Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[CH2:14][CH:13]([O:15][CH3:16])[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[C:25]([C:28]1[CH:29]=[N:30][N:31]([CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[CH:32]=1)[CH:24]=[CH:23][CH:22]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[CH2:12][CH:13]([O:15][CH3:16])[CH2:14]2)=[O:10])[CH:6]=[CH:5][C:4]=1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[C:25]([C:28]1[CH:29]=[N:30][N:31]([CH:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]3)[CH:32]=1)[CH:24]=[CH:23][CH:22]=2
Reactant: COc1cc(C(=O)N2CC(OC)C2)ccc1Nc1cc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cccc2cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2CC(OC)C2)ccc1Nc1cc2c(-c3cnn(C4CCNCC4)c3)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 4-(4-(3-((2-methoxy-4-(3-methoxyazetidine-1-carbonyl)phenyl)-amino)isoquinolin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Example 3, 23 mg, 0.038 mmol) in DCM (8 mL) at 0° C. was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 hours. The solvents were removed in vacuo and the residue was purified by SCX-2 column eluting with 2M NH3/MeOH to afford the title compound as yellow oil (19 mg, 98%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([CH:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)#[N:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[C:8]([C:10]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: Fc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C#N)(c2ccccn2)C1
Reaction time: 6 h

Procedure:
A solution of 2-fluoropyridine (2.6 mL, 30.2 mmol) and tert-butyl 3-cyanoazetidine-1-carboxylate (I-1, 5.0 g, 27.5 mmol) in THF (200 mL) at room temperature was treated with LHMDS (55 mL of a 1.0 M solution in THF, 55 mmol). After 6 h, the reaction mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (3×150 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl 3-cyano-3-pyridin-2-ylazetidine-1-carboxylate (I-2) as a yellow-brown oil. Analytical LCMS: single peak (214 nm), 3.004 min. This material was used in subsequent reactions without further purification.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]2[C:43]([F:44])=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]=2[F:45])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1>>[F:44][C:43]1[CH:42]=[C:38]([CH:37]=[C:36]([F:45])[C:35]=1[N:24]1[CH2:25][CH2:26][CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:23]1)[C:39]([OH:41])=[O:40]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(C(=O)O)cc2F)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CN(c2c(F)cc(C(=O)O)cc2F)CCC1c1ccccc1F)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To 135 mg of 4-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]-3,5-difluorobenzoic acid was added 3.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the obtained residue were added chloroform and a saturated aqueous sodium hydrogen carbonate solution, followed by stirring, and the organic layer was then separated, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to obtain 111 mg of 3,5-difluoro-4-[4-(2-fluorophenyl)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]benzoic acid as a colorless amorphous substance. The obtained amorphous substance was dissolved in chloroform, and hexane was added thereto to precipitate a white solid, which was collected by filtration to obtain 93 mg of 3,5-difluoro-4-[4-(2-fluorophenyl)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]benzoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl[CH2:19][C:20]1[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][C:21]=1[O:22][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:33]([C:30]1[CH:31]=[CH:32][C:20]([CH2:19][O:17][C:14]2[CH:13]=[CH:12][C:11]([C:3]3[N:4]=[C:5]([CH3:10])[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]=3[Cl:1])=[CH:16][CH:15]=2)=[C:21]([CH:29]=1)[O:22][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH3:34]
Reactant: Cc1nc(-c2ccc(O)cc2)c(Cl)n1C(C)C
Reactant: CCc1ccc(CCl)c(OC(C)C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(COc2ccc(-c3nc(C)n(C(C)C)c3Cl)cc2)c(OC(C)C(=O)OC)c1

Procedure:
This compound is prepared in a manner analogous to that of Step I of Example 1, using 0.75 gram (0.0030 mole) of 4-[5-chloro-1-(1-methylethyl)-2-methylimidazol-4-yl]phenol, 0.84 gram (0.0036 mole) of methyl 2-(2-chlormethyl-5-ethylphenoxy)propanoate (prepared in Steps A through C of Example 1), and 0.62 gram (0.0045 mole) of potassium carbonate in N,N-dimethylformamide, yielding the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1)[CH3:13]
Reactant: CNC
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Product: CN(C)Cc1cc(=O)[nH]c(=O)[nH]1

