Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH2:5]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+:24]([O-])([OH:26])=[O:25]>O>[N+:24]([C:21]1[CH:22]=[C:17]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:18]=[CH:19][C:20]=1[OH:23])([O-:26])=[O:25]
Reactant: CCCCCCCCCCCCc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 310 g of acetic acid and 262 g (1 mole) of 4-dodecyl phenol maintained at 20° C. is slowly added with stirring 76 ml (1.2 moles) of HNO3 in 40 ml of water. After 30 minutes, ice water (800 ml) is added to the reaction vessel and the resulting mixture is extracted with methylene chloride. The methylene chloride phase is withdrawn and washed successively with water, an aqueous solution of NaHCO3 (5 percent) and water. The methylene chloride is then removed under vacuum to obtain the desired 2-nitro-4-dodecylphenol. A solution of 46 g (0.15 mole) of the nitrated phenol, 550 ml of absolute ethanol and 1.2 g of platinum oxide is maintained at 20° C. under 50 psi of hydrogen for 23 hours. The reaction mixture is filtered and then subjected to vacuum to remove solvent. Essentially quantitative yield of the desired 2-amino-4-dodecylphenol is recovered. A solution of 200 ml of acetone, 200 ml of water and 38.8 g (0.14 mole) of the amino phenol is stirred with 200 ml of a carbonate form (CO3=) quaternary ammonium styrene/divinyl benzene, ion exchange resin sold by The Dow Chemical Company under the trade name, Dowex® SBR, forty-nine ml (0.787 mole) of methyl iodide is added to the aforementioned solution through a dry ice condenser. After refluxing the reaction mixture with stirring for 20 hours, the mixture is filtered and excess methyl iodide is removed under vacuum. The resulting solution is contacted with the hydroxide form of the aforementioned ion exchange resin to provide the desired quaternary ammonium zwitterion.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][CH2:9][C@H:10]2[CH2:14][O:13]C(C)(C)[O:11]2)=[CH:5][CH:4]=1.Cl.C(=O)([O-])O.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][C@H:10]([OH:11])[CH2:14][OH:13])=[CH:17][CH:18]=1
Reactant: COc1ccc(COC[C@H]2COC(C)(C)O2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(COC[C@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
The crude product of (S)-(+)-4-(4-methoxybenzyloxymethyl)-2,2-dimethyl-1,3-dioxolane (4.1 g) was dissolved in methanol (10 mL), added with 1 N hydrochloric acid and stirred at room temperature for one day. The reaction solution was adjusted to pH 6 by addition of saturated aqueous sodium hydrogencarbonate and extracted four times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography to obtain (R)-(+)-3-(4-methoxybenzyloxy)-1,2-propanediol (2.4 g, yield: 69%).
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16].C(N(C(C)C)CC)(C)C>C(O)CCC>[Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH3:20])=[C:13]([OH:12])[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ncnc2[nH]c(Br)cc12
Reactant: Cc1ccc(N)cc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(Nc2ncnc3[nH]c(Br)cc23)cc1O
Temperature: 120 °C
Yield: 70.3 %

Procedure:
6-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.41 mmol), prepared as in reference 1, is mixed with 3-hydroxy-4-methylaniline (150 mg, 1.22 mmol) and diisopropylethylamine (213 μL, 1.22 mmol) in n-butanol (1.3 mL). The mixture is heated to 120° C. for 18 hours, with stirring. The reaction is then cooled to ambient temperature and the solvent is removed. The resultant crude product is purified by flash column chromatography using a gradient of 3-5% MeOH in DCM to yield 5-(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methyl-phenol (92 mg; 70%).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[C:6]([CH:19]=[O:20])=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[C:4]([C:5]1[C:6]([CH:19]=[O:20])=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:15])([CH3:16])[C:13]=2[CH:14]=1)#[CH:3]
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 7.21 g (23.1 mmol) of 3-(2-trimethylsilyl-ethynyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde in 150 mL of methanol was added 6.38 g (46.2 mmol) of potassium carbonate. After 1 hour, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product was purified by flash chromatography on silica gel (3% ethyl acetate/hexane) to afford 4.04 g (73%) of 3-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p.=94.0-94.6° C.).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:37]=[CH:36][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]([NH:31][CH2:32][C@H:33](O)[CH3:34])=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:38])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[N:1]1([C:5]([C:7]2[CH:37]=[CH:36][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29]5[O:30][C@@H:33]([CH3:34])[CH2:32][N:31]=5)=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:38])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-N-[(2R)-2-hydroxypropyl]-1H-pyrrole-2-carboxamide (464 mg, 0.883 mmol) synthesized in Example (69a) was dissolved in tetrahydrofuran (17 mL), and anhydrous methanesulfonic acid (558 mg, 3.20 mmol) and triethylamine (860 μL, 6.20 mmol) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. To the reaction solution, saturated aqueous sodium hydrogencarbonate solution was added, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=3%-9%) to afford the desired compound (228 mg, yield 51%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:35][CH:34]=[CH:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:39](O)[CH3:40].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]([O:21][CH2:39][CH3:40])=[O:20])[CH:17]=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:32][CH:33]=[CH:34][CH2:35]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccc2c(c1)CN(C(=O)c1ccc(Cl)cc1)CC(=O)N2Cc1ccc(C(=O)N2CC=CC2)cc1
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CN(C(=O)c1ccc(Cl)cc1)CC(=O)N2Cc1ccc(C(=O)N2CC=CC2)cc1
Reaction time: 8 h

