 110 mL of methylene chloride at −78° C. is added DMSO (2.2 mL, 30.6 mmol) dropwise. The reaction is stirred for 20 min. and {1-[1-(2-Hydroxy-1,1-dimethyl-ethyl)-1H-imidazol-4-ylcarbamoyl]-butyl}-carbamic acid tert-butyl ester (4.2 g, 11.8 mmol) is added in 10 mL of methylene chloride. The reaction is stirred for 1 h, triethylamine (8.2 mL, 58.9 mmol) is added, and the reaction warmed to 0° C. for 20 min. The reaction is quenched with 100 mL of sodium bicarbonate, extracted with methylene chloride, dried, and concentrated to afford the title compound (4.5 g): MS m/z 353.2 (M+1).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Cl:12][Si](CC)(CC)CC.ClC1C=CC([C:27]([C:29]2[CH:30]=[CH:31][C:32]3[C:33]([CH:44]=2)=[C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39](Cl)[CH:38]=2)[O:35][N:36]=3)=[O:28])=CC=1>C1COCC1>[Cl:12][C:40]1[CH:41]=[CH:42][C:37]([C:34]2[O:35][N:36]=[C:32]3[CH:31]=[CH:30][C:29]([CH:27]([C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[OH:28])=[CH:44][C:33]=23)=[CH:38][CH:39]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Cn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccc2noc(-c3ccc(Cl)cc3)c2c1
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
Butyllithium in hexanes (10 ml) was added slowly at −70° C. under N2 flow to a solution of 1-methylimidazole (1.31 g) in THF (30 ml). The mixture was stirred at −70° C. for 45 minutes. Chlorotriethylsilane (2.7 ml) was added. The mixture was allowed to warm to 15° C. and cooled to −70° C. Butyllithium (10 ml) was added slowly. The mixture was stirred at −70° C. for 1 hour, allowed to warm to −15° C. and cooled to −70° C. A solution of intermediate (6-b) (4.9 g) in THF (60 ml) was added. The mixture was stirred at −70° C. for 30 minutes, then hydrolyzed with water, extracted with ethyl acetate and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue (8.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.2) and crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried, yielding 1.5 g (25%) of (±)-3-(3-chlorophenyl)-α-(4-chlorophenyl-α-(1-methyl-1H-imidazol-5-yl)-2,1-benzisoxazole-5-methanol (interm. 6-c).
Reaction SMILES: C([O:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[N:21]([CH3:22])[C:20]2[C:19](OC3C=CC=CC=3)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1)(=O)C1C=CC=CC=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][C:37]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=1)[NH2:34].Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:30][C:31]1[CH:32]=[C:33]([NH:34][C:19]2[C:20]3[N:21]([CH3:22])[C:13](/[CH:12]=[CH:11]/[CH2:10][OH:9])=[CH:14][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:35]=[CH:36][C:37]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=1
Reactant: Cn1c(/C=C/COC(=O)c2ccccc2)cc2ncnc(Oc3ccccc3)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Cn1c(/C=C/CO)cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 140 °C
Yield: 39.5 %

Procedure:
A mixture of (2E)-3-(5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl benzoate (100 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (130 mg), pyridine hydrochloride (36 mg) and 1-methyl-2-pyrrolidone (0.518 mL) was stirred with heating at 140° C. for 4 hrs. After cooling to room temperature, aqueous sodium hydrogen carbonate (20 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.518 mL)/ethanol (0.518 mL), 1N aqueous sodium-hydroxide solution (0.518 mL) was added, and the mixture was stirred at room temperature for 2 hrs. Tetrahydrofuran/ethyl acetate (1:1, 50 mL) and saturated brine (30 mL) were added, and the mixture was extracted. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→85:15) to give the title compound (45 mg) as crystals.
Reaction SMILES: NC1C=CC(CP(=O)(OCCO)OCCO)=CC=1OC.[F:21][C:22]([F:46])([F:45])[CH2:23][O:24][P:25]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-])=O)=[C:36]([O:43][CH3:44])[CH:35]=1)(=[O:32])[O:26][CH2:27][C:28]([F:31])([F:30])[F:29]>>[F:46][C:22]([F:21])([F:45])[CH2:23][O:24][P:25]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([O:43][CH3:44])[CH:35]=1)(=[O:32])[O:26][CH2:27][C:28]([F:29])([F:30])[F:31]
Reactant: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1[N+](=O)[O-]
Agent: COc1cc(CP(=O)(OCCO)OCCO)ccc1N
Product: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1N
Yield: 77 %

