Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][N:9]2[CH3:19])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][N:9]2[CH3:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(C)n(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (1.6 g, 5.9 mmol) in tetrahydrofuran (6 mL)/methanol (5 mL) was added 4N aqueous sodium hydroxide solution (9 mL), and the mixture was stirred at 60° C. for 1 hr. Tetrahydrofuran and methanol were evaporated under reduced pressure. 6N Aqueous hydrochloric acid solution was added to the residue with stirring, and the precipitated solid was collected by filtration. The filtrate was washed with water and ethyl acetate/hexane (1/5), and dried under reduced pressure to give the title compound (1.1 g, 79%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4](C)[CH:3]=1.BrC1C=CC(C=C)=[C:15]([O:21]CC)[CH:14]=1.B1C2CCCC1CCC2>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([O:21][CH2:15][CH3:14])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CCO
Reactant: C=Cc1ccc(Br)cc1OCC
Agent: B1C2CCCC1CCC2
Product: CCOc1cc(Br)ccc1CCO
Yield: 82 %

Procedure:
Using a procedure analogous to that used to prepare 30B, 62D (700 mg, 3.3 mmol) was heated in a pressure vessel with 9-BBN at 100° C. for 10 h and worked up as in 30B to yield 62E (620 mg, 82%) as solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (t, J=6.95 Hz, 3 H) 2.85 (t, J=6.32 Hz, 2 H) 3.81 (t, J=6.32 Hz, 2 H) 4.02 (q, J=7.07 Hz, 2 H) 6.96 (s, 1 H) 6.99-7.03 (m, 2 H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: NCCN1CCOCC1
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1

Procedure:
Using 1-iodo-4-nitro-benzene (500 mg) instead of 1-bromo-3-nitro-benzene, and 2-morpholin-4-yl-ethylamine (316 mg) instead of morpholine, in the same manner as Step A in Example 1-D-105, the desired compound was obtained (315 mg, 62%).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[C:6]([OH:11])(=[O:10])/[CH:7]=[CH:8]/[CH3:9].[Cl:12][C:13]([Cl:17])([Cl:16])[CH2:14]O.S(=O)(=O)(O)O>O>[Cl:12][C:13]([Cl:17])([Cl:16])[CH2:14][O:10][C:6](=[O:11])/[CH:7]=[CH:8]/[CH3:9]
Reactant: C/C=C/C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: C/C=C/C(=O)OCC(Cl)(Cl)Cl
Yield: 95 %

Procedure:
In 200 ml. carbon tetrachloride are dissolved 0.5 mole (43.07 g.) crotonic acid and the equimolar amount of 2,2,2-trichloroethanol, 1 ml. concentrated sulphuric acid is added thereto and the reaction mixture is heated under reflux on a water separator until the theoretical amount of water (9 ml.) has separated off. Subsequently, the organic phase is shaken out twice with, in each case, 100 ml. aqueous 2N sodium hydrogen carbonate solution and twice with, in each case, 50 ml. of water, the organic phase is then dried with anhydrous magnesium sulphate and the solvent is distilled off in a vacuum. There is finally obtained the desired product (i) in the form of a bright yellow oil in a yield of 95% of theory. C6H7O2Cl3 (217.4791)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])=[N:9][CH:8]=[CH:7]2)([O-])=O.[H][H]>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([N:14]([C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:15]([C:17]([CH3:19])([CH3:20])[CH3:18])=[O:16])=[N:9][CH:8]=[CH:7]2
Reactant: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1nccc2cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)N(C(=O)C(C)(C)C)c1nccc2cc(N)ccc12
Yield: 104 %

