Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:7]2[CH3:22].[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl.C([O-])(O)=O.[Na+]>ClCCCl.CCOC(C)=O>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:8]2[CH:7]([CH3:22])[C:6]3[C:10](=[C:2]([NH:1][CH2:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[CH:3]=[CH:4][CH:5]=3)[C:9]2=[O:11])=[CH:17][CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC1c2cccc(N)c2C(=O)N1c1ccc(C(C)(C)C)cc1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC1c2cccc(NCc3ccncc3)c2C(=O)N1c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of 7-amino-2-(4-tert-butyl-phenyl)-3-methyl-2,3-dihydro-isoindol-1-one (0.11 g, 0.37 mmol, Step G), 4-pyridinecarboxaldehyde (0.14 mL, 0.93 mmol), and NaBH(OAc)3 (0.41 g, 1.85 mmol) in 5 mL of 1,2-dichloroethane was stirred at RT for 48 h, and diluted with 20 mL of EtOAc. 1.0 N HCl (aq) was added to bring pH to 1-2. After stirring for 30 min, NaHCO3 (aq) was added to bring pH to 10. The organic portion was washed with brine, condensed, and the titled compound was obtained as a white solid after flash column chromatography (0 to 35% of EtOAc in CH2Cl2). MS (ES+): 386.3 (M+H)+. Calc'd for C25H27N3O-385.50
Reaction SMILES: C([O:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH3:22])[CH2:11]1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[OH:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH3:22])[CH2:11]1
Reactant: C[C@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of the ester of step B (1.0 g, 3.48 mmol) in MeOH (30 mL) was added K2CO3 (1.2 g, 8.7 mmol). After being stirred at room temperature for 4 hours, the solution was concentrated. The residue was taken up in ether. The resulting solution was washed with brine, dried over MgSO4 and concentrated. Flash chromatography eluting with a gradient of 0% to 20% to 40% EtOAc/hexanes provided 0.56 g of the title compound. MS calculated (M+H)+ 202. found 202.1.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[Br:16]Br>C(Cl)Cl>[Br:16][C:14]1[CH:13]=[N:12][N:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:15]=1
Reactant: CC(C)(C)n1cccn1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)n1cc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a suspension of Na2CO3 (3.6 g, 33.9 mmol) in CH2Cl2 (30 mL) was added 1-tert-butyl-1H-pyrazole (2.1 g, 17 mmol) and Br2 (0.9 mL). The mixture was stirred at room temperature overnight. The formed solid was removed by filtration and the filter cake was washed with CH2Cl2 (30 mL). The filtrates were washed with water (20 mL) and brine (20 mL), dried (MgSO4), and concentrated under reduced pressure to afford crude 4-bromo-1-tert-butyl-1H-pyrazole (2.9 g, 85%), which was used in next step without further purification. MS (ESI) m/z: 203 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([OH:18])=O)=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[NH2:26].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O.O>[NH2:1][C:2]1[C:3]([C:16]([NH:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[Cl:19])=[O:18])=[N:4][C:5]([C:8]2[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])=[CH:6][CH:7]=1
Reactant: Nc1cnccc1Cl
Reactant: Nc1ccc(-c2c(F)cccc2F)nc1C(=O)O
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1Cl
Yield: 21 %

Procedure:
A solution of 3-amino-6-(2,6-difluorophenyl)picolinic acid (1.0 equiv.), 4-chloropyridin-3-amine (2.0 equiv.), HOAt (1.0 equiv.), and EDC (1.0 equiv.) in DCM at a concentration of (0.2M) was stirred for 24 hr. Water was added to the reaction, followed by EtOAc. The organic layer was separated, dried with brine, MgSO4, and concentrated. The crude material was purified via SiO2 column chromatography eluting with EtOAc and hexanes (1:1) to give the product as a light yellow solid (21% yield). LCMS (m/z): 361.1 (MH+); LC Rt=3.28 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:47]([O:49]C(C)(C)C)=[O:48])[CH2:43][CH2:44][S:45][CH3:46].Cl>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CSCC[C@H](NC(=O)CCCc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1)C(=O)O

