Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:26]([N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])[C:27]#[CH:28].C(NCC)C>[Cu]I.CN(C)C=O>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[CH:8]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:4]1[CH:3]=[C:2]([C:28]#[C:27][CH2:26][N:29]2[C:33](=[O:34])[C:32]3[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]2=[O:39])[CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3[nH]2)CC1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CN1CCC(OC(c2cccc(C#CCN3C(=O)c4ccccc4C3=O)c2)c2nc3ccccc3[nH]2)CC1
Reaction time: 24 h

Procedure:
A screw-cap tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (200 mg), dichloro-bis(triphenylphosphine) palladium(II) (9.2 mg), copper(I) iodide (16.4 mg), N-propargylphthalimide (400 mg), diethylamine (310 μL) and N,N-dimethylformamide (2 mL). The tube is evacuated, filled with argon and sealed. After stirring at room-temperature for 24 h, the mixture is diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 95/5/0.5 to give 2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][NH2:5].C[N:8](N=O)[C:9]([NH:11][N+:12]([O-:14])=[O:13])=N>CCO.O>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][NH:5][C:9]([NH:11][N+:12]([O-:14])=[O:13])=[NH:8]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: CC(C)=CCN
Solvent: CCO
Solvent: O
Product: CC(C)=CCNC(=N)N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-methyl-2-butenylamine (3.0 g) is added dropwise at room temperature to a slurry of 1-methyl-3-nitro-1 -nitrosoguanidine (4.3 g) in 50 ml of EtOH/H2O (1/1). After stirring the mixture at room temperature for 18 hours, the precipitate which forms is removed by filtration. The solid is then slurred with dilute hydrochloric acid, collected by filtration and washed with ethanol/water (30/70). Recrystallization from ethanol gives a white solid with mp 134°-136° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]([N:28]1[C:32]([C:33]([OH:35])=O)=[CH:31][CH:30]=[N:29]1)[CH3:27].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>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:33]([C:32]4[N:28]([CH:26]([CH3:25])[CH3:27])[N:29]=[CH:30][CH:31]=4)=[O:35])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: CC(C)n1nccc1C(=O)O
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: CC(C)n1nccc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.17 h

Procedure:
To a solution of HATU (0.253 g) in DMF (3 ml) was added 1-(1-methylethyl)-1H-pyrazole-5-carboxylic acid (0.102 g) and DIPEA (0.211 ml) and the mixture was left to stand for 10 min. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (0.075 g) dissolved in DMF (3 ml) was added and the solution was left to stand at RT for 18 h. DMF was removed by blow down (not to dryness) and the residue was dissolved in chloroform (1 ml) and loaded onto an aminopropyl SPE (2 g) (pre-conditioned with methanol (6 ml) and chloroform (6 ml)). The mixture was left on the column for 2 h then eluted with ethyl acetate:methanol (1:1, 10 ml). The solvent was blown down to dryness and the residue was dissolved in DMSO:methanol (1 ml, 1:1) and purified by MDAP (method K). The solvent was removed in vacuo and dried in an vacuum oven (50° C.) overnight to give title compound, 18 mg.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[F:2].[CH2:6]([NH:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]([CH2:4][CH:3]([OH:5])[CH2:1][F:2])[CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FCC1CO1
Reactant: OCCNCc1ccccc1
Solvent: CCO
Product: OCCN(Cc1ccccc1)CC(O)CF
Yield: 95.2 %

Procedure:
A solution of 22.20 g (0.3 mole) of epifluorohydrin and 67.95 g (0.45 mole) of N-benzylethanolamine dissolved in 200 ml of ethanol was heated under reflux for 5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel using ethyl acetate as the eluent, to give 64.93 g of N-benzyl-N-(3-fluoro-2-hydroxypropyl)ethanolamine as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N+:12]2[O-])=[CH:7][CH:6]=1)=[O:4].[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19].CC1C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>ClCCl>[F:16][C:17]([F:21])([F:20])[CH2:18][NH:19][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[N:12]=1
Reactant: COC(=O)c1ccc2ccc[n+]([O-])c2c1
Reactant: NCC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2ccc(NCC(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 205.1 %

