Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][CH3:18])=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]([CH3:11])[C:7](=[O:10])[CH:8]=[CH2:9].C(N(C(C)C)CC)(C)C.Br[C:29]1[CH:42]=[N:41][C:32]2[NH:33][C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[NH:36][CH2:37][C:31]=2[CH:30]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][CH3:18])=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]([CH3:11])[C:7](=[O:10])/[CH:8]=[CH:9]/[C:29]1[CH:42]=[N:41][C:32]2[NH:33][C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[NH:36][CH2:37][C:31]=2[CH:30]=1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1cccc(Cl)c1OCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1c(Cl)cccc1CN(C)C(=O)/C=C/c1cnc2c(c1)CNC(C)(C)C(=O)N2
Yield: 59.1 %

Procedure:
A solution of N-(3-chloro-2-propoxybenzyl)-N-methylacrylamide (0.392 g, 1.47 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.40 mL, 2.33 mmol) and 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.11 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.111 mmol) and P(o-tol)3 (0.067 g, 0.222 mmol) were then added and the solution was deoxygenated again with Ar for 20 min. The mixture was heated to reflux for 18 h, then allowed to cool. The mixture was diluted with EtOAc (30 mL) and was washed with H2O (3×50 mL). The organic layer was washed with brine (1×100 mL), dried (Na2SO4) and concentrated to an orange oil. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.30 g, 59%) as a light yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.78 (m, 1H), 8.40-8.37 (m, 1H), 8.01-7.92 (m, 1H), 7.54-7.49 (m, 1H), 7.41-7.25 (m, 2H), 7.15-7.05 (m, 2H), 4.86-4.68 (m, 2H), 3.91-3.84 (m, 4H), 3.14-2.95 (m, 4H), 1.83-1.76 (m, 2H), 1.31-1.29 (m, 6H), 1.05-0.99 (m, 3H).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.[C:30]([O-])([O-])=[O:31].[K+].[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:30]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]3)=[CH:4][CH:3]=2)=[O:31])[CH:22]=1
Reactant: OB(O)c1cccnc1
Reactant: CCOC(=O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1=Cc2ccc(C(=O)c3cccnc3)cc2OC1C(F)(F)F
Temperature: 80 °C
Yield: 4.1 %

Procedure:
The ethyl 7-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 9a, Step 2 (1.0 g, 2.51 mmol), pyridin-3-ylboronic acid (0.34g, 2.76 mmol), K2CO3 (1.04 g, 7.53 mmol), and PdCl2(PPh3)2 (53 mg, 0.075 mmol) were mixed in dioxane (10 mL) in a sterling bomb. The reactor was charged withcarbon monoxide (40 psi). The reaction was heated to 80° C. for 6 h then room temperature overnight. After filtration, the reaction was quenched with NH4Cl and extracted with EtOAc. The organic layer was washed and dried over MgSO4. The filtrate was evaporated and dried in vacuo to afford crude which was purified by RPHPLC with 50 to 95% ACN in water to give yellow solid (39 mg, 4%): LCMS m/z 378.10 (M+H). 1H NMR (CDCl3/400 MHz) 9.08 (s, 1H), 8.97 (d, 1H, J=5.2 Hz), 8.48 (d, 1H, J=8.0 Hz), 7.81 (dd, 1H, J=7.6, 5.2 Hz), 7.75 (s, 1H), 7.40 (m, 3H), 5.76 (q, 1H, J=6 Hz), 4.34 (m, 2H), 1.36 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([CH3:11])[C:3]=1[C:12](O)=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:11][C:4]1[C:5]([F:10])=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[C:3]=1[CH2:12][OH:13]
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1c(F)c(F)c(F)c(F)c1CO
Yield: 42.9 %

