Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4([C:29](=[O:38])[NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:28][CH2:27]4)=[O:25])=[CH:19][C:18]=3[F:39])[N:13]=[CH:12][N:11]=2)C=CC=CC=1.Cl.Cl.[N:43]1([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44]1.C(N(CC)CC)C.O>CN(C)C=O>[N:43]1([CH:47]2[CH2:52][CH2:51][N:50]([C:8]([NH:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]5([C:29]([NH:30][C:31]6[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=6)=[O:38])[CH2:27][CH2:28]5)=[O:25])=[CH:19][C:18]=4[F:39])[CH:15]=3)=[O:7])[CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44]1
Reactant: C1CN(C2CCNCC2)C1
Reactant: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1)N1CCC(N2CCC2)CC1
Reaction time: 21 h
Yield: 68.8 %

Procedure:
[6-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyrimidin-4-yl]carbamic acid phenyl ester (35.5 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 4-(azetidin-1-yl)piperidine dihydrochloride (21 mg), triethylamine (0.0198 ml) and water (0.10 ml) were added thereto in this order, followed by stirring for 21 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (26.5 mg, 68.8%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.FC(F)(F)S(O[C:33]1[C:45]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)(=O)=O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:33]2[C:45]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38][C:37]=3[CH:36]=[CH:35][CH:34]=2)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1cccc2[nH]c3ccccc3c12)C(F)(F)F
Reactant: OB(O)c1cncc(OCc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1ccc(COc2cncc(-c3cccc4[nH]c5ccccc5c34)c2)cc1
Yield: 80.2 %

Procedure:
1.63 g of [5-(benzyloxy)pyridin-3-yl]boronic acid, 6.4 g of caesium carbonate and 0.182 g of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride as a complex with dichloromethane (1/1) [PdCl2(dppf).CH2Cl2] are successively added, under argon, to a solution of 1.57 g of 4-trifluoromethanesulphonyloxycarbazole, obtained in stage 1 of Example 1, in a mixture of 71 ml of dioxane and 24 ml of water. The reaction mixture is refluxed for 5 hours, filtered through celite and concentrated under reduced pressure. The residue is subsequently purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (80/20 by volume), so as to give 1.4 g of 4-[5-(benzyloxy)pyridin-3-yl]-9H-carbazole in the form of a pale yellow oil, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[Cl:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)n1c(O)nc2ncc(Cl)c(I)c21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)n1c(O)nc2ncc(Cl)c(-c3ccccc3)c21
Temperature: 135 °C
Yield: 36.5 %

Procedure:
6-Chloro-7-iodo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol (190 mg, 0.52 mmol), phenylboronic acid (76 mg, 0.63 mmol), and (DPPF)PdCl2 (38 mg, 0.052 mmol) were added to a microwave vial equipped with stirbar. A septum was affixed to the vial and the vessel was purged with nitrogen for 5 min. Degassed dioxane (5 mL), and degassed 2 M K2CO3 (aq.) (1 mL, 2 mmol) were added by syringe, and the septum was replaced with a crimped vial cap. The reaction was heated to 135° C. for 20 min. The reaction mixture was diluted with EtOAc and water, and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative LCMS provided the title compound as a white solid (60 mg). The compound was characterized by LCMS (m/z=316.1 [M+H]+) and 1H NMR.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([CH3:16])[C:11]([O:13]CC)=[O:12])=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1.[OH-].[Na+]>CO>[CH3:20][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([CH3:16])[C:11]([OH:13])=[O:12])=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(N(C)C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=Cc1ccc(N(C)C)cc1[N+](=O)[O-])C(=O)O
Temperature: 45 °C
Reaction time: 5.5 h

Procedure:
Into 150 ml of methanol, 15.0 g (53.9 mmol) of (E) ethyl 3-(4-dimethylamino-2-nitrophenyl)-2-methyl-2-propenate were dissolved; and, with 3.2 g (80 mmol) of sodium hydroxide being added thereto, the mixture was stirred at 45° C. for 5.5 hours. After the solvent was evaporated from the reaction liquid under a reduced pressure, the residue was dissolved in 100 ml of water. Thus obtained solution was adjusted to neutral with 2-N hydrochloric acid being added thereto. The precipitated crystal was filtered out, fully washed with water, and then dried, whereby 12.1 g of the aimed compound were obtained as a crystal (yield: 89.7%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH3:24])[N:18]=[C:17]3[CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[NH:34][N:33]=[C:32]([CH2:35][C:36](O)=[O:37])[N:31]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH3:24])[N:18]=[C:17]3[CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:11][CH2:12][N:13]1[C:36](=[O:37])[CH2:35][C:32]1[NH:33][N:34]=[C:30]([CH3:29])[N:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Reactant: CCn1nc(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc21
Product: CCn1nc(C2CCC2)c2cc(N3CCN(C(=O)Cc4nc(C)n[nH]4)[C@@H](Cc4ccccc4)C3)ccc21
Yield: 37 %

