Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.C(OCC)C.I[C:11]1[N:12]=[C:13]2[CH2:19][CH2:18][O:17][C:16]3[CH:20]=[C:21]([C:24]([O:26][CH3:27])=[O:25])[CH:22]=[N:23][C:15]=3[N:14]2[C:28]=1[I:29].O1CCCC1>[NH4+].[Cl-]>[I:29][C:28]1[N:14]2[C:15]3[N:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]2=[N:12][CH:11]=1
Reactant: COC(=O)c1cnc2c(c1)OCCc1nc(I)c(I)n1-2
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cnc2c(c1)OCCc1ncc(I)n1-2
Reaction time: 0.29 h

Procedure:
Ethylmagnesium bromide in ethyl ether (3.0 M, 0.104 mL, 0.31 mmol)) was added dropwise to a suspension of methyl 9,10-diiodo-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate (130 mg, 0.26 mmol) in Tetrahydrofuran (5.0 mL, 62 mmol) at −15° C. The mixture was stirred for 15-20 min (a completion was monitored by LCMS), pour into 20 ml of sat. aq. NH4Cl and extracted with ethyl acetate. The organic extracts were washed with water (2×20 ml), brine, dried over MgSO4 and concentrated in vacuum. Weight 92 mg (94%). MS(ESI+): 372.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:3]=1[CH:4]=[O:5].P([O-])([O-])([O-])=[O:13].[Na+].[Na+].[Na+].OO.Cl([O-])=O.[Na+].S(=O)(O)[O-].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:3]=1[C:4]([OH:13])=[O:5]
Reactant: CCc1cccc(Cl)c1C=O
Reactant: O=P([O-])([O-])[O-]
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCc1cccc(Cl)c1C(=O)O
Reaction time: 15 h
Yield: 384.7 %

Procedure:
To a room temperature suspension of 2-chloro-6-ethylbenzaldehyde (13.5 mmol, 2.27 g) in acetonitrile (25 mL) was added a solution of monobasic sodium phosphate (3.4 mmol, 0.465 g) in water (7.5 mL) followed by hydrogen peroxide (1.8 mL, 30%). Then, a solution of sodium chlorite (23.7 mmol, 2.15 g) in water (20 mL) was added dropwise at 0° C. while maintaining the temperature below 3° C. After addition, the yellow suspension was stirred for 15 h at 0° C. to room temperature. At this time TLC analysis of the mixture indicated the absence of starting material. Then, a solution of sodium bisulfite (20.5 mmol, 2.8 g) in water (10 mL) was added dropwise at 0° C. until the yellow color disappeared (KI-paper positive). Cooling is essential to control the exothermic reaction. After 1 h, the solvent was removed under vacuum. The neutral impurities were extracted with diethyl ether (200 mL). Then, the basic aqueous solution was neutralized with 10% HCl to pH ˜1. The precipitated white solid was collected by filtration and dried at in air to afford 2.415 g (97% yield) of 2-chloro-6-ethylbenzoic acid as an amorphous white solid. EI-HRMS m/e calcd for C9H9ClO2 (M+) 184.0291, found 184.0295.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[K+].[C:8]([C:10]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=CC([O-])=O)#[N:9]>C(Cl)Cl>[C:8]([C:10]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:1][C:2]([Cl:4])=[O:3])#[N:9]
Reactant: N#CC(=CC(=O)[O-])c1cccs1
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Product: N#CC(=CC(=O)Cl)c1cccs1
Yield: 94.8 %

Procedure:
To a stirring solution of oxalyl chloride (81.17 mL, 0.93 mol) in CH2Cl2 (350 mL) was added 3-cyano-3-thiophen-2-yl-acrylic acid potassium salt 21 (100 g, 0.45 mol) portion-wise over 20 min. An additional 250 mL of CH2Cl2 were added to assist stirring. The slurry was stirred at room temperature for 30 min and was then filtered. The potassium chloride salts were washed with copious CH2Cl2. Collected organic rinses were combined and solvent removed under vacuum to afford 84.3 g of 22, which was carried on to the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([N:5]([CH2:14][C:15]#[N:16])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:4].[H][H]>C(OCC)(=O)C.[Pt]=O>[CH3:17][N:2]([CH3:1])[C:3]([N:5]([CH2:14][CH2:15][NH2:16])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:4]
Reactant: Cc1cc(C)nc(N(CC#N)C(=O)N(C)C)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(N(CCN)C(=O)N(C)C)c1

