Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:28]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1)#[C:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: C#CCCCC
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (180 mg, 0.48 mmol), bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.05 mmol), copper (I) iodide (2 mg) and triethylamine (1.0 mL) in CH2Cl2 (3 mL) was added 1-hexyne (8.3 mL, 0.72 mmol). The mixture was refluxed overnight and cooled to room temperature. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with EtOAc:hexane 1:1 to afford the title compound (102 mg, 56% yield). MS (CI/NH3) m/z 379 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 0.96 (t, J=6.6 Hz, 3H), 1.43 (s, 9H), 1.46-1.69 (m, 4H), 2.20-2.40 (m, 2H), 2.44-2.56 (m, 2H), 3.83-3.92 (m, 2H), 4.06-4.15 (m, 1H), 4.26-4.38 (m, 1H), 4.45-4.57 (m, 1H), 7.34 (br s, 1H), 7.51-7.58 (m, 1H).
Reaction SMILES: [CH:1]([CH:4]1[C:9](=O)[NH:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:3])[CH3:2].Br[C:19]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:20]=1[NH2:21].CN[C@@H]1CCCC[C@@H]1NC>CN1C(=O)CCC1.O>[CH:1]([CH:4]1[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:7][N:8]2[C:19]3[CH:25]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:23]=[CH:22][C:20]=3[N:21]=[C:9]12)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(N)c(Br)c1
Reactant: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Agent: CN[C@H]1CCCC[C@H]1NC
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a solution of tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (200 mg, 0.83 mmol) in NMP (3 mL) was added 2-bromo-4-(methylsulfonyl)aniline (207 mg, 0.83 mmol), (1R,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (12.0 mg, 0.08 mmol), K3PO4.3H2O (660 mg, 2.48 mmol), Cul (16 mg, 0.08 mmol). The mixture was stirred at 150° C. for 1 h under microwave. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC with CH2Cl2/MeOH 35/1 to afford tert-butyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (110 mg, 34% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[O:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](O)=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>ClCCl.O>[O:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11])=[O:15]
Reactant: Nc1cccc2c1COC2=O
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc2c1COC2=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 4-aminoisobenzofuran-1(3H)-one (4.0 g, 26.8 mmol), 2-oxo-2-phenylacetic acid (4.1 g, 26.8 mmol), and HBTU (15.2 g, 40.2 mmol) in dichloromethane (240 mL) was added TEA (8 mL). The reaction mixture was stirred at room temperature overnight. The resulting mixture was added water and adjusted to pH=6-7 with 1% aq. HCl, and then was filtered. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was evaporated and the crude product was purified by gradient chromatography (silica gel, petroleum ether/ethyl acetate 6:1 to 3:1) to give the title compound (5.0 g, yield 66%). LC-MS (ESI) m/z: 282 (M+1)+.
Reaction SMILES: Br[C:2]1[C:25](=[O:26])[N:24]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:32].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:45]([O:47][CH2:48][CH3:49])=[CH2:46])CCC>C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:27]1([N:24]2[C:5]3[N:6]=[C:7]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[CH:13][N:12]=4)[N:8]=[CH:9][C:4]=3[C:3]([CH3:32])=[C:2]([C:45]([O:47][CH2:48][CH3:49])=[CH2:46])[C:25]2=[O:26])[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C)CC4)cn3)ncc12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Reaction time: 12 h
Yield: 90.6 %

Procedure:
A 6-dram vial was charged with 6-bromo-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (266 mg, 0.53 mmol) and tetrakis(triphenylphosphine)palladium(0) (61 mg, 0.053 mmol) and the atmosphere replaced with argon. Toluene (5 ml) was added followed by tributyl-(1-ethoxy-vinyl)-stannane (289 mg, 0.80 mmol). The vial was heated to 110° C. and stirred for 12 h. The reaction mixture was diluted with chloroform (25 ml) and adsorbed onto silica gel. Chromatographic purification on silica gel (chloroform/2-propanol+1% TEA gradient) gave the 8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (237 mg, 0.48 mmol). MS (APCI+) 490 (M+1, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:9]([NH:63][C:56]2[CH:55]=[C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[C:53]4[C:48]=3[CH:47]=[CH:46][NH:45]4)[CH:62]=[C:61]3[C:57]=2[CH:58]=[N:59][NH:60]3)=[O:11])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of 3,6-dichloro-2-pyridinecarboxylic acid (available from Matrix Scientific, 930 mg, 4.8 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1840 mg, 4.8 mmol) were dissolved in DMF (15 ml) and treated with DIPEA (2.53 ml). The mixture was stirred at room temperature for 30 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (600 mg, 2.4 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to approx. 5 ml which was added to 2×50 g aminopropyl cartridges that had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 3 h before being eluted with MeOH. The mixture was concentrated in vacuo and a precipitate occurred, which was collected by filtration to give the title compound (0.55 g) as a yellow solid.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[I-:12].[Na+].CCCCCC>CC(C)=O>[CH:6]1([CH2:5]/[CH:4]=[CH:3]/[CH2:2][I:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ClC/C=C/CC1CCCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: IC/C=C/CC1CCCCC1
Reaction time: 8 h
Yield: 76 %