Procedure:
To a solution of 7-(methoxycarbonyl)quinoline 1-oxide (200 mg, 0.984 mmol) and 2,2,2-trifluoroethylamine (292 mg, 0.295 mmol) at 0° C. was added 4-methylbenzenesulphonic anhydride (964 mg, 2.95 mmol) portionwise over a period of 45 minutes. The reaction was allowed to warm up to room temperature and stirred overnight. The reaction was diluted with dichloromethane and washed with a saturated solution of ammonium chloride. The aqueous layer was extracted into dichloromethane (1×). The organics were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography gave the title compound (172 mg, 62%). +ESI (M+H) 285.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C1CNCCN1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CCN1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-piperazinone according to conditions described in general procedure C. Mp: 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 1.62-1.69 (m, 6 H), 3.25-3.28 (m, 6 H), 3.82 (s, 2 H), 4.14 (s, 2 H), 6.20 (d, J=5.5 Hz, 1 H), 6.38 (s, 1 H), 6.76 (d, J=11.7 Hz, 1 H), 7.00 (d, J=8.0 Hz, 1 H), 7.26 (d, J=8.0 Hz, 1 H), 7.32 (s, 1 H), 7.46-7.55 (m, 2 H), 7.83-7.92 (m, 3 H), 8.20-8.21 (m, 1 H), 8.36 (s, 1 H).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1O)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:25])=O.O>CN(C=O)C>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[Br:25])=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1c(Cc2ccccc2)nnc2c(C(F)(F)F)cccc12
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cccc2c(Br)c(Cc3ccccc3)nnc12
Reaction time: 1 h
Yield: 105.2 %

Procedure:
A solution of 3-benzyl-8-trifluoromethyl-cinnolin-4-ol (1.6 g, 4.4 mmol) and POBr3 (2.5 g, 8.7 mmol) in DMF (30 ml) was heated to 75° C. After 1 hr, the reaction was cooled and poured into water. The aqueous layer was extracted with EtOAc which was dried (MgSO4) and concentrated to give a solid. The solid was triturated with MeOH and filtered to give 3-benzyl-4-bromo-8-trifluoromethyl-cinnoline (1.7 g). MS (ES) m/z 366.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[OH:23][C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=3[C:27]3[CH:26]=[CH:25][C:24]([OH:23])=[N:29][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Reactant: CC1(C)OB(c2ccc(O)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccc(O)nc2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 6-hydroxypyridine-3-boronic acid pinacol ester (124 mg, 0.562 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)pyridin-2-ol. 1H NMR (TFA salt, CD3OD) d (ppm): 7.59-7.68 (m, 3H), 7.4 (s, 1H), 7.3 (s, 1H), 6.98-7.18 (m, 3H), 6.82 (d, 1H), 6.23 (d, 1H), 4.7 (d, 1H), 4.37 (d, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.0 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[Cl:26][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])[N:9]=1
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(Sc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(Cl)c2cc(Sc3ccccc3)ccc2c1O

Procedure:
194 mg of 1-chloro-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol) were reacted with glycine and sodium methylate analogously to Example D-1 g). 168 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.17 (t, 1H), 8.24 (d, 1H), 7.51 to 7.79 (m, 7 H), 4.00 (d, 2 H).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[OH:6][C@H:7]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:30]2[C:29](=[O:35])[CH2:28][C@@:27]2([CH3:36])[C@H:13]3[CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]4)[C@@H:17]([CH3:18])[C@@H:16]32)[CH2:8]1.C(N(CC)CC)C.CC1C=CN=C(N)C=1C>ClCCl>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:6][C@H:7]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:30]2[C:29](=[O:35])[CH2:28][C@@:27]2([CH3:36])[C@H:13]3[CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]4)[C@@H:17]([CH3:18])[C@@H:16]32)[CH2:8]1
Reactant: C[Si](C)(C)Cl
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]3(C)[C@H]1[C@@H]2C
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C)CC[C@]5(C)[C@H]4C(=O)C[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.3 %