Procedure:
3,4,5,6-tetrafluoro-2-toluic acid (500 mg) was dissolved in dry diethyl ether (5.0 ml) added dropwise to a suspension of lithium aluminium hydride (100 mg) in dry ether (10 ml) under an argon atmosphere at the ambient temperature. When the addition was complete and the effervescence has subsided the mixture was heated at the reflux temperature for a period of 1 hour. After allowing the mixture to cool to the ambient temperature water (10 ml) was cautiously added and the resultant mixture extracted with diethyl ether (2×20 ml), the extracts washed with water and dried over anhydrous magnesium sulphate. After filtration the filtrate was concentrated by evaporation of the solvent. The residual low melting solid was recrystallised from petroelum ether (boiling range 40°-60° C.) to yield 2-methyl-3,4,5,6-tetrafluoro-benzyl alcohol (200 mg). N.m.r. ('H(ppm)CDCl3): 2.18(s,1H); 2.32(t,3H); 4.86(s,2H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:7][CH:8]([CH3:10])[CH3:9])=[C:4]([CH:20]=[O:21])[CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:22])=[O:16])[CH2:7][CH:8]([CH3:10])[CH3:9])=[C:4]([CH:20]=[O:21])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)CN(CCCCC(=O)O)c1ccc(Br)cc1C=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCN(CC(C)C)c1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a suspension of 5-(4-bromo-2-formyl-N-isobutylanilino)pentanoic acid (15.0 g), potassium carbonate (7.0 g) in DMF (50 ml) was added dropwise a solution of iodomethane (8.4 g) in DMF (10 ml) at 0° C. under a nitrogen atmosphere. The mixture was warmed to room temperature, and stirred for 2 hours under a nitrogen atmosphere. After addition of water, the solution was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to hexane:ethyl acetate=1:1) to obtain brown oil of methyl 5-(4-bromo-2-formyl-N-isobutylanilino)pentanoate (13.1 g).
Reaction SMILES: Br.[N:2]12[CH2:8][C:5]([C:9]([O:11]CC)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.S(Cl)(Cl)=O.Cl.[CH3:19][NH:20][O:21][CH3:22].N1C=CC=CC=1>Cl.O>[N:2]12[CH2:8][C:5]([C:9]([N:20]([O:21][CH3:22])[CH3:19])=[O:11])([CH2:4][CH2:3]1)[CH2:6][CH2:7]2
Reactant: CNOC
Reactant: CCOC(=O)C12CCN(CC1)C2
Agent: Br
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CON(C)C(=O)C12CCN(CC1)C2
Temperature: -30 °C
Yield: 84.6 %

Procedure:
Ethyl 1-azabicyclo[2.2.1]hept-4-yl carboxylate hydrobromide salt (D13) (34 g, 0.136 mole) in concentrated hydrochloric acid (200 ml) and water (50 ml) was heated under reflux for 17 h. The solution was concentrated in vacuo to afford a white solid. Thionyl chloride (250 ml) was added and the solution heated under reflux for 3 h when a homogenous solution was obtained. The excess thionyl chloride was then removed in vacuo and the residue azeotroped with dry toluene to remove the last traces of thionyl chloride. The residue was dissolved in dry acetonitrile (250 ml) and treated with N,O-dimethyl hydroxylamine hydrochloride (16 g, 0.165 mole) and cooled to -30° C. Pyridine (53 g, 0.67 mole) was then added to the stirred reaction mixture at such a rate that the temperature did not rise above -20° C. The reaction was then allowed to warm to room temperature over 16 h. The reaction was then concentrated in vacuo to a gum and the residue partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to a gum. The gum was dissolved in dichloromethane and treated with decolourising charcoal filtered and reconcentrated to a gum. Recrystallisation from ether afforded 1-azabicyclo[2.2.1]hept-4-yl-N-methoxy-N-methyl carboxamide (D21) (21.2 g, 0.115 mole, 84%) as needles.
Reaction SMILES: [Cl:1][Si:2]([Cl:8])([Cl:7])C(C=C)=C.[SiH3]C=CC=C.[Cl:14][CH2:15][C:16]#[C:17][CH2:18][Cl:19].Cl[SiH](Cl)Cl>[Pt]>[Cl:14][CH2:15][C:16]([Si:2]([Cl:8])([Cl:7])[Cl:1])=[CH:17][CH2:18][Cl:19]
Reactant: C=CC(=C)[Si](Cl)(Cl)Cl
Reactant: ClCC#CCCl
Agent: [Pt]
Agent: C=CC=C[SiH3]
Agent: Cl[SiH](Cl)Cl
Product: ClCC=C(CCl)[Si](Cl)(Cl)Cl

