Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1>O=S(Cl)Cl.CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:1]([C:4]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
The product of Step 1 (6.4 g, 0.026 mol) was heated in SOCl2 (30 mL) at reflux for 2 h. The excess reagent was then evaporated and chased with toluene (2×10 mL). The residue was dissolved in dry CH2Cl2 (20 mL) and added dropwise to a solution of 4-(dimethylamino)pyridine (3.2 g, 0.026 mol) and 4-aminobenzotrifluoride (4.3 g, 0.026 mol) in CH2Cl2 (40 mL) cooled in ice. When addition was complete (10 min), the mixture was stirred and warmed to room temperature over 1 h, then washed with 2N HCl (15 mL), 2N Na2CO3 solution (15 mL), brine (10 mL), dried (MgSO4) and concentrated to give 8.4 g (84% yield) of product as a buff solid. 1H NMR (360 MHz, CDCl3): 7.40 (1H, d, J 1.4 Hz), 7.44 (1H, dd, J 1.4 and 8.5 Hz), 7.63 (2H, d, J8.5 Hz), 7.80 (2H, d, J 8.5 Hz), 8.14 (1H, d, J 8.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([C:12]#[N:13])=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.[Li]CCCC.CN([CH:43]=[O:44])C>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([C:12]#[N:13])=[C:10]([CH:43]=[O:44])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: N#Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
To a solution of THF (20 mL) was added N-[4-(4-amino-7-bromo-6-cyanopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea (230 mg, 0.430 mmol) which was cooled to −77° C. n-BuLi (2.5 M in hexanes, 0.86 mL, 2.15 mmol) was slowly added to the solution via syringe. The solution was stirred for 10 min and then DMF (0.20 mL, 2.58 mmol) was added. The cooling bath was removed and the reaction was allowed to warm to ambient temperature over the following 17 h. EtOAc (20 mL) and water (20 mL) were added to the reaction which was then transferred to a separatory funnel. The organic layer was washed with aq 1 N NaOH (20 mL) followed by water (20 mL). The organic was isolated, dried (MgSO4), filtered, and concentrated to dryness yielding 207 mg (0.428 mmol, yield 99%) of product. 1H-NMR (DMSO-d6) δ 10.38 (s, 1H), 9.43 (s, 1H), 8.99 (d, J=2.7 Hz, 1H), 8.68 (br s, 1H), 8.61 (dd, J=6.8, 1.8 Hz, 1H), 8.27 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.52 (m, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.40 (m, 1H), 6.06 (br s, 1H); MS [M+H]+=484.1; LCMS RT=3.34.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[N:3]1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[P:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.[OH-].[Na+]>>[CH3:7][C@@H:4]1[CH2:5][CH2:6][C@@H:2]([CH3:1])[N:3]1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[P:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@@H]1CC[C@@H](C)N1Cc1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H]1CC[C@@H](C)N1Cc1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 120 °C
Yield: 25.6 %

Procedure:
A two-necked eggplant flask containing 110 mg of 1-((2R,5R)-2,5-dimethylpyrrolidinylmethyl)-2-diphenylphosphinylnaphthalene was purged with nitrogen, and 8 ml of anhydrous xylene was put in and dissolved. Then, 0.22 ml of triethylamine and 0.15 ml of trichlorosilane were added thereto, and the mixture was slowly heated to 120° C. to react for 5 hours. The reaction was ceased with 2N NaOH, and the reaction mixture was extracted with ethyl ether, washed with water, and dried over anhydrous magnesium sulfate. The crude product was purified by silica gel column chromatography to obtain 27.1 mg (26%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Br:71][C:72]1[CH:73]=[CH:74][C:75](I)=[C:76]([CH:79]=1)[C:77]#[N:78].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:71][C:72]1[CH:73]=[CH:74][C:75]([N:20]2[CH2:19][CH2:18][O:17][C:16]3[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]2=3)=[C:76]([C:77]#[N:78])[CH:79]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: N#Cc1cc(Br)ccc1I
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(Br)cc2C#N)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A microwave vial was charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M, 0.320 g, 0.766 mmol), Xantphos (0.089 g, 0.153 mmol), 5-bromo-2-iodobenzonitrile (Combi-Blocks) (0.354 g, 1.150 mmol), Pd2(dba)3 (0.070 g, 0.077 mmol) and sodium tert-butoxide (0.147 g, 1.533 mmol). The mixture was diluted with toluene (7.66 ml), and purged with nitrogen, and stirred at 130° C. in the microwave for 30 minutes, until clean conversion to the desired product. The reaction was filtered over a plug of Celite, washing well with DCM. The filtrate was concentrated in vacuo and the crude material was directly adsorbed onto a 12-g RediSep Gold column and purified by silica gel chromatography, eluting with a gradient of 0% to 100% ethyl acetate in heptane, to provide 4-(4-bromo-2-cyanophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.248 g, 0.415 mmol, 54.2% yield) as yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C(OCC)C>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11](/[CH:19]=[CH:21]/[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1
Solvent: CCOCC
Product: O=C1CC(/C=C/c2ccncc2)=Nc2ccccc2N1Cc1ccccc1
Yield: 36 %