Procedure:
Trimethylsilylchloride (3.27 mL, 25.8 mmol) was added to a solution of (3β,5α,25R)3-hydroxy-spirostan-11-one (4.0 g, 9.3 mmol) and triethylamine (6.5 mL, 46 mmol) in dichloromethane (60 mL) at room temperature. One gram of dimethyl aminopyridine was added and the reaction was stirred at room temperature for 12 hours. The reaction was quenched with methanol (1 mL) and diluted with ethyl acetate, washed with water (5×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The product was triturated with methanol, filtered and dried to afford 3.94 g (85%) product as a white solid. 1H NMR (250 MHz, CDCl3) 6 4.5 (q, 1H, J=6Hz); 3.45 (m, 2H); 2.35 (t, 1H, J=10 Hz); 2.4 (dt, 1H, J=12.2 Hz); 2.2 (s, 2H); 2.1-1.1 (m, 12H); 1.02 (s, 3H); 0.9 (d, 3H, J=7.0 Hz); 0.78 (d, 3H, J=7 Hz); 0.69 (s, 3H); 0.1 (s, 9H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[NH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[NH:13][C:12]2=[O:22])[CH2:7][CH2:6]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[O:22]=[C:12]1[N:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:1]([Cl:4])=[O:2])[CH2:6][CH2:7]2)[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[NH:13]1
Reactant: O=C(Cl)Cl
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6 g (12.1 mmol) phosgene (20 percent by weight in toluene) were added to a solution of 2.5 g (10.2 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 2.6 mL (14.9 mmol) ethyldiisopropylamine in 75 mL DCM cooled to 0° C. and the reaction mixture was stirred for 30 min at this temperature. The mixture was allowed to warm up to RT, evaporated down i.vac. to approx. 50 mL and filtered through silica gel, this was washed with 200 mL DCM/EtOAc (1:1) and the combined organic filtrates were again evaporated down i.vac. The residue was stirred with DIPE, suction filtered and dried i.vac.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH3:31]>CO.O1CCOCC1>[NH2:31][C:2]1[CH:7]=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4ccnc(F)c4)n4ccnc34)cc2)CC1
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccnc(N)c4)n4ccnc34)cc2)CC1
Temperature: 120 °C
Reaction time: 96 h
Yield: 16 %

Procedure:
A solution of [5-(2-fluoro-pyridin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.0272, 0.067 mmol) (from Example 125) in a mixture of aq. NH3 (2.5 mL):1M NH3 in MeOH (2.5 mL) is stirred at 100° C. overnight. Additional aq. NE3 (5 mL) and 0.5M NH3 in dioxane (2 mL) are added and the mixture stirred at 120° C. for 4 days. The mixture is concentrated in vacuo and purified by reverse phase HPLC affording the title compound (4.2 mg, 16%). LCMS: Rt 3.76 min (95%) m/z (APCI) 401 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm). 2.26 (3H, s), 2.49-2.53 (4H, t), 3.12-3.15 (4H, m), 6.18 (2H, br s) 6.76 (1H, s), 6.81 (1H, d), 6.97 (2H, d), 7.51 (1H, s), 7.72 (1H, s), 7.88 (2H, d), 8.04 (1H, s), 8.09 (1H, d), 9.55 (1H, s).
Reaction SMILES: [C:1]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([N+:23]([O-])=O)[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C.CO>[C:1]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc2c1ccn2S(=O)(=O)c1cccc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Nc1cccc2c1ccn2S(=O)(=O)c1cccc2ccccc12

Procedure:
A mixture of 722 mg (1.97 mmole) 1-(naphthalene-1-sulfonyl)-4-nitro-1H-indole and 100 mg 10% palladium on carbon in 15 mL ethanol and 5 mL methanol was shaken under 40 psi hydrogen at room temperature for 4 hrs. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ether/hexane to provide 1-(naphthalene-1-sulfonyl) -1H-indol-4-ylamine as light yellow-green crystals, 480 mg, m.p. 133-134° C.
Reaction SMILES: [C:1]1([P:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:3]1[CH:2]=[C:1]([P:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: OP(O)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(P(O)O)c1

