Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[S:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=1>CN(C)C=O>[C:1]1([C:9]2[S:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: Sc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1csc(-c2ccccc2)c1
Temperature: 135 °C

Procedure:
In an open flask, thiophenol (2.86 g., 13 mmoles), cuprous oxide (1.86 g., 13 mmoles) and dimethyl formamide (30 ml.) were combined and heated in a 135° C. oil bath. The reaction mixture was allowed to cool slightly, 5-bromothiophene-3-carboxylic acid [2.5 g., 13 mmoles; Fournari et al., Bull. Chim. Soc. Fr., 4115 (1967)] in 50 ml. of dimethylformamide was added, and the mixture refluxed for 2 days. The reaction mixture was cooled, clarified by filtration, the filtrate evaporated to an oil, the oil triturated with 1 N hydrochloric acid, and gummy solids recovered by filtration and taken up in 1 N sodium hydroxide. The basic solution was extracted with ether, reacidified with conc. hydrochloric acid, product recovered by filtration, triturated with hexane and refiltered (912 mg., m.p. 97°-100° C., m/e 220). Recrystallization from methanol/water afforded purified 5-phenylthiofuran-3-carboxylic acid (439 mg., m.p. 101°-103° C.).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2ccccc2cc1C1=CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ccccc2cc1C1CCNCC1

Procedure:
A solution of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one (0.25 g. 0.29 mmol) and 10% Pd/C (130 mg) in MeOH (20 ml) was stirred at 40° C. for 6 hours. The catalysis was filtered and solvent evaporated affording the desired product. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=229; tR=1.27.
Reaction SMILES: [C:1]1([CH2:7][O:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C([NH:16][C:17]1[N:26]=[C:25]([NH:27]C(C(C)(C)C)=O)[C:24]2[CH2:23][C:22](=O)[CH2:21][CH2:20][C:19]=2[N:18]=1)=O)(C)C>>[NH2:16][C:17]1[N:26]=[C:25]([NH2:27])[C:24]2[CH2:23][C:22](=[N:9][O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:21][CH2:20][C:19]=2[N:18]=1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=O)CC2
Reactant: NOCc1ccccc1
Product: Nc1nc(N)c2c(n1)CCC(=NOCc1ccccc1)C2

Procedure:
When the bridging group n is =NOCH2 --, an appropriately substituted or unsubstituted phenylmethyl chloride, for example, 3-trifluoromethylphenylmethyl chloride, is reacted under basic conditions with N-hydroxyphthalimide in dimethyl sulfoxide, yielding the corresponding N-(phenylmethoxy)phthalimide. The so-prepared phthalimide is in turn reacted with hydrazine monohydrate in ethanol, affording an O-(phenylmethyl)hydroxylamine, for example, O-(3-trifluorophenylmethyl)hydroxylamine. The O-(phenylmethyl)hydroxylamine is then reacted with 2,4-di[(1,1 -dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone, as described above, yielding the targeted 2,4-diamino-6-phenylmethoxyimino-5,6,7,8-tetrahydroquinazoline. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([OH:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.5 h

Procedure:
To a solution of 0.25 g (0.82 mmol) (4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 2 ml N,N-dimethylformamide, 40 mg (0.90 mmol) sodium hydride (55–65% dispersion in oil) was added. After 30 min, 0.10 ml (0.23 g, 1.64 mmol) methyl iodide was added. After 1 h the reaction mixture was poured onto water and extracted three times with ethyl acetate. The organic layers were washed twice with water, then brine and were dried over magnesium sulfate. After filtration and evaporation of the solvent the product was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:5) as eluant.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:20]([CH:21]([OH:23])[CH3:22])=[CH:19][C:18]([Cl:24])=[C:17]([CH3:25])[C:13]=1[C:14](O)=[O:15])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>Cl.O1CCOCC1.C(OCC)(=O)C.CN(C)C=O>[Cl:24][C:18]1[CH:19]=[C:20]([CH:21]([OH:23])[CH3:22])[C:12]2[O:11][CH2:10][CH2:9][NH:8][C:14](=[O:15])[C:13]=2[C:17]=1[CH3:25]
Reactant: Cc1c(Cl)cc(C(C)O)c(OCCNC(=O)OC(C)(C)C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C(C)O)c2c1C(=O)NCCO2
Yield: 76 %