Procedure:
Prepared using the same procedure described in Example 189 from 5-((S)-3-benzyl-piperazin-1-yl)-3-cyclobutyl-1-ethyl-1H-indazole and (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid to afford the title compound as colorless solid (61 mg, 37%). LC/MS (Method B) 3.32 min, [M+1]+ 498.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[C:26]12([C:36](Cl)=[O:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(N(CC)CC)C>[C:26]12([C:36]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[N:16]=[C:15]([NH2:17])[C:14]5[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=5)[N:8]=4)[CH2:2][CH2:3]3)=[O:37])[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(C(=O)C45CC6CC(CC(C6)C4)C5)CC3)nc(N)c2cc1OC

Procedure:
To a mixture of 2-piperazino-4-amino-6,7-dimethoxyquinazoline (1 g), chloroform (50 ml) and triethylamine (0.42 g), was gradually added 1-adamantanecarbonyl chloride (0.83 g). The almost dissolved mixture was heated at 45°-50° C. for 2 hours. After cooling, the mixture was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 2-{4-(1-adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquinazoline, m.p. 240°-242° C.
Reaction SMILES: Br[CH2:2][C:3]([C@H:5]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:12][CH:11]=2)[C:7](=[O:25])[CH2:6]1)=O.[C:26]([NH2:29])(=[S:28])[CH3:27]>O1CCCC1>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([N:8]2[CH2:9][C@H:5]([C:3]3[N:29]=[C:26]([CH3:27])[S:28][CH:2]=3)[CH2:6][C:7]2=[O:25])=[CH:15][CH:14]=1
Reactant: O=C(CBr)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CC(N)=S
Solvent: C1CCOC1
Product: Cc1nc([C@@H]2CC(=O)N(c3ccc(OCc4cccc(F)c4)cc3)C2)cs1
Temperature: 40 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
(R)-4-(2-Bromo-acetyl)-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one (0.040 g, 0.098 mmol) was dissolved in tetrahydrofuran (1 ml) and thioacetamide (0.007 g, 0.098 mmol) was added and the mixture was stirred at 40° C. for 24 hours. The tetrahydrofuran was evaporated and the residue was purified by column chromatography on silica gel using at first a 1:1-mixture then a 4:1-mixture of ethyl acetate and hexane as the eluent to yield the title compound as a light yellow solid (0.030 g, 80% of theory). MS (m/e)=383.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:28][OH:29]>C(O)C.O>[Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:28][OH:29])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Yield: 51.2 %

Procedure:
13 g (39.5 mmol) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile were stirred with 7.5 g (71 mmol) of sodium carbonate and 5.7 g (82 mmol) of hydroxylamine hydrochloride in 200 ml of ethanol and 40 ml of water at 50° for 1 hour and at 75° for 10 minutes. After dilution with 50 ml of water the suspension was suction filtered, whereupon the crystals were dried. There were obtained 7.33 g (51%) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime of m.p. 265°-266°.
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:6]([O:23][CH3:24])=[N:7][C:8]2[C:13]([N:14]=1)=[C:12]([N+:15]([O-])=O)[C:11]([Cl:18])=[C:10]([C:19]([F:22])([F:21])[F:20])[CH:9]=2>C(O)C.[Ru]>[NH2:4][C:5]1[C:6]([O:23][CH3:24])=[N:7][C:8]2[C:13]([N:14]=1)=[C:12]([NH2:15])[C:11]([Cl:18])=[C:10]([C:19]([F:22])([F:20])[F:21])[CH:9]=2
Reactant: COc1nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c2nc1N
Agent: [Ru]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1nc2cc(C(F)(F)F)c(Cl)c(N)c2nc1N
Reaction time: 0.33 h
Yield: 100.5 %

Procedure:
Hydrazine hydrate (0.34 ml, 7.0 mmol) was added to a stirred solution of 3-amino-6-chloro-7-trifluoromethyl-2-methoxy-5-nitroquinoxaline (0.55g, 1.7 mmol) in ethanol (25 ml) containing suspended 10% ruthenium-on-carbon (55 mg) under nitrogen at reflux. After 20 minutes, additional hydrazine hydrate (0.17 ml, 3.4 mmol) was added, and the mixture was stirred at reflux for 30 minutes, then allowed to stand at room temperature overnight. The mixture was filtered through Arbocel filter aid, and the filter cake was washed with ethanol and dichloromethane. The filtrate was concentrated under reduced pressure to give the title compound (0.50 g, 100%) as an off-white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][CH2:7][CH2:8][O:9][C:10](=[O:32])[C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[Cl:28])[CH:14]=[CH:13][C:12]=1[N+:29]([O-:31])=[O:30].C(N(CC)CC)C>CCOCC.O>[Cl:1][CH2:2][C:3]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:32])[C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][C:19]=2[Cl:28])[CH:14]=[CH:13][C:12]=1[N+:29]([O-:31])=[O:30])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=C(OCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCl)OCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 33.2 %