Procedure:
A solution of N,N-dimethyl-N'-(cyanomethyl)-N'-(4,6-dimethyl-2-pyridyl)urea from Part B (5.3 g., 0.023 mole) in ethyl acetate (100 ml.) containing platinum oxide (0.8 g.) is hydrogenated in a Parr apparatus at 50 psi of hydrogen until the required amount is taken up (12 hours). The catalyst is filtered off and the solvent removed under vacuum to give 4.6 g. of oily product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[OH:14][C:15]([C@H:18]1[CH2:22][CH2:21][NH:20][C@H:19]1[CH3:23])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:14][C:15]([C@H:18]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[C@H:19]1[CH3:23])([CH3:17])[CH3:16]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)cc1C(F)(F)F

Procedure:
Using 4-fluoro-3-(trifluoromethyl)benzonitrile (300 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (359 mg) and lithium carbonate (140 mg), the title compound was obtained as a colorless solid (yield: 180 mg) by an operation similar to that in Example 3.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[NH2:35][C:21]1[N:22]=[C:23]([C:25]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][N:31]([C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:32]3)=[CH:27][CH:26]=2)[CH:24]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]2)[N:20]=1
Reactant: O=C=NCc1ccccc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NCc3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from benzyl isocyanate (Aldrich, Cat. #227969) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=458.4.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20]CC)=[O:19])[CH2:14][C@H:13]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1>[C:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14]1)([OH:20])=[O:19]
Reactant: CCOC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
(1S,2R,4S)—N1-Benzyloxycarbonyl-N2-(tert-butoxy-carbonyl)-4-ethoxycarbonyl-1,2-cyclohexanediamine (620 mg) was dissolved in tetrahydrofuran (10 ml), and an aqueous solution (5.0 ml) of lithium hydroxide monohydrate (93 mg) was added to stir the mixture at room temperature for 16 hours. After lithium hydroxide monohydrate (221 mg) was additionally added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours, the reaction mixture was neutralized with 1N hydrochloric acid and extracted with methylene chloride. An organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (580 mg) as a colorless foamy substance.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:10][CH:11]=1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Reactant: NCCO
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NCCO)cn1
Yield: 90 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (80 mg, 0.26 mmol) was converted, using ethanolamine instead of 4-aminotetrahydropyran, to the title compound (82 mg, 90%) which was obtained as an off white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [OH-].[Li+].[C:3]([NH:6][C@@H:7]1[C@@H:12]([CH2:13][CH:14]2[CH2:16][O:15]2)[CH2:11][C:10]([C:17]([O:19]C)=[O:18])=[CH:9][C@H:8]1[O:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])(=[O:5])[CH3:4]>C1COCC1>[C:3]([NH:6][C@@H:7]1[C@@H:12]([CH2:13][CH:14]2[CH2:16][O:15]2)[CH2:11][C:10]([C:17]([OH:19])=[O:18])=[CH:9][C@H:8]1[O:21][CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])(=[O:5])[CH3:4]
Reactant: CCC(CC)O[C@@H]1C=C(C(=O)OC)C[C@H](CC2CO2)[C@H]1NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(CC)O[C@@H]1C=C(C(=O)O)C[C@H](CC2CO2)[C@H]1NC(C)=O
Reaction time: 10 h
Yield: 96.4 %

Procedure:
Aqueous lithium hydroxide solution (0.1N, 15 mL) was added to a room temperature solution of Example 4A (40 mg, 0.118 mmol) in THF (5 mL). The solution was stirred for 10 hours, acidified to pH 5-6 with DOWEX® 50WX2-200 ion-exchange resin, filtered and concentrated. The concentrate was purified by flash chromatography on silica gel using acetic acid/ethyl acetate (1/5) to afford 37 mg (96%) of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(OCC)(=O)C>[CH3:14][S:15]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(F)(F)F
Reaction time: 1 h