Procedure:
For instance, 2-trichlorosilyl-1,3-butadiene [II-d]and 2-triloweralkoxy silyl-1,3-butadiene [II-a]can be synthesized by reacting 1,4-dichloro-2-butyne [IV]and trichlorosilane [V]in the presence of a platinum type catalyst to obtain 1,4-dichloro-2-(trichloro)silyl-2-butene [VI]is then reacted with Zn in a tetrahydrofuran solvent to prepare 2-(trichloro)silyl-1,3-butadiene[II-d], and further reacting the 2-(trichloro)silyl-1,3-butadiene II-d with a lower alcohol in the presence of a base, such as triethylamine, as shown by the following Formula (C): ##STR14##
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>>[CH:38]([O:37][C:35]([N:30]1[CH2:31][CH2:32][CH:27]([N:12]2[C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=4[N:16]=[CH:15][C:14]=3[C:25](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[C:11]2=[O:33])[CH2:28][CH2:29]1)=[O:36])([CH3:40])[CH3:39]
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(C(=O)OC(C)C)CC3)c12

Procedure:
4-[3-(3-Chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (47 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.105 mmol) and isopropyl chloroformate. LCMS: m/z 523 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].O1CCOCC1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(OCC)(=O)C>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:22]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)cc1Cl
Yield: 85 %

Procedure:
Combine 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol) with dioxane (20 mL). Treat mixture with 2-chloro-4-fluorobenzoyl chloride (1.6 g, 8.3 mmol). Stir the reaction overnight at room temperature. Transfer the reaction mixture into ethyl acetate (220 mL), then wash successively with aqueous HCl (1N, 50 mL), aqueous NaOH (1N, 50 mL), saturated aqueous NaCl (50 mL). Dry the organic layer over anhydrous sodium sulfate, then evaporate the solvent under reduced pressure. Further purify the residue by chromatography on silica gel, using a gradient of 10–30% ethyl acetate in hexanes to obtain the title intermediate (1.7 g, 85% yield): mass spectrum (ion spray): m/z=313.0 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:5]1(=[O:20])=[O:19].[N:21]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:19]=[S:5]1(=[O:20])[N:4]([CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][CH2:27][N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][CH2:23]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=S1(=O)N(CCBr)c2ccccc2N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(CCN2c3ccccc3N(c3ccccc3)S2(=O)=O)CC1
Temperature: 90 °C