Procedure:
reacting 6-(chloromethyl)uracil with dimethylamine to form crystalline derivative of 6-(dimethylaminomethyl)uracil,
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[C:15]([OH:16])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:26]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[C:15]([O:16][CH3:26])=[C:10]3[CH:9]=[CH:8]2)=[CH:21][CH:22]=1
Reactant: CI
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
To methyl 1-(4-fluorobenzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.25 g, 0.83 mmol) in DMF (10 mL) were added sodium hydride (0.037 g, 0.92 mmol, 60% in mineral oil) and iodomethane (0.057 mL. 0.92 mmol). The solution was stirred for 3 h at ambient temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL), and extracted with ethyl acetate (3×50 mL). The organic extracts were washed with brine (3×50 mL), dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography. Elution with ethyl acetate provided the title compound as a solid (0.10 g, 38% yield). 1H NMR (CD3OD) δ: 8.43 (s, 1H), 7.61 (d, 1H, J=3.1 Hz), 7.24 (t, 2H, J=8.8 Hz), 7.05 (t, 2H, J=8.8 Hz), 6.92 (d, 1H, J=3.1 Hz), 5.52 (s, 2H), 4.16 (s, 3H), 3.91 (s, 3H). LCMS (APCI, M+H+): 315.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13](F)[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:18][C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH:29]=[CH:28][N:27]=[CH:26]5)=[CH:23][CH:24]=4)[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: Fc1cccc(Oc2ccc3c(c2)OCO3)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: c1cc(Oc2ccc(-n3ccnc3)cc2)nc(Oc2ccc3c(c2)OCO3)c1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
To DMSO (5 mL) was added 2-(1,3-benzodioxol-5-yloxy)-6-fluoropyridine (1.3 g, 5.3 mmol), 1-(4-hydroxyphenyl)imidazole (0.92 mL, 5.8 mmol), and cesium carbonate (1.82 g, 5.6 mmol). After heating at 90° C. for 18 hour, the reaction was partitioned with water and ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4) and the solvent was removed in vacuo. The residue was chromatographed on silica with ethyl acetate/hexane to get 1.1 g of 2-(1,3-benzodioxol-5-yloxy)-6-[4-(1H-imidazol-1-yl)phenoxy]pyridine; NMR (CDCl3) δ 7.8 (s, 1H), 7.7 (t, 1H), 7.35 (d, 2H), 7.2 (m, 3H), 6.75 (d, 1H), 6.6 (m, 3H), 6.55 (m, 2H), 5.9 (s, 2H) ppm.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12>>[CH2:1]([N:8]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[C:11]=2[CH:18]=[CH:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccnc2[nH]ccc12
Product: Nc1nccc2c1ccn2Cc1ccccc1
Temperature: 180 °C
Yield: 55 %

Procedure:
Benzylamine (1.8 mL, 16.4 mmol, 5 eq) was added to 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.50 g, 3.3 mmol, 1.0 eq; see, generally, Cheng, C.-C. et al. J. Physical Chem. 2003, 107, 1459-1471, incorporated by reference in its entirety) in a sealed tube and the reaction mixture was heated at 180° C. for 8 h. The reaction mixture was purified by loading it directly onto a C-18 YMC 30×500 mm reverse phase column (eluting 20-90% aqueous methanol with 0.1% TFA over a 30 minute gradient) and the appropriate fractions were isolated and concentrated in vacuo. The residue was neutralized with saturated aq. NaHCO3 solution and the mixture was extracted with CHCl3. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the product (0.40 g, 55%) as a solid. 1H NMR (DMSO-d6) δ 7.51-7.52 (m, 1H), 7.16-7.36 (m, 6H), 6.63-6.68 (m, 2H), 6.09 (s, 2H); MS(ESI+) m/z 224 (M+H)+. Calculated: 224.1188, found: 224.1178
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:30]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([O:26][CH2:27][C:28]#[N:29])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:30][C:17]1[C:18]([NH:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([O:26][CH2:27][C:28]#[N:29])[CH2:24][CH2:25]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: N#CCO[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#CCO[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A suspension of trans [4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyloxy]-acetonitrile (350 mg, 770 μmol) in a mixture of ethanol (2.5 mL) and water (800 μL) was treated with ammonium chloride (250 mg, 4.60 mmol) and iron powder (170 mg, 3.10 mmol) and heated at 80° C. for 90 minutes. The reaction mixture was hot filtered through Celite® washing several times with ethanol/water. The filtrate was concentrated under vacuum, the residue diluted with water and extracted in to DCM (3×). The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The iron filter cake was stirred in 20% methanol in DCM, filtered and repeated until no further product was extracted. The combined filtrates were washed with water and the phases separated. The aqueous phase was extracted with DCM (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, concentrated under vacuum and combined with the material isolated above to afford 300 mg (91%) of trans [4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyloxy]-acetonitrile as a yellow solid. LCMS (Method Q, ESI): RT=2.76 min, m+H=426.1; 1H NMR (400 MHz, CDCl3) δ: 8.14 (m, 2H), 7.83 (s, 1H), 7.53 (t, 1H), 7.49 (d, 1H), 7.45 (t, 2H), 6.52 (d, 1H), 4.72 (d, 1H), 4.30 (s, 2H), 3.73 (m, 1H), 3.58 (m, 1H), 2.80 (br s, 2H), 2.16 (m, 4H), 1.48 (m, 2H), 1.33 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11]1>C1COCC1>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:16]1([OH:19])[CH2:17][CH2:18][C:13]2([O:20][CH2:10][CH2:11][O:12]2)[CH2:14][CH2:15]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1ccccc1CCl
Solvent: C1CCOC1
Product: Cc1ccccc1CC1(O)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A solution of 2-methylbenzyl chloride (0.579 g, 4.12 mmol) in THF (20 mL) was treated with Mg (0.180 g, 7.50 mmol) and strirred at room temperature until all the Mg had dissolved. The mixture was cooled to 0° C., treated with a solution of 1,4-cyclohexanedione mono-ethylene ketal (0.579 g, 4.12 mmol) in THF (50 mL), warmed to room temperature, stirred overnight, quenched with saturated NH4Cl (100 mL), and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/ethyl acetate to provide the desired product (0.48 g, 44%) MS (ESI) m/e 262 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][NH2:23]>Cl.C(O)C>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:23]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2
Reactant: O=C(CC1CSCCC1=O)c1ccc(Br)cc1
Reactant: CN(C)CCCN
Agent: Cl
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccc(Br)cc2)cc2c1CCSC2
Reaction time: 8 h