Procedure:
Using 1-benzyl-4-methyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one and isonicotinaldehyde, the titled compound was synthesized in substantially the same manner as in Working Example 144 in a yield of 36%, m.p. 208°-210° C. (diethyl ether).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11](Cl)[NH:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:30])([F:29])[C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([N:26]3[CH2:27][CH2:28][N:23]([C:18]4[C:17]([C:16]([F:30])([F:15])[F:29])=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:24][CH2:25]3)[NH:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: CC(C)(C)c1ccc2nc(Cl)[nH]c2c1
Product: CC(C)(C)c1ccc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The reaction of 6-tert-butyl-2-chloro-1H-benzoimidazole (0.209 g, 1 mmol, Example 17b) with 1-(3-trifluoromethylpyridin-2-yl)piperazine (0.346 g, 1.65 mmol, Maybridge) under the conditions of Example 3c afforded the title compound as a white solid. M.P. 247-249° C. MS (ESI, pos. ion) m/z: 404 (M+1).
Reaction SMILES: [C:1](=[O:9])([O:5][CH:6]([CH3:8])[CH3:7])[O:2][CH2:3]I.[Na].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][NH:20][C:21]([C:23]1[C:24](=[O:39])[C:25]([OH:38])=[C:26]2[C:31](=[O:32])[N:30]3[C@@H:33]([CH3:36])[CH2:34][O:35][C@@H:29]3[CH2:28][N:27]2[CH:37]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1](=[O:9])([O:5][CH:6]([CH3:8])[CH3:7])[O:2][CH2:3][O:38][C:25]1[C:24](=[O:39])[C:23]([C:21]([NH:20][CH2:19][C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[F:11])=[O:22])=[CH:37][N:27]2[C:26]=1[C:31](=[O:32])[N:30]1[C@@H:33]([CH3:36])[CH2:34][O:35][C@@H:29]1[CH2:28]2
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Reactant: CC(C)OC(=O)OCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Product: CC(C)OC(=O)OCOc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@H]1OC[C@H](C)N1C2=O

Procedure:
The title compound was prepared from iodomethyl 1-methylethyl carbonate (140 mg, 0.574 mmol), 1b (50 mg, 0.117 mmol), potassium carbonate (48 mg, 0.351 mmol), and tetrabutylammonium hydrogen sulfate (40 mg, 0.117 mmol), using a similar process to that described in example 1. 1H NMR (CDCl3) δ 10.29 (m, 1H), 8.44 (s, 1H), 7.29 (m, 1H), 6.77 (m, 2H), 5.84 (s, 2H), 5.27 (dd, J=9.6, 3.6 Hz, 1H), 4.88 (m, 1H), 4.56 (m, 2H), 4.40-4.29 (m, 3H), 3.89 (m, 1H), 3.65 (m, 1H), 1.37 (d, J=6.4 Hz, 3H) 1.26 (m, 6H). ES+ MS: 522 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH2:5][C@H:6]([CH2:15][CH2:16][OH:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C>[Si:22]([O:17][CH2:16][CH2:15][C@H:6]1[CH2:5][C:4]2[C:3]3[C:2]([Cl:1])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC[C@@H]1CCc2sc3ncnc(Cl)c3c2C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1CCc2sc3ncnc(Cl)c3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A solution of 2-[(12R)-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]ethan-1-ol (300 mg, 1.12 mmol, 1.00 equiv) in 5 mL of distilled DMF was added TBSCl (252 mg, 1.50 equiv) and imidazole (137 mg, 2.01 mmol, 1.80 equiv) at room temperature under nitrogen. The resulting solution was stirred for 1 h at ambient temperature and then quenched water, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to provide (12R)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene (420 mg, 98%) as a light yellow solid. LC-MS (ES, m/z): 384, 386 [M+H]+.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.C(O)(C(F)(F)F)=O.[NH2:28][C@H:29]([C:31]([NH:33][C@H:34]([C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][Br:43])=[O:37])[CH3:35])=[O:32])[CH3:30]>C1COCC1.CCOC(C)=O.CN(C=O)C>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:28][C@H:29]([C:31]([NH:33][C@H:34]([C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][Br:43])=[O:37])[CH3:35])=[O:32])[CH3:30])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)NCCCCBr
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCCBr
Temperature: 25 °C