Procedure:
The title compound was prepared according to the procedure for Compound 113A using bis(2,2,2-trifluoroethyl)(3-methoxy-4-nitrobenzyl)phosphonate (Compound 114B, 2.8 g, 6.81 mmol). The reaction mixture was filtered and the filtrate was concentrated to give the desired product (2 g, 77%). 1H NMR (DMSO-d6, 400 MHz): δ=3.29 (d, J=21.2 Hz, 2 H), 3.68 (s, 3 H), 4.50-4.61 (m, 4 H), 4.64 (s, br, 2 H), 6.50-6.60 (m, 2 H), 6.67 (s, 1 H).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1>CN(C=O)C.CCOC(C)=O>[CH2:1]([S:8][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([Br:11])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cncc(SCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Benzyl mercaptan (1 g, 7.35 mmol) was dissolved in DMF (10 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.294 g, 7.35 mmol) was added, the ice bath was removed, and the reaction stirred for 15 minutes. 3,5-Dibromopyridine (1.74 g, 7.35 mmol) was added and the reaction was heated to 130° C. After heating for 1 hour the reaction was cooled then diluted with EtOAc and hexanes (1:1) and washed with 4× H2O and brine, with back-extraction. The combined organics were dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel (0-40% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:20][CH2:19][CH2:18][N:9]2[C:10](=[O:17])[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O>C1COCC1>[Br:21][C:15]1[CH:16]=[C:11]2[C:10](=[O:17])[N:9]3[CH2:18][CH2:19][NH:20][C:8]3([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][N:12]2[CH:14]=1.[Br:21][C:14]1[N:12]2[CH2:13][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:20][CH2:19][CH2:18][N:9]3[C:10](=[O:17])[C:11]2=[CH:16][CH:15]=1
Reactant: O=C1c2cccn2CC2(c3ccc(Cl)cc3)NCCN12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: O=C1c2cc(Br)cn2CC2(c3ccc(Cl)cc3)NCCN12
Product: O=C1c2ccc(Br)n2CC2(c3ccc(Cl)cc3)NCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (100 mg, 0.35 mmol) dissolved in THF (20 mL) was added N-bromosuccinimide (62 mg, 0.35 mmol) and the reaction mixture was stirred at room temperature for 1 h. LCMS analysis showed a mixture of mono brominated product (366/368 m/z), a small amount of dibrominated pyrrole (446 m/z) and debrominated starting material (288 m/z). The reaction mixture was partitioned with water (25 ml) and CH2CL2 (25 mL) and the organic layer was separated and concentrated in vacuo to give crude product (light yellow oil). The crude mixture was then purified using flash chromatography (Biotage SP4, 12 g cartridge, 0-10% MeOH gradient in CH2Cl2) to give 7-bromo-10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (A) and 8-bromo-10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (B) in a 0.6:1 ratio (98.4 mg, yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3Cl)[CH:15]=[C:16]([CH:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:33].[ClH:34].[CH3:35][NH:36][CH3:37].C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:17](=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[Cl:34])[CH:15]=[C:14]([CH:26]3[CH2:27][CH2:28][CH:29]([N:36]([CH3:37])[CH3:35])[CH2:30][CH2:31]3)[CH:13]=2)[CH2:12][NH:11][C:10]1=[O:33]
Reactant: Cl
Reactant: CNC
Reactant: O=C1CCC(c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C1CCC(c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-(2,6-Dichlorophenyl)-5-(2-chlorophenyl)-7-(1-cyclohexanon-4-yl)-3,4-dihydro-2(1H)-quinazolinone (33 mg, 0.066 mmol) (INTERMEDIATE 73) in 1,2-dichloroethane (1.0 mL) at RT (under a nitrogen atmosphere) was added dimethylamine hydrochloride (11 mg, 0.132 mmol) followed by triethylamine (18 μL, 0.132 mmol). The reaction-mixture was stirred for 10 min then NaBH(OAc)3 (21 mg, 0.099 mmol) was added to the reaction. After 1.5 h the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 solution followed by brine, and dried over Na2SO4. The crude residue was purified by preparative thin layer chromatography using 5% MeOH in DCM as the eluent to give 1-(2,6-Dichlorophenyl)-5-(2-chlorophenyl)-7-(1-dimethylaminocyclohexan-4-yl)-3,4-dihydro-2(1H)-quinazolinone (diastereomer A and diastereomer B).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23])(C1C=CC(C)=CC=1)(=O)=O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.N12CCCN=C1CCCCC2>CN(C=O)C>[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[CH2:22]([OH:23])[CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:11]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO)cc1
Agent: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: OCCOCCOCCOCCO
Temperature: 70 °C

