Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@H:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>CN(C=O)C>[CH3:25][N:26]([CH3:30])[C:27](=[O:28])[NH:14][C@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15]
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-tert-butyl-2-amino-2-phenylacetate (1.0 g, 4.10 mmol) and Hunig's base (1.79 mL, 10.25 mmol) in DMF (40 mL) was added dimethylcarbamoyl chloride (0.38 mL, 4.18 mmol) dropwise over 10 minutes. After stirring at room temperature for 3 hours, the reaction was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with H2O, 1N aq. HCl and brine, dried (MgSO4), filtered and concentrated under reduced pressure. (R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate was obtained as a white solid (0.86 g; 75%) and used without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 2.82 (s, 6H) 5.17 (d, J=7.63 Hz, 1H) 6.55 (d, J=7.32 Hz, 1H) 7.24-7.41 (m, 5H). LCMS: Anal. Calcd. for C15H22N2O3 278.16 found 279.23 (M+H)+; HPLC Phenomenex LUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.26 min, 97% homogeneity index.
Reaction SMILES: CS([O-])(=O)=O.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[S+:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.CO.[F:23][C:24]([F:51])([S:47]([OH:50])(=[O:49])=[O:48])[C:25]([F:46])([F:45])[C:26]([F:44])([F:43])[C:27]([F:42])([F:41])[C:28]([F:40])([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32]>O>[F:51][C:24]([F:23])([S:47]([O-:50])(=[O:49])=[O:48])[C:25]([F:45])([F:46])[C:26]([F:44])([F:43])[C:27]([F:41])([F:42])[C:28]([F:40])([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[S+:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CS(=O)(=O)[O-]
Agent: c1ccc2cc([S+]3CCCC3)ccc2c1
Solvent: O
Solvent: CO
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
6.0 g of 1-(naphthalen-2-yl)tetrahydrothiophenium methane sulfonate synthesized in the same manner as in Example 1 was added dropwise to 5.0 g of previously prepared 30 wt % methanol solution of perfluoro-n-octane sulfonic acid. After the addition, the reaction solution was poured into 50 g of water. White precipitate was collected by filtration, washed several times with water, and dried under vacuum to obtain 2.1 g of 1-(naphthalen-2-yl)tetrahydrothiophenium perfluoro-n-octane sulfonate as a white solid.
Reaction SMILES: [F:1][C:2]1([F:32])[O:6][C:5]2[CH:7]=[C:8]([OH:31])[C:9]([CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[O:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)[C:12]3=[O:30])=[CH:10][C:4]=2[O:3]1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]3[O:31][CH2:33][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:20][C:21]5[O:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=5)[C:12]4=[O:30])[C:9]3=[CH:10][C:4]=2[O:3]1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OC(F)(F)O3)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1cc3c(cc12)OC(F)(F)O3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (55%) as an off-white solid: mp 59-60° C. (recrystallized from the melt); 1H NMR (300 MHz, CDCl3) δ7.37-7.30 (m, 1H), 7.21-7.15 (m, 1H), 7.14-7.07 (m, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.79-6.74 (m, 1H), 6.72 (s, 1H), 6.44-6.40 (m, 1H), 6.36 (s, 1H), 5.12-4.83 (m, 3H), 4.73 (d, J=9.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.7, 157.0, 151.8, 144.7, 142.2, 141.7, 141.5, 138.5, 135.4, 132.0, 131.4, 129.6, 128.6, 124.2, 122.4, 120.7, 117.1, 112.8, 109.6, 109.3, 104.6, 94.4, 80.6, 58.0, 37.1; MS (ES+) m/z 465.7 (M+1).