Procedure:
10 mg (0.019 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepine-7-carboxylic acid was dissolved in 2 ml of dichloromethane. 0.022 ml (0.38 mmol) of ethanol, 4 mg (0.023 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.005 ml (0.038 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[Cl:34][C:30]1[CH:29]=[C:28]([C:7]2[N:8]=[C:9]([N:11]3[C:15]4[CH:16]=[C:17]([CH2:20][N:21]5[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]5)[CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[S:10][C:6]=2[C:4]([OH:5])=[O:3])[CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(CN4CCN(C)CC4)cc32)nc1-c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(=O)O)s4)c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 0.250 g (0.5 mmole) of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid ethyl ester (I.2d) in 10 mL of tetrahydrofuran and 10 mL of water was added 0.12 g (5 mmole) of lithium hydroxide. The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure, 40 mL of water was added and the pH adjusted to 6-7 by the addition of 1M hydrochloric acid. The precipitate was collected by filtration to give 0.145 g of 4-(3-chloro-phenyl)-2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-thiazole-5 carboxylic acid (I.2f) as a white solid.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH:7]([CH3:9])[CH3:8])=[N:4][C:3]=1[CH3:10].C(C1C[CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]C1)=O>>[I:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:9][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:8]2)=[N:4][C:3]=1[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Cc1nc(C(C)C)[nH]c1I
Product: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 159.2, except tert-butyl 4-formylpiperidine-1-carboxylate was used in place of isobutyraldehyde. m/z (ES+) 392 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])[NH2:34].O1CCOCC1>O>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([N:8]=[CH:9][N:10]=4)[C:2]([C:39]4[CH:40]=[CH:41][C:36]([C:33]([NH2:34])=[O:35])=[CH:37][CH:38]=4)=[CH:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1)[CH2:25][CH3:26]
Reactant: CCCN1CCN(c2ccc(Nc3ccc(Cl)n4ncnc34)cc2)CC1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCN1CCN(c2ccc(Nc3ccc(-c4ccc(C(N)=O)cc4)n4ncnc34)cc2)CC1
Temperature: 107.5 °C
Yield: 42.2 %

