Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[NH:7][CH:8]([C:21](=[O:48])[N:22]([CH:34]([C:36]1[NH:37][CH:38]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2Br)[N:40]=1)[CH3:35])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](=[O:19])[NH2:18])=[CH:12][C:11]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2].[CH3:50][N:51](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:1]([O:5][C:6](=[O:49])[NH:7][CH:8]([C:21](=[O:48])[N:22]([CH:34]([C:36]1[NH:37][CH:38]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:50]#[N:51])[N:40]=1)[CH3:35])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](=[O:19])[NH2:18])=[CH:12][C:11]=1[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN(C(=O)C(Cc2c(C)cc(C(N)=O)cc2C)NC(=O)OC(C)(C)C)C(C)c2nc(-c3ccccc3Br)c[nH]2)cc1OC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc(CN(C(=O)C(Cc2c(C)cc(C(N)=O)cc2C)NC(=O)OC(C)(C)C)C(C)c2nc(-c3ccccc3C#N)c[nH]2)cc1OC
Temperature: 100 °C

Procedure:
To a solution of [1-[{1-[4-(2-bromo-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (294 mg; 0.4 mmol) in DMF (2 mL) was added Zn(CN)2 (28 mg; 0.24 mmol). The resulting mixture was degassed with Argon for 5 min, then Pd(PPh3)4 (92 mg; 0.08 mmol) was added neat, and the system was immediately warmed to 100° C. After heating for 6 h, the reaction was cooled to rt and partitioned between EtOAc and water. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was subjected to reverse phase HPLC (water/acetonitrile/0.1% TFA). The fractions of interest were combined, basified with saturated aqueous NaHCO3 and extracted twice with EtOAc. The EtOAc extracts were combined, dried over Na2SO4, filtered, and concentrated to afford 146 mg (54%) of desired {2-(4-carbamoyl-2,6-dimethyl-phenyl)-1-[{1-[4-(2-cyano-phenyl)-1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-carbamic acid tert-butyl ester (HPLC: 96% @ 254 nm and 97% @ 214 nm). This sample was of sufficient quality to use in the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[N:9]([CH2:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=1
Reactant: O=C1NS(=O)(=O)c2cc(Br)ccc21
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)c3ccc(Br)cc3S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 60% NaH (10.1 mg, 0.254 mmol) in DMF (1 mL), 6-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (55.4 mg, 0.212 mmol) was added portionwise at 0° C. The resulting mixture was stirred at rt for 15 min and p-methoxy benzyl chloride (27.6 μL, 0.212 mmol) was added dropwise. The reaction mixture was heated to 70° C. overnight, allowed to cool to rt, and treated with water (20 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting solid was recrystallized from hexane/DCM to obtain compound 38a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.08 (d, J=1.5 Hz, 1H), 7.89 (dd, J=8.2, 1.6 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 4.76 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[C:2]=[S:3].[CH:19]1([CH2:27][NH:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([O:37][CH2:38][O:39][CH3:40])[CH2:33][CH2:32]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[CH3:40][O:39][CH2:38][O:37][CH:34]1[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][N:28]([CH:4]([N:1]=[C:2]=[S:3])[CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:27][CH:19]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:36][CH2:35]1
Reactant: COCOC1CCN(CCNCC2CCCCCCC2)CC1
Reactant: O=c1ccc2cc(OCCCN=C=S)ccc2[nH]1
Solvent: ClC(Cl)Cl
Product: COCOC1CCN(CCN(CC2CCCCCCC2)C(CCOc2ccc3[nH]c(=O)ccc3c2)N=C=S)CC1
Yield: 74.6 %