Procedure:
2-{2-[(tert-Butoxycarbonyl)amino]ethoxy}-5-chloro-3-(1-hydroxyethyl)-6-methylbenzoic acid (27 mg, 0.072 mmol) was stirred in 4.0 M hydrogen chloride in 1,4-dioxane (3 mL) and evaporated. 1-Hydroxybenzotriazole hydrate (13 mg, 0.087 mmol), N,N-diisopropylethylamine (63 μL, 0.36 mmol) and N,N-dimethylformamide (2.0 mL) were added and the mixture was stirred for ten minutes. Benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (38 mg, 0.087 mmol) was added and the mixture was stirred at 30° C. overnight. The mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated to give the desired product (14 mg, 76%). LCMS calculated for C12H15ClNO3 (M+H)+: m/z=256.1; found: 256.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:57][C:58]([F:68])([F:67])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[CH2:65][NH2:66]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:66][CH2:65][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=3[C:58]([F:57])([F:67])[F:68])=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)O
Reactant: NCc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)NCc1ccccc1C(F)(F)F
Yield: 17.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoic acid (Intermediate-15, 0.100 g, 0.270 mmol), THF (5 mL), di-isopropyl ethyl amine (1.0 mL), TBTU (0.177 g, 0.540 mmol) and 1-[2-(trifluoromethyl)phenyl]methanamine (0.072 g, 0.410 mmol) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.96 (s, 3H), 4.70 (d, J=4.8 Hz, 2H), 7.45-7.50 (m, 3H), 7.57 (t, J=8.4 Hz, 2H), 7.67 (t, J=8.7 Hz, 2H), 7.71 (d, J=9.3 Hz, 2H), 7.92 (d, J=8.4 Hz, 1H), 8.80 (t, 1H), 12.77 (br s, 1H); MS (m/z): 519.43 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])/[CH:9]=[CH:10]/[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:28][CH:29]3[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]3)=[O:17])=[CH:18][CH:19]=2)=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1
Reactant: NC1CCC(O)CC1
Reactant: O=C(O)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC1CCC(O)CC1)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A mixture of 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-benzoic acid (0.2 g, 0.53 mmol), 4-amino-cyclohexanol (61 mg, 0.53 mmol), EDCI (152 mg, 0.8 mmol), HOBt (25 mg), DIPEA (1 mL) in THF (50 mL) was stirred at RT overnight. The resulting mixture was evaporated under reduced pressure, and the residue partitioned between water and EtOAc. The resulting precipitate was collected by filtration and dried in a vacuum oven, the filtrate separated, the organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by preparative TLC (EtOAc/hexane, 75:25) and combined with the solid collected to yield 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-N-(4-hydroxy-cyclohexyl)-benzamide (197 mg). MS=475 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:28][N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:41]2[CH2:42][CH2:43][N:38]([C:30]3[N:29]([CH3:28])[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=3)[CH2:39][CH2:40]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-methyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].Cl.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1>O>[C:10]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCNC(=O)c1cccnc1
Reaction time: 5 h
Yield: 96.5 %

Procedure:
Ten grams of β-alanine and 9 g of sodium hydroxide were dissolved in 100 mL of purified water, and 18.15 g of nicotinoyl chloride hydrochloride were added dropwise under freezing conditions. After stirring for five hours, the product was filtered, the resulting crude product was recrystallized with aqueous ethanol, and 19.1 g of the desired product was obtained (yield of 84%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34]C)=[O:33])[CH2:29]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:15]([F:26])[CH:14]=2)[O:10][N:9]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:15]([F:26])[CH:14]=2)[O:10][N:9]=1)[CH3:2]
Reactant: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1
Yield: 76.5 %

Procedure:
The title compound (0.11 g) was synthesized in a yield of 77% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using methyl 1-({4-ethyl-5-[5-(3-fluoro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylate (0.15 g, 0.30 mmol) that was obtained in Example 14 (14b) and a 1 N aqueous solution of sodium hydroxide (0.9 mL, 0.9 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:25])([F:24])[S:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([S:14]([C:13]([F:25])([F:12])[F:24])(=[O:16])=[O:15])=[CH:18][CH:19]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: O=C(Nc1ccc(S(=O)(=O)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 169.2 using 5-bromo-6-chloro-nicotinic acid and 4-trifluoromethanesulfonyl-aniline to afford a solid. UPLC-MS (Condition 3) tR=1.23 min, m/z=−441 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH2:12][CH3:13].[H][H]>C(O)(=O)C.[Pd]>[CH2:12]([C:4]1[CH:5]=[CH:6][C:7]([NH2:9])=[CH:8][C:3]=1[CH3:2])[CH3:13]
Reactant: [H][H]
Reactant: CCc1ccc([N+](=O)[O-])cc1CCl
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1ccc(N)cc1C

