Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[O:22][N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[O:22][N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1nc(-c2ccc3c(c2)c(-c2cncc(OC(C)C)n2)cn3S(=O)(=O)c2ccc(C)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(-c2ccc3[nH]cc(-c4cncc(OC(C)C)n4)c3c2)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.6 %

Procedure:
To a solution of N-(3-(3-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-yl)acetamide (220 mg, 0.47 mmol) in 1,4-dioxane (2.0 mL) was added 10% aq NaOH (1.0 mL) and the reaction was stirred at RT for 48 h. The mixture was treated with ice cold water (5.0 mL) and the precipitate was filtered and washed with water. The crude product was purified with preparative HPLC (eluent: 50-80% MeCN in water with 0.01% TFA) to give N-(3-(3-(6-isopropoxypyrazin-2-yl)-1H-indol-5-yl)-1,2,4-oxadiazol-5-yl)acetamide (10 mg, 5.6%). MS (ESI, pos. ion) m/z: 379.2 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 12.10 (brs, 2H), 9.17 (s, 1H), 8.74 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.96 (s, 1H), 7.82 (dd, J=8.4, 1.2 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 5.53-5.47 (m, 1H), 2.23 (s, 3H), 1.51 (d, J=6.4 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[CH2:5][CH2:6][C:3]=12.[Mg].C[O:12][B:13](OC)[O:14]C>C1COCC1>[CH:6]1[C:3]2[CH:2]=[CH:9][C:8]([B:13]([OH:14])[OH:12])=[CH:7][C:4]=2[CH:5]=1
Reactant: Brc1cccc2c1CC2
Reactant: COB(OC)OC
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)C=C2
Temperature: 0 °C
Yield: 97.4 %

Procedure:
The process described in Example 8 was performed with a preformed Grignard reagent from the reaction of 4-bromobenzocyclobutene (18.3 g, 0.1 mol) with magnesium turnings (2.92 g, 0.12 mol) in THF (80 mL) and trimethylborate (12.5 g, 0.12 mol) in THF (80 mL). To recover the product, the reactor was cooled to 0° C. and water (50 mL) was slowly added with vigorous stirring. The reaction was neutralized with aqueous H2SO4, and was extracted with ether (2×300 mL). The ether layer was washed with water (2×150 mL), dried over anhydrous MgSO4, then concentrated on a roto-evaporator to afford an off-white color solid (14.22 g, 96 percent). 1H and 13C NMR spectra were consistent with the following structure. ##STR12##
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:32]([C@@H:34]([O:36]C(=O)C)[CH3:35])=[O:33]>>[OH:36][C@@H:34]([CH3:35])[C:32]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH3:30])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:33]
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A178) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])#[N:2].Cl.[CH2:22]([O:24][C:25](=[O:30])[C@H:26]([CH2:28][SH:29])N)[CH3:23].C(O)C>O>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([NH:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[NH:4][C:3]([C:1]1[S:29][CH2:28][CH:26]([C:25]([O:24][CH2:22][CH3:23])=[O:30])[N:2]=1)=[CH:11]2)(=[O:14])=[O:15]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CSC(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)=N1
Yield: 25.5 %

Procedure:
A mixture of N-(2-cyano-1H-indol-7-yl)thiophene-2-sulfonamide (0.30 g), cysteine ethyl ester hydrochloride (0.22 g) and ethanol (10 mL) was heated under reflux overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.11 g, yield 25%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 156-157° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[CH:19]=[C:20]5[CH2:28][C:26](=[O:27])[NH:25][C:21]5=[CH:22][C:23]=4[Cl:24])[CH2:12][CH2:11]3)[C:5]=2[CH:6]=1.[C:29]([OH:38])(=[O:37])[C@@H:30]([C@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>O>[CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]4[CH:19]=[C:20]5[CH2:28][C:26](=[O:27])[NH:25][C:21]5=[CH:22][C:23]=4[Cl:24])[CH2:14][CH2:15]3)[C:5]=2[CH:6]=1.[C:34]([CH:32]([CH:30]([C:29]([O-:38])=[O:37])[OH:31])[OH:33])([O-:36])=[O:35]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 50 °C

Procedure:
1 g of ziprasidone free base was added to 60 mL of water and the resulting slurry was heated to 50° C. for 3 hours with stirring. 900 mg of L-tartaric acid was added. Heating at 50° C. and stirring were continued for 6 more hours, and then the mixture was stirred at 40° C. overnight. The solution was then allowed to cool and the salt harvested as in Example 5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C.S(=O)(=O)(O)O>CO>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)n1
Yield: 42 %

