Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P([CH:7]([CH:13]([CH3:15])C)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(CC)=O)C.[H-].[Na+].C([O:25][C:26]1[CH:33]=[CH:32]C(C=O)=[CH:28][CH:27]=1)C1C=CC=CC=1>O1CCCC1.CN(C)C=O.O>[OH:25][C:26]1[CH:27]=[CH:28][C:15]([CH2:13][CH:7]([O:25][CH:26]([CH3:33])[CH3:27])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(C(C)C)P(=O)(CC)CC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(O)cc1)OC(C)C
Reaction time: 0.33 h
Yield: 151.4 %

Procedure:
5.2 g of Ethyl 2-(diethylphosphoryl)-2-isopropylacetate was dissolved in 40 ml of tetrahydrofuran, and 0.53 g of 60% sodium hydride was added under ice-cooling, and the mixture was stirred for 20 minutes under ice-cooling. The reaction solution was treated with a solution of 3.0 g of 4-benzyloxybenzaldehyde in 15 ml of tetrahydrofuran and 10 ml of N,N-dimethylformamide, and stirred at room temperature for 16 hours. The reaction solution was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography, and the fraction eluting with 5% ethyl acetate-hexane was concentrated. The residue was dissolved in 40 ml of ethanol, and 0.4g of 10% palladium carbon was added, the atmosphere was replaced with hydrogen, and the mixture was stirred at room temperature for 5 hours. Then, the atmosphere was replaced with nitrogen, the catalyst was filtered off, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (20% ethyl acetate-hexane), to give 2.7 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=O)=[CH:6][C:5]=1[CH3:18].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:17]=[CH:16][C:7]([C:8](=[S:29])[NH:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]=1[CH3:18]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1ccc(C(=O)NC[Si](C)(C)C)cc1C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=S)NC[Si](C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 2-methyl-N-trimethylsilanylmethyl-terephthalamic acid methyl ester (Example I7) (1.83 g) in toluene (50 ml) was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson reagent) (2.65 g). The reaction mixture was stirred at ambient temperature for 30 minutes and then at 110° C. for 1.5 hours. The reaction mixture was concentrated and the residue purified by chromatography on silica gel (eluent: ethyl acetate/heptanes 1:5) to give 2-methyl-4-(trimethylsilanylmethyl-thiocarbamoyl)-benzoic acid methyl ester (1.85 g). 1H-NMR (400 MHz, CDCl3): 7.75-7.20 (m, 3H), 3.70 (s, 3H), 3.35 (m, 2H), 2.45 (s, 3H), 0.00 (s, 9H) ppm.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:35]=[CH:34][CH:33]=[CH:32][C:4]=1[O:5][C:6]1[C:20]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[CH:19][C:9]2[NH:10][C:11]([C:13]3[CH:18]=C[CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1.COC(C1C=NC=CN=1)=[NH:41]>>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:35]=[CH:34][CH:33]=[CH:32][C:4]=1[O:5][C:6]1[C:20]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[CH:19][C:9]2[NH:10][C:11]([C:13]3[CH:18]=[N:41][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2C(F)(F)F)cn1
Reactant: COC(=N)c1cnccn1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2C(F)(F)F)cn1

Procedure:
The entitled compound was obtained as a yellow solid in the same method as in Example 205 or in accordance with the method or by combining it with an ordinary method but using 4-(2-trifluoromethyl-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 206, and methylpyrazin-2-imidate.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl[C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl:26])[C:15]=1[C:16]([OH:18])=[O:17].[OH-].[Na+].C(Cl)(Cl)Cl>CN(C)C1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:10][C:14]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl:26])[C:15]=2[C:16]([OH:18])=[O:17])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CCCCOc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCOc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1

Procedure:
A solution of 25 g of p-butoxyaniline and 17.85 g of 2,6-dichloro-3-nitrobenzoic acid in 50 ml of N,N-dimethylaniline was heated under nitrogen at 100° for 18 hours. The reaction mixture was treated with 500 ml of 0.2N sodium hydroxide and 500 ml of chloroform. The aqueous layer was washed with additional chloroform and acidified to provide 2-[(4-butoxyphenyl)amino]-6-chloro-3-nitrobenzoic acid, mp 166°-169° C.
