Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:24]1([S:30][C:31]2[C:32]3[CH:47]=[C:46]4[C:41]([CH:42]=[CH:43][CH:44]=[CH:45]4)=[CH:40][C:33]=3[S:34][C:35]=2[Si](C)(C)C)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([S:30][C:31]2[C:32]3[CH:47]=[C:46]4[C:41]([CH:42]=[CH:43][CH:44]=[CH:45]4)=[CH:40][C:33]=3[S:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[Si](C)(C)c1sc2cc3ccccc3cc2c1Sc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(Sc2csc3cc4ccccc4cc23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At −40° C., a THF solution (5 ml, 5 mmol) of 1 M tetra-n-butyl ammonium fluoride was added to THF (50 ml) and water (0.3 ml) of 3-(phenylsulfenyl)-2-trimethylsilylnaphtho[2,3-b]thiophene (550 mg, 1.5 mmol). After the mixture was stirred for 4 hours at room temperature, the reaction liquid was poured into water (50 ml). The precipitated solid was filtered and washed with ethanol and hexane. Purification was implemented by column chromatography (silica gel, CHCl3, Rf: 0.9), so that a white solid was quantitatively produced.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[C:10]([C:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=3)[CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[C:32]1([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:45]([CH3:44])(=[O:47])=[O:46])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[NH:14][C:15]([C:17]2[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=[C:20]([C:22]#[N:23])[N:21]=2)=[O:16])[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(N)cc2)cc1C1=CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4′-amino-3-cyclohex-1-enyl-biphenyl-4-yl)-amide (as prepared in the Example 28, step (a), 28.1 mg, 0.0547 mmol) in 0.5 mL of DCM was added pyridine (113 μL, 0.16 mmol) followed by methanesulfonyl chloride (5.1 μL, 0.066 mmol). After stirring at RT for 16 h under Ar, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2-4% EtOAc/DCM) to afford 31 mg (95%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.79 (s, 1H), 8.42 (d, 1H, J=8.6 Hz), 7.79 (s, 1H), 7.58 (d, 2H, J=8.6 Hz), 7.48 (dd, 1H, J=8.6, 2.3 Hz), 7.37 (s, 1H), 7.29 (d, 2H, J=8.6 Hz), 6.64 (s, 1H), 5.97 (s, 2H), 5.91 (m, 1H), 3.68 (t, 2H, J=8.2 Hz), 3.05 (s, 3H), 2.24-2.38 (m, 4H), 1.75-1.93 (m, 4H), 0.99 (t, 2H, J=8.2 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C30H37N5O4SSi, 592.2 (M+H), found 591.6.
Reaction SMILES: [CH2:1]([C:3]([OH:33])([CH2:31][CH3:32])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[O:12][CH2:13][C:14]1[CH:15]=[C:16]([C:24](OC)=[O:25])[C:17](=[CH:22][CH:23]=1)[C:18](OC)=[O:19])\[CH3:8])[CH3:2].[BH4-].[Li+]>>[OH:25][CH2:24][C:16]1[CH:15]=[C:14]([CH:23]=[CH:22][C:17]=1[CH2:18][OH:19])[CH2:13][O:12][C:11]1[CH:10]=[C:9](/[C:7](/[CH3:8])=[CH:6]/[CH:5]=[CH:4]/[C:3]([CH2:31][CH3:32])([OH:33])[CH2:1][CH3:2])[CH:30]=[CH:29][CH:28]=1
Reactant: CCC(O)(/C=C/C=C(\C)c1cccc(OCc2ccc(C(=O)OC)c(C(=O)OC)c2)c1)CC
Agent: [BH4-]
Agent: [Li+]
Product: CCC(O)(/C=C/C=C(\C)c1cccc(OCc2ccc(CO)c(CO)c2)c1)CC

Procedure:
In a manner similar to Example 53(e), by reacting 150 mg (0.34 mmol) of dimethyl 4-[3-((1E,3E)-5-ethyl-5-hydroxy-1-methylhepta-1,3-dienyl)phenoxymethyl]phthalate with 30 mg (1.35 mmol) of lithium borohydride, a colourless oil is obtained (m=56 mg; Y=42%).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][OH:6].[O:7]1[CH2:12][CH2:11][O:10]CC1>O.Cl>[O:6]=[CH:5][C@H:12]([C@H:11]([C@H:12]([CH2:11][OH:10])[OH:7])[OH:10])[OH:7]
Reactant: CO
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 40 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
1-O-benzoyl-2,3-O-isopropylidene-L-ribonofuranoate (10 g) prepared in Example 6 was dissolved in a solvent mixture of methanol (30 ml) and 1.0N aqueous sodium-hydroxide solution (10 ml) and then reacted for about 3 hours. After TLC revealed the completion of reaction, the reaction solution was distilled under reduced pressure, water (10 ml) was added, and the reaction mixture was extracted two to three times with ethyl acetate. The extract was dried over magnesium sulfate and distilled under reduced pressure to give 2,3-isopropylidene-L-ribose (6.0 g). The compound thus obtained was dissolved in a solvent mixture of dioxane (12 ml) and water (12 ml), 1.0N