Procedure:
α-Chloro-2-ethyl-5-nitrotoluene (40.0 g.) was dissolved in glacial acetic acid and shaken with 5% Pd/C in a hydrogen atmosphere (6.7 g.) in a Parr hydrogenator. When reduction was complete, the crude product was isolated, taken up in ether, washed with water, dilute base and water. After stirring the ether solution over solid K2CO3, the product was isolated as a liquid, 96% pure by glc.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]1[CH:16]=[C:17]([C:21]2[N:30]=[C:29]([NH:31][C:32]([C:34]3([C:37]4[CH:47]=[CH:46][C:40]5[O:41][C:42]([F:45])([F:44])[O:43][C:39]=5[CH:38]=4)[CH2:36][CH2:35]3)=[O:33])[CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][CH:20]=1)=[O:14])(C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:45][C:42]1([F:44])[O:41][C:40]2[CH:46]=[CH:47][C:37]([C:34]3([C:32]([NH:31][C:29]4[N:30]=[C:21]([C:17]5[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=5)[C:13]([OH:14])=[O:12])[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=4)=[O:33])[CH2:36][CH2:35]3)=[CH:38][C:39]=2[O:43]1
Reactant: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
TFA (1 mL) was added to a solution of methyl 2-(3-(tert-butoxycarbonyl)-phenyl)-6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)nicotinate (290 mg, 0.50 mmol) in CH2Cl2 (2.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with CH2Cl2 and neutralized with saturated aqueous NaHCO3. A white precipitate formed which was filtered, washed with H2O and air-dried to yield the product as a white solid (240 mg, 91%). ESI-MS m/z calc. 496.1. found 497.5 (M+1)+. Retention time 1.91 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.98-7.96 (m, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, 2H), 7.40-7.33 (m, 2H), 3.62 (s, 3H), 1.55-1.52 (m, 2H), 1.22-1.19 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Br:11])=[CH:9][N:8]=[C:7](SC)[N:6]=1)=[O:4].ClC1C=CC=C(C(OO)=O)C=1.Cl.CN.C[CH2:29][N:30](C(C)C)C(C)C>C(Cl)Cl.C1COCC1>[Br:11][C:10]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]([NH:30][CH3:29])=[N:8][CH:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1nc(SC)ncc1Br
Agent: CN
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNc1ncc(Br)c(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Methyl-5-bromo-2-(methylthio)pyrimidine-4-carboxylate (1.0 eq, 661 mg, 2.52 mmol) was dissolved in CH2Cl2 (10 ml). meta-chloro perbenzoic acid (m-cpba, 77% pure grade, 2.5 eq, 1.42 g, 6.34 mmol) was added and the mixture was stirred at room temperature for 1 hour. To the resulting suspension was added anhydrous THF (10 ml), methylamine hydrochloride (10 eq, 1.7 g, 25.18 mmol) and DIEA (10 eq, 4.3 ml, 24.69 mmol) and the mixture stirred at room temperature overnight. The solvents were removed in vacuo prior to adding CH2Cl2 and a saturated aqueous sodium bicarbonate solution. The two phases were decanted and two further CH2Cl2 extractions were carried out. The combined extracts were dried over Na2SO4 and the solvents evaporated. Purification by flash chromatography on silica gel (20-30% ethylacetate in hexanes) provided methyl 5-bromo-2-(methylamino)pyrimidine-4-carboxylate as an off-white solid (461 mg, 75% yield). LCMS (ES): >95% pure, m/z 246 [M]+, 248 [M+2]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: CC(=O)Nc1ccc(-c2ccc(C)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CC(=O)Nc1ccc(-c2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (0.041 g, 0.23 mmol) was reacted with the product from Example 215b (0.062 g, 0.23 mmol) for 46 h at 100° C. following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.073 g, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.98 (s, 3 H) 2.42 (s, 3 H) 2.72 (s, 3 H) 6.28 (d, J=6.99 Hz, 1 H) 7.27-7.56 (m, 7 H) 7.74 (d, J=8.46 Hz, 1 H) 8.33 (d, J=7.35 Hz, 1 H) 8.94 (d, J=8.82 Hz, 1 H) 9.95 (s, 1 H) 11.06 (s, 1 H); MS (ESI+) m/z 383.1 (M+H)+, (ESI−) m/z 381.1 (M−H)−.
Reaction SMILES: [Li+].[OH-].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:22][C:21]=3[CH3:33])=[N:17][CH:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>O.C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=3[CH3:33])=[N:17][CH:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1ccc(-c2ncc(-c3ccc(OC(C)C)c(C#N)c3)s2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)O)ccc1-c1ncc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 50 °C
Yield: 64.1 %

