Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH:4]([C:7]1[CH:11]=[C:10]([N:12]2[CH2:43][CH2:42][C:15]3[N:16]=[C:17]([C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[C:24]([CH3:41])=[CH:25][N:26]5[S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[N:18]=[C:19](OC)[C:14]=3[CH2:13]2)[N:9]([CH3:44])[N:8]=1)([CH3:6])[CH3:5].[ClH:45].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:45][C:19]1[C:14]2[CH2:13][N:12]([C:10]3[N:9]([CH3:44])[N:8]=[C:7]([CH:4]([CH3:5])[CH3:6])[CH:11]=3)[CH2:43][CH2:42][C:15]=2[N:16]=[C:17]([C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24]([CH3:41])=[CH:25][N:26]3[S:31]([C:34]2[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=2)(=[O:32])=[O:33])[N:18]=1
Reactant: Cl
Reactant: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C(C)C)nn1C)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4cc(C(C)C)nn4C)C5)cccc32)cc1
Temperature: 87 °C

Procedure:
Ethanol (1.8 mL) was added to 6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (195 mg, 0.342 mmol) followed by 12 N aqueous hydrochloric acid (1.8 mL, 21.8 mmol). The mixture was then heated to 87° C. for ca. 15 hours. The mixture was then cooled to room temperature, diluted with dichloromethane, and slowly neutralized with saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layers were extracted an additional time with dichloromethane. The organic layers were combined and dried by passing through a phase separator and then concentrated. The resulting residue was diluted with 1,2-dichloroethane (3.5 mL) and place at 0° C. Then N-chloromethylene-N,N-dimethyl ammonium chloride (Vilsmeier reagent) (85 mg, 067 mmol) was added. The resulting mixture was then heated to 35° C. After 5 minutes at 35° C. the mixture was diluted with dichloromethane, and slowly neutralized with saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layers were extracted an additional time with dichloromethane. The organic layers were combined and dried over Na2SO4, filtered and concentrated to furnish 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine without the need for further purification. MS (ESI+) m/z 575.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[O:11])=[C:4]([C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH:3]=1.[C:25]([O-])(=O)C.[NH4+:29]>CO>[CH3:25][O:11][C:10]1[NH:29][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]2=[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=12
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: [NH4+]
Solvent: CO
Product: COC1=c2ccccc2=c2ccc(Cl)cc2=C(c2ccccc2F)N1
Reaction time: 16 h

Procedure:
The mixture of 1.0 g of the 2-[4-chloro-2-(2-fluorobenzoyl)-phenyl]-benzaldehyde, 2.3 g of ammonium acetate and 30 ml of methanol is stirred at 25° for 16 hours and evaporated. The residue is taken up in methylene chloride, the solution washed with aqueous sodium bicarbonate, dried and evaporated. The foamy residue is taken up in hexane-diethyl ether (7:3), the solution filtered through a bed of silica gel, evaporated, and the residue crystallized from diethyl ether-hexane, to give the 5-methoxy-9-chloro-7-(o-fluorophenyl)-dibenz[c,e]azepine melting at 136°-138°.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:25](=[O:27])[CH3:26])[CH2:9][CH2:8]1)(=O)=O.[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(#N)C.O1CCOCC1>[C:25]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([CH2:6][N:31]3[CH2:32][CH2:33][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:30]3)[CH2:8][CH2:9]1)=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)(=[O:27])[CH3:26]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 70 °C

Procedure:
To a solution of ((trans-4-((3-acetyl-6-bromoquinolin-4-yl)amino)cyclohexyl)methyl methanesulfonate (300 mg, 0.66 mmol) and tert-butyl piperazine-1-carboxylate (566 mg, 3.0 mmol) in acetonitrile (5 mL) and dioxane (5 mL) was added KI (500 mg, 3.0 mmol) and N,N-diisopropylethylamine (0.60 mL, 3.44 mmol) and the reaction mixture was heated at 70° C. for 16 h. The solution was cooled to room temperature, diluted with satd. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica, 0-20% methanol/dichloromethane) to afford the desired product (248 mg, 69%) as an off-white solid. ESI MS m/z 545 [C27H37BrN4O3+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:30](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:30][C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(-c5ccccc5)n43)n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(-c5ccccc5)n43)[nH]1)cn2C
Temperature: 90 °C
Yield: 9.9 %

