Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[BH4-].[Li+].[Cl:5][C:6]1[CH:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[NH:26][N:25]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:24][N:23]=1>O1CCCC1>[Cl:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[NH:26][N:25]([C:27]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:24][N:23]=1
Reactant: COC(=O)c1ccc(-c2ccccc2C2=NNN(C(c3ccccc3)(c3ccccc3)c3ccccc3)N2)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccccc2C2=NNN(C(c3ccccc3)(c3ccccc3)c3ccccc3)N2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
1.27 g of methanol (39.6 mmol) and 1.29 g of lithium borohydride (59.4 mmol) are added to a solution of 22.0 g (39.6 mmol) of the compound from Example XXXIV in 180 ml of tetrahydrofuran, and the mixture is then stirred at room temperature for 30 minutes and under reflux for 1 hour. Addition of a further 0.63 g of methanol (0.20 mmol) and stirring under reflux for 1 hour brings the reaction to completion. The reaction mixture is concentrated; the residue is taken up in 200 ml of methylene chloride and 100 ml of 1N potassium hydrogen sulphate solution are slowly added under a vigorous stream of argon, using an ice-bath. After the phases have been separated, the aqueous phase is extracted with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated, to give 20.5 g of white crystals [98.19% of theory; melting point 186°-7° C. (decomposition), Rf 0.15 (hexane:ethyl acetate=3:1)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:32][CH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC

Procedure:
To a solution of methyl 2-methoxy-4-methylbenzoate (2.07 g, 11.5 mmol) in chloroform (30 mL) was added benzoyl peroxide (0.14 g, 0.57 mmol) and N-bromosuccinimide (2.04 g, 11.5 mmol). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was washed with saturated sodium hydrogen carbonate and the organic phase was poured through a hydrophobic frit and the solvent evaporated at reduced pressure. The crude material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]O)=[CH:17][CH:16]=2)=[C:10]([F:25])[CH:9]=1)=[O:6].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:31][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:2]([Cl:1])[CH:3]=3)=[CH:9][C:10]=2[F:25])=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc(Oc2ccc(CCCO)cc2)c(F)c1)c1ccc(Cl)c(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccc(CCCBr)cc2)c(F)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 3,4-dichloro-3′-fluoro-4′-[4-(3-hydroxypropyl)phenoxy]benzanilide (2.32 g, 5.34 mmol) in dichloromethane (46 mL) were added carbon tetrabromide (2.13 g, 6.41 mmol) and triphenylphosphine (1.54 g, 5.88 mmol), and the resulting solution was stirred for 12 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 2.41 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C=O.[BH3-][C:27]#N.[Na+]>CO>[Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([CH3:27])[CH2:22][CH2:23]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Nc2ccc(N3CCNCC3)cn2)n1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(c2ccc(Nc3nc(Br)cn4ccnc34)nc2)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of 106b (210 mg, 0.52 mmol), formaldehyde (150 mg, 5 mmol), and NaBH3CN (220 mg, 3.5 mmol) in methanol (8 mL) was stirred at 20° C. for 3 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column-chromatography eluting with CH2Cl2/methanol (20:1) to afford 106c (200 mg, 90%). MS: [M+H]+ 388.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)(=[O:25])=[O:24])[C:16]([C:19](O)=[O:20])=[N:17][CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCN(CC)CC>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([NH:22][C:15]2[C:16]([C:19]([N:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:11]=4[O:10][CH2:9][CH2:8]3)=[O:20])=[N:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)(=[O:25])=[O:24])=[CH:27][C:28]=1[C:33]([F:34])([F:36])[F:35]
Reactant: Fc1cccc2c1OCCN2
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCOc2c(F)cccc21

Procedure:
8-Fluoro-3,4-dihydro-2H-benzo[1,4]oxazine, 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid, T3P, and Et3N were reacted according to the procedure D to provide the title compound. HPLC purification provided 4-chloro-N-[5-chloro-2-(8-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 2.986 min. MS m/z 550.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([O:28][CH3:29])[N:20]=1.C(N(CC)CC)C>C(O)C>[CH3:29][O:28][C:21]1[N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc3[nH]cc(CC4CCCN4C)c3c2)n1
Yield: 54 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 2-chloro-6-methoxy-3-nitropyridine were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 5.5 hours. Column chromatography afforded the title compound (54%) as a red amorphous solid: 1H NMR (CDCl3) δ 8.80 (br s, NH), 8.37 (d, J=9.1 Hz, 1H), 7.85 (s, 1H), 7.34-7.28 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.14 (d, J=9.1 Hz, 1H), 3.85 (s, 3H), 3.19-3.11 (m, 2H), 2.61 (dd, J=13.8 and 9.5 Hz, 1H), 2.54-2.45 (m, 1H), 2.45 (s, 3H), 2.24 (dd, J=17.1 and 9.3 Hz, 1H), 1.91-1.54 (m, 4H); 13C NMR (CDCl3) δ 166.9, 151.3, 138.2, 134.0, 129.6, 127.8, 123.3, 122.0, 118.6, 114.1, 113.3, 111.1, 102.0, 66.5, 57.5, 54.7, 40.8, 31.6, 29.9, 21.9; HRMS calculated for C20H23N5O3 381.1803, found 381.1799.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:20](=[O:32])[C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1
Yield: 58.4 %