Reaction SMILES: [Na].[Cl:2][C:3]([Cl:8])([Cl:7])[C:4]([NH2:6])=[NH:5].[C:9]([CH2:11][C:12](OCC)=[O:13])#[N:10].O>CO.C(O)(=O)C>[NH2:10][C:9]1[N:6]=[C:4]([C:3]([Cl:8])([Cl:7])[Cl:2])[N:5]=[C:12]([OH:13])[CH:11]=1
Reactant: CCOC(=O)CC#N
Reactant: N=C(N)C(Cl)(Cl)Cl
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(O)nc(C(Cl)(Cl)Cl)n1
Yield: 71 %

Procedure:
To a solution of 5.8 g (0.025 g atom) sodium in 150 ml methanol at 15° C. was added 11.5 g (0.1 mole) trichloroacetamidine. To this was added 11.5 g (0.1 mole) ethyl cyanoacetate in 100 ml methanol. The solution was refluxed 1 hour and then the solvent was removed under rotary evaporation to give a red paste. This was dissolved in 20 ml warm water and 100 ml of 50% aqueous acetic acid was added, causing product to precipitate. Filtration, washing, and drying of the product gave 16.1 g (71% yield; mp 225°-230° C. (decomposed). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:14][S:15]([N:18]1[CH2:23][CH2:22][CH:21](OS(C)(=O)=O)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C(O)C.CO>[CH3:14][S:15]([N:18]1[CH2:23][CH2:22][CH:21]([S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)OC1CCN(S(C)(=O)=O)CC1
Reactant: Sc1cccc2nccn12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CS(=O)(=O)N1CCC(Sc2cccc3nccn23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (1.50 g, 10 mmoles) in ethanol (100 ml) was added a solution of 4.1M sodium methylate (2.44 ml, 10 mmoles) in methanol and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 1-methylsulfonyl-4-methylsulfonyloxypiperidine (2.83 g, 11 mmoles) at room temperature and the mixture was heated under reflux for 14 hours. After the solvent was distilled off, the residue was dissolved in chloroform, which was washed in turn with an aqueous 1N sodium hydroxide solution and water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/ethanol (10:1)] to obtain 1.27 g of the desired product (40.8%, light brown solid).
Reaction SMILES: [CH:1](OC)(OC)OC.[CH2:8]([O:15][C:16]1[CH:31]=[CH:30][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:28][C:17]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][CH:1]=[N:35][N:34]=2)=[CH:28][C:17]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NNC(=O)c1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reactant: COC(OC)OC
Product: O=C(OCc1ccccc1)c1cc(-c2nnco2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A trimethyl orthoformate (2 mL) suspension of the obtained benzyl 2-(benzyloxy)-5-(hydrazinocarbonyl)benzoate (0.20 g) was heated to reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue, and 0.16 g of the solid substance was collected by filtration. The obtained solid substance (0.11 g) was stirred at 200° C. for 15 minutes. The reaction mixture was cooled to room temperature and then purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 0.079 g of benzyl 2-(benzyloxy)-5-(1,3,4-oxadiazol-2-yl)benzoate as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([O:17]CC)=O)[O:12][N:11]=2)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl.[CH2:30]([NH:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:30]([NH:37][NH:38][C:15]([C:13]1[O:12][N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=2)[N:14]=1)=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NNCc1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(NNCc1ccccc1)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 70 °C
Yield: 40.1 %

Procedure:
To a suspension of ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (Intermediate A) (1.0 g, 3.3 mmol) and K2CO3 (1.1 g, 13 mmol) in THF (17 mL) was added benzylhydrazine dihydrochloride (780 mg, 5.0 mmol). The mixture was heated to 70° C. for 3 h. The mixture was cooled to RT, filtered (Celite), and concentrated under reduced pressure. The crude oil was purified by Biotage (5% EtOAc/Hexane—60% EtOAc) to provide a white solid (500 mg, 40%): MS (ES+) C17H13F3N4O3 requires: 378. found: 379 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][C@H:9]1[C:15](=[O:28])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[S:36](Cl)([CH3:39])(=[O:38])=[O:37].Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:9]([C:15](=[O:28])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:25])([F:26])[F:27])[CH:18]=2)[CH2:10][CH2:11][C@@H:12]1[CH2:13][O:14][S:36]([CH3:39])(=[O:38])=[O:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](CO)CC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](COS(C)(=O)=O)CC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S,5R)-5-hydroxymethyl-2-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (390 mg, 0.97 mmol) in CH2Cl2 (3.5 mL) was added at 0° C. under nitrogen atmosphere Et3N (296 μl, 2.12 mmol) and mesylchloride (167 μl, 2.12 mmol) and the mixture was further stirred at RT for 3 h. CH2Cl2 and HCl 0.1N were added, the layers were separated and the aqueous one re-extracted with CH2Cl2. The crude organic extracts were washed with brine dried over Na2SO4, filtered and concentrated. The crude material was used without purification in the next step. MS (LC-MS): 383 [MH−Boc]+; tR (HPLC conditions b) 5.1 min.