Procedure:
6-Nitro-1-bis(tert-butyl carbonyl)aminoisoquinoline (75.00 g, 0.193 mol) in methanol/THF (500 ml/500 ml) was hydrogenated with a hydrogen balloon in the presence of Pd/C (5%, 5 g) for 2.0 h. Filtration of the Pd/C and concentration gave a solid, which was recrystallized from methanol to give 65.72 g (94.97%) of 1B as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (m, 18H) 4.18 (s, 2H) 6.89 (d, J=2.20 Hz, 1H) 6.99 (dd, J=9.01, 2.42 Hz, 1H) 7.35 (d, J=6.59 Hz, 1H) 7.75 (d, J=8.79 Hz, 1H) 8.22 (d, J=5.71 Hz, 1H). LC-MS: 741 (2M+Na)+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:19])[CH:7]=[CH:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]([CH3:4])[CH3:3].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:1]([NH:5][C:6](=[O:19])/[CH:7]=[CH:8]/[CH2:9][CH2:10]/[CH:11]=[CH:12]\[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)CNC(=O)C=CCCC#Cc1ccccc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC(C)CNC(=O)/C=C/CC/C=C\c1ccccc1
Yield: 60.5 %

Procedure:
N-Isobutyl-7-phenylhept-2-en-6-ynamide (100 mg) and 5% Pd/BaSO4 (17 ml) in dry methanol (3 ml) at 20° C. was treated with hydrogen until hydrogen uptake was 85% of theoretical. The mixture was diluted with methanol, filtered and the solvent was removed from the filtrate. The residue was treated with ether and the solvent removed in a stream of nitrogen. The product was purified by chromatography on silica (15 g), eluting with 1:1 ether:hexane grading to 100% ether to give N-isobutyl-7-phenylhepta-2E,6Z-dienamide (61 mg) as a yellow oil which crystallised on standing mp 42°-5° C.
Reaction SMILES: [CH3:1][C:2](=[C:5]([CH3:8])[CH2:6][CH3:7])[CH2:3][CH3:4].[CH3:9][SiH:10]([CH3:12])[Cl:11].[Al+3].[Cl-].[Cl-].[Cl-]>>[CH2:3]([C:2]([Si:10]([CH3:12])([CH3:9])[Cl:11])([CH3:1])[CH:5]([CH2:6][CH3:7])[CH3:8])[CH3:4]
Reactant: C[SiH](C)Cl
Reactant: CCC(C)=C(C)CC
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(C)C(C)(CC)[Si](C)(C)Cl

Procedure:
According to Example 2, 200 mg of 3,4-dimethylhex-3-ene, 0.2 ml (1.8 mmol) of dimethylchlorosilane and 50 mg (0.37 mmol) of AlCl3 are reacted and the product is worked up. This gives 180 mg (50% of theory) of colourless liquid of boiling point=95°-97° C./0.26 mbar.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([S:15]([NH:18][C:19]3[N:24]=[C:23]([NH:25]C(=O)OC(C)(C)C)[CH:22]=[C:21]([CH3:33])[CH:20]=3)(=[O:17])=[O:16])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:25][C:23]1[N:24]=[C:19]([NH:18][S:15]([C:11]2[S:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:13][C:12]=2[CH3:14])(=[O:17])=[O:16])[CH:20]=[C:21]([CH3:33])[CH:22]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(-c3ccc(C#N)cc3)nc2C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(NS(=O)(=O)c2sc(-c3ccc(C#N)cc3)nc2C)c1
Temperature: 24 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To a solution of tert-butyl [6-({[2-(4-cyanophenyl)4-methyl-1,3-thiazol-5-yl]sulfonyl}amino)-4-methylpyridin-2-yl]carbamate (0.334 g, 0.68 mmol, 1 equiv) in dichloromethane (3 mL) was added trifluoroacetic acid (0.21 mL, 4 equiv). The reaction mixture was stirred at 24° C. for 48 h. The solution was neutralized with saturated aqueous sodium bicarbonate, and the resulting solution was extracted with dichloromethane (3×20 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0→1% methanol in dichloromethane) provided the titled product N-(6-Amino-4-methylpyridin-2-yl)-2-(4-cyanophenyl)-4-methyl-1,3-thiazole-5-sulfonamide (0.22 g, 81%). 1H NMR (400 MHz, DMSO-d6), δ: 12.08 (br s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.95 (d, J=8.3 Hz, 2H), 6.62 (br s, 2H), 6.12 (s, 1H), 5.79 (s, 1H), 2.59 (s, 3H), 2.08 (s, 3H); HRMS (ESI): Calculated for C17H16N5O2S2 m/z 386.0740. Found: 386.0745;. Anal. Calcd for C17H15N5O2S2: C, 52.97; H, 3.92; N, 18.17; Found: C, 52.75; H, 3.76; N, 18.03.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:18]2[C:19](=[O:30])[C:20]3[C:25]([C:26](=[O:29])[C:27]=2[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=[CH:5][CH:4]=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>C1COCC1>[CH2:31]([NH:33][C:34]([O:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:18]1[C:19](=[O:30])[C:20]2[C:25]([C:26](=[O:29])[C:27]=1[CH3:28])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:35])[CH3:32]
Reactant: CCN=C=O
Reactant: COc1ccc(C(CCCCC(=O)NO)C2=C(C)C(=O)c3ccccc3C2=O)cc1
Solvent: C1CCOC1
Product: CCNC(=O)ONC(=O)CCCCC(C1=C(C)C(=O)c2ccccc2C1=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 49.4 %