Procedure:
A mixture of 1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure VI, 112 mg, 0.317 mmol), tert-butyl 1-homopiperazinecarboxylate (381 mg, 1.90 mmol, 6 equiv.), sodium carbonate (202 mg, 1.90 mmol, 6 equiv.) and ethanol (4 mL) in a sealed reaction vessel was heated at 90° C. for 8 h. After cooling, solvent was removed, and the residue was dissolved in ethyl acetate (15 mL). The resulting solution was washed with an aqueous potassium carbonate solution, water, dried (anhydrous sodium sulfate), and concentrated. The crude liquid was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (4-g redisep silica gel column, 10-60% ethyl acetate/hexane) to give tert-butyl 4-[2-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)ethyl]-1,4-diazepane-1-carboxylate as a viscous, colorless liquid. Yield: 121 mg (81%). MS (ESI) m/z 473.0 ([M+H]+). HPLC purity 100.0% at 210-370 nm, 9.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[H][H].Br[C:16]1[C:21]([O:22][CH3:23])=[CH:20][N:19]=[CH:18][C:17]=1[O:24][CH3:25]>CN(C=O)C>[CH3:25][O:24][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([O:22][CH3:23])[C:16]=1[O:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: COc1ccc(CO)cc1
Reactant: [H][H]
Reactant: COc1cncc(OC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(OC)cncc2OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
To an ice-cooled suspension of sodium hydride (60% dispersion in mineral oil, 650 mg, 16.3 mmol) in dry DMF (10 ml) was added 4-methoxybenzyl alcohol (2.24 g, 16.3 mmol) drop-wise via syringe. Vigorous evolution of hydrogen was observed and the reaction was allowed to warm to room temperature and stirred for 15 minutes. 4-Bromo-3,5-dimethoxypyridine (1.17 g, 5.41 mmol) was added and the reaction heated to 90° C. overnight. After cooling, only trace starting material could be detected by TLC analysis and the reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water 3 times then brine, dried over MgSO4 and concentrated onto silica-gel under reduced pressure. The solid residue was purified by flash chromatography (silica-gel, eluted sequentially with EtOAc:hexanes, 2:1, 1:0) to give the product as a tan solid (865 mg, 58%). 1H—NMR (300 MHz, CDCl3) δ 7.96 (s, 2H), 7.33 (d, J=8.5 Hz, 2H), 6.84 (d, J=8.5 Hz, 2H), 5.11 (s, 2H), 3.89 (s, 6H), 3.78 (s, 3H). MS (ES+) m/z 276.1 (M+H+).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:21]1[CH2:25][CH2:24][NH:23][C:22]1=[S:26].C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>CN(C1C=CN=CC=1)C.C1CCC(N=C=NC2CCCCC2)CC1>[C:1]([N:23]1[CH2:24][CH2:25][S:21][C:22]1=[S:26])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)O
Reactant: S=C1NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C/CCCCCCCC(=O)N1CCSC1=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of elaidic acid (2.0 g, 7.1 mmol), DMAP (86 mg, 0.7 mmol), 1,3-thiazolidine-2-thione (1.0 g, 8.4 mmol) and DCC (1.7 g, 8.2 mmol) in dichloromnethane (20 ml) was stirred under N2 at 0° C. for 1 hour and then at ambient temperature for another 5 hours. Additional DCC (41 mg, 0.2 mmol) was added, andthe reaction was stirred at the same temperature for 2 hours. Work up followed by flash chromatography (SiO2; carbon tetrachloride-chloroform 1:0, 1:1, 0:1) gave 2.56 g (94%) of the title compound as a yellow waxy solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=[O:8].[CH2:12](Cl)Cl.CO.C[Si](C=[N+]=[N-])(C)C>CCOCC>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]=1[CH3:11])[C:7]([O:9][CH3:12])=[O:8]
Reactant: ClCCl
Reactant: Cc1c(Br)cncc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cncc(Br)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 5-bromo-4-methylnicotinic acid (223.4 mg, 1.034 mmol) in methylene chloride (3.0 mL, 47 mmol) and methanol (3.0 mL, 74 mmol) was added 2.0 M of trimethylsilyldiazomethane in ether (0.70 mL). The reaction mixture was stirred at room temperature for one hour, and then 2.0 M of tTrimethylsilyldiazomethane in ether (0.50 mL) was added. After an additional two hours, the crude reaction mixture was evaporated in vacuo to yield 237.2 mg (100%) of methyl 5-bromo-4-methylnicotinate which was carried forward without further purification. LCMS (ESI): M+H=230.2; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.82 (s, 1H), 3.89 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1.[C:30]1([CH3:36])C=CC=CC=1>C(O)(=O)C>[C:30]([O:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=1)(=[O:26])[CH3:36]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCc1ccc(OCCSCCO)cc1
Reactant: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)OCCSCCOc1ccc(CCC(=O)O)cc1
Yield: 88 %