Procedure:
7-(5-Methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.054 g, 0.103 mmol) in DMF (3 mL) was treated with ethylenediamine (0.207 ml, 3.09 mmol) and TBAF (1 M in THF, 0.412 mL, 0.412 mmol). The solution was heated to about 90° C. for about 70 min. The mixture was cooled to ambient temperature and the mixture was diluted with EtOAc (10 mL), washed with water (6 mL), dried over anhydrous MgSO4, filtered, and concentrated to give a yellow residue. The residue was purified by silica gel chromatography eluting with 1-6% MeOH/DCM to provide a yellow solid. The solid was triturated with heptane (2 mL) to provide 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.004 g, 10%): LC/MS (Table 2, Method a) Rt=2.26 min; MS m/z: 394 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCN(C[C@H](O)C(F)(F)F)CC2
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCN(C[C@H](O)C(F)(F)F)CC3)ncc1Cl

Procedure:
(S)-3-{7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-1,1,1-trifluoro-propan-2-ol was prepared from (S)-3-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 328. Product isolated as a white solid (179 mg, 86%). m.p.=170-172° C.; LCMS (m/e) 593 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.24 (d, 1H, J=8.7 Hz), 8.03 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.32-7.26 (m, 1H), 7.04 (d, 1H, J=8.1 Hz), 6.87 (s, 1H), 6.57 (s, 1H), 6.51 (d, 1H, J=8.7 Hz), 4.50-4.32 (m, 1H), 4.10-4.00 (m, 1H), 3.94 (s, 3H), 3.93-3.89 (m, 4H), 3.21-3.15 (m, 4H), 2.97-2.79 (m, 7H), 2.77-2.67 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)=[CH:4][C:3]=1[O:24][Si](C(C)C)(C(C)C)C(C)C.CN1CCOCC1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[OH:24][C:3]1[CH:4]=[C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH:22]=[CH:23][C:2]=1[NH:1][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(NC(=O)c2ccccc2)c(O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a solution of (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (65 mg, 0.11 mmol) in tetrahydrofuran (6 mL) is added 4-methylmorpholine (36 μL, 0.33 mmol), and the mixture is cooled to 0° C. in an ice-water bath. Benzoyl chloride (38 μL, 0.33 mmol) is added and the mixture is allowed to stir at room temperature for one hour. To the mixture is then added 1.0 M tetrabutylammonium fluoride solution in tetrahydrofuran (1 mL, 1 mmol). After heating for 10 minutes at 55° C., water is added. The precipitated solid is collected by filtration, washed with water and acetonitrile, and dried under house vacuum to give N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]benzamide (34 mg, 58%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:34])([F:33])[F:22])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Temperature: 120 °C

Procedure:
0.13 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2-trifluoromethylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.18 g of the title compound. ES MS (+) m/z 411.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34](Cl)(Cl)=[O:35].[F:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>C(Cl)Cl>[CH3:14][CH:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:34]([NH:42][C:41]3[CH:43]=[CH:44][CH:45]=[C:39]([F:38])[CH:40]=3)=[O:35])[CH:7]=[CH:6][CH:5]=2)([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)[CH2:9][CH2:10]1
Reactant: Nc1cccc(F)c1
Reactant: CC1CCC(c2cccc(N)c2)(N2CCN(c3ccccc3)CC2)CC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCC(c2cccc(NC(=O)Nc3cccc(F)c3)c2)(N2CCN(c3ccccc3)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-aminophenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane (cis isomer, 205 mg, 0.587 mmol) and triethylamine (205 μL, 1.47 mmol) in dry CH2Cl2 (15 mL) was brought to 0° C. using an ice bath. Phosgene (1.93 M in toluene, 365 μL) was added dropwise and the resulting mixture was stirred at 0° C., under a dry N2 atmosphere, for 30 minutes. 3-fluoroaniline (68 μl, 0.705 mmol) was added via syringe and the reaction was allowed to come to room temperature. After 3 h the mixture was diluted with an equal volume of CH2Cl2, washed with H2O, dried (Na2SO4) and concentrated to give the crude urea. The residue was triturated with ether and the resulting solid collected on a sintered glass funnel and washed with ether. Preparative plate chromatography (50% EtOAc/hexanes) afforded pure N-[3-[4-methyl-1-(4-phenyl-1 piperazinyl)cyclohexyl]phenyl]-N'-3-fluorophenyl-urea (cis isomer) as an off-white solid. The HCl salt was prepared by adding excess saturated EtOAc/HCl solution to the free base in dry MeOH. Concentration of the homogeneous solution yielded a solid which was washed with EtOAc and dried under vacuum. mp=149-151° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:29])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:17][CH2:18][C:13]([F:29])([F:12])[CH2:14][CH2:15]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)C2CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)C2CCC(F)(F)CC2)cn1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=448.1, tR (minutes, Method F)=2.95. [α]D20=+49.6 (c=4.8 mg/mL,CHCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[N+:33]([O-])=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.CO.O>[NH2:33][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)c([N+](=O)[O-])c4)cc3)c2cc1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)c(N)c4)cc3)c2cc1OC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 41.5 %