Procedure:
To a solution of 6-(4-methoxyphenyl)-6-(3-methyl-1,4-naphthoquinon-2-yl)hexanohydroxamic acid (0.5 g) in THF was added a THF (2 ml) solution of ethyl isocyanate (0.1 g) at room temperature and the mixture was stirred for 2 hours. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1). The resulting oil was crystallized from hexane to provide the title compound (0.29 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[CH3:32][C:33]1([CH3:38])[CH2:37][CH2:36][NH:35][CH2:34]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:35]3[CH2:36][CH2:37][C:33]([CH3:38])([CH3:32])[CH2:34]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(CC(=O)O)cc1NC(=O)c1cnn2cccnc12
Reactant: CC1(C)CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1-c1nn(CC(=O)N2CCC(C)(C)C2)cc1NC(=O)c1cnn2cccnc12

Procedure:
To 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)acetic acid (31.9 mg, 0.075 mmol) in 1 mL DMF was added 3,3-dimethylpyrrolidine HCl (15 mg, 0.11 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (43 mg, 0.11 mmol), then triethylamine (42 uL, 0.30 mmol) and the whole stirred 30 min. The crude mixture was purified by reverse phase HPLC and lyophilized to afford 28.9 mg (76%) as a colorless solid. LCMS (ESI) m+H=508.1. 1H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 9.34 (d, J=6.9 Hz, 1H), 8.77 (s, 1H), 8.67 (s, 1H), 8.28 (s, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.37 (s, 1H), 7.30 (t, J=9.3 Hz, 2H), 5.09 (d, J=17.8 Hz, 2H), 3.85 (s, 3H), 3.62 (t, J=6.7 Hz, 1H), 3.43 (t, J=7.1 Hz, 1H), 3.29 (s, 1H), 3.12 (s, 1H), 1.74 (t, J=7.0 Hz, 1H), 1.63 (t, J=6.9 Hz, 1H), 1.08 (d, J=9.9 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:20]([CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCOc2ccccc2)cc1C(=O)OC