Procedure:
The chloride (B) (38.6 g) was added to a solution of sodium iodide (55.7 g) in acetone (1 litre) and the solution was allowed to stand overnight. Hexane (500 ml) was added and the precipitated solid was removed by filtration. The filtrate was concentrated and the residue partitioned between water (500 ml) and hexane (500 ml). The organic phase was separated, washed with saturated sodium thiosulphate solution (500 ml) and saturated sodium chloride solution (2×500 ml), and dried (MgSO4). The solvent was removed by evaporation and the residual liquid distilled under vacuum to give (2E)-4-cyclohexyl-1-iodobut-2-ene (C) as a dark liquid (44.9 g), b.p. 80°-85° C. at 0.15 mm Hg; NMR: 0.8-1.8(complex m, 11H), 1.9(t, 2H), 3.9(m, 2H), 5.7(m, 2H). (iii) A 1.6M solution of butyllithium in hexane (93.9 ml) was added dropwise over 30 minutes to a stirred solution of diisopropylamine (21.9 ml) in dry tetrahydrofuran (THF) (200 ml) at 0° C. under an atmosphere of argon. The temperature was maintained at 0° C. for 30 minutes and then the solution was cooled to -40° C. A solution of (4S)-4-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (31.3 g) (obtained as described in Tetrahedron. 1987, 44, 5525) in dry THF (70 ml) was added dropwise over 30 minutes. The solution was kept at -40° C. for 30 minutes and then the temperature was allowed to rise to 0° C. A solution of iodide (C) (39.0 g) in dry THF (75 ml) was added dropwise over 30 minutes, and then the solution was stirred at 0° C. for 1 hour. Saturated sodium chloride solution (250 ml) was added and the mixture was extracted with ether (3×250 ml). The extracts were washed with saturated sodium chloride solution (2×250 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (8:92 v/v), to give (4s)-4-benzyl-3-[(2S,4E)-6-cyclohexyl-2-isopropylhex-4-enoyl]oxazolidin-2-one (A) (34.5 g) as a clear oil; NMR: 0.8 -1.2(complex m, 12H), 1.6(m, 6H), 1.85(t, 1H), 2.0(m, 2H), 2.35(m, 2H), 2.6(m, 1H), 3.3(dt, 1H), 3.8(m, 1H), 4.1(d, 1H), 4.7(m, 1H), 5.4(m, 2H), 7.3(m, 5H); mass spectrum (+ve FAB), 398 (M+H+); 22 [α]436 +45.8 (c, 1.04, CHCl3). ##STR1##
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[CH3:26][C@@H:27]1[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:29]4[CH2:28][C@H:27]([CH3:26])[O:31][C:30]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: C[C@H]1CNC(=O)O1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4C[C@H](C)OC4=O)cc3F)CC2)c(C)c1
Yield: 52.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (615 mg) described in Preparation Example 60 and (S)-5-methyloxazolidin-2-one (243 mg) described in Preparation Example 42, the title compound (337 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([NH2:25])([CH3:24])[CH2:3][NH:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(N)(C)CN.C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:52]([N:60]=[C:61]=[S:62])(=[O:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH3:24][C:2]([NH:25][C:61]([NH:60][C:52](=[O:59])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[S:62])([CH3:1])[CH2:3][NH:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(N)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: CC(C)(N)CN
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=S)NC(=O)c1ccccc1
Yield: 44 %

Procedure:
2-Methyl-N1-tritylpropane-1,2-diamine, prepared from 2-methylpropane-1,2-diamine and trityl chloride (EP1204654) in yield of 44%, was coupled with benzoylisothiocyanate to give N-(2-methyl-1-(tritylamino)propan-2-ylcarbamothioyl)benzamide (US2008/45579) which was then reacted with lithium hydroxide to give 1-(2-methyl-1-(tritylamino)propan-2-yl)thiourea. Yield 79%. 1H NMR (400 MHz, CDCl3) δ 7.40-7.12 (m, 16H), 6.30 (s, 1H), 2.38 (d, J=8.3, 2H), 2.15 (t, J=8.3, 1H), 1.31 (s, 6H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][CH:25]([CH2:30][CH:31]3[O:33][CH2:32]3)[C:26]([O:28]C)=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH:24][CH:25]([CH2:30][CH:31]([OH:33])[CH2:32][S:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[C:26]([OH:28])=[O:27])(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: Sc1cccs1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3cccs3)C(=O)O)cc2)cc1