Reaction SMILES: ClC1C=CC=CC=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[N:15][CH:16]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=NC=1.[Cl:61][C:62]1[CH:67]=[CH:66][C:65](N=C=O)=[C:64]([O:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH:63]=1>>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[C:64]([O:71][C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[CH:63]=1
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Cl)cc4Oc4ccccc4)cn3)cc2C1=O

Procedure:
The compound of example 395 was prepared analogous to the compound of example 393 by reaction of the compound of example 392 with 4-chloro-2-phenoxy phenyl isocyanate. The compound of example 395 was used directly for the preparation of compound of example 396 without purification.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[CH2:30]([C:32]1[N:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=1)[CH3:31].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C>[CH2:30]([C:32]1[N:37]=[CH:36][C:35]([CH2:38][N:6]2[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]3[N:3]=[C:2]([CH3:1])[N:29]=[C:5]23)=[CH:34][CH:33]=1)[CH3:31]
Reactant: CCc1ccc(CO)cn1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(CC)nc2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (6-ethylpyridin-3-yl)methanol (0.46 g) and tributylphosphine (1.1 mL) in THF (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.88 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 49%).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]1[C:72]([CH3:73])=[C:71]([CH:74]=O)[C:70]([CH3:76])=[N:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:74]([C:71]3[C:70]([CH3:76])=[N:69][N:68]([CH3:67])[C:72]=3[CH3:73])[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Cc1nn(C)c(C)c1C=O
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1nn(C)c(C)c1-c1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Reaction time: 6 h
Yield: 33.9 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.85 mL), ethanol (0.15 mL), 1M Na2S2O4 (3 eq, 0.57 mmol, 0.57 mL) and 1,3,5-trimethyl-1H-pyrazole-4-carboxaldehyde (1.1 eq, 0.21 mmol, 29 mg). After 6 h, concentration in vacuo and preparation by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (31 mg, 34%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 2.36 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.60 (s, br, 4H, piperazine N(CH2)2), 3.61 (s, 2H, CH2), 3.64 (t, J=4.2 Hz, 4H, piperazine N(CH2)2), 3.74 (s, 3H, NCH3), 7.38 (dd, J=7.7, 4.8 Hz, 1H, pyridine H-5), 7.77 (dt, J=7.8, 1.5 Hz, 1H, pyridine H-4), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.4 Hz, 1H, pyridine H-6), 8.55 (d, J=1.5 Hz, 1H, pyridine H-2), 12.67 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:21])=[O:20])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:28]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][CH2:17][NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)(=[O:21])=[O:20])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:28]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CCNS(=O)(=O)c2ccccn2)(C(F)(F)F)O1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C1Nc2ccc(Cl)cc2[C@](CCNS(=O)(=O)c2ccccn2)(C(F)(F)F)O1

Procedure:
N-{2-[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]ethyl}pyridine-2-sulfonamide was subjected to optical resolution by HPLC (Chiralpack AD-H, hexane:2-propanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]2)[N:4]=1.C(O)(C(F)(F)F)=O.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[C:33]([F:32])([F:42])[F:43])=[O:23])[CH2:20][CH2:21]2)[N:4]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CNc1nc(N2CCC(C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A solution of 1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid as the TFA salt (44.7 mg, 0.100 mmol, 1.00 equiv), 2-trifluoromethyl benzylamine (26.6 mg, 0.150 mmol, 1.50 equiv) and DMAP (3.3 mg, 0.26 equiv) in dichloromethane (1 ml) was cooled in an ice bath. 1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI, 32 mg, 0.17 mmol, 1.7 equiv) was added. The reaction mixture was stirred at room temperature for 2 h. The solution was diluted with dichloromethane (1 ml) and washed with saturated sodium bicarbonate and water. The solvent was removed, and the residue was purified by reverse-phase HPLC to give the title compound (66 mg, 82.5% yield). MS (ES+): m/e 493.3 [M+H]+.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:25]3[C:21](=[CH:22][CH:23]=[N:24]3)[N:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][N:18]3[OH:26])=[CH:9][CH:8]=1)[CH3:5].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[C:27]([O:26][N:18]1[CH2:17][CH2:16][C:15]2[C:19]1=[N:20][C:21]1[N:25]([C:14]=2[NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:4][CH3:5])=[CH:12][CH:11]=2)[N:24]=[CH:23][CH:22]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(Nc2c3c(nc4ccnn24)N(O)CC3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2c3c(nc4ccnn24)N(OC(C)=O)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a methylene chloride (0.5 mL) solution containing 8-(4-ethoxyphenylamino)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-ol (2.8 mg), triethylamine (50 μL) and acetic anhydride (50 μL) were added. After this solution was stirred at room temperature for 30 min, the solvent was concentrated, and the residue was purified with PTLC (70% ethyl acetate-hexane) to obtain the title compound (2.3 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.ClCCl.COCCN(S(F)(F)[F:31])CCOC.C(=O)(O)[O-].[Na+]>O>[F:31][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(F)CC1
Temperature: 25 °C

Procedure:
A 1-L, round bottom flask was charged with 12.64 g (51.4 mmol) of benzyl 4-oxo-1-piperidinecarboxylate and 300 mL of dichloromethane. To the stirring solution at −78° C. was added 19 mL (102.8 mmol) of [bis(2-methoxyethyl)amino]sulfur trifluoride via addition funnel over a period of about 1 h. The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was added portionwise with caution to a large extractor containing water and saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (3×300 mL). The combined organic layers were washed once with saturated aqueous sodium bicarbonate solution, twice with 10% aqueous hydrochloric acid solution and saturated aqueous brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography on a Biotage® system (gradient, hexane to 65% ethyl acetate/hexane) afforded the desired product. LC/MS 242.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:24])[C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Br)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(Br)ccc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.53 g, 1.5 mmol) in DMF (6 mL) was added NaH (60% weight dispersion in mineral oil, 91 mg, 2.3 mmol) and CH3I (0.14 mL, 2.3 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. Then the reaction was quenched with H2O and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated to give tert-butyl 8-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate, which was used directly without purification.