Procedure:
A solution of 60 g (0.019 mole) of 3-(4-bromophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one, 1.97 g of 3-dimethylaminopropylamine, 20 ml. of ethanol, and one drop of concentrated hydrochloric acid is heated under reflux under nitrogen for 2.5 hours and allowed to stand overnight during which time crystals precipitated. Recrystallization from ethanol gives colorless crystals of 1-(3-dimethylaminopropyl)-2-(4-bromophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]-pyrrole, m.p. 88° to 90°C.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:88]=[CH:89][CH:90]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][CH:74]([OH:77])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:88]=[CH:89][CH:90]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][CH:74]([OH:77])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCC(O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OC1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 35.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 1-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidin-4-ol (130 mg, 0.209 mmol) was hydrolyzed with lithium hydroxide (28 mg, 0.62 mmol) in THF/methanol/water (3/3/1 mL) to yield 35 mg (28.7% yield) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.56 (s, 2H), 8.24 (s, 1H), 7.97-7.94 (m, 3H), 7.74-7.70 (m, 3H), 7.38-7.35 (m, 1H), 7.12-6.99 (m, 3H), 4.10-4.08 (m, 1H), 3.90-3.84 (m, 2H), 3.64-3.57 (m, 2H), 2.27-2.20 (m, 2H), 2.04-1.97 (m, 2H). MS: m/z=468.4 (M+1), HPLC: 91.74% in method B.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]([CH3:11])([CH3:10])[CH2:8][CH3:9])[C:4]([OH:6])=[O:5].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CN(C=O)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:2][CH:3]([C:7]([CH3:11])([CH3:10])[CH2:8][CH3:9])[C:4]([OH:6])=[O:5])(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(C)(C)C(N)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)(C)C(NS(=O)(=O)c1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.1 %

Procedure:
2-amino-3,3-dimethylpentanoic acid hydrochloride (1.63 g), (JCS Chem. Comm. 11, 830-1992) is mixed with diisopropylethylamine (3.6 g, 3.1 equivalent) in dry THF (100 mL). The 4-methoxybenzenesulfonyl chloride (1.86 g, 1 equivalent) is added as a solid. DMF (25 mL) is added to the resulting suspension. After stirring overnight at room temperature the solvents are removed under vacuum. The residue is partitioned between ethyl acetate (200 mL) and 1N HCl (100 mL). The organic phase is separated and the aqueous phase extracted with several more portions of ethyl acetate. The combined organic phases are washed with 1N HCl and then brine. The organic phase are dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting crude product is loaded onto a reverse phase column as a DMSO solution. The column is eluted using a step gradient (10% increments), starting with 30% acetonitrile/water and ending at 90% acetonitrile/water. Combination of the appropriate fractions gave 116 mg of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[CH:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].O1CCNC1=O.[Cl:20][C:21]([Cl:31])([O:23][C:24](=[O:30])[O:25][C:26]([Cl:29])([Cl:28])[Cl:27])[Cl:22]>>[NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:8][CH2:9]1)=[O:5].[Cl:20][C:21]([Cl:22])([O:23][C:24](=[O:30])[O:25][C:26]([Cl:29])([Cl:27])[Cl:28])[Cl:31]
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C1NCCO1
Product: CCC[C@H](N)[C@H](O)C(=O)NC1CC1