Procedure:
4-[5-(4-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.45 mmol) was dissolved at rt in a mixture of 30% TFA in CH2Cl2. The reaction mixture was stirred until TLC indicated consumption of starting material (30 min). The mixture was then partitioned between EtOAc and water. The water layer was basified with solid NaOH to pH 12. The organic layer was separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was washed with water, dried over Na2SO4, filtered and concentrated to afford the product (89 mg, Yield: 56%). HRMS m/z calcd for C20H26N4O [M+H]+: 339.2180. Found: 339.2180.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].C1(C)C=CC=CC=1>O>[CH:1]([C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C(=Cc1nc2ccccc2s1)c1ccccc1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 2-methylbenzothiazole (1.49 g, 0.01 mol), benzaldehyde (1.27 g, 0.012 mol), 50% sodium hydroxide solution (3 ml), toluene (5 ml) and compound 1 (1 mmol) was stirred at reflux temperature for 4 hours. The reaction mixture was allowed to cool to room temperature and then diluted with water (10 ml). The organic layer was separated and the aqueous phase extracted with toluene. The combined organic portions were dried over magnesium sulphate and evaporated to give a solid residue which was crystallized from ethanol to give the corresponding 2-styrylbenzothiazole.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[CH2:8]2)[CH2:4][CH2:3]1.Cl.[O:18]([NH2:20])[CH3:19]>>[CH3:19][O:18][N:20]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:8]1
Reactant: CN1CCC2(CC1)CC(=O)c1ccccc12
Reactant: CON
Agent: Cl
Product: CON=C1CC2(CCN(C)CC2)c2ccccc21

Procedure:
The product of Example 138B and the HCl salt of methoxylamine were processed according to the method of Example 135A to provide the product. MS (ESI+) m/z 245 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:34])[N:6]([CH3:33])[C:7]2[C:12]([C:13]=1[NH:14]C(=O)C)=[CH:11][C:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:9]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])[N:8]=2)(=[O:3])[CH3:2].Cl>O1CCOCC1.CCOC(C)=O>[C:1]([C:4]1[C:5](=[O:34])[N:6]([CH3:33])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[C:9]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])[N:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To 16 mg of the product of Example 1 in 1,4-dioxane (1 mL) was added 0.5 mL of 1 M aqueous HCl solution. The reaction stirred at 50° C. for 5 hours. LC/MS indicated little product forming and an additional 0.2 mL of concentrated HCl solution was added. The temperature was increased to 90° C. for 4.5 hours at which point the reaction was cooled to room temperature and diluted with EtOAc. The solution was washed with saturated aqueous NaHCO3 solution before drying with Na2SO4 and concentrating. The residue was purified by preparative TLC (silica gel) eluted with 20% EtOAc in CH2Cl2 affording the title compound. HPLC/MS: 471.9 (M+1), 473.9 (M+3); Rt=4.32 min.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[C:16]([Cl:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([Cl:22])=[C:12]([Cl:21])[C:13]=2[N+:18]([O-])=O)[N:8]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:18][C:13]1[C:12]([Cl:21])=[C:11]([Cl:22])[CH:10]=[C:9]2[C:14]=1[N:15]=[C:16]([Cl:17])[C:7]([Cl:6])=[N:8]2
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)cc2nc(Cl)c(Cl)nc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1c(Cl)c(Cl)cc2nc(Cl)c(Cl)nc12
Yield: 83.7 %