Procedure:
Example 34 is prepared from 2-thiophenethiol and 1d using the procedure described for compound 20.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[CH:24][CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(CCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(O)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.36 g-see Preparation 3), 4-hydroxyphenethyl bromide (0.26 g), sodium bicarbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (40 ml) and aqueous sodium bicarbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give a foam which was further purified by column chromatography on alumina eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.09 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=O)[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[N:14][OH:15])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NO
Reactant: CC(=O)c1ccc2[nH]ncc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccc2[nH]ncc2c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
To a suspension of 1-(1H-indazole-5-yl)-ethanone (334 mg, 2.09 mmol) in EtOH-H2O (4:1, 10 ml) were added hydroxylamine hydrochloride (444 mg, 6.39 mmol) and sodium acetate (449 mg, 5.47 mmol). The reaction mixture was stirred at 80° C. for 15 hours and concentrated in vacuo. The residue was stirred with H2O at room temperature for 10 min. The solid obtained was collected by filtration, and rinsed with H2O. After drying, the title compound (260 mg, 71%) was obtained as a white solid. 1H NMR (270 MHz, DMSO-d6) δ ppm 2.22 (3H, s), 7.52 (1H, d, J=8.6 Hz), 7.79 (1H, d, J=8.6 Hz), 7.98 (1H, s), 8.10 (1H, s), 11.05 (1H, s), 13.13 (br.s, 1H). MS (ESI) m/z 176 (M+H)+, 174 (M−H)−.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([F:47])[CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:41][C:42]=1[F:47])=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C(N=C=S)c1c(Cl)cccc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4c(Cl)cccc4Cl)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
2,6-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,6-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][S:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:35].ClCCl.CO.ClCl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][S:27](=[O:35])[CH2:26]1)=[O:24])[C:5]([NH:7][CH:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: CC(NC(=O)c1ccc(C(=O)N2CCSC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: ClCl
Solvent: ClCCl
Solvent: CO
Product: CC(NC(=O)c1ccc(C(=O)N2CCS(=O)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 46 %

Procedure:
Prepared analogously to Example 85 from rac.-3-chloro-N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]4-(thiazolidin-3-ylcarbonyl)benzamide and 3-chloroperoxybenzoic acid in dichloromethane/glacial acetic acid. Yield: 46%; Rf value: 0.20 (silica gel; dichloromethane/methanol=9:1); C20H18Cl2N4O3S (465.36); mass spectrum: (M+H)+=465/467 (chlorine isotope) and (M−H)−=463/465 (chlorine isotope).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH:11]1([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1>S(=O)(=O)(O)O.O1CCOCC1>[CH:11]1([N:14]2[CH2:19][CH2:18][C:17]3[NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][C:7]=4[C:16]=3[CH2:15]2)[CH2:13][CH2:12]1
Reactant: O=C1CCN(C2CC2)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)CN(C1CC1)CC3
Temperature: 25 °C
Yield: 65.3 %

Procedure:
A solution of (4-methylphenyl)hydrazine hydrochloride (1.5 g, 0.00948 mol) and 1-cyclopropylpiperidin-4-one (1.3 g, 0.00948 mol) in 7% sulfuric acid in dioxane (20 mL) was heated at 80° C. for 2 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was cooled to RT and the dioxane layer was decanted. The residue was basified with 10% sodium hydroxide solution and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated affording crude material, which was purified by silica gel column chromatography (2% MeOH:DCM) to yield 2-cyclopropyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.4 g, 66% yield).
Reaction SMILES: [F:1][C:2]1[N:3]=[C:4]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=2)[S:5][C:6]=1[N:7](C(OC(C)(C)C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].FC(F)(F)C(O)=O>ClCCl>[C:11]([O:10][C:8](=[O:9])[NH:7][C:6]1[S:5][C:4]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=2)=[N:3][C:2]=1[F:1])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1sc(-c2cncc(F)c2)nc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1sc(-c2cncc(F)c2)nc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To a solution of di(tert-butyl) 4-fluoro-2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-ylimidodicarbonate (320 mg, 0.77 mmol) in DCM (7 mL) was added trifluoroacetic acid (TFA) (0.7 mL). The solution was stirred at room temperature for 10 minutes, before quenched slowly with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane (DCM). The combined organic layer was dried over Na2SO4, filtered and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give product as a pale yellow solid (166 mg, 68%): mp 188-191° C.; 1H NMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 8.46 (d, J=2.7 Hz, 1H), 7.85 (ddd, J=9.1, 2.6, 1.7 Hz, 1H), 6.92 (br s, 1H), 1.55 (s, 9H); ESIMS m/z 312 (M-1).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](Cl)(=[O:13])[CH2:11][CH3:12].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:20][C:19]=1[F:42].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+]>ClCCl>[Cl:41][C:38]1[CH:39]=[CH:40][C:27]2[N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:10](=[O:13])[CH2:11][CH3:12])=[C:19]([F:42])[CH:20]=3)=[O:25])[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]=2[CH:37]=1
Reactant: CCC(=O)Cl
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(F)c1)C2
Agent: Cl
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)cc1F
Reaction time: 2 h
Yield: 56 %

Procedure:
DIEA (0.27 ml, 1.56 mmol) and propionyl chloride (0.048 ml, 0.55 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (220 mg, 0.52 mmol) in dichloromethane (6 ml) at room temperature. The mixture was stirred for 2 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (129 mg, 56%).