Procedure:
To a mixture of 2,2,2-trifluoroethanol (5 g), triethylamine (14 ml) and ethyl acetate (120 ml) was added dropwise methanesulfonyl chloride (5.8 ml) with cooling it on ice, and stirred at this temperature for 1 hour. The reaction solution was filtered through a small amount of silica gel, followed by NH silica gel, which in turn was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to yield the title compound (9.5 g).
Reaction SMILES: [CH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.[Li]C(CC)C.CN(CCN(C)C)C.[Si:20](Cl)([CH3:23])([CH3:22])[CH3:21]>>[CH:1]1([Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:6]=[CH:5][CH2:4][CH:3]=[CH:2]1
Reactant: C[Si](C)(C)Cl
Reactant: C1=CCC=CC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Product: C[Si](C)(C)C1C=CCC=C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
1,4-Cyclohexadiene (0.47 mL, 5 mmol, 1 eq.) was dissolved in TBF (8 mL), cooled to −78° C. and s-BuLi (4.5 mL, 1.2 M, 5.5 mmol, 1.1 eq.) was added slowly. The resulting solution was treated with TMEDA (0.77 mL, 5 mmol, 1 eq.) and the reaction was allowed to warm to −45° C. over 2 hours. Me3SiCl (0.7 mL, 5.5 mmol, 1.1 eq.) was added, the reaction mixture was stirred for 1 hour at room temperature and then quenched with H2O and Et2O. The organic layer was separated and washed with H2O (2×30 mL), (aq) sat. NH4Cl (30 mL), brine (30 mL) and dried over MgSO4. Removal of the solvent in vacuo and distillation using Kugelrohr apparatus (30 mbar, 70° C.) afforded the product as colourless oil (0.53 g, 3.47 mmol, 70% yield): 1H NMR (400 MHz, CDCl3), δ 5.56 (2H, m, H-3), 5.55 (2H, m, H-4), 2.69 (2H, m, H-5), 2.22 (1H, m, H-2), 0.03 (9H, s, H-1); 13C NMR (100 MHz, CDCl3) δ 126.31 (C-3), 121.33 (C-4), 31.52 (C-5), 26.40 (C-2), −3.55 (C-1); IR (CDCl3, cm−1) 3027 (m, C—H), 2959 (m, C—H), 1622 (w, C═C), 743, (m, C—H); MS (FI+, m/z), 152.10 [M].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[NH:7][CH:6]=1)=O.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([NH2:30])=[S:29])[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C([O-])(O)=O.[Na+]>C1COCC1>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[S:29][CH:2]=[C:3]([C:5]3[C:13]4[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=4)[NH:7][CH:6]=3)[N:30]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(CBr)c1c[nH]c2ncc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3c[nH]c4ncc(Br)cc34)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a solution of 70 (1.71 g, 5.38 mmol) in THF (20 mL) was added 1-Boc-4-aminothiocarbonyl piperidine (1.31 g, 5.36 mmol) and the solution was allowed to stir at r.t. for 3 h. The reaction mixture was then poured onto saturated aqueous NaHCO3 (50 mL) and extracted with AcOEt (2×50 mL). The combined organic portions were then evaporated to afford 71 (2.58 g, 5.41 mmol, 100%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.64-1.84 (m, 4H), 2.07-2.17 (m, 2H), 2.81-2.94 (m, 2H), 3.13-3.24 (m, 1H), 7.17 (s, 1H), 7.74 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.97 (br s, 1H).
Reaction SMILES: N#N.Br[C:4]1[C:12]2[O:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[Li]CCCC.CON(C)[C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)=[O:26]>C1COCC1>[C:13]([C:10]1[O:11][C:12]2[C:4]([C:25]([C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]3)=[O:26])=[CH:5][CH:6]=[CH:7][C:8]=2[CH:9]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)c1cc2cccc(Br)c2o1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc3cc(C(C)(C)C)oc23)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
Under protection of N2, a solution of 7-bromo-2-tert-butyl-benzofuran (0.5 g, 1.98 mmol) in anhydrous THF (5 mL) was cooled to −78° C. and 2.5 M n-BuLi solution in hexanes (0.87 mL, 2.18 mmol) was added dropwise slowly. The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (0.65 g, 2.38 mmol) in anhydrous THF (5 mL) was added dropwise slowly. The reaction mixture was warmed to rt and stirred overnight. The mixture was quenched with satd aq NH4Cl (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4. Solvent removal and flash column chromatography afforded (R)-tert-butyl 3-(2-tert-butylbenzofuran-7-carbonyl)piperidine-1-carboxylate (0.41 g, 54%). 1H NMR (CDCl3): 7.83 (d, 1H), 7.19 (d, 1H), 7.26 (t, 1H), 6.440 (s, 1H), 4.1 (d, 1H), 3.75 (s, 1H), 2.83 (t, 1H), 2.27 (d, 1H), 1.82 (d, 1H), 1.590 (m, 4H), 1.426 (s, 9H), 1.406 (s, 9H)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C(C)Br
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)n1ccnc1
Temperature: 25 °C
Yield: 10.9 %