Procedure:
Tin (II) chloride dihydrate (346.3 g, 1.54 mol) was added to a solution of 2,3,6,7-tetrachloro-5-nitro-quinoxaline (96.2 g, 0.31 mol) in ethyl acetate (1.8 l). The mixture was heated under reflux for 4 hours, cooled and poured cautiously into an excess of aqueous saturated sodium bicarbonate. The mixture was filtered through "Celite", (Trade Mark), washing well with ethyl acetate. The filter cake was macerated with more ethyl acetate and the solid material filtered off. The combined ethyl acetate solutions were dried (MgSO4) and concentrated under reduced pressure to give 5-amino-2,3,6,7-tetrachloroquinoxaline (73.4 g, 84%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[NH:8])=[N:4][O:5][N:6]=1.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)(O)[O-].[Na+]>CC(O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)=[N:4][O:5][N:6]=1
Reactant: CC(C)CNC(=N)c1nonc1N
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(CC(C)C)c(-c2nonc2N)n1

Procedure:
A mixture of 4-amino-N-isobutyl-1,2,5-oxadiazole-3-carboxamidine (18 mg, 0.1 mmol), ethyl bromopyruvate (28 μL, 0.2 mmol) and sodium bicarbonate (17 mg, 0.2 mmol) in iPrOH (1 mL) was microwaved for 20 minutes at 150° C. Crude reaction mixture was purified via preparative HPLC to afford the title compound as a white solid. MS 280.2 as M+1 peak. HPLC Method B Rt 3.5 min. 1HNMR (CDCl3) 7.65 (s, 1H); 5.65 (s, 2H); 5.32 (q, 2H); 4.2 (d, 2H); 2.1 (m, 1H); 1.35 (t, 3H); 0.91 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21]O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:25][NH:26][CH2:27][CH2:28][OH:29]>>[CH3:25][N:26]([CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:1])[F:23])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:27][CH2:28][OH:29]
Reactant: CNCCO
Reactant: OCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CN(CCO)CCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 19.1, 4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and 2-Methylaminoethanol were converted to yield 2-(Methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amino)-ethanol as yellow oil, MS: 405 (MH+).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:14](OCC)=[O:15].[Na:19]>C(OCC)C>[Na:19].[CH:14]([CH:2]([CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([O:11][CH2:12][CH3:13])=[O:10])=[O:15]
Reactant: CCOC(=O)CCCC(=O)OCC
Reactant: CCOC=O
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)CCC(C=O)C(=O)OCC

Procedure:
Prepared from diethyl glutarate and ethyl formate in the presence of sodium metal in diethyl ether according to the literature procedure (J. Bigs, P. Sykes, J. Chemical Society (1959), 1849-55). Obtained solid (28 g; 45%). LCMS (ES+) m/z 238 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:6]=2Cl.[OH-:22].[K+]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:22])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: FC(F)(F)c1ccc(-n2nc3cc(Br)ccc3c2Cl)cc1
Agent: [K+]
Solvent: CO
Product: O=c1c2ccc(Br)cc2[nH]n1-c1ccc(C(F)(F)F)cc1
Yield: 44 %

Procedure:
A solution of the product of Step 3 (2.4 g, 0.0064 mol) in 1M KOH in MeOH (16 mL) was heated at 150° C. in a sealed tube via microwave irradiation for 15 min. The mixture was then concentrated, diluted with H2O, acidified with 1N HCl and the resulting precipitate collected by filtration to give 1.0 g (44% yield) of product. 1H NMR (360 MHz, CDCl3): 7.37 (1H, dd, J 1.4 and 8.5 Hz), 7.66 (1H, d, 1.4 Hz), 7.73 (1H, d, 8.5 Hz), 7.89 (2H, d, 8.5 Hz), 8.13 (2H, d, 8.5 Hz), 11.0 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[K+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([CH3:21])[N:15]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:13][C:14]1[N:15]=[C:16]([CH3:21])[N:17]=[C:18]([NH:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:19]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CN)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(4-methoxyphenyl)methanamine (1.51 g, 11 mmol) was added in DMF (15 mL), potassium hydroxide was added and stirred at room temperature for 10 minutes. The reaction was cooled to −2° C., 4,6-dichloro-2-methylpyrimidine (1.63 g, 10 mmol) in DMF (5 mL) was added drop-wise at a speed the internal temperature was controlled <0° C. After 30 minutes, the reaction was added ethyl acetate (50 mL), washed with brine (20 mL×2). The organic phase was dried by magnesium sulfate, filter, concentrated and purified by column chromatography through a 110 gram AnaLogix™ silica gel cartridge eluting with 30% ethyl acetate/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[C:6](=[O:13])[CH:5]=[C:4]([Cl:14])[N:3]=1.[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CN(C=O)C>[C:15]([O:19][C:20](=[O:28])[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:7]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[C:6](=[O:13])[CH:5]=[C:4]([Cl:14])[N:3]=2)[CH2:24][CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COCCCn1c(Cl)nc(Cl)cc1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(Cl)cc1=O
Yield: 74.2 %