Procedure:
To a stirred solution of 31.96 g (0.092 mol) of 2a in 400 mL of anhydrous DMF was added 14.2 g (1.05 equiv.) of phthalimide and 14.4 mL (1.05 equiv.) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The solution was heated at 70° C. for 18 h then concentrated in vacuo. The crude yellow oil was purified by flash chromatography using 1600 mL of silica gel and eluting with 25% EtOAc-50% EtOAc-75% EtOAc in hexane, then EtOAc, then 10% MeOH-20% MeOH in EtOAc to afford 23.8 g (80%) of 3a as an oil. Upon standing, 3a became a waxy white solid. 1H NMR (300 MHz, CDCl3) d 7.84-7.78 (m, 2H), 7.70-7.66 (m, 2H), 3.86 (t, J=5.6 Hz, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.64-3.51 (m, 12H), 2.67 (bs, 1H); 13C NMR (75 MHz, CDCl3) d 168.2, 133.8, 132.0, 123.1, 72.4, 70.5, 70.4, 70.2, 70.0, 67.8, 61.6, 37.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: Cc1cccc(Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(CBr)c1Cl

Procedure:
2,3-Dichlorotoluene (8.05 g., 0.05 mol.) dissolved in 150 ml. of carbon tetrachloride containing N-bromosuccinimide (8.9 g., 0.05 mol.) was heated to reflux and irradiated with a 275-watt sunlamp for two hours. The mixture was cooled, filtered and evaporated to give α-bromo-2,3-dichlorotoluene. The α-bromo-2,3-dichlorotoluene (2.4 g., 0.01 mol.) and thiourea (0.38 g., 0.005 mol.) were dissolved in 25 ml. of ethanol and refluxed for about sixteen hours. The mixture was cooled, concentrated, treated with ether, filtered and the filter cake recrystallized from water to give carbamimidothioic acid 2,3-dichlorobenzyl ester, m.p. 238°-243° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1[C:9]([CH3:19])=[N:10][NH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.P(Cl)(Cl)(Cl)=O>ClCCl.CO>[CH3:19][C:9]1[C:8]2[N:7]=[C:5]([C:4]3[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[CH:3]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]=2[NH:11][N:10]=1
Reactant: Cc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccccc2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(-c2nc3c(C)n[nH]c3c3ccccc23)c1
Reaction time: 4 h

Procedure:
The preparation took place in analogy to example 34 (D) using 404 mg of 3-methyl-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-benzamide, except 10 ml of phosphorous oxychloride was used and the reaction was stirred for 4 hrs. Trituration of the residue with dichloromethane/methanol (95/5) gave the title compound as an off white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4]O.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>N1C=CC=CC=1>[CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1

Procedure:
As depicted in Scheme 10, 2-Trimethylsilylethanol is treated with tosyl chloride in pyridine to give 2-trimethylsilyl-1-tosylethane.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Br[CH2:10][CH2:11][CH2:12][OH:13]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: OCCCBr
Solvent: Cc1ccccc1C
Product: C[C@@H]1CCC[C@H](C)N1CCCO

Procedure:
A stirred solution of 460 g. of cis-2,6-dimethylpiperidine in 300 ml. of xylene is treated with 278 g. of 3-bromopropanol over a period of 15 minutes. The mixture is stirred and heated at reflux for 2 hours, then allowed to cool while stirring for 16 hours. The mixture is filtered and the filtrate evaporated at reduced pressure. The residue is distilled at reduced pressure to give cis-2,6-dimethyl-1-piperidinepropanol; b.p. 147°-149° C./25 mm.
Reaction SMILES: [C:1]([O:17]C1C[C@H]2N(C)[C@H](CC2)C1)(=[O:16])[CH2:2][CH2:3][C:4]([O:6][CH:7]1[CH2:13][C@H:12]2[N:14]([CH3:15])[C@H:9]([CH2:10][CH2:11]2)[CH2:8]1)=[O:5].COC1C=CC(OC)=CC=1C[Br:32].[C:39]([O:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][C:50]=1[O:51][C:52](=[O:54])[CH3:53])[CH2:46][Br:47])(=[O:41])[CH3:40]>CC(C)=O>[Br-:32].[Br-:47].[C:4]([O:6][CH:7]1[CH2:8][C@H:9]2[N+:14]([CH2:46][C:45]3[CH:48]=[CH:49][C:50]([O:51][C:52](=[O:54])[CH3:53])=[C:43]([O:42][C:39](=[O:41])[CH3:40])[CH:44]=3)([CH3:15])[C@H:12]([CH2:11][CH2:10]2)[CH2:13]1)(=[O:5])[CH2:3][CH2:2][C:1]([O-:17])=[O:16]
Reactant: CC(=O)Oc1ccc(CBr)cc1OC(C)=O
Reactant: CN1[C@@H]2CC[C@H]1CC(OC(=O)CCC(=O)OC1C[C@H]3CC[C@@H](C1)N3C)C2
Reactant: COc1ccc(OC)c(CBr)c1
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(C[N+]2(C)[C@@H]3CC[C@H]2CC(OC(=O)CCC(=O)[O-])C3)cc1OC(C)=O
Product: [Br-]
Temperature: 50 °C