Procedure:
To a reaction vial (40 mL), is added 5-chloro-N-(4-(4-propylpiperazin-1-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (55 mg, 0.15 mmol), potassium carbonate (104 mg, 0.75 mmol, 5 eq.), 4-carbamoylphenylboronic acid (50 mg, 0.30 mmol, 2 eq), PddppfCl2 (20 mg, 15%), dioxane (4.0 mL) and water (1.0 mL). The reaction mixture is degassed and filled with argon. The reaction is heated at 105-110° C. for 20 h. After cooling to rt, ethyl acetate (10 mL) is added to each reaction vial. The organic phase was filtered through a pat of celite and then is evaporated to give a dry residue that was purified by preparatory HPLC to give the title compound, 28.9 mg, yield 42.2%; LCMS-ESI (m/z): calcd for C26H29N7O, 455; [M+H]+ found, 456.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:9]=[CH:10][C:11]2[CH:17]=[C:16]([C:18]3[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=3[Cl:29])[C:15](=[O:30])[N:14]([CH2:31][CH3:32])[C:12]=2[N:13]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:45])[CH:43]=[CH2:44]>ClCCl>[Cl:24][C:23]1[C:22]([O:25][CH3:26])=[CH:21][C:20]([O:27][CH3:28])=[C:19]([Cl:29])[C:18]=1[C:16]1[C:15](=[O:30])[N:14]([CH2:31][CH3:32])[C:12]2[N:13]=[C:8]([NH:7][C@@H:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[NH:1][C:42](=[O:45])[CH:43]=[CH2:44])[N:9]=[CH:10][C:11]=2[CH:17]=1
Reactant: C=CC(=O)Cl
Reactant: CCn1c(=O)c(-c2c(Cl)c(OC)cc(OC)c2Cl)cc2cnc(N[C@@H]3CCC[C@@H]3N)nc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)c(=O)n(CC)c2n1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 2-(((1R,2S)-2-aminocyclopentyl)amino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one (0.105 mmol) in dichloromethane (2.1 mL) at −20° C. was added DIEA (0.018 mL, 0.105 mmol) and acryloyl chloride (0.008 mL, 0.105 mmol) and the reaction was stirred for 1 h. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)cyclopentyl)acrylamide (36 mg, 65%). MS (ES+) C25H27Cl2N5O4 requires: 531, found: 532.
Reaction SMILES: [Br-].[CH3:2]C(C)([O-])C.[K+].[C:8]([O:12][C:13]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>C1COCC1>[C:8]([O:12][C:13]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:2])=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)Oc1ccc(C=O)cc1
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A suspension of 34.1 g of methylriphenylphosphonium bromide in 400 mL of dry THF was treated with 10.7 g of potassium t-butoxide under a nitrogen atmosphere. After stirring for 10 min at room temperature, the yellow solution was treated with a solution of 21.2 g of p-t-butoxycarbonyloxybenzaldehyde in 100 mL of dry THF. After stirring for one hour, the mixture was poured into cold water and extracted with ethyl acetate. The organic phase was washed, dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC to yield 16.6 g (79%) of pure p-t-butoxycarbonyloxystyrene. Alternately, IIIc was purified by distillation under reduced pressure.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][C:15]3[O:18][C:19]([Br:21])=[CH:20][C:14]=3[C:13]2=[O:22])=[CH:8][C:7]=1[CH3:23]>CC(O)=O.O>[Br:21][C:19]1[O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:8]=[C:7]4[C:6](=[CH:11][CH:10]=3)[NH:5][N:1]=[CH:23]4)[C:13](=[O:22])[C:14]=2[CH:20]=1
Reactant: Cc1cc(-n2ccc3oc(Br)cc3c2=O)ccc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2cc(Br)oc2ccn1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.8 %

Procedure:
NaNO2 (174 mg, 2.52 mmol) was added to a solution of crude 5-(4-amino-3-methylphenyl)-2-bromofuro[3,2-c]pyridin-4(5H)-one (800 mg, 2.52 mmol) in 5:1 AcOH/H2O (24 mL) and the resulting solution was stirred at 25° C. for 14 h. The solution was concentrated under reduced pressure. Flash chromatography on silica gel (49:1 CH2Cl2/MeOH) afforded the title compound (373 mg, 44%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 13.30-13.25 (br s, 1H, NH), 8.16 (s, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.35 (dd, J=8.7, 1.8 Hz, 1H), 7.19 (d, J=0.6 Hz, 1H), 6.85 (dd, J=7.5, 0.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[CH:25]=3)=[CH:22][C:15]=2[N:14]=1.C=O.[C:43](O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][CH:34]4[CH2:35][CH2:36][N:37]([CH3:43])[CH2:38][CH2:39]4)[CH:25]=3)=[CH:22][C:15]=2[N:14]=1
Reactant: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)CCC4CCNCC4)c3)ccc21
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(CCC(=O)Nc2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-piperidin-4-ylpropanamide (1 eq) in methanol was added formalin (2 eq) and acetic acid(5%) followed by sodium cyanoborohydride (2 eq) and the resulting mixture was stirred at ambient temperature for 3 h. LC/MS showed formation of the product. The crude mixture was then concentrated and to it was added sodium bicarbonate and the resulting mixture was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and purified by preparative chromatography to yield N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}-3-(1-methylpiperidin-4-yl)propanamide. MS: MH+=571.6.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:15][C:45](=[O:46])[C:44]([S:43][CH2:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:48]([OH:49])[CH:14]=2)[CH:8]=1
Reactant: CC(=O)c1cccc(-c2ccccc2)c1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1oc(-c2cccc(-c3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-phenylacetophenone (2.00 g, 10.21 mmol), trimethylsilyltriflate (2.36 mL, 12.24 mmol), triethylamine (2.84 mL, 20.40 mmol), methylene chloride (26 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 93°-94° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.79 (t, 2 H), 3.01 (t, 2 H), 6.92 (s, 1 H), 7.21 (m, 5 H), 7.42 (t, 1 H), 7.52 (t, 2 H), 7.64 (t, 1 H), 7.75 (d, 2 H), 7.82 (t, 2 H), 8.02 (s, 1 H).
Reaction SMILES: [C:1]1(=O)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[NH3:15].[ClH:16]>C(OCC)C>[ClH:16].[C:1]1(=[NH:15])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: N
Agent: Cl
Solvent: CCOCC
Product: N=C1C=CC=C2C1=Cc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
The fluorenone (4.0 g, 22.2 mmol) was stirred in an autoclave of 110° C. for three days in an ammonia atmosphere (7 to 8 atm). After the reaction, it was allowed to dissolve in diethyl ether. And, hydrogen chloride was blown into it. It was stirred for one hour at room temperature. The obtained suspension was filtered, and the filtrate was cleaned with the diethyl ether. With this, fluorenone imine hydrochloride (3.4 g, 71%) was obtained. This hydrochloride was allowed to decompose with an ammonia aqueous solution. And, it was recrystallized by using the methylene chloride and hexane. And, Fluoren-9-ylideneamine (2.3 g, 58%) was obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH3:23][C:24]1[CH:41]=[CH:40][CH:39]=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:27]>C(Cl)Cl>[CH3:23][C:24]1[CH:41]=[CH:40][CH:39]=[CH:38][C:25]=1[C:26]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:7]2[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:34])=[CH:31][CH:30]=1)=[O:27]
Reactant: O=C1c2ccccc2NCc2cccn21
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3C(=O)c3ccccc32)cc1
Reaction time: 6 h