Procedure:
A solution of imidazole (5.0 g, 0.074 mol), ethyl 2-bromopropanoate (7.6 ml, 0.06 mol) and K2CO3 (11.2 g, 0.08 mol) in DMF (120 ml) was heated at 90° C. for 2 h. After this time the solution was cooled to room temperature, filtered and the filtrate diluted with EtOAc (200 ml). The mixture was washed with water (2×20 ml) and the organic phase separated. The combined aqueous layers were washed with EtOAc (200 ml) and the combined organic layers washed with brine (200 ml). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica, eluting with CH2Cl2 :MeOH (95:5), to afford the ester (1.1 g, 9%) as a pale yellow oil. 1H NMR (250 MHz, CDCl3) δ 1.26 (3H, t, J=7.1 Hz), 1.75 (3H, d, J=7.3 Hz), 4.20 (2H, q, J=7.1 Hz), 4.85 (1H, q, J=7.3 Hz), 7.02-7.04 (1H, m), 7.08-7.10 (1H, m), 7.58 (1H, s).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][CH:9]=[N:8]1)C.[CH3:15][NH2:16]>C(O)C>[CH3:15][NH:16][C:4](=[O:3])[CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: CCOC(=O)CCn1ncccc1=O
Reactant: CN
Solvent: CCO
Product: CNC(=O)CCn1ncccc1=O
Temperature: 40 °C
Reaction time: 30 h
Yield: 82 %

Procedure:
Next a mixture of 1.96 g (0.01 mole) of ethyl-3-(3-oxo-2-pyridazinyl)propionate and 20 ml of methylamine (30% ethanol solution was stirred at 40° C. for 30 hours and distilled to give white crystals. Recrystallization from ethanol gave 1.6 g (82% yield of N-methyl-3-(3-oxo-2-pyridazinyl)propionamide, m.p. 94°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=43)[C:8](=[O:26])[C:7]=2[CH:27]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=43)[C:8](=[O:26])[C:7]=2[CH:27]=1
Reactant: COC(=O)CCc1c2n(c(=O)c3cc(OC)ccc13)CCc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(CCC(=O)O)c3n(c(=O)c2c1)CCc1ccccc1-3

Procedure:
3.4 g (9.36 mmol) of methyl 10-methoxy-8-oxo-5,8-dihydro-6H-dibenzo[a,g]quinolizine-13-propanoate dissolved in 50 ml of ethanol are introduced into a 100 ml round-bottomed flask, 3 ml of aqueous 30% sodium hydroxide are added and the mixture is heated at reflux for 3 h.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].C(C1C=C(C=C(OC(C)C)C=1)C(O)=O)#N>>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][C:14]([F:15])([F:16])[F:17])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(C#N)cc(OC(F)(F)F)c1
Agent: CC(C)Oc1cc(C#N)cc(C(=O)O)c1
Product: N#Cc1cc(OC(F)(F)F)cc(C(=O)O)c1

