Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.B#B.[Cl:9][C:10]1[C:18]2[O:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH:13]=[C:12]([C:20](O)=[O:21])[C:11]=1[N:23]1[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]1>COCCOCCOC.C1COCC1>[Cl:9][C:10]1[C:18]2[O:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH:13]=[C:12]([CH2:20][OH:21])[C:11]=1[N:23]1[CH2:24][C@H:25]([CH3:30])[O:26][C@H:27]([CH3:29])[CH2:28]1
Reactant: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(C(=O)O)cc12
Agent: B#B
Agent: FB(F)F
Agent: [BH4-]
Solvent: COCCOCCOC
Solvent: C1CCOC1
Product: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of NaBH4 (78 mg, 2.43 mmol) in diglyme (1 mL) was added BF3 (1.6 mL, 2.59 mmol), and the thus generated diborane gas was purged into solution of 7-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3-methyl-1,2-benzoxazole-5-carboxylic acid (Intermediate 302, 250 mg, 0.8 mmol) in THF (1 mL). The mixture was stirred at room temperature for 30 minutes before being quenched with methanol (1 mL) and concentrated. The residue was purified by column chromatography to give product as solid. Yield: 130 mg (52%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][CH:26]([CH3:30])[CH2:27][CH:28]=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:28][CH2:27][CH:26]([CH3:30])[CH3:25])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: CC(C)CC=O
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CC(C)CC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 71.4 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3-methylbutanal (0.5 g, 5.8 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.083 g, 71%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1nc(-c2ccccc2)cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc(-c5ccccc5)cc5ccccc45)cc3CC[C@@H]12
Yield: 41.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (86 mg, 0.33 mmol), potassium carbonate (158 mg, 1.14 mmol), 1-chloro-3-phenyl-isoquinoline (95 mg, 0.40 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 64 mg (42%) of the title compound as an off white solid. mp 183°-189°. FDMS: m/e=464. α[D]589 =+54.61 (c=0.53, chloroform).
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].B(F)(F)F.CCOCC.[CH3:16][C:17]([CH3:31])=[CH:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30]>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1](=[O:6])[NH:2][C:17]([CH3:31])([CH3:16])[CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30])[CH3:5]
Reactant: CC(C)=CCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(N)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(C)(C)CCN1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
34.2 g of ethyl carbamate are put in the solution in the toluene, 22 mL of BF3.Et2O are added and heating is performed for 1 h 30 mins at 70° C. 11 g of 2-(3-methylbut-2-en-1-yl)-1H-isoindole-1,3-dione are added and heating with reflux is performed for 12 h. After returning to RT, the mixture is dry evaporated and then taken up in an H2O/AcOEt mixture. The organic phase is decanted, washed with a solution saturated with NaCl and then dried on magnesium sulfate. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 99/1). 5.12 g (yield=31%) of ethyl[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,1-dimethylpropyl]-carbamate are obtained as a brown powder used as such.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:10][CH:9]2[C:11](O)=[O:12])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:10][CH:9]2[C:11](=[O:12])[N:18]([CH3:17])[C:14]3=[O:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C2(C(=O)O)CC2C(=O)O)cc1
Reactant: CN
Solvent: CO
Product: CN1C(=O)C2CC2(c2ccc(N)cc2)C1=O
Temperature: 100 °C
Reaction time: 168 h

Procedure:
A mixture of 220 mg of 1-(4-aminophenyl)-1,2-cyclopropanedicarboxylic acid, 10 ml of methanol and 0.26 ml of methylamine (40%) is stirred in a glass bomb tube for 7 days at 100° C. The mixture is concentrated in vacuo and the residue is chromatographed over a column of silica gel with a 4:6 mixture of hexane/ethyl acetate. Recrystallisation from ethyl acetate/petroleum ether affords yellow crystals of the title compound, which is identical with the title compound of Example 3(a).