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Met-OtBu HCl (48 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.65-13.33 (br.s, 1 H), 8.95 (s, 1 H), 8.07 (d, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (m, 1 H), 6.97 (m, 2 H), 6.89 (m, 4 H), 4.30 (m, 1 H), 4.05 (s, 2 H), 4.02 (s, 2 H), 2.91 (s, 3 H), 2.55 (m, 2 H), 2.46 (m, 2 H), 2.39 (s, 3 H), 2.14 (m, 2 H), 2.03 (s, 3 H), 1.95 (m, 1 H), 1.80 (m, 3 H); MS (APCI+) m/z 646 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7](=NO)[CH2:8][P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11].ClC1C=C(C=CC=1)[O:24]CC(=NNC(N)=O)CP(=O)(OC)OC.C(OCC)(=O)C.CO>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7](=[O:24])[CH2:8][P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11]
Reactant: COP(=O)(CC(COc1cccc(Cl)c1)=NO)OC
Reactant: COP(=O)(CC(COc1cccc(Cl)c1)=NNC(N)=O)OC
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COP(=O)(CC(=O)COc1cccc(Cl)c1)OC

Procedure:
The process described in Example 1 was repeated, using a solution in toluene of dimethyl 3-(3-chlorophenoxy)-2-oximinopropylphosphonate in place of the solution in toluene of dimethyl 3-(3-chlorophenoxy)-2-semicarbazonopropylphosphonate, to give dimethyl 3-(3-chlorophenoxy)-2-oxopropylphosphonate, RF = 0.29 (ethyl acetate), RF = 0.58 (5% v/v methanol in methylene dichloride).
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=O)[CH3:3].C([Sn](CCCC)(CCCC)[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)CCC.C(=O)([O-])O.[Na+]>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:19]1[CH:20]=[CH:21][C:17]([C:8](=[O:10])[CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:11])=[CH:18]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Reactant: CCOC(=O)CCC(=O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCOC(=O)CCC(=O)c1ccsc1
Yield: 59.9 %

Procedure:
Under argon atmosphere, a mixture of succinic acid monoethyl ester monochloride (2.0 g), tributyl(3-thienyl) tin (5.44 g) and bis (triphenylphosphine) palladium chloride (853 mg) in dioxane (40 ml) was refluxed for 3 hours. After cooling, to the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: hexane:ethyl acetate=6:1), and recrystallized from ethyl acetate-hexane to obtain ethyl 4-(3-thienyl)-4-oxobutyrate (1.4 g) as pale yellowish powder.
Reaction SMILES: OC1NC2C(C=1)=CC=CC=2.CC1C(C)(C)C2C(=CC=C(CC(O)=O)C=2)N=1.Cl.[C:28]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38]N)=[CH:34][CH:33]=1)([OH:30])=[O:29].[OH:40][CH2:41][CH:42]([CH2:46][OH:47])[C:43](=O)[CH3:44]>C(O)(=O)C>[OH:40][CH2:41][C:42]1([CH2:46][OH:47])[C:36]2[C:35](=[CH:34][CH:33]=[C:32]([CH2:31][C:28]([OH:30])=[O:29])[CH:37]=2)[N:38]=[C:43]1[CH3:44]
Reactant: CC(=O)C(CO)CO
Reactant: NNc1ccc(CC(=O)O)cc1
Agent: CC1=Nc2ccc(CC(=O)O)cc2C1(C)C
Agent: Cl
Agent: Oc1cc2ccccc2[nH]1
Solvent: CC(=O)O
Product: CC1=Nc2ccc(CC(=O)O)cc2C1(CO)CO