Procedure:
Prepared from methyl 3-cyano-5-(trifluoromethoxy)benzoate according to the procedure for 3-cyano-5-isopropoxybenzoic acid. LCMS-ESI (m/z) calculated for C9H4F3NO3: 231.1; no m/z observed, tR=2.38 min.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[CH2:12][CH2:13][CH2:14][CH3:15])(=O)OC.[CH3:19][O:20][C:21](=[O:43])[CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][C@H:28]1[C@H:32]([Cl:33])[CH2:31][C@@H:30]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C@@H:29]1[CH:41]=O.C(O)(=O)C>C(COC)OC.O1CCCC1.C(OCC)C.O>[CH3:19][O:20][C:21](=[O:43])[CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][C@H:28]1[C@H:32]([Cl:33])[CH2:31][C@@H:30]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C@@H:29]1/[CH:41]=[CH:9]/[C:10](=[O:18])[C:11]([CH3:16])([CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(C)(C)C(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1OC1CCCCO1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
294 mg of 55% sodium hydride is suspended in 25 ml of dimethoxyethane, and 1.53 g of 3,3-dimethyl-2-oxoheptanephosphonic acid dimethyl ester is instilled. It is stirred for another 30 minutes, cooled to -20° C., and a solution of 1.98 g of VII in instilled in 10 ml of dimethoxyethane and 10 ml of tetrahydrofuran. After 1 hour it is allowed to warm to room temperature, mixed with 0.5 ml of glacial acetic acid, diluted with 200 ml of diethyl ether, shaken three times with 20 ml of salt water each, dried over magnesium sulfate and evaporated in a vacuum to dryness. The residue is chromatographed on silica gel with hexane/5-25% diethyl ether. 1.62 g of VIII is obtained as colorless oil. IR: 2998, 2955, 2863, 1730, 1684, 1621, 1437, 1060, 978/cm.
Reaction SMILES: [CH3:1][C:2](O)([CH3:5])[CH2:3][NH2:4].O=S(Cl)Cl.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[S:21]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]1[NH:4][CH2:3][C:2]([CH3:5])([CH3:1])[S:21]1
Reactant: CC(C)(O)CN
Reactant: S=C=Nc1cccc(Cl)c1Cl
Solvent: O=S(Cl)Cl
Product: CC1(C)CNC(=Nc2cccc(Cl)c2Cl)S1

Procedure:
2-Methyl-2-hydroxypropylamine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-5,5-dimethyl-1,3-thiazolidine. 2-(2,3-Dichlorophenylimino)-5,5-dimethyl-1,3-thiazolidine was reacted with ethylene oxide according to Method B5b to afford 2-(2,3-dichlorophenylimino)-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[O:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=1)[N+:1]([O-:4])=[O:3]
Reactant: OCc1cccc(Cl)n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])OCc1cccc(Cl)n1

Procedure:
Fuming nitric acid (1.57 ml) was added dropwise to acetic anhydride (3.54 ml) with stirring at 0° to 5° C. 2-Hydroxymethyl-6-chloropyridine (3.59 g) was added thereto. The resulting mixture was stirred for 20 minutes at 0° C. to 5° C. The resulting mixture was alkalized weakly with an aqueous potassium carbonate solution, extracted with chloroform, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to column chromatography on aluminum oxide (40 g) and eluted with toluene. The fractions containing the desired compound were concentrated under reduced pressure to give colorless viscous oil of 2-nitroxymethyl-6-chloropyridine (2.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH3:12])(=[O:10])=[O:9].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][CH3:12])(=[O:10])=[O:9])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: CNS(=O)(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 45 °C
Reaction time: 15 h
Yield: 49.5 %

Procedure:
A mixture of 2-amino-N-methyl-benzenesulfonamide (2.93, 15.75 mmol), 2,4,5 trichloropyrimidine (2.9 g, 15.84 mmol) and K2CO3 (4.5 g, 32.6 mmol) in dry DMF (25 mL) was stirred at 45° C. for 15 h. The solvent was removed and the residue was taken in water and was extracted twice from ethylacetate. Combined organic was washed with water and brine. After drying solvent was removed. Upon triturating with ether and filtration gave the product 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide 7 as a white solid (2.6 g, 50%); 1H NMR (400 MHz, CDCl3) δ9.61 (s, 1H), 8.6 (d=12.89 Hz, 1H), 8.53 (s, 1H), 8.27 (s, 1H), 7.68 (m, 1H), 7.27 (m, 1H0, 1.66 (br s, 1H0, 2.66 (s, 3H).