Reaction SMILES: C1([C@@H]([N:9]2[CH2:13][C@H:12]([C:14]3([NH:18]C(OC(C)(C)C)=O)[CH2:17][CH2:16][CH2:15]3)[C@H:11]([F:26])[CH2:10]2)C)C=CC=CC=1.[NH2:27][C:28]1[C:37]([F:38])=[C:36](F)[C:35]([CH3:40])=[C:34]2[C:29]=1[C:30](=[O:48])[C:31]([C:45]([OH:47])=[O:46])=[CH:32][N:33]2[C@@H:41]1[CH2:43][C@@H:42]1[F:44].C(N(CC)CC)C>C(O)C.[C].[Pd].CS(C)=O>[NH2:27][C:28]1[C:37]([F:38])=[C:36]([N:9]2[CH2:13][C@H:12]([C:14]3([NH2:18])[CH2:17][CH2:16][CH2:15]3)[C@H:11]([F:26])[CH2:10]2)[C:35]([CH3:40])=[C:34]2[C:29]=1[C:30](=[O:48])[C:31]([C:45]([OH:47])=[O:46])=[CH:32][N:33]2[C@@H:41]1[CH2:43][C@@H:42]1[F:44]
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](F)[C@@H](C2(NC(=O)OC(C)(C)C)CCC2)C1
Agent: [Pd]
Solvent: CS(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(N2C[C@@H](F)[C@@H](C3(N)CCC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 50 °C
Reaction time: 18 h

Procedure:
cis 1-(1-(S)-phenylethyl]-4-(1-tert-butoxycarbonylaminocyclobutyl)-3-fluoropyrrolidine (optical isomer B; 1.13 g, 3.12 mmol) was dissolved in ethanol (20 ml). After adding a 10% palladium-carbon catalyst (moisture content: 55.6%, 1.0 g), the mixture was stirred under a hydrogen atmosphere at 50° C., for 18 hours. After filtering off the catalyst through celite (washed with methanol), the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dimethyl sulfoxide (10 ml), and 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (1.18 g, 3.78 mmol) and triethylamine (5 ml) were added thereto. Then, the mixture was stirred in a nitrogen atmosphere at 140° C. for 4 days. After allowing it to cool, dimethyl sulfoxide was evaporated under reduced pressure and the residue was dissolved in chloroform (50 ml) and washed successively with a 10% aqueous solution of citric acid (50 ml) and a saturated aqueous solution of sodium chloride (100 ml). The organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was then subjected to flash silica gel column chromatography (eluent:chloroform:methanol=9:1) and the eluate was concentrated under reduced pressure. Under ice cooling, concentrated hydrochloric acid (5 ml) was dropped into the residue followed by stirring at room temperature for 30 minutes. After adding 1 N hydrochloric acid (30 ml), the liquid reaction mixture was washed with chloroform (50 ml×2) and its pH value was adjusted to 12.0 with an aqueous solution of sodium hydroxide. The liquid reaction mixture was washed with chloroform (100 ml) and then its pH value was adjusted to 7.4 with 1 N hydrochloric acid followed by extraction with chloroform (150 ml×3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC (developed at the bottom layer of chloroform:methanol:water=7:3:1) to obtain the title compound as a crude product. After recrystallizing from ethanol/ether, 157 mg (17%) of the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccncc1Nc1cccc(O)c1
Solvent: CCO
Product: Nc1ccncc1Nc1cccc(O)c1
Reaction time: 5 h

Procedure:
A suspension of 3-[(4-nitro-3-pyridinyl)amino]phenol, N-oxide (6.2 g) in 250 ml ethanol containing 0.6 g platinum oxide was hydrogenated at 60 psi (pounds per square inch) for five hours and thereafter filtered through Celite and concentrated to 5 g oil. This was purified by flash chromatography (silica, 25% methanol in dichloromethane) to give 4.5 g solid. This was recrystallized from acetonitrile to give 3.9 g crystals, mp 174°-176°. This solid was recrystallized from acetonitrile to yield 3.2 g crystals, mp 175°-177°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1.Br[C:27]1[N:35]2[C:30]([CH:31]=[N:32][C:33]([NH:36][C:37]3[CH:38]=[N:39][C:40]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[CH:41][CH:42]=3)=[N:34]2)=[CH:29][CH:28]=1.[Cl:49][C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:49][C:50]1[CH:55]=[C:54]([C:27]2[N:35]3[C:30]([CH:31]=[N:32][C:33]([NH:36][C:37]4[CH:38]=[N:39][C:40]([N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[CH:41][CH:42]=4)=[N:34]3)=[CH:29][CH:28]=2)[CH:53]=[CH:52][CH:51]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)nc3)nn12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)nc4)nn23)c1
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
Into a 30 mL vial, Palladium Acetate (12 mg, 0.000053 mol) and Triphenylphosphine (40 mg, 0.0002 mol) were added and purged under an atmosphere of Nitrogen for 10 minutes. 1,4-Dioxane (2.0 mL, 0.026 mol) was added and stirred for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(6-morpholin-4-yl-pyridin-3-yl)-amine (0.085 g, 0.00023 mol), 3-chlorophenyl boronic acid (0.0712 g, 0.000455 mol), N,N-Dimethylformamide (2.0 mL, 0.026 mol) and 1.50 M of Sodium carbonate in Water (0.842 mL, 0.00126 mol) were added and heated at 85° C. for 8 hours. The reaction was partitioned with DCM. The solid was filtered and washed with DCM. The organic solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded [7-(3-Chloro-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(6-morpholin-4-yl-pyridin-3-yl)-amine as a yellow solid. MP 221-222° C. LCMS (E/I+) 407.19 (M+H). NMR 1H (DSMO-d6)-9.29 (s, 1H), 8.98 (s, 1H), 8.41 (d, 1H, J=2.48 Hz), 8.37 (s, 1H), 8.03 (d, 1H, J=7.52 Hz), 7.99 (dd, 2H, JJ=2.68, 6.41 Hz), 7.50 (t, 1H, J=7.88 Hz), 7.40 (d, 1H, J=8.00 Hz), 7.26 (d, 1H, J=4.84 Hz), 6.94 (d, 1H, J=4.74 Hz), 6.86 (d, 1H, J=9.12 Hz), 3.71 (t, 4H, J=4.64 Hz), 3.37 (t, 4H, J=4.92 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([Br:18])=[CH:16][N:15]=[C:14]3[NH:19][CH:20]=[C:21]([NH:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=4)[C:13]=23)[CH2:8][CH2:7]1)=[O:5].[CH3:31][C:32]([CH3:34])=O.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)Cl.CCOCC.CN(C=O)C.ClCCCl>[Br:18][C:17]1[C:12]([N:9]2[CH2:8][CH2:7][N:6]([C:4](=[O:5])[CH2:3][CH2:2][NH:1][CH:32]([CH3:34])[CH3:31])[CH2:11][CH2:10]2)=[C:13]2[C:21]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)=[CH:20][NH:19][C:14]2=[N:15][CH:16]=1
Reactant: NCCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)NCCC(=O)N1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)CC1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
N-(4-(4-(3-aminopropanoyl)piperazin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.060 g, 0.103 mmol, see Example 62) and acetone (0.0599 g, 1.03 mmol) were placed in 1:1 DCE:DMF (5 mL). DIEA (d 0.742; 0.0898 mL, 0.516 mmol) was then added, followed by the addition of NaBH(OAc)3 (0.0437 g, 0.206 mmol). The reaction was then stirred for 30 minutes, and poured into Na2CO3 and extracted into DCM (3×30 mL). The organic fractions were combined, dried, filtered and concentrated. The resulting residue was purified by reverse phase HPLC to give a pure product. The product was then dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether (10 mL). The resulting solid was collected to give N-(5-bromo-4-(4-(3-(isopropylamino)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.030 g, 46.6% yield) as the trihydrochloride salt. MS APCI (+) m/z 515 detected.