Procedure:
A solution of 0.22 g of 6-(3-isothiocyanatopropoxy)carbostyril and 0.3 g of 1-[2-(cyclooctylmethylamino)ethyl]-4-methoxymethoxypiperidine in 30 ml of chloroform was stirred at room temperature for 5 hours. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluant: 3% methanol/dichloromethane) to obtain 0.36 g of 6-[3-{N-2-(4-methoxymethoxy-1-piperidinyl)ethyl-N-cyclooctylmethylamino}-thiocarbonylaminopropoxy]carbostyril.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])[CH:4]=[N:3][CH:2]=1.N1C=CC=CC=1.[C:20]1([C:33](Cl)=[O:34])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1>ClCCl>[N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([NH:10][C:33]([C:20]3[C:32]4[CH2:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[O:34])[CH:11]=[CH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2c1Cc1ccccc1-2
Reactant: Nc1cccc(-c2cncnc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2cncnc2)c1)c1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a suspension of 3-(pyrimidin-5-yl)aniline (0. 17g) and pyridine (0.24 ml) in dichloromethane (3 ml) was dropwise added a solution of the fluorene-1-carbonyl chloride (0.23 g) in dichloromethane (5 ml) followed by stirring for 2 hours. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[3-(pyrimidin-5-yl)phenyl]fluorene-1-carboxamide (0.222 g, 61.2 %).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[Br:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:8][C:9]([F:16])([F:15])[C:10]([NH:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: NCc1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccco1)C(F)(F)Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a solution of 1-(furan-2-yl)methanamine (1 g, 10.3 mmol) in 15 mL of dry DMF, ethyl bromo(difluoro)acetate (2.3 g, 11.3 mmol) and K2CO3 (2.13 g, 15.4 mmol) were added. The solution was stirred for 18 h at room temperature. The mixture was diluted with 30 mL of water and extracted with 2×20 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2-bromo-2,2-difluoro-N-(furan-2-ylmethyl)acetamide as red oil (2.3 g, 88% yield). HPLC-MS (ESI+): m/z 255.03 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14]CC)=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18]C(C)C)[CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC(C)C)cc(Cl)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1OB(O)c2cc(O)cc(Cl)c21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 2-(4-chloro-1-hydroxy-6-isopropoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (200 mg, 0.74 mmol) in 10 mL THF was added LiOH (100 mg, 2.22 mmol) in 5 mL H2O dropwise at 0° C. The mixture was stirred at room temperature for 1.5 h and acidified to pH=5.0 using 1N HCl (8 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was use directly in next step reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl-].[Na+]>COCCOCCOC.O>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: C1CNCCN1
Reactant: Cc1cc(C)nc(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: Cc1cc(C)nc(N2CCNCC2)c1
Reaction time: 18 h

Procedure:
A solution of 2-chloro-4,6-dimethylpyridine (30 g, 0.212 mol) in diglyme (100 mL) was added over 25-30 min. to a refluxing solution of anhydrous piperazine (147 g, 1.70 mol) in diglyme (150 mL). Heating was continued for 18 h (whereby TLC showed absence of 2-chloro-4,6-dimethylpyridine), then the mixture was cooled to room temperature and diluted with water (3 L). Sodium chloride (50 g) was added and the solution was extracted with ethyl acetate (300 mL×3); the combined extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo (up to 110° C. & ˜15 mmHg; to remove maximum diglyme) to afford 1-(4,6-dimethyl-pyridin-2-yl)-piperazine (42 g, 103.3%, the G.C. spectrum showed 86.4% product, 10.7% diglyme, and 2.1% dimer.)
Reaction SMILES: C([C@@H]1CC[C@@H](C)C[C@H]1[O:11][C:12]([C@@H:14]1[CH2:27][C:26]2[CH:25]=[C:24]3[C:19]([O:20][C@H:21]([C:30]4[CH:35]=[CH:34][C:33]([O:36]CC5C=CC(Cl)=C(Cl)C=5)=[CH:32][CH:31]=4)[C:22](=[O:29])[N:23]3[CH3:28])=[CH:18][C:17]=2[CH2:16][N:15]1[C@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:13])(C)C.B(Cl)(Cl)Cl>C(Cl)Cl.CCCCCC>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([C@H:21]2[O:20][C:19]3[C:24](=[CH:25][C:26]4[CH2:27][C@@H:14]([C:12]([OH:13])=[O:11])[N:15]([C@H:46]([C:49]5[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=5)[CH2:47][CH3:48])[CH2:16][C:17]=4[CH:18]=3)[N:23]([CH3:28])[C:22]2=[O:29])=[CH:31][CH:32]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Reaction time: 3 h
Yield: 129.1 %