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][CH3:36])[C:32]([Pb+3])=[C:31]([CH2:38][CH3:39])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][CH3:36])[C:32]([CH:4]2[C:5](=[O:10])[C@H:6]3[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:11])=[C:31]([CH2:38][CH3:39])[CH:30]=1
Reactant: CCc1cc(Br)cc(CC)c1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(Br)cc(CC)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 4.2 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (1 g, 6.5 mmol) and 4-dimethylamino-pyridine (3.96 g, 32.5 mmol) are added to a mixture of chloroform (20 ml) and toluene (5 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2,6-diethylphenyllead triacetate (4.25 g, 7.14 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×25 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4-bromo-2,6-diethylphenyl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.1 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.C([O-])=O.[NH4+].CCCCCC>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1
Reactant: COCCOCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCCCCC
Product: COCCOCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
A mixture of 200 mg (0.88 mmol) of 1-[(2-methoxyethoxy) methoxy]-4-nitrobenzene (21), 100 mg of 10% Pd/C and 550 mg (8.7 mmol) of ammonium formate in 10 mL of absolute ethanol was stirred at room temperature for 18 hours. The reaction mixture was diluted with 100 mL of absolute ethanol and passed through a small pad of celite. The filtrate was concentrated and purified by silica gel column chromatography using 8:2 ethyl acetate:hexane as the eluent to yield 130 mg (0.65 mmol, 75%) of 4-[(2-methoxyethoxy)methoxy]benzenamine (22). NMR, IR and MS data confirmed compound identity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9](O)=[O:10])=O.O.[NH2:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:4]=1[C:5]1[C:7]2[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:9](=[O:10])[NH:26][N:25]=1
Reactant: COc1ccc(OC)c(C(=O)c2ccc(OC)cc2C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc(OC)c(-c2n[nH]c(=O)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(2,5-dimethoxybenzoyl)-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[C:34]([CH3:41])=[C:35]([CH:39]=O)[NH:36][C:37]=2[CH3:38])[CH2:28][CH2:27]1)(=[O:25])[CH3:24]>C(O)C.N1CCCCC1>[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[C:34]([CH3:41])=[C:35](/[CH:39]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:36][C:37]=2[CH3:38])[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: CC(=O)N1CCN(Cc2c(C)[nH]c(C=O)c2C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)N1CCN(Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (357 mg, 1 mmol) was condensed with 4-(4-acetyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (263 mg, 1 mmol) in ethanol (3 mL) and piperidine (3 drops) at 95-100° C. for 2 hours to give the titled compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH2:23].C(N(CC)CC)C>C1COCC1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CNCc1ccc(Cl)cc1Cl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(3-nitrophenyl)ethanone (10.0 g, 41.15 mmol, 1.00 equiv) in THF (150 mL), (2,4-dichlorophenyl)methanamine (7.16 g, 40.91 mmol, 1.00 equiv) and triethylamine (5.96 g, 59.01 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25° C. The solids were filtered out. The filtrate was concentrated to dryness and used for next step, assuming theoretical yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][N:7]2[C:8]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)[C:5]3[C@@H:16]4[NH:17][C@H:12]([CH2:11][C:6]2=3)[CH2:13][CH2:14][CH2:15]4)=[CH:21][CH:20]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)cc2)C[C@@H]2CCC[C@H]1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (226 mg, 1.0 mmol; Example 118A) and 1-chloro-4-vinylbenzene (277 mg, 1.99 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minute) to afford the title compound as the second-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.04-1.20 (m, 1H), 1.29-1.44 (m, 2H), 1.66 (dd, J=13, 2 Hz, 1H), 1.78-2.04 (m, 3H), 2.40 (s, 3H), 2.92 (dd, J=17, 7 Hz, 1H), 2.98-3.17 (m, 2H), 3.50-3.57 (m, 1H), 4.21 (ddd, J=15, 