Procedure:
(3S)-3-Amino-N-cyclopropyl-2-hydroxyhexanamide was converted to the corresponding oxazolidinone by reaction with triphosgene. The resulting product was analyzed by proton NMR and the stereochemistry of the product was determined by the coupling constants (J value) for the protons at C-4 and C-5 of the cyclized derivatives. Based on literature values for similar products (Tsuda, M.; Muraoka, Y.; Nagai, M.; Aoyagi, T.; Takeuchi, T. J. Antibiotics 1996, 49, 281-286, Herranz, R.; Castro-Pichel, J.; Vinuesa, S.; Garcia-López. M. T. J. Org. Chem. 1990, 55, 2232, Williams, T. M.; Crumbie, R.; Mosher, H. S. J. Org. Chem. 1985, 50, 91-97), the cis-isomer (J4,5=8.8 Hz) was obtained exclusively from the reaction of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide with triphosgene, indicating that the absolute configuration of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide was (2S,3S).
Reaction SMILES: [C:1]1([CH:7]([CH2:13][S:14]([OH:17])(=[O:16])=[O:15])[CH2:8][S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[N+:23]([O-])([OH:25])=[O:24]>>[N+:23]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH2:13][S:14]([OH:17])(=[O:16])=[O:15])[CH2:8][S:9]([OH:12])(=[O:11])=[O:10])=[CH:2][CH:3]=1)([O-:25])=[O:24]
Reactant: O=S(=O)(O)CC(CS(=O)(=O)O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(C(CS(=O)(=O)O)CS(=O)(=O)O)cc1

Procedure:
2-Phenyl-propane-1,3-disulfonic acid (as prepared in the previous step) is treated with concentrated H2SO4 and fuming HNO3 according to the procedure of Example 2, step (a) to afford the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[CH:13]=[CH2:14]>ClCCl>[O:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:12][CH:13]1[CH2:14][OH:9]
Reactant: C=CCc1ccccc1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: OCC1Cc2ccccc2O1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of meta-chloroperbenzoic acid (96.4 g, 335 mmol) in dichloromethane (500 mL) was added to an ice-cold solution of 2-allylphenol (30 g, 224 mmol) in dichloromethane (1 L) and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 18 hours. The reaction mixture was then re-cooled to 0° C., quenched with 2M sodium hydroxide solution (700 mL) and stirred for 30 minutes. The organic layer was then separated, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by HPLC using a Chiralpak AD 250*4.6 mm column and hexane:isopropanol (90:10) as the eluant, to afford the title compound.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH3:10][S-:11].[Na+]>C1(C)C=CC=CC=1>[CH3:10][S:11][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([Cl:9])[N:1]=1
Reactant: C[S-]
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1nc(Cl)nc(Cl)n1
Yield: 90 %

Procedure:
In a comparison experiment there were present in a 2 liter multinecked flask 184.4 grams of cyanuric chloride dissolved in 760 grams of toluene and there were dropped in at about 40°-50° C. in the course of 1 hour 252 ml of an aqueous sodium methyl mercaptide solution which contained 70.1 grams of sodium methyl mercaptide. From the organic phase there could be isolated about 90% of 2-methylmercapto-4,6-dichloro-s-triazine. The content of 2,4-dimethylmercapto-6-chloro-s-triazine was about 10%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COCCOC.[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[C:23](=O)[C:24]([N:26]1[CH2:31][CH2:30][N:29]([N:32]=O)[CH2:28][CH2:27]1)=O)=[CH:20][CH:19]=[CH:18][CH:17]=2>O>[NH2:32][N:29]1[CH2:30][CH2:31][N:26]([CH2:24][CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:13])[CH2:27][CH2:28]1
Reactant: Cc1[nH]c2ccccc2c1C(=O)C(=O)N1CCN(N=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]c2ccccc2c1CCN1CCN(N)CC1
Temperature: -5 °C

Procedure:
To a stirred mixture of 9.0 g of lithium aluminum hydride in 400 ml. of 1,2-dimethoxyethane is added 10.52 g (0.35 mol) of 1-(2-methylindol-3-ylglyoxyloyl)-4-nitrosopiperazine slowly to maintain reaction temperature below 35° C. After all the material is added, the mixture is refluxed for 14-16 hours. The reaction mixture is cooled to -5° C. and a solution of 50 ml. of water and 50 ml. of 1,2-dimethoxyethane is slowly added while maintaining the temperature below 15° C. Another 50 ml. of water is added. The mixture is then filtered, the solvent is removed, and the residual solid is recrystallized from hot benzene, producing the pure crystals of 3-[2-(4-aminopiperazin-1-yl)ethyl]-2-methylindole, m.p. 118°-120° C. Analysis: Calculated for C15H22N4 : 71.08% C; 8.21% H; 20.72% N Found:71.11% C; 8.28% H; 20.75 % N.