Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[Li+].[OH-].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>CCOCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:18]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)=[O:19])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1cc(Cl)ccc1NN
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(Cl)ccc1NNC(=O)c1ccco1
Reaction time: 0.25 h

Procedure:
To a suspension of 1-(4-chloro-2-methylphenyl)hydrazine as the hydrochloride salt (96 mg, 0.5 mmol) in Et2O (10 mL) was added a 2 N solution of LiOH (3 mL), and the resulting mixture was stirred for 15 minutes. After the system became homogenous, furan-2-carbonyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with water (100 mL) and extracted with EtOAc (70 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The crude material of N′-(4-chloro-2-methylphenyl)furan-2-carbohydrazide obtained after the removal of the solvent was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][O:28][NH:29][CH3:30]>C1COCC1>[CH3:27][O:28][N:29]([CH3:30])[C:11](=[O:13])[CH2:10][CH2:9][N:8]([CH3:14])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CON(C)C(=O)CCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl(methyl)amino)propanoic acid (130 g, 0.64 mol) in anhydrous THF was added CDI at 0° C. The resulting mixture was stirred for 1 h at 0° C. To this mixture was added a solution of O,N-dimethylhydroxylamine hydrochloric salt (145.2 g, 0.9 mol) and TEA (90.1 g, 0.9 mol) in THF at rt. The resulting mixture was stirred overnight. Solvent and volatiles were removed under reduced pressure. The residue was purified via column chromatography to give tert-butyl 3-(methoxy(methyl)amino)-3-oxopropyl(methyl)carbamate (120 g, 75.5%) as a colorless oil. 1HNMR (CDCl3, 400 MHz) 1.45 (s, 9H), 2.62-2.71 (m, 2H), 2.87 (s, 3H), 3.17 (s, 3H), 3.48-3.56 (m, 2H), 3.68 (s, 3H)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:28]3[C:19](=[CH:20][C:21]4[O:26][CH2:25][CH2:24][O:23][C:22]=4[CH:27]=3)[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].BrC1C=CC=C2C=1C1(C3C(=CC4OCCOC=4C=3)OC1)C(=O)[N:34]2C>>[NH2:34][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:28]3[C:19](=[CH:20][C:21]4[O:26][CH2:25][CH2:24][O:23][C:22]=4[CH:27]=3)[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(N)cccc21

Procedure:
Following the procedure described in EXAMPLE 16.19 and making non-critical variations using 4′-bromo-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′-amino-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (79%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 7.11-7.05 (m, 1H), 6.48 (s, 1H), 6.36-6.32 (m, 3H), 4.78 (s, 2H), 4.21-4.11 (m, 4H), 3.84-3.58 (m, 2H), 1.76-1.66 (m, 2H), 1.39-1.33, (m, 4H), 0.91 (t, J=6.6 Hz, 3H); MS (ES+) m/z 380.9 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11]>>[CH2:1]([O:8][C:14]([NH:13][S:10]([Cl:9])(=[O:12])=[O:11])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: OCc1ccccc1
Product: O=C(NS(=O)(=O)Cl)OCc1ccccc1

Procedure:
The procedure of Example 6 was followed scaling the reaction to 0.2 moles each of benzyl alcohol and chlorosulfonyl isocyanate to give benzyloxycarbonylsulfamoyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1)([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1

Procedure:
1B, in tetrahydrofuran, was treated with hydrogen (40 psi pressure in a Parr-shaker, 10% palladium-on-carbon catalyst), to give ethyl 2-(4-(2-amino-4-(trifluoromethyl)phenylamino)phenoxy)propionate (1C), as a solid, m.p.: 78° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:12][CH2:13][CH:14]([NH2:17])[CH2:15][CH3:16]>C(#N)C>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:17][CH:14]([CH2:15][CH3:16])[CH2:13][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(N)CC
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: CC#N
Product: CCC(CC)NCCNC(=O)OC(C)(C)C

Procedure:
By using 1.0 g of tert-butyl(2-bromoethyl)carbamate, 2.5 mL of pentan-3-amine, and 10 mL of acetonitrile as starting materials, the reaction similar to Preparation Example 9 was performed, thereby obtaining 890 mg of tert-butyl[2-(pentan-3-ylamino)ethyl]carbamate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1.O.O.O.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:14]1[C:13]([CH3:12])=[N:17][CH:16]=[N:15]1
Reactant: Cc1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Yield: 22.3 %