Reaction SMILES: [C:1]([CH:9](Br)[CH2:10][CH2:11][Cl:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][C:16](=[S:18])[S-:17].C[NH3+]>>[CH3:14][N:15]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]([CH2:10][CH2:11][Cl:12])[S:18][C:16]1=[S:17]
Reactant: CNC(=S)[S-]
Reactant: O=C(c1ccccc1)C(Br)CCCl
Agent: C[NH3+]
Product: Cn1c(-c2ccccc2)c(CCCl)sc1=S
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 3-methyl-4-phenyl-5-β-chloroethyl-4-thiazoline-2-thione is prepared in the following manner: A solution of 33 g of 1-benzoyl-1-bromo-3-chloropropane in 150 cc of absolute alcohol is added slowly to a suspension of 20 g of methyl ammonium N-methyldithiocarbamate in 150 cc of absolute alcohol. The mixture is agitated for 2 hours at ambient temperature and the solvent is then evaporated under reduced pressure. The residue is redissolved in chloroform, washed with water and the separated organic phase is dried over Na2SO4 and then evaporated to dryness.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[CH2:13]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C=O)cc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (4.2 g of 60% dispersion in oil) is added to a solution of 4-hydroxybenzaldehyde (12.2 g) in dimethylformamide. The mixture is stirred for 30 min, and 1-bromooctane (18 ml) is added. The reaction mixture is stirred at 90° for five hours, cooled, and the solvent removed in vacuo. The residue is shaken with water, and extracted with three portions of hexane. The hexane extracts are dried, concentrated, and distilled in vacuo to provide 20.3 g of 4-octyloxybenzaldehyde.
Reaction SMILES: [CH:1]1([CH2:5][NH2:6])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:40]([C:44]1[N:48]([CH2:49][CH:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[C:47]2[CH:56]=[CH:57][C:58]([S:60]([N:63]3[CH:67]=[C:66]([C:68](O)=[O:69])[CH:65]=[N:64]3)(=[O:62])=[O:61])=[CH:59][C:46]=2[N:45]=1)([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C>[C:40]([C:44]1[N:48]([CH2:49][CH:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[C:47]2[CH:56]=[CH:57][C:58]([S:60]([N:63]3[CH:67]=[C:66]([C:68]([NH:6][CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:69])[CH:65]=[N:64]3)(=[O:62])=[O:61])=[CH:59][C:46]=2[N:45]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: NCC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NCC4CCC4)cn3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in example 53, step A, using (cyclobutylmethyl)amine (12 mg, 0.13 mmol), HATU (37 mg, 0.09 mmol), DIPEA (0.02 mL, 0.10 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (40 mg, 0.09 mmol) in DMF (5 mL). The crude product was purified by MPLC on silica gel using EtOAc/DCM (1:1) to provide the title compound as a white solid. The product was converted to its TFA salt. Yield: 27 mg (48%); 1H NMR (400 MHz, CD3OD) δ 1.43-1.51 (m, 3 H), 1.55 (dd, J=12.30, 3.91 Hz, 1 H), 1.61 (s, 9 H), 1.66-1.78 (m, 2 H), 1.81-1.93 (m, 2 H), 1.99-2.10 (m, 2 H), 2.26-2.37 (m, 1 H), 2.48-2.59 (m, 1 H), 3.26-3.36 (m, 4 H), 3.90 (dd, J=11.13, 3.71 Hz, 2 H), 4.45 (d, J=7.42 Hz, 2 H), 7.94-8.04 (m, 2 H), 8.05 (d, J=0.78 Hz, 1 H), 8.36 (d, J=1.37 Hz, 1 H), 8.76 (s, 1 H); MS (ESI) (M+H)+=513.7; Anal. Calcd for C26H35N5O4S+1.8 TFA+2.4H2O: C, 46.65; H, 5.50; N, 9.19. Found: C, 46.74; H, 5.61; N, 8.97.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1I.[CH3:22][Si:23]([CH3:40])([CH3:39])/[CH:24]=[CH:25]/[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1/[CH:25]=[CH:24]/[Si:23]([CH3:40])([CH3:39])[CH3:22]