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[CH3:22])[NH2:18]>C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8](=[NH:9])[NH:18][C:17]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:15]([F:14])[CH:16]=1
Reactant: Cc1ccc(N)cc1F
Reactant: N#Cc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=N)c2ccccc2Br)cc1F
Temperature: 140 °C
Reaction time: 14 h

Procedure:
Solid aluminum chloride (3.66 g, 27.5 mmol, 1 equiv) was added to a neat mixture of 2-bromobenzonitrile (1-1, 5.0 g, 27.5 mmol, 1.0 equiv) and 3-fluoro-4-methylaniline (3.44 g, 27.5 mmol, 1.00 equiv) at 80° C., and the resulting mixture was heated at 140° C. for 30 min. The reaction mixture was cooled to 23° C., allowed to stand for 14 h, then dissolved in chloroform (35 mL). The solution was washed with aqueous NaHCO3 solution (40 mL) and concentrated to afford 2-bromo-N-(3-fluoro-4-methylphenyl)benzenecarboximidamide (1-2) as a dark oil. LRMS m/z: Calc'd for C14H12BrFN2 (M+H) 308.2, found 308.2.
Reaction SMILES: [C:1]([N:4]1[C:10]([CH3:11])=[CH:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[C:10]([CH3:11])=[CH:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2C=C1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)ccc2C=C1C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
0.78 g (2.1 mmoles) of 3-acetyl-8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3H-2,3-benzodiazepine are dissolved in the mixture of 15 ml of methanol and 15 ml of dichloromethane, and about 0.5 g of wet Raney-nickel catalyst and 0.26 ml (5.25 mmoles) of 98% hydrazine hydrate are subsequently added to it under vigorous stirring. The mixture is stirred for further 1 hour. The catalyst is filtered off, washed with dichloromethane, the filtrate is evaporated and the residue is solidified by rubbing with 15 ml of water. The crude product is recrystallized from ethanol. Thus 0.56 g (79%) of the desired compound melting at 209-211° C. is obtained.
Reaction SMILES: F[C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>CN1C(=O)CCC1.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:8]2[C:6]3=[N:7][C:2]([NH:34][CH2:33][C:32]4[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:3][CH:4]=[C:5]3[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:9]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(Cn2nc(C(=O)OC(C)(C)C)c3ccc(F)nc32)cc1
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2ccc3c(C(=O)OC(C)(C)C)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 6-fluoro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (2.55 g, 7.14 mmol) in NMP (30 mL) was added 4-methoxybenzylamine (2.80 mL, 21.41 mmol). The resulting mixture was then heated to 80° C. for 2 hours, after which the mixture was diluted with water (200 mL) and extracted with EtOAc (2×200 mL). The combined extracts were washed with water (100 mL), dried with MgSO4, filtered, absorbed onto silica gel (17 g) and removed the solvent in vacuo. This solid was purified on silica gel (80 g) column (0-100% EtOAc/CH2Cl2 to give the title compound. LRMS (M+1)=474.0