Procedure:
3,4-Difluoronitrobenzene (514 mg, 3.23 mmol), 3-methyl-1H-1,2,4-triazole (325 mg, 3.72 mmol) and di-potassium hydrogen phosphate trihydrate (1.49 g, 6.46 mmol) in dimethyl sulfoxide (1.5 mL) were stirred for 6 hours at 70° C. The mixture was concentrated in vacuo; the residue was diluted in water and extracted three times with ethyl acetate. The combined organic layers were washed four times with water, twice with brine, dried with magnesium sulfate and evaporated. Column chromatography (30 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound (160 mg, 22%) as white crystals MS ISP (m/e): 223.2[(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.22 (m, 2H), 8.04 (s, 1H), 7.74 (dd, 1H), 2.48 (d, 3H). Mp 56-58° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][NH:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)C(C)(C)N
Agent: Cl
Product: CCOC(=O)C(C)(C)NCc1ccc(OC)c(O[Si](C)(C)C(C)(C)C)c1
Yield: 94 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)-4-methoxybenzaldehyde (Example 12-2c) and ethyl 2-amino-2-methylpropanoate hydrochloride. Yield 94%, colorless liquid. MS 382 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:32]1[CH:31]=[C:30]([C:29]([F:44])([F:43])[F:28])[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:10]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (142 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3,5-bis-trifluoromethyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](F)[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:21]3[CH2:22][CH2:23][CH2:24][CH:20]3[CH3:19])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Fc1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reactant: CC1CCCN1
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Temperature: 205 °C
Yield: 63.9 %

Procedure:
A suspension of 6-chloro-N-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (132 mg, 0.5 mmol) and 2-methylpyrrolidine (64 mg, 0.75 mmol) in water (0.3 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=200:1) to give 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (105 mg, 63.8%) as a yellow solid. LC-MS: [M+H]+, 329.1, tR=2.019 min.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:40])[C@@H:37]([CH3:39])[NH2:38])=[CH:31][CH:30]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[C:22]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:40])[C@@H:37]([CH3:39])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1Oc1ccc(N2C(=O)N[C@H](C)C2=O)cn1
Temperature: 0 °C
Yield: 174.6 %

Procedure:
In a 50 mL round-bottomed flask N1-{6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 44, 173.8 mg) was dissolved in dichloromethane (5 mL) to give a yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (36.5 mg, 0.298 mmol), triethylamine (0.208 mL, 1.492 mmol) and triphosgene (89 mg, 0.298 mmol) were added. The reaction mixture was stirred at 0° C. After 20 min the solvent was evaporated under vacuum to afford a yellow solid. This residue was purified by silica gel chromatography (Biotage instrument, 10 g SNAP Silica column) eluting with Cyclohexane/EtOAc from 2:1 Cyclohexane/EtOAc to 1:3 Cyclohexane/EtOAc in 20 CV; then 1:3 Cyclohexane/EtOAc for 5 CV. The collected fractions afforded the title compound as a colourless oil (162 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10]>O1CCCC1.S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([O:11][CH2:17][CH2:3][CH2:2][CH2:20][CH3:19])=[O:10]
Reactant: CC(Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCCOC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
First, 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionic acid (compound b-1) is dissolved in tetrahydrofuran, to which thionyl chloride is added under stirring, and the mixture is heated and stirred under reflux. After left for cooling and the subsequent concentration, the residue is dissolved in tetrahydrofuran (hereinafter referred to as solution A). Tetrahydrofuran is added to 1-pentyl alcohol, to which solution Aid added and pyridine is then added. After stirring at room temperature, 2% aqueous hydrochloric acid is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated. The residue is subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to give pentyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate (compound b-19).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:35]([O:37][C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=1)=[O:36]>C1COCC1>[C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([C:35]([O:37][C:38]3[CH:39]=[CH:40][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:46][CH:47]=3)=[O:36])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NCC1CNCCC1c1ccccc1)c1cccc2ccccc12
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2CCC(c3ccccc3)C(CN[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 175 mg of the crude product of (1R)-1-(1-naphthyl)-N-[(4-phenylpiperidin-3-yl)methyl]ethaneamine and 142 μL of triethylamine in 3.5 mL of THF was added 120 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka) under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 237 mg of 4-(methoxycarbonyl)phenyl 3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidine-1-carboxylate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCCC1CCOCC1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Br:27])[C:11]2=[O:28])=[C:6]([Cl:29])[CH:5]=1.Cl>C1COCC1.O>[Br:27][C:12]1[C:11](=[O:28])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][C:6]=2[Cl:29])[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccc(C(=O)O)cc1Cl
Reaction time: 8 h
Yield: 67.1 %