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1I
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1/C=C/[Si](C)(C)C
Temperature: 120 °C
Yield: 79.5 %

Procedure:
Methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-iodopicolinate (350 mg, 0.824 mmol), and tetrakis triphenylphosphine palladium(0) (95 mg, 0.082 mmol) were combined in a Biotage microwave reaction vessel that was then sealed and purged with nitrogen. (E)-trimethyl(2-(tributylstannyl)vinyl)silane (417 mg, 1.072 mmol) in dioxane (4122 μl) was added and the reaction mixture was heated in a microwave reactor at 120° C. for 30 min The cooled reaction mixture was diluted with ethyl acetate and washed with saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated on to silica. The product was purified by flash chromatography. (SiO2, 0-20% EtOAc:Hex gradient) to provide the title compound as a tan solid (260 mg, 0.655 mmol, 79% yield); 1H NMR (400 MHz, DMSO-d6) d 0.17 (s, 9H), 3.76 (s, 3H), 6.09 (d, J=19.2 Hz, 1H), 6.60 (s, 2H), 6.91 (d, J=19.2 Hz, 1H), 7.75 (dd, J=3.8, 1.9 Hz, 2H), 7.83 (dd, J=10.8, 1.3 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −145.16 , −115.98; ESIMS m/z 398 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][O:4][P:5]([CH:11]([OH:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([O:7][O:8][CH2:9][CH3:10])=[O:6])[CH3:2].[N:21]([CH2:24][C:25]([O:27][CH2:28]C)=[O:26])=[N+:22]=[N-:23].CO.C[O-].[Na+]>C>[N:21]([C:24](=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([CH:11]([P:5]([O:7][O:8][CH2:9][CH3:10])([O:4][O:3][CH2:1][CH3:2])=[O:6])[OH:20])=[CH:13][CH:14]=1)[C:25]([O:27][CH3:28])=[O:26])=[N+:22]=[N-:23]
Reactant: CCOOP(=O)(OOCC)C(O)c1ccc(C=O)cc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOOP(=O)(OOCC)C(O)c1ccc(C=C(N=[N+]=[N-])C(=O)OC)cc1
Temperature: -78 °C
Yield: 48.1 %

Procedure:
To a dry 1 L round bottom flask was added 10.9 g (40 mmol) of 37, 52 g (400 mmol, 10 equivalents) of ethyl α-azidoacetate and 200 mL of anhydrous MeOH and the solution stirred under argon at -78° C. To this was added via syringe over 10 minutes, 59 mL (320 mmol, 8 equivalents) of NaOMe, 5.4M in MeH. The reaction was stirred briefly (5 minutes) at -78° C., then at 0° C. (1 hour). The yellow suspension was partitioned between ice-cold brine (400 mL) and EtOAc (3×250 mL). The combined EtOAc was washed with brine (1×400 mL); dried well (MgSO4) and rotovapped (20° C.) to a light yellow solid. Trituration with ether:petroleum ether (35°-60° C.) provided 38 as a light yellow solid (7.72 g, 52%), mp 106°-110° C. 1H NMR (250 MHz, DMSO-d6) δ: 7.86 (d, 2H, J=8.2 Hz, aromatic) , 7.48 (dd, 2H, J=8.2, 1.8 Hz, aromatic), 6.95 (s, 1H, vinylic), 6.30 (dd, 1H, J=15.3, 5.5 Hz, OH), 5.01 (dd, 1H, J=14.3, 5.5 Hz, P--CH), 3.98 (m, 4H, OCH2), 3.87 (s, 3H, CO2CH3), 1.18 (t, 3, J=7.0 Hz, CH3), 1.16 (t, 3H, J=7.0 Hz, CH3); mp 106°-110° C. (dec).