Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11](Cl)(=O)C>CO>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][NH:3]1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccnc(O)c1
Solvent: CO
Product: COC(=O)c1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-hydroxypyridine-4-carboxylic acid (5.0 g) in MeOH (50 ml) was added acetyl chloride (26 ml) dropwise at 0° C. over 15 min. The reaction mixture was slowly warmed to room temperature, and stirred for 20 h. The reaction mixture was concentrated in vacuo, and diluted with EtOAc and water. The organic layer was washed with saturated NaHCO3 solution, concentrated in vacuo, and purified by column chromatography (MeOH/DCM) to afford the title compound (3.5 g) as an off-white solid.
Reaction SMILES: O[CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(Cl)([Cl:22])=O>>[Cl:22][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)CCc1ccc(OC(C)C)cc1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(Cl)CCc1ccc(OC(C)C)cc1
Yield: 27 %

Procedure:
According to the same manner as that described in Reference Example 34, ethyl 2-hydroxy-4-(4-isopropoxyphenyl)-butyrate was chlorinated with thionyl chloride to give ethyl 2-chloro-4-(4-isopropoxypheyl)butyrate as an oil (yield: 27%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Cl:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc2ccccc2n1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-chlorobenzimidazole (100 g, 0.65 mol) in 500 ml of dimethylformamide (DMF) was added dropwise to a stirred suspension of 60% sodium hydride-mineral oil dispersion (28 g, 0.70 mol) in 500 ml of DMF. Mild intermittent cooling was required. After the addition was completed the mixture was stirred an additional 15 min and benzylbromide (82.6 g, 0.49 mol) was added dropwise with mild intermittent cooling. The reaction mixture was stirred an additional 1.5 h and 1 L of water was added. The mixture was extracted with benzene. The extract was dried (Na2SO4), concentrated and the residue crystallized from isopropyl ether to obtain 110 g (93%), mp 102°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:35]1C=C(S(Cl)(=O)=O)C=CC=1Cl>>[CH3:35][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)CC2
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3,4-dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 525.18 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(3,4-dichloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH:12]=O)=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:21])[N:3]=1.[C:22]([O-])([O-])=O.[Cs+].[Cs+].[Si](C=[N+]=[N-])(C)(C)C>CO>[CH3:21][C:4]1[N:3]=[C:2]2[NH:1][CH:22]=[CH:12][C:11]2=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(C)nc(N)c(C=O)c1-c1ccc(C)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cs+]
Solvent: CO
Product: COC(=O)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of methyl 6-amino-5-formyl-2-methyl-4-(p-tolyl)nicotinate (2.45 g, 8.62 mmol) and Cs2CO3 (5.62 g, 17.23 mmol) in methanol (70 ml) was treated with TMS-diazomethane (2M in hexane) (17.23 ml, 34.5 mmol) dropwise at 60° C. The mixture was stirred at 60° for 1 hour, cooled to rt, quenched with sat NH4Cl, extracted with EtOAc, washed with water, Brine, dried with Na2SO4, filtered, and concentrated to afford methyl 6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.15 g, 7.67 mmol, 89% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.86 (br. s., 1 H), 7.40 (d, J=8.1 Hz, 2 H), 7.31-7.26 (m, 3 H), 6.43 (dd, J=2.0, 3.5 Hz, 1 H), 3.64 (s, 3 H), 2.71 (s, 3 H), 2.43 (s, 3 H); LCMS (m/z) ES+=281 (M+1).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[O:16][C:17](=O)[CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>CC1C=CC(C)=CC=1>[CH2:1]([O:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:17](=[O:16])[CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(N)cc1
Reactant: COC(=O)CC(=O)C(C)(C)C
Solvent: Cc1ccc(C)cc1
Product: CCCCCCOc1ccc(NC(=O)CC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
4-Hexyloxyaniline (1, 1.00 g, 5.17 mmol) and methyl-4,4-dimethyl-3-oxopentanoate (1.65 mL, 10.3 mmol) were suspended in 5 mL p-xylene and heated to reflux for 17 hours. The reaction was cooled to room temperature and purified by flash chromatography on silica gel eluting with 10% acetone, hexane to yield a brown solid. Recrystallization from hexane provided 1.35 g (82%) of a white solid. mp 70-72° C.; Analysis calculated for C19H29NO3: C, 71.44; H, 9.15; N, 4.38. Found: C, 71.72; H, 9.42; N, 4.30.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:7])[O:5][CH3:6].[H-].[Na+].[CH3:10][C:11]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.O>CN(C)C=O>[CH3:1][O:2][N:3]([CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]=1[CH3:10])[C:4](=[O:7])[O:5][CH3:6]