Procedure:
Methyl-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-3-chlorobenzoate (2.30 g, 4.61 mmol) was taken up in THF (20 ml) and H2O (4 ml). 2.5 N NAOH (9.2 ml) was added to the vessel and the reaction stirred overnight to completion. Concentrated HCl was added dropwise until reaction was made acidic (pH=1). H2O (100 ml) and THF (100 ml) were added to the mixture. The contents were poured into a separatory funnel and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, the solvent removed in vacuo, and the residue was taken up in a 50% mixture of ethyl acetate/hexane. The precipitate was collected on a filter pad to yield a white powder (1.5 g, 67%). 1H NMR (300 MHz, DMSO) δ 13.59 (1H), 8.16 (d, J=1.81 Hz, 1H), 8.06 (dd, J=6.24, 1.81 Hz, 1H), 7.73 (app q, J=8.46, 1H), 7.68 (d, J=8.26 Hz, 1H), 7.38 (dt, J=9.48, 2.62 Hz, 1H) 7.26-7.18 (m, 1H), 6.80 (s, 1H), 5.39 (s, 2H), 3.93 (s, 3H), 1.96 (s, 3H); ES-MS m/z 483 (M+H). ES-HRMS m/z 483.9749 (M+H calcd for C20H14BrClF2NO4 requires 483.9757).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.C(N(C(C)C)CC)(C)C>ClCCl>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[NH:10][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:8]
Reactant: Nc1nccs1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
Cyclohexanecarbonyl chloride (4.38 g, 30 mmol) was added dropwise to a solution of 2-aminothiazole (3.00 g, 30 mmol) and di-isopropylethylamine (3.87 g, 30 mmol) in dichloromethane (50 ml) at 0° C. The mixture was warmed to room temperature, stirred for 18 h, washed with 1 N--HCl (2×50 ml) and 1 N--NaOH (2×50 ml), dried (MgSO4), and evaporated in vacuo to give the product (4.59 g) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9](Cl)[CH:8]=2)=[C:4]([CH3:17])[CH:3]=1.[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([Br:18])=[CH:20][CH:21]=3)[CH:8]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1cc(Br)cc(C)c1Oc1ccnc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1Oc1ccnc(Nc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.7 %

Procedure:
In a flask outfitted with a reflux condensor, 15 (1 g, 3.2 mmol) and 4-bromoaniline (1.1 g, 6.4 mmol, 2 equiv) were melted together at 190° C. for 5 h. The reaction was cooled to room temperature and the resulting black solid was dissolved in 4:1 THF-1N NaOH soln (5 mL) stirring overnight. The reaction was diluted with EtOAc and the organic phase was washed with 1 N NaOH soln, 0.1 M HCl soln. Activated charcoal was added and the organic phase was stirred at room temperature for 0.5 h, filtered through celite and concentrated. The resulting brown solid was recrystallized from CH2Cl2 (˜4 mL) to provide the purified product as a white solid (1.2 g, 86%). 1H NMR (300 MHz, CDCl3) δ8.03 (d, J=5.9 Hz, 1H), 7.39 (d, J=8.8 Hz, 2H), 7.23 (m, 3H), 6.42 (s, NH), 6.19 (m, 2H), 6.14 (d, J=1.9 Hz, 1H), 2.10 (s, 6H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[NH:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:3]([CH3:5])=[CH:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C1CCNC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C=C(C)C1CCCN1

Procedure:
Ethyl 3-tetrahydropyrrolyl-2-butenoate was prepared (21 g, 99%) from ethyl acetoacetate (15.0 g, 115.26 mmol) and pyrrolidine (71.1 mL, 345.78 mmol) in the same manner as described in the above Example 1 (1), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH3:25])([CH2:23][CH3:24])[C:20]([NH2:22])=[O:21]>>[NH2:22][C:20](=[O:21])[C:19]([NH:18][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)([CH3:25])[CH2:23][CH3:24]
Reactant: CCC(C)(N)C(N)=O
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CCC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-2-methyl-butanamide (CAN 59209-90-4) as starting materials, LC-MS (UV peak area/ESI) 96%, 332.1982 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27](O)=[O:28])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH-].[NH4+]>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([N:14]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[CH2:18][O:17][CH2:16][C@H:15]2[CH2:26][C:27]([NH2:31])=[O:28])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reaction time: 2 h
Yield: 32.4 %

Procedure:
A solution of compound 21a (100 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), DIPEA (77 mg, 0.6 mmol) in DCM (5 mL) was stirred at it for 0.5 hr. Ammonium hydroxide (12 mg, 0.36 mmol) was added and the mixture was stirred at it for 2 hr. The reaction mixture was quenched with water and extracted with DCM. The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC to give the desired compound 23 (32 mg, 32% yield). LCMS (m/z): 412.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[O:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: Nc1cc(Cl)ccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(N)c1
Temperature: 150 °C
Reaction time: 120 h
Yield: 45.7 %

Procedure:
2-Amino-4-chloropyridine (5.0 g), N-methyl pyrrolidone (40 ml), 2-hydroxy-5-nitrotoluene (11.9 g) and diisopropylethylamine (20.1 g) were put in a reaction vessel, followed by heating and stirring under a nitrogen atmosphere at 150° C. for 5 days. The reaction mixture was cooled down to room temperature and concentrated under a reduced pressure. To the resultant residue was added a saturated aqueous solution of sodium hydrogencarbonate, followed by stirring at room temperature overnight. To the reaction mixture was added tetrahydrofuran (200 ml) to partition. The aqueous layer was extracted with diethyl ether (100 ml). The organic layer was washed with brine (100 ml×2), dried over anhydrous sodium sulfate, and concentrated under a reduced pressure. The precipitated solid was suspended in diethyl ether and filtered off. The solid was washed with diethyl ether:ethyl acetate=1:1, and dried under aeration to provide the titled compound (4.36 g, 45.7%) as a yellow solid.