Procedure:
To a solution of (3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (0.2 mmol) in DCM (3 mL) was added 1N BCl3 solution in hexane (0.5 mL) at 0° C. and the mixture was stirred for 3 h. The mixture was evaporated to dryness and the residue was quenched with water. The mixture was basified using sodium bicarbonate solution to pH 7. The residue was extracted with EtOAc and 10% THF. The organic layer was washed and dried to get (3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid as a yellow solid (122 mg). This solid was used as is for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>CS(C)=O>[CH3:33][N:30]1[CH2:31][CH2:32][CH:27]([O:1][C:2]2[CH:3]=[C:4]([S:8]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH2:28][CH2:29]1
Reactant: CN1CCC(Cl)CC1
Reactant: O=S(=O)(c1cccc(O)c1)n1ccc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCC(Oc2cccc(S(=O)(=O)n3ccc4ccccc43)c2)CC1
Temperature: 42.5 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
1-(3′-Hydroxybenzenesulfonyl) indole, (0.36 mmol, 0.1 grams) (obtained from preparation 1), was dissolved in dimethyl sulfoxide (2 mL). Potassium carbonate (0.074 grams) was added and the resulting reaction mixture was stirred 40-45° C. for a period of one hour. In another round bottom flask, 4-chloro-N-methylpiperidine (0.54 mmol, 0.072 grams) was dissolved in dimethyl sulfoxide (1.5 mL). The content of the first flask were added to the second flask at 40-45° C. The resulting reaction mass was further heated to 140-145° C. and maintained there for a period of 5 hours while monitoring the reaction by thin layer chromatography. Cooled the reaction mass to room temperature, poured it onto water (25 mL) and extracted the product with ethyl acetate (30 mL×3). Combined organic extracts were dried over sodium sulfate and the volatiles were removed under the reduced pressure to obtain 0.110 grams crude compound. The compound was purified by column chromatography using silica gel (100-200 mesh), eluent being ethyl acetate and 1% triethylamine to obtain 50 mg of pure compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([O:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)OC(C)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(OC(C)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Yield: 26 %

Procedure:
A solution of ethyl 2-{1-[4-(4-chlorophenyl)-phenyl]-ethoxy}propionate (3.0 g.) in a mixture of ethanol (150 ml.) and water (5 ml.), containing sodium hydroxide (5.0 g.), was heated under reflux for 5 hours. The mixture was then evaporated and the residue diluted with water (50 ml.) and extracted with ether. The ether extract was discarded and the aqueous alkaline phase was acidified to pH 1-3 by addition of concentrated hydrochloric acid. The mixture was extracted thoroughly with ether. The combined extracts were washed with water, dried (MgSO4), and evaporated. The residue was triturated with petrol (40-60) and the solid which formed was separated and recrystallised from toluene to give 2-{1-[4-(4-chlorophenyl)phenyl]ethoxy}propionic acid, m.p. 144°-146° C. in 26% yield.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH2:21][O:22][CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:24][CH2:25][CH2:26][CH3:27])[CH:9]=2)[CH:4]1[C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:1][CH2:2][CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH2:21][O:22][CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:24][CH2:25][CH2:26][CH3:27])[CH:9]=2)[CH:4]1[C:28]1[CH:33]=[CH:32][C:31]2[O:34][CH2:35][O:36][C:30]=2[CH:29]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(CO)C2c1ccc2c(c1)OCO2
Solvent: ClCCl
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCOC)C(COS(C)(=O)=O)C2c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of (1RS,2RS,3RS)-2-hydroxymethyl-3-(4-methoxy-2-methoxymethoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (1.388 g, 2.82 mmol) in methylene chloride (10 ml) with TEA (1.2 ml) stirred under argon at 0° C. was added methanesulfonyl chloride (0.41 g, 3.5mmol). The cooling bath was removed and stirring continued for 1 h. The mixture was partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo to afford the title compound as an oil (1.52 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([NH2:34])[CH:28]=[CH:27]2.CCN(CC)CC.[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43]>CN(C=O)C>[CH2:42]([NH:44][C:45]([NH:34][C:29]1[CH:28]=[CH:27][C:26]2[C:31](=[CH:32][CH:33]=[C:24]([O:23][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH:25]=2)[CH:30]=1)=[O:46])[CH3:43]
Reactant: COc1cc2c(Oc3ccc4cc(N)ccc4c3)ccnc2cc1OCCCN1CCOCC1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc2cc(Oc3ccnc4cc(OCCCN5CCOCC5)c(OC)cc34)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-[6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-quinolyloxy]-2-naphthylamine (prepared similar to that described in Example 1, Step c) (46.0 mg, 0.1 mmol) in anhydrous DMF (5 mL, Aldrich) was added Et3N (50.5 mg, 0.5 mmol, Aldrich) and ethyl isocyanate (35.5 mg, 0.5 mmol, Aldrich) at RT. The reaction was stirred at RT for 16 h, then was quenched with saturated aqueous solution of NaHCO3 (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (FPNH-25S, Biotage, EtOAc) to give the title compound as white solid. MS (ESI, pos. ion) m/z: 531.3 (M+1); 529.3 (M−1). Calc'd for C30H33N4O5−530.25.
Reaction SMILES: Br.O=[C:3]1[CH:12]([CH2:13][C:14]([O:16]C)=O)[CH2:11][CH2:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]1=2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:14](=[O:16])[CH2:13][CH:12]3[C:3]([C:4]4[CH:5]=[CH:6][N:7]=[CH:8][C:9]=4[CH2:10][CH2:11]3)=[N:26]2)=[CH:21][CH:20]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: COC(=O)CC1CCc2cnccc2C1=O
Agent: Br
Product: O=C1CC2CCc3cnccc3C2=NN1c1ccc(Cl)cc1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8-tetrahydro-5-oxoisoquinoline-6-acetate hydrobromide and 4-chlorophenylhydrazine.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[OH:12])=[CH:7][CH:6]=1.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)C>C1C=CC=CC=1>[N:27]1([CH2:26][CH2:25][O:12][CH:11]([C:8]2[CH:9]=[CH:10][C:5]([S:4][CH3:3])=[CH:6][CH:7]=2)[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CSc1ccc(C(O)c2cccc3ccccc23)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CSc1ccc(C(OCCN2CCCCC2)c2cccc3ccccc23)cc1