Procedure:
A solution of 2,6-dichloro-3-(3-methoxy-propyl)-3H-pyrimidin-4-one (400 mg, 1.68 mmol), piperidin-4-yl-carbamic acid tert-butyl ester (405 mg, 2 mmol) and DIEA (260 mg, 2.0 mmol) in DMF (20 mL) was stirred at 85° C. for 2 h. The solvent was concentrated, and the residue was purified by silica chromatography to give 500 mg of the title compound (75%). [M+H] Calc'd for C18H29ClN4O4, 400. Found, 400.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[NH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>C(O)C>[O:18]=[C:19]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:9][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(Nc1ccccc1)c1cccnc1
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2cccnc2)n(-c2ccccc2)c1=O
Temperature: 160 °C

Procedure:
A suspension of the N-phenyl-3-pyridinecarboximidamide (i.e. the product from Example 7, Step A) (36.5 g, 185 mmol) in diethyl ethoxymethylenemalonate (60 g, 280 mmol) was heated to 160° C. for 8 h. Ethanol formed in the reaction was collected using a distillation head attached to the flask containing the heated reaction mixture. The reaction mixture was then cooled to ambient temperature when the formation of a solid was observed. A mixture of diethyl ether/petroleum ether (8:2) was added to the reaction mixture was filtered. The collected solid was washed with additional ether/petroleum ether (4:1) followed by n-chlorobutane/petroleum ether (1:1) to obtain 51 g of the title compound as a light brown powder.
Reaction SMILES: [C:1]([C:5]([N:7]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:15]=1)[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:34])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:10]([C:8]([N:7]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][Br:34])=[C:16]([O:21][CH2:22][C:23]([F:24])([F:25])[F:26])[CH:15]=1)[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[O:6])=[O:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccc(N(C(=O)C(C)(C)C)C(=O)C(C)(C)C)cc1OCC(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1ccc(CBr)c(OCC(F)(F)F)c1

Procedure:
To a stirred solution of 4-(N,N-di-(tert-butyl-carbonyl)-amino)-2-(2,2,2-trifluoroethoxy)toluene (2.0 g, 5.0 mmol) from Step 3 above in CCl4 (75 mL) was added NBS (0.90 g, 5.0 mmol) and AIBN (0.2 g, 1.2 mmol). The mixture was refluxed for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (2×50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 5-15% EtOAc:hexanes to give 4-(N,N-di-(tert-butylcarbonyl)amino)-2-(2,2,2-trifluoroethoxy)benzyl bromide as a colorless gum (TLC Rf =0.50 (15% EtOAc:hexanes)).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH3:12][N:13]=[C:14]=[S:15].O>C(O)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:14]([NH:13][CH3:12])=[S:15])=[CH:7][CH:6]=1)=[O:2]
Reactant: CN=C=S
Reactant: Nc1ccc(NNC=O)cc1
Solvent: O
Solvent: CCO
Product: CNC(=S)Nc1ccc(NNC=O)cc1

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (1.51 g, 0.01 mole) and methyl isothiocyanate (0.73 g, 0.01 mole) were mixed in ethanol (20 ml) and the mixture was refluxed for 30 minutes. The mixture was chilled in ice, and water was added to precipitate the product. The product came out of solution in an oily form, but solidifed upon scratching and standing. The solid material was filtered off and washed thoroughly with ether. The product was dried to give a white crystalline powder. Yield 1.3 g (58%), m.p. 176°-178° C.
Reaction SMILES: CO[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)[N:4]=1.[NH3:17]>>[N+:9]([C:8]1[C:3]([NH2:17])=[N:4][C:5]([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)=[CH:6][CH:7]=1)([O-:11])=[O:10]
Reactant: N
Reactant: COc1nc(-c2ncco2)ccc1[N+](=O)[O-]
Product: Nc1nc(-c2ncco2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 77 %

Procedure:
A suspension of 2-methoxy-3-nitro-6-(1,3-oxazol-2-yl)pyridine (0.187 g, 0.85 mmol) in aqueous ammonia (32%, 5 mL) was heated in a sealed tube to 100° C. with stirring. After 2.5 hours the mixture was cooled and the precipitate was filtered and washed with water and then dried in vacuo to give the title compound (0.134 g, 77%) as a yellow solid.
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[H-].[Na+]>CS(C)=O>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: Cc1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C)cc2)cc1

Procedure:
(4-methoxy-phenyl)-acetic acid methyl ester Compound 22a was reacted with p-toluidine and sodium hydride in DMSO at room temperature to provide 2-(4-methoxy-phenyl)-N-p-tolyl-acetamide Compound 22b.