Procedure:
Chloroacetyl chloride (3 g, 0.027 mole) was added dropwise to a stirred solution of [2-hydroxyethyl]5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (8.1 g, 0.02 mole), triethylamine (2.5 g), and ether (150 ml). The heat given off during the reaction raised the temperature of the ether solution to reflux. After completion of addition, the mixture was kept at reflux for 10 min. The mixture then was allowed to cool to room temperature, poured into 200 ml of water, and 400 ml of ether was added. The ether extract was washed three times with water, dried CaSO4 and condentrated to 8.6 g of yellowish oil. The oil was column chromatographed through silica gel with 20% ethyl acetate-80% hexane as eluent to afford 3.2 g of pure [2-chloroacetoxyethyl]5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate, as a pale yellow gummy material; nmr (CDCl3) δ 4.16 (S, 2H), 4.50 (S, 4H), 6.98-8.18 (m, 6H); ir (CHCl3) 1752, 1765.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:16])[NH:14][C:13](=O)[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:17][NH2:18]>O1CCCC1.C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:16])[CH2:10][O:11][CH2:12][C:13]([CH2:17][NH2:18])=[N:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C)COCC(=O)N2)cc1
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C2(C)COCC(CN)=N2)cc1
Temperature: 0 °C

Procedure:
A solution of 69.5 mmol of 5-(4-methoxyphenyl)-5-methylmorpholin-3-one in 200 ml of tetrahydrofuran and 25 ml of benzene is cooled to 0° C. and saturated with methylamine. A solution of 19 g of titanium tetrachloride in 25 ml of benzene is added dropwise over the course of 15 minutes. After addition is complete, the reaction mixture is heated to reflux for 3 hours. The reaction mixture is then cooled to 0° C. and cautiously quenched with 60 ml of water. It is filtered through Hyflo, and the filter cake is washed several times with tetrahydro-furan. The phases of the filtrate are separated, and the organic phase is dried with sodium sulphate and evaporated. The title compound is identified from the residue oh the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[N:14]#[C:15][NH2:16].[N+:17]([O-:20])([OH:19])=[O:18]>CO>[N+:17]([O-:20])([OH:19])=[O:18].[NH2:16][C:15]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)=[NH:14]
Reactant: N#CN
Reactant: COC(=O)c1ccc(N)cc1OC
Solvent: O=[N+]([O-])O
Solvent: CO
Product: COC(=O)c1ccc(NC(=N)N)cc1OC
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
Into a reactor at room temperature was added methyl 4-amino-2-methoxybenzoate (4, 38 kg, 210 mol) and methanol (224 L). The mixture was stirred at 25 to 30° C. for 30 min. Aqueous cyanamide (50% w/w, 43 kg, 512 mol) was added over a minimum of 30min at 20 to 25° C. The reaction mixture was heated to reflux using a maximum jacket temperature of 75° C. Concentrated nitric acid (45 kg, 499 mol) was added over a minimum of 60 min. The resulting mixture was heated at reflux for 2 h. A suspension of seed crystals (16 g in 600 mL methanol) was added and the mixture was stirred using a 75° C. jacket temperature for 60 to 90 min. The mixture was cooled to 20 to 25° C. over at least 2 h and stirred for an additional 2 h. The mixture was filtered and washed with methanol (180 L) while stirring for 1 h. The wet cake was washed a second time with methanol (180 L) while stirring for 1 h. The resulting wet cake was dried under vacuum at 25° C. to provide 30.0 kg (50% yield) of 5. 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.57 (s, 4H), 6.97 (d, J=2.3 Hz, 1H), 6.84 (dd, J=2.3, 8.2 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H); MS (ESI) m/z 224.4 (M+, 100%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[C:10]([NH2:25])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:26][C:27](O)=O>>[CH3:26][C:27]1[N:13]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:11]2=[N:12][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:8][CH:9]=[C:10]2[N:25]=1
Reactant: Nc1ccc(N2CCOCC2)nc1NCc1cccc2ccccc12
Reactant: CC(=O)O
Product: Cc1nc2ccc(N3CCOCC3)nc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 14 %