Procedure:
To a solution of 18.2 g (50 mmol) of bis(tropan-3-yl) succinate in 500 mL of dry acetone in a sealed bottle is added 11.6 g (50 mmol) of 2,5-dimethoxybenzyl bromide. After the mixture is heated at 50° C. for 24 hours, 14.3 g (50 mmol) of 3,4-diacetoxybenzyl bromide is added to the cooled mixture. Then the mixture is heated again at 70-75° C. for another 10 hours. The resulting white precipitate is collected by filtration, and purified by recrystallization (2×) from MeOH-methylene chloride to yield 9.0 g (20%) of [N-(2,5-dimethoxybenzyl)tropanium-3-yl], [N-(3,4-diacetoxybenzyl)tropanium-3-yl] succinate dibromide as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O>[ClH:1].[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]([CH3:15])[CH3:16])[C:4]=23)[CH2:19]1
Reactant: CC(C)CC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Yield: 173.2 %

Procedure:
A solution of (R)-tert-butyl 1-(5-chloro-3-(3-methylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (128 mg, 0.284 mmol) in neat TFA (3 mL) was stirred at room temperature for 30 minutes and concentrated in vacuo. The oily residue was evaporated from CH3CN (4×10 mL) to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide hydrochloride (95 mg, 79% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.77 (s, 1H), 9.26 (s, 1H), 8.22 (br s, 3H), 8.12 (s, 1H), 7.58 (br s, 1H), 3.47-3.31 (m, 3H), 3.25-3.17 (m, 1H), 3.13-3.08 (m, 1H), 2.25 (d, 2H), 2.14-2.09 (m, 2H), 1.87-1.81 (m, 1H), 1.74-1.63 (m, 1H), 1.54-1.47 (m, 1H), 0.98 (dd, 6H). LCMS (APCI+) m/z 350 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:26])([F:25])[F:24])=[O:22].[OH:27]O.O>C(O)(=O)C.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:25])([F:24])[F:26])(=[O:27])=[O:22]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Reactant: OO
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Yield: 110.3 %

Procedure:
0.17 g (0.4 mmol) of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl) phenyl)-4-((trifluoromethyl) sulfinyl)-1H-pyrazol-3-carbonitrile, 0.01 g (0.03 mmol) of sodium tungstate.2H2O, and 0.07 g (0.6 mmol) of 30% aqueous hydrogen peroxide were dissolved in 1 mL acetic acid and reacted at 55° C. for 6 hours. The reaction solution was cooled, 10 mL water was added, and the reaction mixture was extracted twice with 10 mL ethyl acetate. The ethyl acetate layer was washed with water, then dehydrated over anhydrous magnesium sulfate, filtered and concentrated to give 0.2 g pale yellow crystal of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl) phenyl)-4-((trifluoromethyl) sulfonyl)-1H-pyrazol-3-carbonitrile.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7])([CH3:3])[CH3:2].CCO.[BH4-].[Na+].CCCCCCC>CCOC(C)=O>[CH:1]([C:4]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:5]=1[CH2:6][OH:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(C)C)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)c1ccc(C(C)C)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.6 %

Procedure:
In a 2-neck RBF equipped with magnetic stir bar and N2 inlet, 2,5-diisopropylbenzaldehyde (1.7 g, 9 mmol) was dissolved into 30 mL of EtOH and NaBH4 (0.37 g, 10 mmol) was added over 20 min (portion-wise). After 18 h stirring at RT, ˜95% of solvent was removed on a rotary evaporator and then 5 mL of 0.5 M HCl was added and product was extracted with 25 mL of EtOAc. Organic layer was washed with 15 mL of H2O and 15 mL of brine, dried over Na2SO4, filtered and concentrated to dryness to obtain crude product. This material was subjected to chromatography using heptane: EtOAc as mobile phase to provide 1.1 g of pure product. Yield 65%. 1H NMR (300 MHz, CDCl3) δ 1.2-1.3 (d, 12H), 2.8 (septet, 1H), 3.2 (septet, 1H), 5.7 (s, 2H), 7.1-7.3 (m, 3H).