Reactant: CONC(=O)OC
Reactant: Cc1c(CBr)cccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1cccc(-c2ccccc2)c1C)OC
Reaction time: 3 h
Yield: 50.6 %

Procedure:
0.40 g of methyl N-methoxycarbamate in N,N-dimethylformamide (20 ml) was stirred together with 0.18 g of 60% sodium hydride at room temperature for 30 minutes. 1.00 g of 2-methyl-3-phenylbenzyl bromide was added dropwise at room temperature, and the resulting solution was stirred for 3 hours. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 0.55 g of methyl N-methoxy-N-(2-methyl-3-phenylbenzyl)carbamate as a transparent viscous liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1.CCOCC.C([Li])CCC.CON(C)[C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27]>C1COCC1>[F:12][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9])[C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27]
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Reactant: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(C(F)(F)F)c(F)c1
Temperature: -78 °C
Yield: 35 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (4.854 g, 19.98 mmol) and ether (50 mL) cooled to −78° C. was added butyl lithium (7.990 mL, 19.98 mmol) slowly over 10 min. The reaction was transferred via cannula to a solution of 74 (4.30 g, 16.65 mmol) in THF (50 mL) cooled to −78° C. The reaction was stirred for 10 min after all aryl lithium was added. The reaction was quenched with water and extracted with DCM. The organic layer was concentrated and the crude product purified by SiO2 chromatography eluting with an EtOAc/hexane (1 to 5% EtOAc). A close running impurity was not removed by this purification. A SiO2 column was run eluting with an Et2O/hexane gradient (1 to 3% Et2O). The impurity was still present and the compound was finally purified on a SP4 reverse phase column chromatography eluting with MeCN/water gradient (65 to 100% MeCN) to afford 2.105 g (33.2%) of (R)-tert-butyl 2-(3-fluoro-4-(trifluoromethyl)benzoyl)-pyrrolidine-1-carboxylate (76).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH3:29])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([OH:28])=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[N:20]([CH3:29])[C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc2cc(O)ccc21
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)cc(C(=O)N1CCN(c3ccccc3C(C)(C)C)CC1)n2C
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
A mixture of 2-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1-methyl-1H-indol-5-ol obtained in Example 28 (510 mg), methyl bromoacetate (239 mg), potassium carbonate (276 mg), and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 3 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford crystals. Crystals were washed with diethyl ether and dried under reduced pressure to provide the title compound (509 mg, 84%) as crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)(=[O:4])[CH2:2][CH3:3].[BH4-].[Na+]>C(O)C.C1COCC1>[OH:4][CH:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)[CH2:2][CH3:3]
Reactant: CCC(=O)c1ccc2c(c1)NC(=O)C(C)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(O)c1ccc2c(c1)NC(=O)C(C)O2
Yield: 95 %

Procedure:
6-(Propionyl)-2-methyl-1,4-benzoxazin-3-(4H)-one (1.1 g) is stirred with a half equivalent of sodium borohydride in 30 ml of ethanol/THF 1:1 for three hours at room temperature. The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. A yield of 95% results.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1.[CH2:12]([Si:14]([CH2:24][CH3:25])([CH2:22][CH3:23])[O:15][C:16](/[C:18](/[CH3:21])=[CH:19]/[CH3:20])=[CH2:17])[CH3:13]>>[CH3:21][C:18]1[CH:19]([CH3:20])[O:8][CH:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:9]([O-:11])=[O:10])[CH2:17][C:16]=1[O:15][Si:14]([CH2:22][CH3:23])([CH2:12][CH3:13])[CH2:24][CH3:25]
Reactant: C=C(O[Si](CC)(CC)CC)/C(C)=C/C
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Product: CC[Si](CC)(CC)OC1=C(C)C(C)OC(c2c([N+](=O)[O-])cnn2C)C1
Temperature: 65 °C

Procedure:
To a solution of (E)-3-methylpent-3-en-2-one (2.69 mL, 24.1 mmol) in DCM (200 mL) cooled to 0° C. was added Et3N (10.5 mL, 79.5 mmol) followed by TESOTf (6.0 mL, 26.5 mmol). The mixture was warmed to room temperature and stirred for 18 hr. Saturated aqueous NaHCO3 solution (100 mL) and DCM (200 mL) were added. The aqueous layer was extracted with DCM (3×200 mL) and the combined organic layers were washed with brine (100 mL), separated, dried over MgSO4 and concentrated under reduced pressure to give (E)-triethyl((3-methylpenta-1,3-dien-2-yl)oxy)silane. To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (1.0 g, 8 mmol, intermediate 3) in CDCl3 (28 mL) was added (E)-triethyl((3-methylpenta-1,3-dien-2-yl)oxy)silane (1.6 g, 7.55 mmol) followed by EuFOD (220 mg, 0.50 mmol). The reaction mixture was heated at 65° C. behind a blast shield for 18 hr in a pressure tube. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-(5,6-dimethyl-4-((triethylsilyl)oxy)-3,6-dihydro-2H-pyran-2-yl)-1-methyl-4-nitro-1H-pyrazole as a colourless oil (2.92 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.64 (dd, J=10.9, 3.6 Hz, 1H), 4.33-4.28 (m, 1H), 4.25-3.94 (m, 3H), 2.50-2.41 (m, 1H), 2.31 (m, 1H), 1.61 (s, 3H), 1.31 (d, J=6.4 Hz, 3H), 1.05-0.97 (m, 6H), 0.73-0.61 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH:22]=[CH:23][C:24](O)=O>>[CH3:31][O:30][C:28]1[CH:27]=[C:21]([CH:20]=[C:19]([O:18][CH3:17])[CH:29]=1)/[CH:22]=[CH:23]/[C:24]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cc(OC)cc(OC)c3)nc2n(CCC)c1=O
Yield: 54.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.95 g (17.5 mmol) of 5,6-diamino-1,3-dipropyluracil and 4.0 g (19.2 mmol) of 3,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 3.78 g (yield 54%) of Compound 32 as a white powder.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][C:15]1([CH3:22])[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][O:16]1>C1COCC1>[CH3:14][C:15]1([CH3:22])[CH2:20][C:19]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)([OH:21])[CH2:18][CH2:17][O:16]1
Reactant: Cc1ccc(Br)cc1
Reactant: CC1(C)CC(=O)CCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCOC(C)(C)C2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (26.3 ml, 1.6 M in hexane, 42 mmol) was added dropwise to a solution of 4-bromo-toluene (7.70 g, 45 mmol) in THF (100 ml) at −78° C. under N2. The resulting mixture was stirred at −78° C. for 30 min and a solution of tetrahydro-2,2-dimethyl-4H-pyran-4-one (3.84 g, 30 mmol) in THF (20 ml) was added. The resulting mixture was stirred at −78° C. for another 20 min and quenched by adding MeOH (10 ml). The reaction was concentrated under vacuum and the resulting residue was diluted with EtOAc (500 ml) and washed with sat. NH4Cl (250 ml), brine (250 ml), dried and concentrated to give 2,2-dimethyl-4-(4-methylphenyl)oxan-4-ol as a white solid, which was used without further purification (5.41 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2O.C(=O)=O.CC(C)=O.CCN(S(F)(F)[F:33])CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2[F:33]
Reactant: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C(O)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C(F)C1
Temperature: 25 °C

Procedure:
To a flask containing tert-butyl 8-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-4) (622 mg, 1.895 mmol) was added anhydrous DCM (10 ml). The reaction mixture was then capped & cooled to −78 C (dry ice/acetone bath) while stirring under N2. Then added DAST (1.4 ml, 10.60 mmol) at −78 C. The reaction mixture was then stirred at −78 C. Followed by LC/MS. After 5 minutes at −78 C the reaction was quenched by dropwise addition of a saturated solution of NaHCO3 in water at −78 C (with a vent needle), then permitted to warm to room temperature, then the reaction mixture was suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated to yield. Purification by silica gel chromatography (0-15% EtOAc/Hex; 40 g ISCO); desired fractions concentrated to yield tert-butyl 8-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-5).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH:24]=[CH:23][N:22]=[CH:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>CC(C)=O.O1CCOCC1.[Pd]>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([C:30](=[O:32])[CH3:31])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Nc1nc2cnccc2nc1N1CCN(Cc2ccc(F)cc2F)CC1
Agent: [Pd]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCc2nc(N3CCN(Cc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 45 °C
Reaction time: 9.5 h