Procedure:
The hydroxy-indole compound is readily prepared by literature method (P. L. Southwick, J. G. Cairns, L. A. Ernst, and A. S. Waggoner, One pot Fischer synthesis of (2,3,3-trimethyl-3-H-indol-5-yl)-acetic acid derivatives as intermediates for fluorescent biolabels. Org. Prep. Proced. Int. Briefs, 1988, 20(3), 279-284). Reaction of p-carboxymethylphenylhydrazine hydrochloride (30 mmol, 1 equiv.) and 1,1-bis(hydroxymethyl)propanone (45 mmole, 1.5 equiv.) in acetic acid (50 mL) at room temperature for 30 minutes and at reflux for 1 gives (3,3-dihydroxymethyl2-methyl-3-H-indol-5-yl)-acetic acid as a solid residue. The reaction of 3-bromopropyl-N,N-bis(carboxymethyl)amine, which was prepared as described in Example 5, with the intermediate indole and subsequent reaction of the indole intermediate with glutaconaldehyde dianil monohydrochloride (see Example 1) gives the desired product.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1
Reactant: OCc1cccnc1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COCc1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(Step 4-i) Sodium hydride (60%) (0.44 g, 11 mmol) was added to a solution of (pyridin-3-yl)methanol (1.09 g, 10 mmol) in THF. The reaction mixture was stirred at room temperature for 10 min and ethyl bromoacetate (1.8 g, 11 mmol) was added, followed by the addition of 20 mg of tetrabutyl ammonium iodide. The reaction mixture was stirred overnight, diluted with ethyl acetate/saturated sodium bicarbonate, and the organic layer was dried over sodium sulfate. The solution was concentrated to an oil, which was purified by silica gel column chromatography to give the product, ethyl 2-((pyridin-3-yl)methoxy)acetate, as a brown oil (0.63 g, 3.2 mmol, 32% yield): 1H-NMR (500 MHz, DMSO-d6) 8.63 (d, J=1.8 Hz, 1H), 8.59 (dd, J=1.5, 4.8 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.34 (dd, J=4.9, 7.7 Hz, 1H), 4.68 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 4.15 (s, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[CH3:12].[CH:13]([Mg]Br)=[CH2:14].O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]2[C:7]=1[CH:13]=[CH:14][NH:8]2
Reactant: C=C[Mg]Br
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2[nH]ccc2c1Br
Temperature: -40 °C
Reaction time: 4 h
Yield: 31.5 %

Procedure:
To a solution of 1-bromo-2,4-dimethyl-5-nitro-benzene (7.5 g, 32.6 mmol) in THF (100 mL) at −78° C. was added vinylmagnesium bromide (110 mL of 1.0 M solution in THF, 1.1 mol) dropwise. The reaction was allowed to warm slowly to −40° C. then stirred for 4 h. Water was added, and the reaction mixture allowed to warm slowly to rt and extracted with EtOAc. The organic phase was then dried over Na2SO4 and concentrated to give 4-bromo-5,7-dimethylindole (2.3 g) which was used in the subsequent step without purification.
Reaction SMILES: C1O[C:4](OCC)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13])[O:3]C1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[O:14]=[C:12]([CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC1(CCCCCCCC(C)=O)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=O)CCCCCCCCO
Reaction time: 18 h
Yield: 116.6 %