Procedure:
A mixture of dimethyl 4-hydroxyphthalate (2.1 g; 0.01 mole), 1-bromo-3-phenoxypropane (2.15 g; 0.01 mole) and anhydrous potassium carbonate (1.52 g; 0.015 mole) in dry butanone (30 ml) was stirred at reflux overnight and the cooled mixture filtered. Evaporation in vacuo afforded the title compound in quantitative yield. νmax (film) 1730, 1605 cm-1 ; τ(CDCl3) 7.77 (2H, quintet, J 6.5 Hz); 6.16 (3H,s); 6.11 (3H, s); 5.86 (2H, t, J 6.5 Hz); 5.78 (2H, t, J 6.7 Hz); 3.20°-2.55 (7H, m); 2.19 (1H, d, J 8.5 Hz); (Found; C, 65.98; H, 5.89; C19H20O6 requires; C, 66.27; H, 5.85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([N:27]2[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]2)=[CH:38][CH:37]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(N3CCN(C)CC3)cc2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 4-(4-methylpiperazin-1-yl)benzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-(4-methylpiperazin-1-yl)benzamido)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 532.0 (M)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](C(O)=O)=[CH:7][C:6]=2[C:13]=1[O:14][CH3:15].C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[C:13]=1[O:14][CH3:15]
Reactant: COc1c(F)ccc2sc(C(=O)O)cc12
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(F)ccc2sccc12
Temperature: 200 °C
Yield: 23.5 %

Procedure:
(2Z)-3-(3-Fluoro-2-methoxyphenyl)-2-mercapto-2-propenoic acid (4.865 g, 21.315 mmol) was added in one portion to a solution of iodine (8.255 g, 31.973 mmol) in dimethoxyetheane (30 mL). This was heated in the microwave with 300W at 120° C. for 25 mins. After this time the reaction was allowed to cool to room temperature and poured onto saturated sodium metabisulphite (200 mL) and ether (400 mL). Ether layer was separated and product extracted with aqueous sodium hydroxide (2 N, 2×100 mL). This was then acidified to pH 2 with aqueous hydrochloric acid (2 N, 250 mL), and product extracted with ether (2×150 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a tan coloured solid (3.240 g, 14.322 mmol, 67%). Which was used without further purification in the next step. 5-Fluoro-4-methoxy-1-benzothiophene-2-carboxylic acid (0.883 g, 3.903 mmol) was added in one portion to DBU (2.04 mL, 13.661 mmol) and dimethyl acetamide (10 mL). This was heated in the microwave with 300 W at 200° C. for 1 h. Reaction was allowed to cool and poured onto water (100 mL). Product was extracted with hexane (2×100 mL), washed with aqueous hydrochloric acid (2 N, 50 mL), aqueous sodium hydroxide (2 N, 50 mL), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ethyl acetate [96:4] to give a pale yellow oil (0.167 g, 23%); δH (300 MHz, CDCl3) 7.60-6.80 (4H, m, Ar), 4.10 (3H, s, OCH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14])=[O:23]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: Cc1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Cl)c1
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-methylphenyl isocyanate (0.60 ml, 5.01 mmol) in THF (20 ml) was added Et3N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-methylphenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-[N′-(2-methylphenyl)ureido]phenylacetate (1.23 g, 74%) as a colorless powder. 1H-NMR (CDCl3) δ2.34 (s, 3H, 3.54 (s, 2H), 3.68 (s, 3H), 6.24 (br, 1H), 6.99 (br, 1H), 7.15 (dd, J=8.3, 2.0 Hz, 1H), 7.21-7.31 (m, 5H), 7.44 (d, J=7.6 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H); MS (ESI) m/z 333 (M++1), 335 (M++3).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].O>O1CCOCC1>[CH3:1][NH:2][C:3]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:15](=[O:16])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a suspension of 4-(methylcarbamoyl)aniline (1.0 g) in 1,4-dioxane (10 ml) were added 1N sodium hydroxide solution (13.4 ml) and phenyl chloroformate (1.26 g) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was poured into water and extracted with a mixture of chloroform and methanol. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate to give phenyl 4-(methylcarbamoyl)phenylcarbamate (1.70 g) as pale yellow crystals.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].C([O:10][C:11](=O)[CH:12]([CH2:18][CH3:19])[C:13](OCC)=[O:14])C.[O-]CC.[Na+]>C(O)C>[CH2:18]([C:12]1[C:13]([OH:14])=[N:6][CH:5]=[N:7][C:11]=1[OH:10])[CH3:19]
Reactant: N=CN
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(O)ncnc1O