Yield: 61.1 %

Procedure:
To a pressure reactor charged with a red-orange solution of 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine (0.5 g, 1.255 mmol) in acetone (25 mL) and dioxane (25 mL) was added palladium, 10 wt % on activated carbon (0.053 g, 0.502 mmol) as a slurry in dioxane (3 mL) under nitrogen. Next, acetic anhydride (1.179 mL, 12.55 mmol) was added at 23° C. The mixture was stirred under hydrogen at 45° C. and 310 kPa for 9.5 hr. The reaction mixture was filtered through Celite™, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in toluene (5 mL) and purified via medium pressure chromatography using a 10% to 100% gradient eluant of EtOAc in heptane on an NH 60 μM size 400 column (Shoko Scientific Purif-Pack™) to give the title compound (341 mg, 61.1%) as an off-white foam. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.14-1.19 (m, 6H), 2.08 (s, 1.2H), 2.09 (s, 1.8H), 2.52-2.65 (m, 5H), 2.70 (t, J=5.9 Hz, 1H), 2.98 (br s, 4H), 3.58 (s, 2H), 3.70 (dt, J=12.0, 5.7 Hz, 2H), 4.00-4.15 (m, 1H), 4.40 (s, 0.8H), 4.43 (s, 1.2H), 5.35 (d, J=7.8 Hz, 0.4H), 5.38 (d, J=8.3 Hz, 0.6H) 7.08 (td, J=8.3, 2.4 Hz, 1H), 7.21 (td, J=10.0, 2.4 Hz, 1H), 7.44-7.51 (m, 1H); ESI-MS m/z [M+H]+ 445.0.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:29]([O:31]C)=[O:30])=[CH:19][N:20](COC(=O)C(C)(C)C)[C:15]3=[N:14][CH:13]=2)=[N:3]1.[OH-].[K+]>O1CCOCC1.O.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:29]([OH:31])=[O:30])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(C)ccc34)nc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a stirred solution of methyl 2-(1,6-dimethyl-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (1 g, 2.3 mmol) in dioxane/H2O (40 mL/10 mL) was added a solution of KOH (1.39 g, 34.5 mmol) in water (10 mL) at room temperature. Then the reaction mixture was heated to reflux for 4 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was diluted with water and acidified to pH 3-4 with HCl (aqueous, 2 M). The mixture was filtered and the filter cake dried to give 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (0.6 g, 84.5%) as a solid, which was used in the next step without further purification. MS: (M+H)+=308.1.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH2:25]([O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1)[CH3:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:31]4[CH:30]=[N:29][C:28]([O:27][CH2:25][CH3:26])=[N:33][CH:32]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCOc1ncc(B(O)O)cn1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: CCOc1ncc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cn1
Yield: 2.5 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-ethoxypyrimidine-5-boronic acid (available from Combi-Blocks Inc.; 84 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(2-ethoxy-pyrimidin-5-yl)-benzoic acid (3 mg, 3%). LCMS analysis indicated that the material was ˜69% pure, as measured by UV at 214 nm. LRMS m/z 471.8 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: Brc1ccccc1I
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccccc3Br)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-bromo-2-iodobenzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.30-7.53 (m, 11H), 7.04-7.09 (m, 2H), 6.62-7.04 (m, 3H), 6.42 (d, 1H), 6.02 (d, 1H), 4.88-5.05 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4].I[CH3:17]>CCCCCC.O1CCCC1>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:15][CH3:17])([CH3:14])[CH3:13])[CH:7]=1)[CH3:4]
Reactant: CI
Reactant: CCOc1cccc(C(C)(C)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1cccc(C(C)(C)OC)c1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
Sodium hydride (3.261 g, 81.54 mmol, 60% in mineral oil, Aldrich) was washed twice with hexane, and tetrahydrofuran (60 mL) was added. To this suspension was added 2-(3-ethoxy-phenyl)-propan-2-ol (4.9 g, 27.18 mmol). The mixture was stirred at 45° C. for 1.5 h until the bubbling subsided. It was cooled down to 0° C. and iodomethane (5.08 mL, 81.54 mmol, Aldrich) was added. After 4 h of stirring at room temperature, another portion of iodomethane (5.08 mL, 81.54 mmol) was added. The mixture was stirred at room temperature for 4 d then quenched at 0° C. with cold 20% solution of ammonium chloride. The product was extracted with ethyl acetate (2×1 L). The organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 1-ethoxy-3-(1-methoxy-1-methyl-ethyl)-benzene (5.15 g, 97%).