Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:14]([Br:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]1[CH2:10][CH2:9][CH2:8]1)=[O:5].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[Br:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:3]2[C:2]=1[NH:1][C:17](=[O:19])[N:6]([CH:7]1[CH2:8][CH2:9][CH2:10]1)[C:4]2=[O:5]
Reactant: Nc1c(Br)cccc1C(=O)NC1CCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CCC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 326.4 %

Procedure:
A mixture of 2-amino-3-bromo-N-cyclobutylbenzamide (2.127 g, 7.90 mmol) and triphosgene (0.797 g, 2.69 mmol) in DCM (80 mL) was heated at reflux (using a water-cooled reflux condenser) for 17 h. The reaction mixture was then concentrated in vacuo, and the residue was taken up in toluene (80 mL) and heated at 110° C. for 1.5 h. Additional triphosgene (0.040 g, 014 mmol) was added, and the resulting solution was stirred at 110° C. for 45 min. The reaction mixture was then cooled to RT and concentrated in vacuo to give crude 8-bromo-3-cyclobutylquinazoline-2,4(1H,3H)-dione (2.59 g, 8.78 mmol) as a light-yellow solid. m/z (ESI, +ve) 295.0/297.0 (M+H)+. This material was used directly in the subsequent transformation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[O:30][N:29]=2)[CH:27]=1)[C:22](O)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]2[N:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[O:30][N:29]=2)[CH:27]=1)[C:22]([NH:15][CH2:14][C:13]([C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)([CH3:17])[CH3:16])=[O:23]
Reactant: CC(C)(CN)c1nc(-c2ccc(F)cc2)cs1
Reactant: O=C(O)c1cc(F)cc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cc(F)cc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(F)cc2)cs1
Yield: 32 %

Procedure:
This compound was synthesized from 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and 3-fluoro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (23 mg, yield 32%): 1H NMR (400 MHz, CDCl3) δ 8.32 (br s, 1H), 8.23 (br t, J=5 Hz, 1H), 7.94 (br d, J=8 Hz, 1H), 7.86-7.75 (m, 3H), 7.06-7.00 (m, 2H), 3.78 (d, J=4 Hz, 2H), 1.55, (s, 6H). MS (ESI) m/z: Calculated for C23H17F6N4O2S: 508.10. found: 509.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]([O:20]CC)=[O:19].[Li+].[OH-]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CCCOc1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1[nH]c2ccccc2c1CCCOc1cccc(Cl)c1

Procedure:
A mixture of EXAMPLE 3B (0.035 mg) and LiOH (0.1 g) in methanol/water (1:1, 5 mL) was heated at 150° C. under microwave (CEM Discover) conditions (70 W) for 10 minutes. The reaction mixture was concentrated, diluted with water (2 mL), treated with 5 MHCl, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered and concentrated. The concentrate was purified by reverse phaseHPLC (Zorbax SB, C-18, 20% to 100% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (400 MHz, DMSO-d6) δ 12.88 (brs, 1H), 11.40 (s, 1H), 7.63 (d, 1H), 7.39 (d, 1H), 7.24 (m, 2H), 6.92 (m, 4H), 3.97 (t, 2H), 3.20 (t, 2H), 2.05 (m, 2H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:21][N:22]([CH3:25])C=O>C(O)C.C1C2C(=CC=CC=2)CCN1>[CH2:21]1[C:9]2[C:8](=[CH:7][CH:6]=[CH:11][CH:10]=2)[CH2:12][CH2:25][N:22]1[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:7]=1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Reactant: CN(C)C=O
Agent: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCc2ccccc2C1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 1,2,3,4-tetrahydroisoquinoline in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=402.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]=[C:11]=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:18](=[O:19])[CH2:17][N:16]([CH:13]([CH3:15])[CH3:14])[C:11]3=[S:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)NCC(=O)O
Reactant: S=C=Nc1ccc2c(c1)CCC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)N1CC(=O)N(c2ccc3c(c2)CCC3)C1=S
Yield: 36.1 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 17.5 g of indan-5-yl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (9.9 g) as a white solid, m.p. 178°-180° C. Anal. Calcd. for. C15H18N2O S: C, 56.66; H, 6.61; N, 10.21. Found: C, 56.70; H, 6.67; N, 10.22. Mass spectrum (EI, M.+) m/z 274.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14](=[O:35])[N:15]([CH2:32][CH2:33][CH3:34])[C:16](=[O:31])[N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:18]=1[NH2:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[NH:12][C:13]3[C:14](=[O:35])[N:15]([CH2:32][CH2:33][CH3:34])[C:16](=[O:31])[N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)[C:18]=3[N:19]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3ccc(F)cc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 4-fluorophenylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By the methods of Example 3 and Example 4, 8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is alkylated with a mixture of 1,2-dichloroethane and 2-(ethylamino)ethanol, to afford 7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-fluorobenzyl-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine, which, in turn, is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-8-(4-fluorobenzyl)-1-propylxanthine free base. The corresponding dihydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][CH3:16])[C:13]([CH2:17][CH2:18][OH:19])=[N:12][C:11]=2[CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:25]([N:27]=C=O)=[O:26]>O1CCCC1.O>[C:25]([O:19][CH2:18][CH2:17][C:13]1[N:14]([CH2:15][CH3:16])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:20]([CH3:21])[CH3:22])[N:12]=1)(=[O:26])[NH2:27]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCn1c(CCO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(CCOC(N)=O)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 88.8 %