Procedure:
To a cold (−15° C.) solution of Boc-Ala-OH (118 mg, 0.63 mmol) and NMM (103 μl, 1.03 mmol) in THF (8 mL) was added ECF (61 μl, 0.64 mmol) and stirred vigorously. After 2 min. a solution of the TFA salt of Ala-Ala-NH(CH2)4—Br (280 mg, 0.69 mmol) in a mixture of THF:DMF (4 mL:2 mL) was added to it followed by NMM (170 μL, 1.7 mmol) and stirred for further 30 minutes. The mixture was warmed to r.t. and stirred for 6 h. The solvent was removed under reduced pressure to give a residue which was diluted with EtOAc and washed with saturated citric acid, saturated NaHCO3 and the organic layer was dried over Na2SO4 and concentrated under vacuum to give a residue, which was purified by silica gel flash column chromatography (EtOAc:Hexanes—9:1) to give the desired product as a solid (m.p.—196-198° C.) in moderate yields (137 mg, 54%). TLC (MeOH:DCM—1:9; Rf—0.53).
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4].[CH3:38][C:39]1([CH3:42])[CH2:41][O:40]1.CCN(C(C)C)C(C)C>CC#N>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([O:26][CH3:27])[CH2:25][CH2:24][CH2:23][N:22]([CH2:38][C:39]([CH3:42])([OH:40])[CH3:41])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:11]=2)[C:8]2[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCNC3)n(C)c2n1
Reactant: CC1(C)CO1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCCN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 90 °C
Yield: 34.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxypiperidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine dihydrochloride (150 mg, 0.27 mmol), 2,2-dimethyloxirane (242 μL, 2.73 mmol) and DIPEA (187 μL, 1.09 mmol) in MeCN (3 mL) was heated at 70° C. r.t. for 3 h before further 2,2-dimethyloxirane (242 μL, 2.73 mmol) was added and the mixture heated at 90° C. for 6 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) affording 791 (51 mg, 34%). LCMS (method I): RT 2.72 min, [M+H]+ 549.3. 1H NMR (DMSO, 400 MHz): δ 8.03-8.02 (1 H, m), 7.64-7.63 (1 H, m), 7.25-7.24 (2 H, m), 4.26 (4 H, brd s), 4.08 (1 H, s), 3.91 (3 H, s), 3.79 (4 H, t, J=4.72 Hz), 3.27-3.26 (2 H, m), 3.20-3.15 (1 H, m), 3.06 (3 H, s), 3.01-2.97 (1 H, m), 2.69-2.61 (1 H, m), 2.46-2.38 (1 H, m), 2.25 (2 H, s), 2.17-2.14 (1 H, m), 1.92-1.75 (3 H, m), 1.33 (3 H, t, J=7.43 Hz), 1.03 (3 H, s), 0.94 (3 H, s)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30](O)=O)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[CH2:33]([NH:35][C:36]([NH:38][NH2:39])=[S:37])[CH3:34].O(Cl)Cl.[P+5]>O1CCOCC1>[CH2:33]([NH:35][C:36]1[S:37][C:30]([C:29]2[C:22]3[C:21]([NH:20][C@H:18]([C:7]4[N:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:9](=[O:11])[C:10]5=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]5[N:6]=4)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=3[NH:27][CH:28]=2)=[N:39][N:38]=1)[CH3:34]
Reactant: CCNC(=S)NN
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Agent: ClOCl
Agent: [P+5]
Solvent: C1COCCO1
Product: CCNc1nnc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
To a suspension of (S)-4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (50 mg, 0.12 mmol) and N-ethylhydrazinecarbothioamide (21 mg, 0.18 mmol) in 1 ml 1,4-dioxane was added phosphorus (V) oxychloride (12.5 μL, 0.13 mmol). The mixture was stirred at 80° C. overnight. The solvent was evaporated and the residue was poured into water and ethyl acetate. The mixture was basified to pH 10 with sodium carbonate and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was precipitated using diethyl ether, filtered, washed with cold diethyl ether and dried in a vacuum oven to obtain 14 mg (29% yield) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=1.[NH2:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][C:22]([Cl:32])=[CH:21][N:20]=1.C([O-])(O)=O.[Na+]>CS(C)=O>[Cl:32][C:22]1[CH:23]=[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:8]3[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][N:9]=3)=[CH:29][CH:30]=2)[C:19]([NH2:18])=[N:20][CH:21]=1
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Reactant: Fc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ncc(Cl)cc1-c1ccc(Oc2cc(C(F)(F)F)ccn2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of potassium carbonate (376 mg), 2-fluoro-4-(trifluoromethyl)pyridine (269 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (300 mg) in DMSO (5 mL) was stirred at 120° C. for 2 hr. The mixture was neutralized with sat. NaHCO3 aq. and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (484 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28](OC)=[O:29])=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.CC(C[AlH]CC(C)C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][OH:29])=[CH:25][CH:26]=3)[C:11]3[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(Cc3ccc(CCO)cc3)c21
Yield: 80.7 %