hydrochloric acid solution (200 μl) was added, and then reaction was carried out for about 24 hours while maintaining the temperature of the reaction vessel of 40° C. After TLC revealed the completion of reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in water (30 ml) and washed with ethyl acetate. Water was removed by distillation under reduced pressure to give a compound in the form of an oil. The compound thus obtained was purified by silica gel column chromatography (eluent: chloroform/methanol=4/1, v/v) to give the title compound (4.1 g, Yield 80%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=[O:6])[CH3:5]>O1CCOCC1>[CH2:1]([NH:3][S:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4](=[O:6])[CH3:5])=[CH:13][CH:12]=1)(=[O:16])=[O:15])[CH3:2]
Reactant: CCN
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Product: CCNS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Ethylamine (0.0114 mMol) is added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is stirred for 1 hour at 0° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a white solid in 48% yield and used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:18]2[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:17]2=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:18]2[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:17]2=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1nc1n2CCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1nc1n2CCC1
Yield: 45.6 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.410 g) was added to a solution of methyl 6-amino-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylate (Intermediate 55, 0.290 g) in pyridine (10 mL) and DCM (10 mL) and the resultant mixture was stirred at room temperature for 24 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-15% to give a sandy coloured solid which was triturated with ether and filtered to give methyl 6-(2-bromo-4-fluorobenzenesulfonylamino)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-5-carboxylate (0.268 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([OH:34])[CH2:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:13]1[CH:14]=[N:15][C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([S:2][CH3:1])[CH:4]=2)=[C:8]([CH:12]=1)[C:9]([NH:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([OH:34])[CH2:29]1)=[O:11]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@@H]1CCC[C@@H](O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCC[C@@H](O)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.6 %

Procedure:
2-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acid (345 mg, 1.26 mmol) was dissolved in dimethylformamide (10 ml) and triethylamine (865 μl, 11.8 mmol) was added followed by (1R,3R)-3-aminocyclohexanol hydroformate (200 mg, 1.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (715 mg, 3.73 mmol) and 1-hydroxybenzotriazole (185 mg, 1.37 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between 10% aq. citric acid solution (50 ml) and diethyl ether (50 ml). The organic was washed with sat. sodium bicarbonate solution (50 ml), water (25 ml) and brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (10:90 to 70:30) as eluant to give 5-fluoro-N-[(1R,3R)-3-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (171 mg) as a colourless gum.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][N:36]([CH3:42])[C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][C@@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and (R)—N,N-dimethylpyrrolidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (m, 1H), 7.85 (1H), 7.48 (m, 2H), 6.69 (1H), 4.66 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.22 (s, 6H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H). m/z: 467 [M+H]
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:15][CH2:16]1)[C:10]([O:12][CH3:17])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a mixture of (S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (CAN 89483-06-7, 6.792 g, 30 mmol) and K2CO3 (8.173 g, 59 mmol) in DMF (100 mL) was added MeI (10.37 g, 73 mmol). The reaction mixture was stirred overnight at room temperature. After filtration, the filtrate was concentrated to give the title compound as yellow oil (6.44 g, 89%); MS (EI): m/e=266.2 [M+Na]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:28]3[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cn1ccnc1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3nccn3C)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 1-methylimidazole