Procedure:
A solution of 2 mg of LiOH in 1 mL water and 1 mL THF was added to ethyl 3-(4-(5-(3-cyano-4-isopropyloxyphenyl)-1,3-thiazol-2-yl)-3-methylphenyl)propanoate (0.003 g, from Step E) and the reaction was heated at 50° C. for 2 h. The reaction was acidified with 0.5 M HCl (25 mL) and the product was extracted with ethyl acetate (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 10% methanol/methylene chloride yielded 1.8 mg of the title compound: 1H NMR (500 MHZ, CDCl3) δ 7.99 (s, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.75 (dd, J=6.9, 2.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.20 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 4.70-4.77 (m, 1H), 3.02 (t, J=7.7 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.64 (s, 3H), 1.47 (d, J=6.0 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][NH:17][C:18]2[C:27]3[C:22](=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18]3[C:27]4[C:22](=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:31][CH:32]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NCc3ccc(NC(=O)c4ccc(F)cc4)cc3)ncnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
4-fluorobenzoyl chloride (220 μL, 0.5 M in anhydrous DCM, 0.10 mmol, 1.1 equiv.) was added to a solution of 4-[(4-aminobenzyl)amino]quinazoline-8-carboxamide (30 mg, 0.09 mmol, 1.0 equiv.) and triethylamine (38 μL, 0.27 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at rt overnight. Ether (2 mL) was added. The precipitate was filtered, washed with ether and DCM to yield the title compound in 72% yield. Mass: M+H+: 416.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:26][C:27]4[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CCO.Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:26][C:27]4[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Sc4cccc(C)c4)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(Sc4cccc(C)c4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To a mixture of 1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.190 g, 0.379 mmol) and EtOH (1 mL) was added 4M HCl in dioxane (1 mL). The mixture was stirred for 3 h at 23° C. The reaction mixture was concentrated and Et2O (10 mL) was added. The solids were filtered and washed with Et2O to yield the titled compound (0.143 g, 91%). MS (ESI/CI): mass calcd. for C20H17ClN4O2S, 412.1; m/z found, 413.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.95 (s, 1H), 8.35 (s, 1H), 7.77 (s, 1H), 7.41 (s, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.19-7.14 (m, 2H), 7.12-7.06 (m, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.29 (s, 3H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.I[CH:14]([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)I
Reactant: Oc1ccc2c(Cl)nccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc2c(Cl)nccc2c1
Yield: 58.6 %

Procedure:
A mixture of 1-chloroisoquinolin-6-ol (898 mg, 5 mmol), 2-iodopropane (1700 mg, 10.00 mmol), and K2CO3 (2073 mg, 15.00 mmol) in acetone (20 mL) was refluxed for 16 h. The reaction mixture was filtrated and washed with acetone. the filtrate was concentrated and purified by silica gel chromatography eluting with 10-20% ethyl acetate in hexane to give 650 mg of the product 1-chloro-6-isopropoxyisoquinoline as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.30-8.13 (m, 2H), 7.47 (d, J=5.3 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.09 (d, J=2.5 Hz, 1H), 4.77 (dt, J=12.2, 6.1 Hz, 1H), 1.45 (d, J=6.0 Hz, 6H); MS: MS m/z 222.16 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].C(O)C.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate (1.45 g) was added ethanol (6.4 mL) followed by a solution of NaOH (0.398 g, 9.96 mmol) in water (6.4 mL). The reaction was stirred at ambient temperature for 1 hour. To the mixture was added 1 N HCl (22.8 mL), and the mixture was stirred for 30 minutes. The solids were collected by filtration, washed with water (2×4 mL), and dried in a vacuum oven at 45° C. for 2.5 days to give 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.89 (s, 1H), 10.67 (s, 1H), 8.09 (d, J=7.7, 1H), 7.88 (d, J=9.9, 1H), 7.32-7.11 (m, 4H); MS (ESI) m/z 346 (M−H)−.