Procedure:
To a suspension of sodium hydride (0.09 g, 3.84 mmol) in dry benzene (15 ml), (4-methylthiophenyl)-naphth-1-yl-carbinol (0.3 g, 1.07 mmol) was added. The contents were refluxed for 10 minutes and then N-[2-chloroethyl]-piperidine hydrochloride (0.4 g, 2.17 mmol) was added. The reaction mixture was refluxed for 24 hours and neutralized by ethyl alcohol and concentrated. The concentrate was extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate and concentrated to give oil, which was purified by column chromatography on basic alumina by using benzene-hexane as eluent to yield the desired product.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)(=[O:4])=[O:3].[C:19](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[CH3:19][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)c2cc[nH]c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1cc(N(C)S(C)(=O)=O)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.2 %

Procedure:
To a mixture of Methyl 4-[(methylsulfonyl)amino]-1H-indole-6-carboxylate (0.6 g) in THF (10 mL) was added potassium carbonate (0.309 g) and iodomethane (0.63 mL). The mixture was stirred at room temperature for 4 h then heated to 40° C. overnight. Iodomethane (0.3 mL) was added and the mixture heated an additional 3 h. The mixture was cooled to room temperature, partitioned between water and diethyl ether, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in ether and decolorizing carbon (2 g) was added and the mixture refluxed for 5 minutes then filtered through celite while hot. The ether was removed under reduced pressure to give 0.437 g of the title compound: MS (ESI+) for C12H14 N2 O4 SI m/z 321.1 (M+K).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc(F)c1
Product: O=C(Nc1cccc(F)c1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 3-Fluoro-phenylamine to produce 4-Chloro-N-(3-fluoro-phenyl)-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].CO[CH:8](OC)[CH2:9][C:10](=O)[CH3:11].[ClH:15]>>[ClH:15].[CH3:11][C:10]1[N:5]=[C:3]([OH:4])[N+:2]([O-:1])=[CH:8][CH:9]=1
Reactant: NC(=O)NO
Reactant: COC(CC(C)=O)OC
Agent: Cl
Product: Cc1cc[n+]([O-])c(O)n1
Temperature: 2 °C

Procedure:
0.10 mol (7.61 g) hydroxy urea were dissolved in 150 ml of 1 M HCl and 0.11 mol (16.15 g, techn. 90%) of 4,4,-dimethoxy-2-butanone was added dropwise under ice cooling whereby the internal temperature was maintained at 1-3° C. The solution was thawed in an ice bath to room temperature and stirred over night, then filtered and evaporated to dryness. The residue was suspended with 100 ml of acetone, the mixture was cooled to −18° C., the solid filtered off and washed with a little ice-cold acetone. After drying, 10.7 g or crude product were obtained. The crude product was recrystallized with 1750 ml ethanol from the boiling heat, cooled in an ice/ethanol bath, filtered off, washed with a little ethanol and dried (fraction 1). The mother liquor was concentrated on a rotary evaporator until again product started to precipitate, cool stored and a second fraction isolated. After drying, 6.15 g (1. fraction) and 1.86 g (2. fraction) product was obtained. Both fractions were combined and recrystallized from the boiling heat with 230 ml 90% ethanol (10 (D/0 water) similarly. After drying, 3.75 g (3. fraction) and 2.36 g (4. fraction) of the title compound were obtained.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>>[Cl:36][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cccc(Oc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94 %

Procedure:
To a solution of (3-phenoxy-phenyl)-methanol (2.00 g, 10.0 mmol) in carbon tetrachloride (40 mL) was added triphenylphosphine (3.15 g, 12.0 mmol) at room temperature. The reaction solution was stirred under nitrogen atmosphere for 5 hours and 40 minutes under reflux. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (2.05 g, 94%).