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH2:15]([OH:19])[CH2:16]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)CO>[Br:1][CH2:2][C:3]1([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[O:19][CH2:15][CH2:16][O:4]1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Product: BrCC1(c2ccc3ccccc3c2)OCCO1
Reaction time: 8 h

Procedure:
To a stirred solution of 74.4 parts of 2-bromo-1-(2-naphthalenyl)-1-ethanone in 240 parts of a butanol are added successively 3 parts of 4-methylbenzenesulfonic acid and 270 parts of benzene. Then there are added dropwise 28 parts of 1,2-ethanediol. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated. The residue is dissolved in 2,2'-oxybispropane and the solution is stirred with a diluted sodium hydroxide solution. The layers are separated and the aqueous phase is extracted with 2,2'-oxybispropane. The extra ct is neutralized with water, dried, filtered and evaporated. The oily residue is crystallized from methanol. The product is filtered off and recrystallized from methanol, yielding 41 parts of 2-(bromomethyl)-2-(2-naphthalenyl)-1,3-dioxolane; mp. 64° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1([CH3:21])[CH2:12][CH2:11][CH2:10][C:9]2[N:8]=[C:7]([O:13]CC3C=CC=CC=3)[CH:6]=[CH:5][C:4]1=2.[ClH:22].[H][H]>C(O)C.CC(O)C.[Pd]>[ClH:22].[CH3:21][C:3]1([NH:2][CH3:1])[CH2:12][CH2:11][CH2:10][C:9]2[NH:8][C:7](=[O:13])[CH:6]=[CH:5][C:4]1=2
Reactant: [H][H]
Reactant: CNC1(C)CCCc2nc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: CNC1(C)CCCc2[nH]c(=O)ccc21
Yield: 25 %

Procedure:
5,6,7,8-Tetrahydro-N,5-dimethyl-2-(phenylmethoxy)-5-quinolinamine (6.3 g) in ethanol (500 ml) was acidified to ca pH2 with a solution of hydrochloric acid in 2-propanol. 10% Palladium-on-carbon (315 mg) was added and the mixture was shaken on Parr hydrogenation apparatus, starting at 55 psi of hydrogen, until hydrogen uptake ceased. The catalyst was collected and the filtrate was neutralized with 4-polyvinylpyridine. The solution was concentrated in vacuo to a volume of about 75 ml and diethyl ether was added. The precipitate was collected and recrystallized first from methanol and then from water/2-propanol to afford 1.3 g (25%) of product, mp 190°-195° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11](C1NC=CN=1)(C1NC=CN=1)=[S:12]>C(OCC)(=O)C>[N:8]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:11]=[S:12]
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN=C=S)cc1
Yield: 153.3 %

Procedure:
To a stirred solution of 0.50 g (3.64 mmols) of the 4-methoxy-benzylamine (M) in 10 mL of ethyl acetate, was added 0.65 g (3.64 mmols) of thiocarbonyl diimidazole (N) portion wise. The resultant mixture was stirred at 50° C. for 10 min. then concentrated. The crude product was then dissolved in 15 mL of dichloromethane and passed through a short pad of silica gel using additional 50 mL of dichloromethane as eluent. Concentration of the filtrate afforded 1.0 g (87%) of (O) as white solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([NH2:26])([C:23](=[O:25])[NH2:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:27](Cl)(Cl)=[S:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C:20]2([NH:26][C:27](=[S:28])[NH:24][C:23]2=[O:25])[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Reactant: S=C(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=S)NC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
N,N-Diisopropylethylamine (1.67 ml, 9.84 mmol) was added to a solution of 4-amino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.1 mmol) in THF (10 ml) at 0° C., and thiophosgene (0.376 ml, 4.9 mmol) was further added dropwise slowly. The reaction solution was warmed to room temperature and stirred overnight. A 10% aqueous citric acid solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off. The residue was purified by silica gel column chromatography to give 4-oxo-2-thioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (944 mg, 81%).