Procedure:
A solution of 95.4 g (370 mmol) of ethyl 9-oxodecanoate ethylene ketal (prepared in Example 22A-1) in 120 ml of ether was added dropwise to a stirred mixture of 10.5 g (277 mmol) of lithium aluminum hydride and 500 ml of ether under argon. The mixture was stirred for 18 hr and then quenched by the dropwise addition of 18 ml of ethyl acetate. To this mixture there was then sequentially added in dropwise fashion, with stirring, 10.5 ml of water, 10.5 ml of 15% aqueous sodium hydroxide and 31.1 ml of water. The mixture was stirred for about 2 to 3 hr and the mixture was then filtered. The filter pad was rinsed several times with ether. The combined filtrates were evaporated in vacuo. The residue was dissolved in a mixture of 250 ml of 10% hydrochloric acid and 120 ml of methanol and left to stand at room temperature for about 4 hr. The solution was evaporated in vacuo. This residue was dissolved in ether and the resulting solution was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 74.3 g of a yellow oil. The product had the following physical characteristics:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].[CH3:27][N:28]([CH:30](O)C)[CH3:29]>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH2:19][CH2:27][N:28]([CH3:30])[CH3:29])=[O:17]
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12
Reactant: CC(O)N(C)C
Product: CN(C)CCOC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12

Procedure:
Using the process of Example 13, methyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate and dimethylamino-ethanol were reacted to form 2-dimethylaminoethyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluorobenzoate which was then dissolved in ethanol. Dry hydrogen chloride in ethanol was added to the solution and anhydrous ether was added to effect precipitation. The mixture was vacuum filtered and the crystals were washed and dried to obtain 2-dimethylamino-ethyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate hydrochloride melting at 220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[C:19](Cl)[CH:18]=[C:17](Cl)[CH:16]=2)=[C:6]1[C:23]([O-:25])=[O:24].[C:33]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1)#[N:34].FC(F)(F)OC1C=CC(CBr)=CC=1>>[Cl:1][C:2]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([C:33]#[N:34])=[CH:36][CH:37]=3)=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]1[C:23]([OH:25])=[O:24]
Reactant: O=C([O-])c1c(-c2cc(Cl)cc(Cl)c2)c2cc(O)ccc2n1Cc1cc2c(cc1Cl)OCO2
Reactant: N#Cc1ccc(CBr)cc1
Agent: FC(F)(F)Oc1ccc(CBr)cc1
Product: N#Cc1ccc(COc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2cc3c(cc2Cl)OCO3)cc1

Procedure:
Following the procedure of Example 26(c)-26(d), except substituting ethyl 1-(2-chloro-4,5-methylenedioxyphenylmethyl)-5-hydroxy-3-phenylindole-2-carboxylate for 1-(2-chloro-4,5-methylenedioxybenzyl)-3-(3,5-dichlorophenyl)-5-hydroxyindole-2-carboxylate and 4-cyanobenzyl bromide for 4-trifluoromethoxybenzyl bromide in step (c), the title compound was prepared as a white solid (41% overall). MS (MH-): 535.0
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].[Br:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28].Cl.N1C=CC=CC=1>C(OC(O)C)C>[Br:24][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]=3)[N:5]=[CH:4][C:3]=2[C:22]#[N:23])[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cnc2ccc(OCCCN3CCOCC3)nc2c1Cl
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1cnc2ccc(OCCCN3CCOCC3)nc2c1Nc1cccc(Br)c1

Procedure:
A mixture of 4-chloro-6-(3-morpholin-4-yl-propoxy)-[1,5]naphthyridine-3-carbonitrile (700 mg, 2.10 mmol), 3-bromoaniline (0.458 ml, 4.2 mmol) and pyridine HCl salt (534 mg, 2.2 mmol) in ethoxyethanol (30 ml) was heated at reflux for 6 hrs under argon. After cooling, the solvent was removed by rotary evaporation. The residue was treated with ice water, made basic with NH4OH, and extracted with ethyl acetate. The combined extracts were washed (sat brine), dried (Na2SO4), and concentrated. The oily residue was dissolved in CH2Cl2, and ether and n-hexane were added to form a solid. The title compound, as a yellow solid, was collected and dried. mass spectrum (electrospray, m/e): 469.9 (M+H); IR cm-1: 2224, 1668, 1628; H-NMR δ (DMSO-d6): 1.88 (2H, m), 2.26-2.29 (6H, m), 2.51 (2H, m), 3.49 (2H, m), 4.34 (2H, m), 7.110-7.311 (3H, m), 7.835 (1H, d, C7-H), 8.240 (1H, d, C8-H), 8.556 (1H, s), 8.721 (1H, s, C2-H), 9.850 (1H, s, NH).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](C2C=CC=CC=2)[N:4]=1)#[N:2].[Na].[C:16](O)(=[O:18])C>C[O-].[Na+].CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[NH:2])[O:18][CH3:16]
Reactant: N#Cc1cccc(-c2ccccc2)n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 8 h