Procedure:
A mixture of 6-morpholino-N2-(naphthalen-1-ylmethyl)pyridine-2,3-diamine (3.2 g, 9.58 mmol) in CH3COOH (50 mL) was refluxed for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography eluted with EtOAc/Pet Ether=1/1 and then recrystallized in EtOAc to afford the desired product as a pale solid (481 mg, 14%); LC/MS: MS (ES+) m/e 359 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 3.39 (t, J=4.8 Hz, 4H), 3.67 (t, J=4.8 Hz, 4H), 5.87 (s, 2H), 6.72-6.77 (m, 2H), 7.37-7.42 (m, 1H), 7.56-7.65 (m, 2H), 7.80 (d, J=8.7 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.98-8.01 (m, 1H), 8.36-8.39 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=[N:21][NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1O
Reactant: NNC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NNC(=O)c1ccccc1)c1cccc(Cl)c1O
Temperature: 60 °C
Yield: 59.1 %

Procedure:
A suspension of 1-(3-chloro-2-hydroxyphenyl)-ethanone (0.100 g, 0.586 mmol), benzoic acid hydrazide (0.080 g, 0.586 mmol), and glacial acetic acid (0.180 mL) in ethanol (1.8 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish benzoic acid [1-(3-chloro-2-hydroxy-phenyl)-ethylidene]-hydrazide as a yellow solid (0.100 g, 59%): mp 202-203° C.; 1H NMR (400 MHz, DMSO) δ 14.36 (s, 1H), 11.50 (s, 1H), 7.96 (d, J=7.3 Hz, 2H), 7.68-7.61 (m, 2H), 7.56 (t, J=6.7 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 6.92 (t, J=8.0 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 289 ([M+H]+), 287 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Reaction time: 8 h
Yield: 105.4 %

Procedure:
3-Chloro-4-nitrobenzoic acid (Apin; 1 g, 4.96 mmol) was suspended in toluene (10 mL) and thionyl chloride (1.11 mL, 14.88 mmol) added. The mixture was heated to 85° C. for 45 min Further thionyl chloride (1.1 mL) was added and the mixture heated at reflux. 0.5 hr. The reaction mixture was allowed to cool and stand overnight. The mixture was concentrated to give the title compound as a yellow liquid (1.15 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.N1C=CC=CC=1.[CH2:32]([O:34]CC)C>>[CH:32]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1])=[O:34]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Reactant: CCOCC
Solvent: c1ccncc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCOC=O)c(Cl)cc2F)c1=O

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)pyrimidinedione with pyridine in diethyl ether there is obtained 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4 -fluorophenoxy}-ethyl formate, 1H-NMR (CDCl3, 400 MHz): 8.11 ppm (t,1H), 7.33 ppm (d,1H), 6.82 ppm (d,1H), 6.35 ppm (s,1H), 4.54 ppm (m,2H), 4.22 ppm (t,2H), 3.56 ppm (d,3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[C:5]2=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=[CH:19][N:4]2[N:3]=1.[C:26]([NH:30][S:31]([C:34]1[C:35]([O:49][CH3:50])=[N:36][CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:26]([NH:30][S:31]([C:34]1[C:35]([O:49][CH3:50])=[N:36][CH:37]=[C:38]([C:2]2[N:7]=[C:6]([N:8]3[CH2:16][C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[CH2:9]3)[C:5]3=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[CH:19][N:4]3[N:3]=2)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1S(=O)(=O)NC(C)(C)C
Reactant: Clc1nc(N2Cc3cccnc3C2)c2c(-c3ccccc3)ccn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ncc(-c2nc(N3Cc4cccnc4C3)c3c(-c4ccccc4)ccn3n2)cc1S(=O)(=O)NC(C)(C)C
Temperature: 100 °C
Yield: 35.6 %

Procedure:
To a solution of 2-chloro-5-phenyl-4-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrrolo[2,1-f][1,2,4]triazine (30.0 mg, 0.0860 mmol) and N-(tert-butyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (48.0 mg, 0.129 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added K2CO3 (24.0 mg, 0.173 mmol). The reaction mixture was purged with nitrogen gas for 10 min. PdCl2(dppf)-CH2Cl2 (7.04 mg, 8.63 μmol) was added and the reaction mixture heated at 100° C. for 12 h. The reaction mixture was allowed to cool to ambient temperature then filtered through CELITE® bed and the bed was washed with EtOAc (2×20 mL). The filtrate was diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition B-97 as described in general methods) to obtain N-(tert-butyl)-2-methoxy-5-(5-phenyl-4-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (17.0 mg, 35.5%) as a pale yellow solid. LCMS Condition B-83: retention time 1.91 min, [M+1]=556.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (s, 9H), 3.74 (s, 3H), 3.74 (br s, 2H), 3.74 (br s, 2H), 6.83 (d, J=2.7 Hz, 1H), 6.90 (s, 1H), 7.25 (dd, J=7.7 Hz, J=4.9 Hz, 1 H), 7.43-7.54 (m, 5H), 7.51 (d, J=1.7 Hz, 1H), 8.00 (d, J=2.7 Hz, 1H), 8.37 (d, J=3.6 Hz, 1H), 8.82 (d, J=2.6 Hz, 1H), 8.96 (d, J=2.6 Hz, 1H).