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH2:22][CH2:23][CH2:24][CH2:25][NH2:26].[H-].[Na+]>>[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:12]1[CH:13]=[C:14]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3
Reactant: NCCCN
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Product: NCCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (118.8 mg, 0.3 mmol) in 1,3-diaminopropane (Aldrich, 3 mL, 35.6 mmol) was added NaH (Aldrich, 90%, 53 mg, 6.6 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated to 120° C. for 2.5 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(3-amino-propylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one (Yield 25.3 mg, 26.0%) as the free base which was further purified by RP-HPLC (C-18, eluted with 1% acetonitrile/0.05% acetic acid in H2O) to afford 5-(3-amino-propylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one acetic acid salt.
Reaction SMILES: [O:1]1C=CC=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]([F:20])([F:19])[F:18])[CH:7]=1.[O-:21][Mn](=O)(=O)=O.[K+].C(O)(C)C>CC(C)=O>[C:11]1([N:10]2[C:6]([C:2]([OH:1])=[O:21])=[CH:7][C:8]([C:17]([F:20])([F:19])[F:18])=[N:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2)n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Intermediate 6 (2.84 g, 10.2 mmol) was dissolved in acetone (120 ml) and KMnO4 (11.2 gms, 71.45 mmol in 135 ml water) solution was added to it. This mixture was heated at 60° C. for 3 h and then cooled to rt. Then isopropyl alcohol was added to the reaction mixture and stirred at rt overnight. The reaction mixture filtered through celite and filtrate was evaporated on high vacuum. The residue was dissolved in 1N NaOH and washed with petether. Aqueous layer was acidified with 2N HCl solution to obtain the solid. Solid was filtered and dried on high vacuum to obtain the title compound (2.3 g) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.57-7.42 (m, 5H), 7.30 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])[CH2:35][CH2:34]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Fc1ccccc1N1CCNCC1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 81 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][O:8][C@H:9]1[O:13][C@@H:12]([N:14]2[CH:21]=[CH:20][C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH:11]=[CH:10]1)([O:5][CH3:6])=[O:4].[Cl:22]N1C(=O)CCC1=O>N1C=CC=CC=1>[CH3:6][O:5][P:3]([CH2:7][O:8][C@H:9]1[O:13][C@@H:12]([N:14]2[CH:21]=[C:20]([Cl:22])[C:18](=[O:19])[NH:17][C:15]2=[O:16])[CH:11]=[CH:10]1)([O:2][CH3:1])=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COP(=O)(CO[C@@H]1C=C[C@H](n2ccc(=O)[nH]c2=O)O1)OC
Solvent: c1ccncc1
Product: COP(=O)(CO[C@@H]1C=C[C@H](n2cc(Cl)c(=O)[nH]c2=O)O1)OC
Yield: 85.1 %

Procedure:
To a solution of the product of Example 57 (400 mg, 1.3 mmol) in pyridine (15 mL) was added N-chlorosuccinimide (200 mg, 1.5 mmol) and the solution was heated at 90°-95° C. for 30 min under nitrogen. All volatiles were removed in vacuo and the oily residue was chromatographed on silica gel using CH2Cl2 /3% MeOH as eluent to give the product (390 mg, 87%) as a colorless oil:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[N:27]=[CH:26][C:25]([CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][C:25]([CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30])=[CH:26][N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OC(c1ccc(Cl)nc1)C(F)(F)F
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(C(O)C(F)(F)F)cn3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.51 mmol) and 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (108 mg, 0.51 mmol) as starting materials.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH:24]=[CH2:25].[OH-].[K+]>CN1C(=O)CCC1>[F:27][C:17]([F:16])([F:26])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH2:24][CH2:25][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: C=Cc1cnccc1C(F)(F)F
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnccc2C(F)(F)F)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.