Procedure:
2-Cyano-6-phenylpyridine (20 g) was dissolved in a solution of sodium methoxide in methanol prepared from methanol (200 ml) and metallic sodium (0.77 g). After the solution was left to stand overnight, acetic acid (2.0 g) was added thereto, followed by concentration under reduced pressure. The resulting residue was dissolved in ether (200 ml) and insoluble materials were filtered out. The filtrate was concentrated under reduced pressure to obtain methyl 2-picoline imidate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[N:15]1[CH2:20][CH2:19][S:18][CH2:17][C:16]1=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.O.Cl>C(O)C.[Fe]>[CH2:19]1[C:20]2[N:15]([C:14]3[C:4]([N:1]=2)=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][CH:13]=3)[CH2:16][CH2:17][S:18]1
Reactant: CCOC(=O)c1ccc(N2CCSCC2=O)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)nc1n2CCSC1
Yield: 53.3 %

Procedure:
Ethyl 3-nitro-4-(3-oxothiomorpholin-4-yl)benzoate (2.00 g, 6.44 mmol) prepared in the Step 40-1-2 was dissolved in ethanol (120 ml). Purified water (12 ml), iron powder (2.62 g, 47.04 mmol) and hydrochloric acid (0.5 ml) was added to the solution, and the mixture was heated under reflux for 4 hours. The mixture was concentrated, and a saturated sodium bicarbonate solution was added thereto, and the resulting mixture was subjected to extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to give the title compound (0.90 g, 53%) as a light-yellow powder.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH3:15])[C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:65][CH:66]1[CH2:71][CH2:70][N:69]([CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[CH2:68][CH2:67]1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[N:9]([CH3:15])[C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:65][CH:66]5[CH2:71][CH2:70][N:69]([CH2:72][C:73]6[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=6)[CH2:68][CH2:67]5)=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NC2CCN(Cc3ccccc3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
A mixture of 0.021 g (0.00005 mole) of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-3), 0.023 g (0.00006 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.018 mL (0.0001 mole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.015 g (0.000075 mole) of 4-amino-1-benzyl-piperidine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (20:80-100:0) to give 0.015 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-benzyl-piperidin-4-yl)-benzamide (I-9) as a white solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[S:22][CH:23]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[O:31])[S:22][CH:23]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2csc(CCCCCCCO)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(-c2csc(CCCCCCC=O)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.4 %

Procedure:
Add anhydrous dimethyl sulfoxide (0.25 mL, 3.52 mmol) dropwise over 2 minutes to a solution of oxalyl chloride (393 mg, 3.10 mmol) in methylene chloride (10 mL) at −78° C. under nitrogen and stir the mixture for 20 minutes. Add a solution of 7-[4-(4-methoxyphenyl)thiazol-2-yl]heptan-1-ol (0.609 g, 1.99 mmol) in methylene chloride (10 mL) dropwise in 5 minutes and then stir the mixture for 30 minutes. To this mixture, add triethylamine (1.0 mL, 7.2 mmol), stir and warm the reaction mixture to room temperature for 40 minutes. Dilute the mixture with ethyl acetate (100 mL), wash with brine (3×30 mL), dry over sodium sulfate and remove the solvent under reduced pressure to provide 7-[4-(4-methoxyphenyl)thiazol-2-yl]heptanal (0.6 g, 99%): APCI mass spectrum m/z 304 [C17H21NO2S+H]+.