Procedure:
N-(4-Chloro-3-nitrophenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (100 mg) was dissolved in chloroform/methanol/water (5ml/15ml/3ml), sodium thiosulfate (358 mg) was added, and the admixture was stirred at 60° C. for 20 minutes. The reaction mixture was extracted 2 times with chloroform, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 39 mg of the title compound (yield: 41%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].CN(C)C1C=CC=CC=1.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.O1CCOCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:35](=[O:38])[CH:36]=[CH2:37])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(/C=C/c2ccc(OCCCCCCO)cc2)cc1
Reactant: C=CC(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Solvent: CN(C)c1ccccc1
Product: C=CC(=O)OCCCCCCOc1ccc(/C=C/c2ccc(C(=O)O)cc2)cc1
Temperature: 60 °C
Yield: 71.3 %

Procedure:
A mixture of 4.38 g (12.8 mmole) of (E)-4-carboxy-4′-[6-hydroxyhexyloxy]stilbene (16), 1.87 g (15.4 mmole) of N,N-dimethylaniline, 1.38 g (15.4 mmole) of acryloyl chloride, 8 mg of 2,6-di-t-butyl-4-methylphenol and 9 ml of 1,4-dioxane was heated at 60° C. under a nitrogen atmosphere. After 3 hours the mixture was cooled and 10 ml of 1,4-dioxane were added. The product was collected on a filter and washed with 40 ml of ethanol. 3.6 g of product (71%) were obtained after drying over silica in a dessicator.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]=O)=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]S([O-])(=O)=O.[Mg+2].[Na]>C(Cl)Cl.C(O)(=O)C.C1COCC1>[CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1
Reactant: Nc1ccccc1
Reactant: CN(C)c1nncc2cc(C=O)ccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)c1nncc2cc(CNc3ccccc3)ccc12
Temperature: 25 °C

Procedure:
A mixture of 1-dimethylamino-phthalazine-6-carbaldehyde (25 mg, 0.13 mmol), aniline (14 μL, 0.15 mmol), THF (1 mL) and MgSO4 (43 mg, 0.357 mmol) were stirred at room temperature. To this mixture was added acetic acid (8 μL) followed by sodium cyanoboroahydride (13 mg, 0.207 mmol) and the reaction stirred for 15 h. The reaction was diluted with CH2Cl2, washed with aq. NaHCO3, dried (Na2SO4) and concentrated. Purification by prep. HPLC yielded the desired compound. m/z 279.22 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13](O)=[O:14])=[C:6]2[O:16][CH:17]([CH3:19])[CH3:18].C(N1C=CN=C1)([N:22]1C=CN=C1)=O.[OH-].[NH4+].O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13]([NH2:22])=[O:14])=[C:6]2[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: COc1ccc2c(c1)c(OC(C)C)c(C(=O)O)n2C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1ccc2c(c1)c(OC(C)C)c(C(N)=O)n2C
Temperature: 0 °C
Yield: 53.4 %