Procedure:
In 15 ml of dry tetrahydrofuran was dissolved 1.5 g (4.2 mmol) of the alcohol compound (123a), and the mixture was cooled to -30° C., followed by addition of 1.2 g (6.4 mmol) of trichloroacetylisocyanate. After 5 minutes, the mixture was warmed to 0° C., and stirred for 10 minutes. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water, and ethyl acetate was distilled off. To the residue was added 15 ml of methanol, 0.26 g of triethylamine and 0.72 ml of water, and the mixture was heated at 50° C. for 0.5 hours. The mixture was diluted with ice-water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% methanol:ethyl acetate), and recrystallized from ethyl acetate-n-hexane to give 1.5 g of Compound I-137 as crystals (yield 89%). mp 161-162° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1B(O)O)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: Cn1cc(Nc2cc(Br)cn(C)c2=O)nn1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3cn(C)nn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 37.3 %

Procedure:
Following the procedure in Example 283b, and starting with 293c (150 mg, 0.53 mmol, 1.0 eq.) and {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (629 mg, 1.59 mmol, 3.0 eq.) afforded 293d as a yellow solid (110 mg, 37%). MS-ESI: [M+H]+ 557.4.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[C:16]2[C:11]3=[C:12]([C:17](=[O:21])N[C:19](=[O:20])[C:10]3=[CH:9][CH:8]=1)[CH:13]=[CH:14][CH:15]=2>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:17](=[O:21])[C:12]2=[C:11]3[C:16](=[CH:15][CH:14]=[CH:13]2)[C:7]([Cl:6])=[CH:8][CH:9]=[C:10]3[C:19]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1NC(=O)c2ccc(Cl)c3cccc1c23
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Yield: 76.2 %

Procedure:
This compound has been reported previously. This preparation is similar to previously reports (see e.g. Daffy et al. Chem-Eur J 1998, 4, 1810-1815; de Silva et al., Chem Rev 1997, 97, 1515-1566). A portion of n-butylamine (5.00 mL, 50.6 mmol) was added to a suspension of 4-chloronaphthalene-1,8-dicarboximide (11.7 g, 50.5 mol) in 160 mL of toluene. This mixture was brought to reflux for 17 hours to give a dark black-brown solution. Crystallization from hexanes/toluene at −10° C. gave 1ax as a pure brownish-yellow powder (11.1 g, 76%). 1H NMR: δ=8.65 (d, 1H, J=7.4 Hz), 8.58 (d, 1H, J=8.6 Hz), 8.49 (d, 1H, J=7.9 Hz), 7.85 (t, 1H, J=7.9 Hz), 7.81 (d, 1H, J=7.9 Hz), 4.18 (t, 2H, J=7.6 Hz), 1.72 (m, 2H), 1.45 (m, 2H), 0.98 (t, 2H, J=7.4 Hz). 13C{1H} NMR: δ=163.8, 163.5, 139.0, 132.0, 131.2, 130.6, 129.3, 129.1, 127.9, 127.5, 123.2, 121.7, 40.5, 30.3, 20.5, 14.0. ESI/MS m/z.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:15]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:15])=[O:8]
Reactant: CO
Reactant: O=C(O)CCCCCBr
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCBr

Procedure:
A solution of 6-bromohexanoic acid (10 g) in 50 ml of methanol to which was added 1.0 ml of concentrated sulfuric acid is heated under reflux for 8 hours. The methanol is distilled off, the residue is dissolved in ether. The ether solution is washed free of acid with water, dried over sodium sulfate and evaporated to dryness. Distillation at 0.8 mm Hg gives methyl 6-bromohexanoate, b.p. 85°-90°/0.8 mm.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1.O>CS(C)=O>[N+:26]([C:23]1[CH:22]=[N:21][C:20]([O:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
7.6 g of anhydrous sodium carbonate and 9.8 g of 2-chloro-4-trifluoromethylphenol were added to 20 ml of dimethyl sulfoxide, and a solution having 7.9 g of 2-chloro-5-nitropyridine dissolved in 10 ml of dimethyl sulfoxide was added dropwise thereto at room temperature (i.e., about 20° to 30° C.) while stirring. After completion of the dropwise addition, the mixture was allowed to react at 50° C. for 30 minutes. After completion of the reaction, the reaction product was poured into water, followed by extracting with methylene chloride. The extracted phase was washed with water and dried, and the solvent was then distilled off to obtain 13 g of a crystal. The thus obtained crystal was recrystallized from n-hexane to obtain 9.8 g of a titled compound having a melting point of 69° to 72° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4](Cl)[CH2:5][S:6][CH3:7].[N-:10]=[N+:11]=[N-:12].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH3:1][O:2][C:3](=[O:9])[CH:4]([N:10]=[N+:11]=[N-:12])[CH2:5][S:6][CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C(Cl)CSC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(CSC)N=[N+]=[N-]
Yield: 87.5 %

Procedure:
6.0 grams (35.5 mmoles) of the 2-chloro-3-methylmercapto-propionic acid methyl ester produced in Example 5 were stirred with 3.47 grams (53.4 mmoles) of sodium azide and 0.82 grams of Aliquat 336 in 15 ml of water for 7 hours at 45° C. After working up according to Example 2 there were obtained 5.44 grams (87% of theory) of 2-azido-3-methylmercapto-propionic acid methyl ester as an analytically pure material.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cu](C#N)[C:14]#[N:15]>CN(C=O)C>[C:14]([C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:15]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1cc(Br)ccc1O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)ccc1O
Temperature: 140 °C
Reaction time: 20 h