Procedure:
Formamidine acetate was reacted with diethyl-ethylmalonate in the presence of sodium ethoxide in dry ethanol to yield 5-ethylpyrimidine-4,6-diol, which was converted to 4,6-Dichloro-5-ethylpyrimidine by POCl3 in the presence of TEA in toluene. 4,6-Dichloro-5-ethylpyrimidine was then reacted with aqueous ammonia in n-butanol at 100° C. to afford 4-amino-5-ethyl-6-chloropyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].N([O-])=O.[Na+].[N-:21]=[N+:22]=[N-].[Na+]>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N+:21]=[N-:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccccc1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of (2-amino-benzyl)-carbamic acid tert-butyl ester [prepared from 2-aminobenzylamine and di-tert-butyl dicarbonate], (100 mg, 0.45 mmol) in acetic acid (2.46 mL), was added water (26 mL). Reaction mixture was cooled to 0° C. and a solution of sodium nitrite (62 mg, 0.9 mmol) in water (4.3 ml) was added. The reaction mixture was stirred for 30 min at the same temperature followed by addition of sodium azide (64 mg, 0.99 mmol). The reaction mixture was stirred at 0° C. for 30 min. When the reaction was complete as confirmed by TLC, reaction mixture was quenched by dropwise addition of 10 N NaOH (5.0 mL). The crude compound was extracted with ethylacetate (2×10 mL). Organic layer was separated, washed with brine, dried over Na2SO4 and the solvents were removed in vacuo to afford (2-azido-benzyl)-carbamic acid tert-butyl ester (105 mg, 96%) which was used as such without any further purification for the next step.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:12]3[CH2:13][N:14]([C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])[CH2:15][CH2:16][N:11]3[C:10](=[O:25])[O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>O1CCCC1.O>[O:25]=[C:10]1[N:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH:12]2[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:9]1
Reactant: O=C(C1CCNCC1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN1CCC(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)CC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 90.4 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-7-[(4-piperidinyl)carbonyl]-3H-oxazolo[3,4-a]pyrazin-3-one hydrochloride (0.20 g, 0.45 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in tetrahydrofuran (5 mL) was added ethyl bromoacetate (0.055 mL, 0.50 mmol) at 0° C., and the mixture was stirred at 0° C. for 2 hours and at room temperature for 20 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated and dried to a solid. The residue was purified with silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=9:1) to obtain the title compound (0.20 g, yield 90%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+].C>CC(C)=O.CC(O)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=c1ccc2ccc(OCCCCl)cc2o1

Procedure:
A mixture of 16.8 g (0.104 mole) of 7-hydroxycoumarin, 31.6 g (0.2 mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 24 hr. The mixture was filtered with difficulty to give a milky filtrate. The filtrate was treated wich charcoal and filtered through celite to give a clear filtrate. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and dried to yield 19.1 g (77%) of fluffy, white solid. An analytical sample, m.p. 100°-102° C., was obtained on recrystallization from 2-propanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[O:12]C>Br.CC(O)=O.C1(C)C=CC=CC=1>[F:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[OH:12]
Reactant: COc1c(F)ccc([N+](=O)[O-])c1F
Agent: Br
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)c(O)c1F

Procedure:
A solution of 1,3-difluoro-2-methoxy-4-nitrobenzene (0.50 g, 2.644 mmol) in 33% HBr in AcOH (4 mL) was heated at 100° C. for 1 h using microwave irradiation. The cooled reaction mixture was diluted with toluene and concentrated in vacuo. The resulting residue was partitioned between aqueous NaHCO3 and EtOAc. The aqueous phase was acidified with 1M HCl and extracted twice with DCM. The combined DCM extracts were washed with water, dried (Na2SO4) and concentrated in vacuo affording the title compound as a buff solid (0.29 g, 63%). 1H NMR (CDCl3, 300 MHz): 7.70 (1H, ddd, J=9.5, 7.8, 5.4 Hz), 7.06 (1H, ddd, J=9.4, 9.0, 2.2 Hz), 5.61 (1H, bs)