Procedure:
A solution of 3-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl]propanoic acid, (35.67 g, 0.13 mol) in a mixture of toluene (500 ml) and acetic acid (500 ml) was treated with p-toluenesulfonic acid (1.2 g) and then heated under reflux using a Dean-Stark apparatus for 2 h. The cooled mixture was concentrated in vacuo and the residue was diluted with ethyl acetate, washed with water and dried (magnesium sulfate). Evaporation of the solvent under vacuum gave a solid which was crystallized from hexane to give 36.13 g (88%) of title material as a white solid: mp 48-49° C.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:12][C:13]=2[O:14][CH3:15])OC1.[Cl:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>CO.[Cu-]=O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:9]2[CH:8]=[C:13]([O:14][CH3:15])[N:12]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]=2)[CH:27]=1
Reactant: Clc1c[nH]cn1
Reactant: CCOC(=O)c1ccc(B2OCC(C)(C)CO2)c(OC)n1
Agent: O=[Cu-]
Solvent: CO
Product: CCOC(=O)c1cc(-n2cnc(Cl)c2)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (49.8 mg, 0.068 mmol) was added to a solution of ethyl 5-bromo-6-methoxypyridine-2-carboxylate (prepared in analogous fashion to methyl 5-bromo-6-methoxypyridine-2-carboxylate (C30) in Preparation 10; 254 mg, 0.97 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (264 mg, 1.17 mmol), and potassium acetate (293 mg, 2.92 mmol) in 1,4-dioxane (8 mL). The reaction was stirred at 85° C. for 6 hours, whereupon it was allowed to cool to room temperature. Dichloromethane was added, and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to afford intermediate ethyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate. To a solution of ethyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methoxypyridine-2-carboxylate (crude) in methanol (50 mL) was added 4-chloro-1H-imidazole (C33) (100 mg, 0.97 mmol) and copper(I) oxide (14 mg, 0.098 mmol) and the reaction was stirred at ambient temperature overnight. The mixture was heated to 50° C. for 2 hours, and additional copper(I) oxide (14 mg, 0.098 mmol) was added. The reaction was heated to reflux for 2 hours and was then filtered through Celite. The Celite pad was washed with methanol, and the combined filtrate and washings were concentrated in vacuo. Purification was carried out twice via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane, then 0% to 40% ethyl acetate in heptane), affording the title compound as a white solid. Yield: 29.3 mg, 0.104 mmol, 11%. LCMS m/z 282.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.44 (t, J=7.1 Hz, 3H), 4.14 (s, 3H), 4.46 (q, J=7.1 Hz, 2H), 7.24 (d, J=1.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.82-7.83 (m, 1H), 7.84 (d, J=7.8 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[C:26](O)(=O)C.C=O.[C:32]([BH3-])#[N:33].[Na+]>C(Cl)Cl.CO.CCOCC>[CH3:26][N:33]([CH3:32])[C:2]1[CH:3]=[C:4]([NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1ccc(NC(=O)c2c[nH]c3ccccc3c2=O)cc1N
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CN(C)c1cc(NC(=O)c2c[nH]c3ccccc3c2=O)ccc1C(C)(C)C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
To a suspension of N-(3-amino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (271) (600 mg, 1.8 mmol) in CH2Cl2 (15 mL) and methanol (5 mL) were added acetic acid (250 μL) and formaldehyde (268 μL, 3.6 mmol, 37 wt % in water). After 10 min, sodium cyanoborohydride (407 mg, 6.5 mmol) was added in one portion. Additional formaldehyde (135 μL, 1.8 mmol, 37 wt % in water) was added at 1.5 and 4.2 h. After 4.7 h, the mixture was diluted with ether (40 mL), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered, and concentrated. The resulting red-brown foam was purified by preparative HPLC to afford N-(3-dimethylamino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (485) (108 mg, 17%). 1H NMR (300 MHz, CDCl3) δ □13.13 (br s, 1H), 12.78 (s, 1H), 8.91 (br s, 1H), 8.42 (br s, 1H), 8.37 (d, J=8.1 Hz, 1H), 7.72-7.58 (m, 2H), 7.47-7.31 (m, 3H), 3.34 (s, 6H), 1.46 (s, 9H); HPLC ret. time 2.15 min, 10-100% CH3CN, 5 min run; ESI-MS 364.3 m/z (Min.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH2:18][CH:17]1[C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27]>CC(CC(C)C)=O>[ClH:1].[O:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH2:18][CH:17]1[C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][C:6]([O:14][CH3:15])=[C:7]([Cl:13])[CH:8]=3)[N:3]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1Cl
Reactant: O=C(C1COc2ccccc2O1)N1CCNCC1
Solvent: CC(=O)CC(C)C
Product: COc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1Cl
Product: Cl

Procedure:
The title compound was prepared by the procedure of Part A, above, by refluxing 2,6-dichloro-4-amino-7-methoxyquinazoline and N-(1,4-benzodioxan-2-carbonyl)-piperazine in methylisobutylketone, M.P. 194°-196° C.