Procedure:
A suspension of methyl 5-bromo-2-hydroxybenzoate (2 g, 8.66 mmol) and copper cyanide (1.861 g, 20.78 mmol) in DMF (30 ml) was stirred under nitrogen at 140° C. for 20 h. The reaction mixture was then cooled, quenched with water (120 ml) and extracted with ethyl acetate (3×80 ml). The organic phase was washed with saturated brine (50 ml), dried over sodium sulphate and evaporated in vacuo to yield the title compound as a white solid. 1 g.
Reaction SMILES: [K].[C:2]([OH:10])(=[S:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][CH2:12]SC#N>CO>[Cl:11][CH2:12][O:10][C:2](=[S:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OC(=S)c1ccccc1
Reactant: N#CSCCl
Agent: [K]
Solvent: CO
Product: S=C(OCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
28 g (0.16 mol) of the potassium salt of thiobenzoic acid were dissolved in 550 ml of methanol, and 17 g (0.16 mol) of chloromethyl thiocyanate were added dropwise at -5°. After slowly warming the reaction mixture to room temperature, it was subsequently stirred at 40° for a further 30 minutes and concentrated, the residue was extracted by shaking with water/ethylene chloride, the organic phase was concentrated and the oily residue was freed from chloromethyl thiocyanate residues by heating to 80°-100°/0.5 to 2 mm Hg for several hours; yield 30 g (this corresponds to a yield of 90% of the theretical conversion).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][CH2:8][C:9]1[CH:17]=[CH:16]C(C(O)=O)=[CH:11][CH:10]=1>ClCCl.CN(C)C=O>[Cl:7][CH2:8][C:9]1[CH:17]=[CH:16][C:1]([C:2]([Cl:4])=[O:3])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(CCl)cc1
Reaction time: 1 h

Procedure:
Oxalyl chloride (4.4 mL of 2M in chloroform, 8.8 mmol) was added to a suspension of 4-(chloromethyl)benzoic acid (1 g, 5.7 mmol) in dichloromethane. N,N-dimethylformamide (4 drops) was added to catalyze the reaction. After 1 hour analysis by HPLC indicated 100% clean conversion. The reaction mixture was concentrated under vacuum to provide 4-(chloromethyl)benzoyl chloride.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[CH2:13][CH2:12][N:11]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: C[C@H]1CC[C@@H](N2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCN([C@H]3CC[C@@H](C)CC3)CC2)cc1
Temperature: 140 °C
Reaction time: 9 h

Procedure:
A mixture of cis-1-(4-methylcyclohexyl)piperazine (29.6 g), ethyl 4-fluorobenzoate (41.0 g) and potassium carbonate (67.3 g) in DMSO (300 ml) was stirred at 140° C. for 9 hours. The reaction mixture was poured into water (1.2 l) and extracted twice with ethyl acetate (400 ml). The extracts were collected, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (1 l) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give ethyl 4-[cis-4-(4-methylcyclohexyl)-1-piperazinyl]benzoate (37.64 g).
Reaction SMILES: COC(C1C=C(C2C=CC(F)=CC=2)SC=1C(=O)[NH:18][CH2:19][C:20]([O:22]CC)=[O:21])=O.CO[C:28]([C:30]1[S:31][C:32]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[CH:33][C:34]=1[C:35](=O)[NH:36][CH2:37][C:38]([O:40]CC)=O)=[O:29]>>[F:50][C:47]1[CH:46]=[CH:45][C:44]([C:32]2[S:31][C:30]3[C:28]([OH:29])=[C:37]([C:38]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:40])[N:36]=[CH:35][C:34]=3[CH:33]=2)=[CH:49][CH:48]=1
Reactant: CCOC(=O)CNC(=O)c1sc(-c2ccc(F)cc2)cc1C(=O)OC
Reactant: CCOC(=O)CNC(=O)c1cc(-c2ccc(F)cc2)sc1C(=O)OC
Product: O=C(O)CNC(=O)c1ncc2cc(-c3ccc(F)cc3)sc2c1O

Procedure:
The title compound was prepared from 2-(ethoxycarbonylmethyl-carbamoyl)-5-(4-fluoro-phenyl)-thiophene-3-carboxylic acid methyl ester and 3-(ethoxycarbonylmethyl-carbamoyl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid methyl ester, example 34-a, under conditions analogous to experimental example 30-f. MS: (+) m/z 362.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH3:31])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH3:31])[C:42](=[O:43])[O:44][CH3:45])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reaction time: 18 h
Yield: 17 %