9, 6 Hz, 1H), 4.32-4.42 (m, 1H), 4.43-4.47 (m, 1H), 6.92-7.00 (m, 3H), 7.14-7.21 (m, 3H), 7.27 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 365 367 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH:19]2[CH2:22][N:21]([CH2:23][CH2:24][OH:25])[CH2:20]2)[CH:5]=[CH:4][N:3]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]([OH:36])([C:34]#[CH:35])[CH3:33])[CH:28]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:35]#[C:34][C:32]([C:29]4[CH:28]=[C:27]([CH3:26])[O:31][N:30]=4)([OH:36])[CH3:33])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH:19]2[CH2:22][N:21]([CH2:23][CH2:24][OH:25])[CH2:20]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(OC3CN(CCO)C3)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OC4CN(CCO)C4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 2 h
Yield: 7.4 %

Procedure:
A mixture of 2-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-ol (80 mg, 0.20 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (160 mg, 1.06 mmol), bis(triphenylphosphine)palladium(II) dichloride (160 mg, 0.23 mmol) and triethylamine (1 mL) in dimethylsulfoxide (2 mL) was stirred under nitrogen for 2 hr at 70° C. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified by preparative HPLC to give 7 mg (7%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[[1-(2-hydroxyethyl)azetidin-3-yl]oxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a white solid: 1H NMR (400 MHz, DMSO) delta 8.41 (d, J=5.6 Hz, 1H), 8.17 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.10 (s, 2H), 7.01 (d, J=5.6 Hz, 1H), 6.45 (s, 1H), 6.37 (s, 1H), 5.37 (t, J=5.2 Hz, 1H), 4.44 (t, J=5.4 Hz, 1H), 3.75 (t, J=7.2 Hz, 2H), 3.41 (t, J=6.0 Hz, 2H), 3.28 (t, J=6.8 Hz, 2H), 2.57 (s, 2H), 2.41 (s, 3H), 1.81 (s, 3H); LC-MS: m/z=+476 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)([N:17]1C=CN=C1)=O.O1CCCC1.N>O>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N)c(C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
A mixture of 23.7 g of 2-amino-4,5-dimethoxybenzoic acid, 19.5 g of 1,1'-carbonyldiimidazole and 600 ml of tetrahydrofuran Was stirred for 2 hours at room temperature and then saturated with anhydrous ammonia with ice bath cooling. After 24 hours, the reaction mixture was diluted with 50 ml of water, heated at reflux for 2 hours and then concentrated under reduced pressure to about 50 ml. This liquid was mixed with 100 ml of 0.1N sodium hydroxide and then extracted with three 200 ml portions of dichloromethane. The extracts were combined, dried and evaporated. The residue was crystallized from acetonitrile, giving 5.5 g of 2-amino-4,5-dimethoxybenzamide as light grey crystals, mp 135°-138° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6]([CH2:12][C:13]([OH:15])=O)([C:9](O)=[O:10])[CH2:5][CH2:4]1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:31][NH:32][NH2:33]>CN(C)C=O>[ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2([C:9](=[O:10])[N:33]([NH:32][CH3:31])[C:13](=[O:15])[CH2:12]2)[CH2:5][CH2:4]1
Reactant: CN1CCC(CC(=O)O)(C(=O)O)CC1
Reactant: CNN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CNN1C(=O)CC2(CCN(C)CC2)C1=O
Reaction time: 1 h

Procedure:
In dimethylformamide (30 ml) was dissolved (1-methyl-4-carboxypiperidin-4-yl)acetic acid.hydrochloride (1.9g). To the solution was added dicyclohexylcarbodiimide (1.82 g), and the mixture was stirred for one hour, to which was added methylhydrazine (0.43 ml). The mixture was stirred at 60° C. for one full day. Precipitates were removed, and the solvent was evaporated off under reduced pressure. The residual oily product was subjected to a silica gel column chromatography [eluent; n-butanol:acetic acid:methanol:water=1:1:1:1 (V/V)]. To the solution containing the desired product was added 4 ml of 1N hydrochloric acid. Then, the solvent was evaporated off, and the residual solid product was recrystallized from ethanol to obtain 0.25 g of colorless solid, m.p. 235° to 260° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[CH:8][N:7]=1.[Cl-].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH3+:26])[CH:21]=[C:20]2[CH3:27].C(N(C(C)C)CC)(C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH:26][C:12]([C:9]1[CH:10]=[N:11][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[N:7][CH:8]=1)=[O:14])[CH:21]=[C:20]2[CH3:27]