Procedure:
Following general procedure E1, methyl 2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetate (0.060 g, 0.13 mmol) was reacted with DIBAL (1.0 M, 0.65 mL, 0.65 mmol) to afford the title compound (0.045 g, 81%) as a white solid. MW=428.93. 1H NMR (DMSO-d6, 500 MHz) δ 8.29-8.25 (m, 2H), 7.67-7.64 (m, 1H), 7.61-7.56 (m, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 4.58 (t, J=5.5 Hz, 1H), 4.51 (s, 2H), 3.76-3.71 (m, 2H), 3.59-3.53 (m, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.40-2.32 (m, 2H); APCI MS m/z 429 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][NH:12][C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:12]1[CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[C:11]1=[O:21]
Reactant: COC(=O)CCCCCCCCBr
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCn1cc(-c2ccccc2)n(-c2ccc(Cl)cc2)c1=O

Procedure:
The product is produced as described in example 1 from 1.35 g of NaH (80% suspension in mineral oil), 12.2 g of 1-(4-chlorophenyl)-5-phenyl-4-imidazolin-2-one, 90 cc. of DMF, 11.3 g of 9-bromo-nonanic acid methyl ester and 1.35 g of NaJ.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:25][CH2:26]O)[C@@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]([CH3:13])[CH3:12])(C(C)(C)C)(C)C.C(N(CC)CC)C.CS(Cl)(=O)=O.C(OCC)(=O)C>C1COCC1>[OH:8][CH:9]1[CH2:25][CH2:26][N:14]([C:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:24])[C@H:10]1[CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(CCO)O[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1C(O)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution (188 mL) of benzyl ((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-1-isopropylbutyl)carbamate (14.9 g) in dehydrated THF was added triethylamine (5.07 g) and a solution (10 mL) of methanesulfonyl chloride (4.96 g) in dehydrated THF was added dropwise to the mixture under ice-cooling. After stirring at the same temperature for 1 hr, the reaction mixture was poured into a mixture of ethyl acetate and ice water and then the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. To a solution (188 mL) of the residue in dehydrated THF was added with stirring under ice-cooling 1 mol/L potassium tert-butoxide—THF solution (37.7 mL), and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into a mixture of ethyl acetate and ice water and the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. To a solution (188 mL) of the residue in dehydrated THF was added with stirring under ice-cooling 1 mol/L tetrabutylammonium fluoride—THF solution (37.7 mL), and the mixture was stirred at the same temperature for 1 hr and at room temperature for 5 hr. The reaction mixture was poured into a mixture of ethyl acetate and ice water and then the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate/19/1→2/3) to give benzyl (2S)-3-hydroxy-2-isopropylpyrrolidine-1-carboxylate as colorless oil (yield: 3.22 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[C:13](Cl)[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C:7]([CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:6][C:5]2=1.ClC1C=C(Cl)C=CC=1NN>>[C:28]1([CH2:27][CH2:26][CH2:25][C:7]2([CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:6][C:5]3[C:4]4[C:12](=[CH:13][CH:14]=[CH:2][CH:3]=4)[NH:11][C:10]=3[CH2:9][CH2:8]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Clc1cc(Cl)c2[nH]c3c(c2c1)CC(CCCc1ccccc1)(CNCc1ccccn1)CC3
Agent: NNc1ccc(Cl)cc1Cl
Product: c1ccc(CCCC2(CNCc3ccccn3)CCc3[nH]c4ccccc4c3C2)cc1

Procedure:
54 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl)-1H-carbazole-3-methanamine 283 is produced analogously with use of 2,4-dichlorophenylhydrazine.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>CO.[C].[Pd]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:24]=1
Reactant: CN1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution of 4-methylpiperazine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (339 mg, 0.903 mmol) in methanol (30 ml) was added 10% palladium carbon (100 mg), followed by stirring under a hydrogen atmosphere at room temperature for 2 hrs. The catalyst was filtered. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=1:1, then ethyl acetate) to provide the titled compound (196 mg, 62.8%) as a yellow oil.