Procedure:
reacting benzenephosphonous acid in a sulfuric acid medium under nitrating conditions by the dropwise addition of nitric acid at a temperature of about 0° C. to about 5° C. to form m-nitrobenzenephosphonous acid in a reaction mixture;
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])=[CH:23][C:15]1=2)C(=O)OC(C)(C)C.Cl.O>CO.C(=O)([O-])[O-].[Na+].[Na+]>[OH:1][CH2:2][CH2:3][NH:4][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])=[CH:23][C:15]1=2
Reactant: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N=C(Nc1ccc2c(c1)N(CCNCCO)CCS2)c1cccs1
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a stirred solution of tert-butyl 2-hydroxyethyl(2-(6-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (334 mg, 0.722 mmol) in methanol (5 mL) was added HCl, 3M in water (2.407 mL, 7.22 mmol). The resulting solution was stirred at 90° C. for 1 hour. The mixture was then cooled to room temperature, diluted with saturated sodium carbonate and extracted with dichloromethane (6×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:9 (2M NH3 in methanol):ethyl acetate, giving the desired product 26 (175 mg, 66.9%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.3 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.34 (brs, 2H), 6.22 (s, 1H), 6.07 (d, J=7.5 Hz, 1H), 4.49-4.43 (m, 1H), 3.63-3.55 (m, 2H), 3.46-3.38 (m, 2H), 3.37-3.28 (m, 2H), 3.01-2.95 (m, 2H), 2.71 (t, J=6.4 Hz, 2H), 2.59 (t, J=5.7 Hz, 2H), 1.91-1.75 (m, 1H); ESI-MS (m/z, %): 363 (MH+, 100), 276 (99), 268 (62); HRMS calculated for C17H23N4OS2 (MH+), calculated: 363.1307, observed: 363.1290; HPLC purity: 97% by area.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Br[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25]>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:10]1[CH:9]=[CH:8][C:7]([CH2:15][S:14][C:9]2[C:10]([O:12][CH3:13])=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]([CH3:15])[CH:8]=2)=[CH:6][CH:11]=1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Reactant: Clc1ccc(Br)c(Cl)c1
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 5A using 1D and 1-bromo-2,4-dichloro-benzene. MS m/z 479 (M+2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[C:17]=2[CH2:18][C:19](O)=[O:20])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH:29][CH2:30][CH3:31].Cl.C(OCC)C>ClCCl>[ClH:1].[CH2:30]([N:29]([CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1)[C:19](=[O:20])[CH2:18][C:17]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:31]
Reactant: CCNCc1ccccn1
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)cc3)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCN(Cc1ccccn1)C(=O)Cc1c(-c2ccc(Cl)cc2)nc2cc(C)ccn12
Yield: 51.2 %

Procedure:
According to the method of Example 13, 2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(2-pyridinylmethyl)ethylamine were used as raw materials for synthesis, salified with hydrochloric acid-ethyl ether solution in dry dichloromethane, then crystallized with methanol-tetrahydrofuran to obtain a corresopnding hydrochloride pure product. Yellow solid powder, yield 51.2%. m.p. 178-180° C., ESI-MS m/z: 420[M+H]+, 1H NMR(D2O, 400 MHz)δ: 0.95(t, 0.5H, J=7.00 Hz), 1.14(t, 2.5H, J=7.00 Hz), 2.38(s, 2.5H), 2.40(s, 0.5H), 3.30(q, 0.4H, J=7.00 Hz), 3.56(q, 1.6H, J=7.00 Hz), 4.14(s, 0.4H), 4.36(s, 1.6H), 4.76(s, 1.6H), 4.86(s, 0.4H), 7.14-7.24(m, 1H), 7.30-7.46(m, 4H), 7.50(s, 1H), 7.69-7.75(m, 2H), 8.11-8.13(m, 1H), 8.33-8.53(m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:20]([NH:21][C:22](=[O:35])[CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])=[CH:19][CH:18]=[C:17]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[CH3:37]N(C)C=O.[H-].[Na+].CI>O>[Cl:1][C:2]1[C:20]([N:21]([C:22](=[O:35])[CH2:23][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[CH3:37])=[CH:19][CH:18]=[C:17]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CN(C)C=O
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(NC(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reaction time: 0.5 h

Procedure:
To a mixture of 8-[2,6-dichloro-3-(phthalimidoacetylamino)benzyloxy]-2-methylquinoline (4.44 g) and N,N-dimethylformamide (44 ml) was added sodium hydride (60% in oil, 375 mg) in an ice-water bath. After stirring for 30 minutes in an ice-water bath, methyl iodide (0.6 ml) was added thereto and the mixture was stirred at ambient temperature for 1 hour. To this mixture was added, water (88 ml) in an ice-water bath and the mixture was stirred at the same temperature for 1.5 hours. The precipitate was collected by vacuum filtration and washed with water and methanol to give 8-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-2-methylquinoline (3.99 g) as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=[O:19])=[O:18].[OH-].[Na+].C(OCC)C>O1CCCC1.C([Li])CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([C:17]([OH:19])=[O:18])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ncsc2C1
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(C(=O)O)sc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (845 mg) in absolute tetrahydrofuran (20 ml), n-butyllithium (1.65N hexane solution, 2.13 ml) was added dropwise at −78° C., and the mixture was stirred for 30 minutes with ice cooling. After passing carbon dioxide gas into the reaction mixture at −78° C. for 1 hour, the reaction mixture was warmed to room temperature. A 5N aqueous solution of sodium hydroxide and diethyl ether were added to the reaction mixture to separate a water layer. 6N Hydrochloric acid was added to the water layer to adjust the pH thereof to 1 to 2. After addition of dichloromethane, an organic layer separated was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (562 mg) as a pale yellow foamy substance.