Reactant: O=C(O)c1cnc(-c2nccs2)nc1
Reactant: Cc1cn([NH3+])c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(NC(=O)c2cnc(-c3nccs3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
A mixture of 2-thiazol-2-yl-pyrimidine-5-carboxylic acid (50 mg, 0.244 mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (49 mg, 0.244 mmol), diisopropylethylamine (31.5 mg, 0.244 mmol) in DMF (1 mL) is stirred at rt for 5 min. 4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride (37 mg, 0.244 mmol) is added. The reaction is heated to 50° C. for 1.5 h and then concentrated in vacuo. The residue is taken up in DMSO-d6 then purified via reverse phase C18 HPLC chromatography eluting with water and acetonitrile containing 0.1% TFA buffer to afford 2-thiazol-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (58%). MS: 354 (M+H); 1H NMR (300 MHz, CDCl3): δ=2.27 (s, 3H), 7.05 (dt, 1H), 7.32 (s, 1H), 7.32-7.44 (m, 2H), 8.11 (d, 1H), 8.19 (d, 1H), 9.42 (s, 2H), 12.12 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])[N:11]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4]>[C:23]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[O:17])[N:11]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:10]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)CCn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Product: CN(C)CCn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1C=O
Reaction time: 3 h

Procedure:
To a solution of 1.160 g of 3-diphenylmethoxy-1-[2(dimethylamino)ethyl]-6-hydroxymethyl-4-pyridone is added 6.0 g of manganese dioxide at room temperature, and the mixture is stirred for 3 hours. Insolubles are removed by filtration, and the filtrate was subjected to flash column chromatography on 50 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (10:1) to perform separation and purification. The title compound is obtained as colorless crystal in a yield of 0.744 g.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[NH2:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH2:25]Br)=[C:19]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])[CH:18]=2)[CH:10]=[CH:9][C:8]=1[N+:36]([O-:38])=[O:37]>CC#N>[NH2:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH2:25][N:2]([CH2:3][CH2:4][OH:5])[CH3:1])=[C:19]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])[CH:18]=2)[CH:10]=[CH:9][C:8]=1[N+:36]([O-:38])=[O:37]
Reactant: CNCCO
Reactant: Nc1nc(NCCNc2ccc(NC(=O)CBr)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Solvent: CC#N
Product: CN(CCO)CC(=O)Nc1ccc(NCCNc2ccc([N+](=O)[O-])c(N)n2)cc1-c1ccc(Cl)cc1Cl
Reaction time: 12 h
Yield: 21 %

Procedure:
N-Methyl ethanolamine (2 eq) was added to a stirred solution N-[4-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-2-(2,4-dichlorophenyl)phenyl]-2-bromoacetamide (8.65 eq) in CH3CN at room temperature. The reaction was monitored by LC/MS and was determined to be complete after 12 hours. The reaction was concentrated and purified by silica column chromatography eluting with MeOH in CH2Cl2 (5:95, v/v). After collecting the purified fractions and concentrating, N-[4-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-2-(2,4-dichlorophenyl)phenyl]-2-[(2-hydroxyethyl)methylamino]acetamide was obtained as a light yellow glass (21% yield, LC/MS m/z 549.4 MH+) in 95% purity.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH:13]=[CH2:14].O>N1C=CC=CC=1>[CH2:1]([O:8][CH2:14][CH2:13][CH2:12][CH:11]=[CH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCCO
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: C=CCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (0.2 mol, 23 ml) was added dropwise to a solution of 4penten-1-ol (0.2 mol, 20 ml) in pyridine and stirred overnight at room temperature. The reaction mixture was poured into 100 mlof water and the organic layer separated. The product mixture was washed, sequentially, with dilute HCl, saturated aqueous Na2CO3, and water. The organic layer was dried over anhydrous Na2CO3 and the product distilled: bp 90°-98° (1.0 mmHg); yield 26.9g, (71%); NMR (neat) δ 1.5 (broad m, 4, alkyl), 3.8 (t, 2, --OCH2 --), 4.6 (m, 2, =CH2), 5.2 (m, 1, =CH--), 7.3 (m, 5, ArH).