Procedure:
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials, 217 mg) and DIPEA (0.2 ml) were stirred in DCM (20 ml). Methyl chloroformate (0.043 ml) was added slowly and the resulting solution was stirred for 18 hours. The solution was evaporated and the residue purified by chromatography, eluting with increasing concentrations of methanol in ethyl acetate (5-10%). The appropriate fractions were evaporated to give an oil, which was triturated with acetonitrile to give the title compound as a solid (43 mg, 17%); NMR spectrum (DMSO-d6 @ 373K) 2.88 (s, 3H), 3.30 (s, 3H), 3.75-3.85 (t, 2H), 4.35-4.55 (bs, 2H), 5.30 (s, 2H), 7.10-7.30 (m, 2H), 7.30-7.40 (m, 2H), 7.50-7.60 (m, 2H), 7.70-7.78 (t, 1H), 7.80-7.95 (m, 2H), 8.43 (bs, 1H), 8.75-8.80 (d, 1H), 9.60-9.80 (bs, 1H); Mass spectrum MH+ 494.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a 0° C. solution of 4-(6-fluorobenzo[b]thien-3-yl)-1-piperazine-butanamine (4.04 g, 13.1 mmol), triethylamine (1.89 g, 18.6 mmol), and dichloromethane (50 mL) under a nitrogen atmosphere was added isobutyryl chloride (1.63 g, 15.3 mmol) over 6 minutes. The reaction was stirred at 0° C. for 4 hours and then was diluted with dichloromethane (140 mL). The mixture was washed successively with 5% aqueous NaOH (100 mL) and water (100 mL), dried (K2CO3), and concentrated in vacuo to give an off-white solid. The crude product was chromatographed on silica gel with 10% methanol/dichloromethane as eluent to afford an off-white solid. Recrystallization from ethyl acetate/heptane gave 2.17 g (43%) of the title compound as beige needles: m.p. 130°-131° C. TLC (silica gel, 10% methanol/dichloromethane) Rf =0.37. The IR(CHCl3), 1H NMR (CDCl3, 200 MHz), and MS (M+ 377, EI, 70 eV) were consistent for the assigned structure.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]([CH3:5])[CH3:4].C([Li])CCC.[CH3:30][C:31]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]=O)=[CH:42][C:41]=1[O:48][CH3:49])=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH3:30][C:31]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]=[CH:2][CH:3]([CH3:5])[CH3:4])=[CH:42][C:41]=1[O:48][CH3:49])=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=C(C)COc1ccc(C=O)cc1OC
Agent: [Br-]
Agent: [Li]CCCC
Product: CCOC(=O)C=C(C)COc1ccc(C=CC(C)C)cc1OC

Procedure:
Following the above procedures, isobutyltriphenylphosphonium bromide (9.60 g, 24.0 mmol), n-butyllithium (9.0 mmol) and ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2butenoate (1.67 g, 6.0 mmol) are reacted together to give ethyl 3-methyl-4-[2-methoxy-4-(3-methyl-1-butenyl)phenoxy]2-butenoate, MS m/e 318 (M+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:18][O-:19].[Na+]>CO.[Cl-].[Na+].O>[F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N:4][C:5]([O:19][CH3:18])=[CH:6][CH:7]=1
Reactant: Fc1cccc(CNc2nc(F)ccc2F)c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(NCc2cccc(F)c2)n1
Temperature: 150 °C
Yield: 62.2 %

Procedure:
3,6-difluoro-N-(3-fluorobenzyl)pyridine-2-amine (0.5209 g, 2.19 mmol), was dissolved in anhydrous MeOH (6.6 mL) and placed under argon. This mixture then was treated with sodium methoxide (0.500 mL, 0.473 g, 2.19 mmol, 25% in MeOH) by slow addition. The resulting mixture was then heated in the microwave at 150° C. for four 30 min. The reaction mixture was then poured into brine (25 mL). This mixture was extracted with EtOAc (3×25 mL), the combined extracts were washed with brine (1×25 mL) and dried (Na2SO4). After filtration the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 100 hexanes to 25 EtOAc/75 hexanes afforded 0.3408 g (62%) of 3-fluoro-N-(3-fluorobenzyl)-6-methoxypyridin-2-amine. LCMS (m/z): 251.1 (MH+), retention time=1.07 min.