Procedure:
A mixture of 5-methoxy-1-methyl-3-(1-methylethoxy)-1H-indole-2-carboxylic acid (4.0 g, 15 mmol; Unangst PC, et al., J. Med. Chem. 1989;32:1360) and 1,1'-carbonyldiimidazole (2.6 g, 16 mmol) in 75 mL of acetonitrile is stirred at reflux for 2 hours. The mixture is cooled slightly and 75 mL of concentrated ammonium hydroxide is added. After stirring for 15 minutes, the mixture is added to 600 g of ice and water. The precipitated solid is filtered, washed with water, and recrystallized from aqueous acetonitrile to give 2.1 g (53%) of product; mp 147°-149° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:35][CH2:34][CH2:33][C@@H:9]3[S:10](=[O:32])(=[O:31])[C:11]([CH3:30])([CH3:29])[C:12]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:13][C@:8]3([CH2:36][F:37])[C:6]=2[CH:7]=1.[C:38]([C:40]1[CH:41]=[C:42]([CH3:49])[C:43]([C:46](O)=[O:47])=[N:44][CH:45]=1)#[N:39].CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:38]([C:40]1[CH:41]=[C:42]([CH3:49])[C:43]([C:46]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:35][CH2:34][CH2:33][C@@H:9]4[S:10](=[O:32])(=[O:31])[C:11]([CH3:29])([CH3:30])[C:12]([N:14]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[N:13][C@:8]4([CH2:36][F:37])[C:6]=3[CH:7]=2)=[O:47])=[N:44][CH:45]=1)#[N:39]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(CF)c3cc(N)ccc3OCC[C@@H]2S(=O)(=O)C1(C)C
Reactant: Cc1cc(C#N)cnc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(CF)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S(=O)(=O)[C@H]1CCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 50-mL round-bottomed flask, tert-butyl N-[(4aS,11bS)-10-amino-11b-(fluoromethyl)-3,3-dimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (102 mg, 0.188 mmol), 5-cyano-3-methylpicolinic acid (36.6 mg, 0.226 mmol), Hunig's base (0.043 mL, 0.245 mmol), and 1-propanephosphonic acid cyclic anhydride (0.120 mL, 0.188 mmol) were added then dissolved in DCM (5 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was then diluted with saturated NaHCO3 and extracted with EtOAc (15 mL). The organic extract was washed with water, brine (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give tert-butyl N-[(4aS,11bS)-10-[(5-cyano-3-methyl-pyridine-2-carbonyl)amino]-11b-(fluoromethyl)-3,3-dimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate as a white solid that was used without further purification. MS m/z=708.0 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=1.CO>CN(C=O)C.CCOC(C)=O.O=[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1C#Cc1ccccc1C(C)C(N)=O
Agent: O=[Pt]=O
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cnc(Cl)nc1CCc1ccccc1C(C)C(N)=O
Reaction time: 72 h

Procedure:
A solution of 2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)propanamide A48 (2.08 g, 6.95 mmol) in DMF (110 mL) and MeOH (10 mL) was stirred with PtO2 (0.395 g, 1.74 mmol) under an atmosphere of H2 for 16 hours at room temperature. An extra portion of PtO2 (0.189 g, 0.832 mmol) was added and stirring was continued under H2 for 72 hours at room temperature. The mixture was diluted with EtOAc (200 mL) and filtered through Celite. The volatiles were removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 120 g SiO2 cartridge, 10-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A49 as a white solid (1.51 g, 72%). LCMS-D: rt 3.15 min; m/z 304 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C1CCN(Cc2ccc(F)cc2F)CC1
Yield: 217 %

Procedure:
28.20 g (0.125 mol) of 2,4-difluorobenzyl bromide was weighed, to which 200 mL of dichloromethane was added and then 62.00 g (0.404 mol) of 4-piperidone hydrochloride monohydrate was added under stirring. And then 86.00 g (0.850 mol) of triethylamine was added dropwise at a bath temperature of 30-40° C. under stirring. After the addition, the reaction was heated, refluxed and reacted overnight. On the next day, the reaction was cooled, filtered to removed solid, washed in sequence with dichloromethane and ethyl ether, combined, washed with water and dried, and the solvent was recovered to obtain 61.10 g of crude product (73.3%), 1H-NMR (CDCl3, ppm) δ: 7.31-7.33 (5H, m), 3.56 (2H, s), 2.64 (2H, s), 2.53-2.62 (4H, m), 1.52-1.86 (4H, m); which was used directly in the next step of reaction.