Procedure:
To a stirred solution of 107 mg of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one in 3 ml of methylene chloride containing 0.084 ml of triethylamine is added 165 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride and stirring continued for 6 hours. The volatiles are removed in vacuo to a residue which is purified on thick layer chromatography plates with 7:3 hexane-ethyl acetate to afford the desired product as a foam.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NS(=O)(=O)c1cc2ccccc2o1
Product: Cc1ccc(NC(=O)NS(=O)(=O)c2cc3ccccc3o2)cc1
Yield: 63.7 %

Procedure:
2-Benzofuransulfonamide (7.6 mmol), prepared as described in Example 2, was reacted with 4-methylphenylisocyanate (7.6 mmol) as described in Example 2 to obtain 1.6 g of the title product as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH:8]([CH:10]([C:12]([OH:14])=[O:13])[OH:11])[OH:9].C(N(CC)CC)C.[C:23](#[N:26])[CH:24]=[CH2:25]>O>[C:23]([CH2:24][CH2:25][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH:8]([CH:10]([C:12]([OH:14])=[O:13])[OH:11])[OH:9])#[N:26]
Reactant: NCCCCNC(=O)C(O)C(O)C(=O)O
Reactant: C=CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: N#CCCNCCCCNC(=O)C(O)C(O)C(=O)O

Procedure:
2.01 Grams (9.127 mmoles) of N-(4-aminobutyl)tartaric acid monoamide (IX) obtained in 1. was dissolved in 40 ml of water, and after adding 1.273 ml of triethylamine and then 0.726 ml of acrylonitrile, the resulting mixture was stirred for 27 hours at room temperature. The reaction solution was then dried to solid under reduced pressure. After adding 20 ml of water to the residual solid, the resulting solution was passed through a column packed with 300 ml of Dowex® 1×4(OH-), and after washing with 1.2 liters of water, eluted with 0.5N aqueous acetic acid solution. The fractions containing the objective compound were collected and concentrated under reduced pressure to obtain 2.235 g of a syrup-form N-[4-(2-cyanoethyl)aminobutyl]tartaric acid monoamide (XI) (yield, 89.6%).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]2[CH2:17][O:16][C:15](=[O:18])[O:14]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.[CH3:32][O+](C)C>>[O:18]=[C:15]1[O:14][CH:13]([CH:12]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:11][CH2:10][CH2:9][CH:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([O:1][CH3:32])=[N:8]2)[CH2:17][O:16]1
Reactant: CC(C)(C)OC(=O)NC(CCCC1CCCCC(=O)N1)C1COC(=O)O1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=NC(CCCC(NC(=O)OC(C)(C)C)C2COC(=O)O2)CCCC1

Procedure:
The product of EXAMPLE 270 is reacted with trimethyloxonium tetrafluoroborate by the method of EXAMPLE 26 to produce the title material.