Procedure:
A solution of 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared as in Example 31(B)(a), 105 mg, 0.25 mmol) in methanol (10 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 68 h. The reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μm, 60 Å, 25 cm×23 cm ID, 75/25 heptane/ethyl acetate) afforded 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester (41.3 mg, 40.7%) as a white solid: mp 156–157° C.; EI-HRMS m/e calcd for C19H21ClN2O3S (M+) 392.0961, found 392.0956.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:34])[C:14](=O)[CH2:15][C@@:16]1([OH:32])[CH2:25][C:24]([F:27])([F:26])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:28])[CH:22]=2)[C@@H:17]1[CH:29]([CH3:31])[CH3:30].N1C2C=CC=CC=2N=C1CCCN(C)CCC1(O)C([2H])([2H])C([2H])([2H])C2C(=CC=C(F)C=2)C1C(C)C>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:34])[CH2:14][CH2:15][C@@:16]1([OH:32])[CH2:25][C:24]([F:27])([F:26])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:28])[CH:22]=2)[C@@H:17]1[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CC(=O)N(C)CCCc1nc2ccccc2[nH]1
Agent: [2H]C1([2H])c2cc(F)ccc2C(C(C)C)C(O)(CCN(C)CCCc2nc3ccccc3[nH]2)C1([2H])[2H]
Product: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CCN(C)CCCc1nc2ccccc2[nH]1

Procedure:
35d is prepared from 17d in a manner analogous to that of Example 2, step 2 for 35b.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH3:35]>>[CH2:34]([N:36]1[CH2:41][CH2:40][N:39]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:38][CH2:37]1)[CH3:35]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCN1CCNCC1
Product: CCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 30 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.5 equivalents of 1-ethylpiperazine as secondary amine. The product was purified by flash chromatography on silica gel.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>C(Cl)Cl>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCBr
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCBr
Yield: 106.3 %

Procedure:
Imidazole (1.1 g, 16.56 mmol) and TBS-Cl (1.37 g, 9.11 mmol) were added to a stirring solution of 6-bromohexanol (1.5 g, 8.28 mmol) in CH2Cl2 (80 mL). The resulting mixture was stirred over night then quenched with H2O (100 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title compound (2.6 g) as clear oil. The compound was used with no further purification.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+].[NH:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.Br[C:43]1[CH:48]=[C:47]([CH3:49])[C:46]([NH:50][C:51](=[O:58])[CH2:52][CH:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)=[C:45]([CH3:59])[CH:44]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[N:35]1([C:43]2[CH:48]=[C:47]([CH3:49])[C:46]([NH:50][C:51](=[O:58])[CH2:52][CH:53]3[CH2:57][CH2:56][CH2:55][CH2:54]3)=[C:45]([CH3:59])[CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCCNCC1
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC1CCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCCCCC2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 110 °C
Yield: 49.7 %

Procedure:
Bis(dibenzylideneacetone)palladium (2.8 mg) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (3.8 mg) were mixed in dry toluene (2.5 mL) under argon for 5 minutes. To this mixture were added sodium tert-butoxide (6 mg), azacycloheptane (7.5 mg) and N-(4-bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (1p, 15 mg) and the reaction was heated to 110° C. in a sealed 4 mL vial under argon for 48 hours. The reaction mixture was concentrated in vacuo, sodium hydroxide (2 M, 1.5 mL) was added and the product was extracted with isopropyl acetate (3×1.5 mL). The combined organic phases were dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 7.9 mg (50% yield) of the title compound as an oil. LC-MS-TOF (m/z) 329 (MH+); tR=2.08, (UV, ELSD) 90%, 99%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])[CH3:2].C(C1CCCC([Cl:24])C1=O)(C)(C)C>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([Cl:24])[C:7]1=[O:12])[CH3:2]
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Product: CCOC(=O)CC1CCCC(Cl)C1=O

Procedure:
The chlorination of ethyl(2-oxo-cyclohexyl)-acetate takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>N1C=CC=CC=1.[Ni](Cl)Cl.[Zn].C(OCC)(=O)C>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([C:2]2[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=2)[CH2:7][N:8]2[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]2=[O:16])=[CH:21][CH:22]=1)#[N:25]
Reactant: COc1nn(C)c(=O)n1Cc1cc(Br)ccc1C
Reactant: N#Cc1ccc(Cl)cc1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1nn(C)c(=O)n1Cc1cc(-c2ccc(C#N)cc2)ccc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 33.7 %

Procedure:
To a solution of 1.80 g (5.77 mmol) of 4-(5-bromo-2-methylbenzyl)-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 299 of the present invention), 0.89 g (5.77 mmol) of 4-chlorobenzonitrile, 75 mg (0.577 mmol) of anhydrous nickel (II) chloride, and 0.31 g (1.15 mmol) of triphenylphosphine in 6 ml of pyridine was heated to 80° C. under an atmosphere of nitrogen. Then, 0.79 g (12.1 mmol) of zinc powder was added thereto, and the mixture was stirred at 80° C. under an atmosphere of nitrogen for 5 hours. After cooling to room temperature, the mixture was poured into a mixture of diluted hydrochloric acid (prepared by mixing 72 ml of water and 8 ml of concentrated hydrochloric acid) and ice, and ethyl acetate was added thereto. The resultant mixture was filtered with cotton and separated, and the organic layer was washed successively with an aqueous solution of sodium bicarbonate and water, then dried and concentrated. The residue (2.17 g) was subjected to silica gel column chromatography (eluted with hexane:ethyl acetate=2:1and then 1:1 for eluting impurities and then 1:2 for eluting the desired compound) to obtain 0.65 g of 4-{5-(4-cyanophenyl)-2-methylbenzyl}-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 489 of the present invention) as crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:13](Cl)=[O:14].C(N(CC)CC)C>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:13]([NH:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: NCCc1cccs1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCc1cccs1)c1cc(Cl)cc(Cl)c1
Yield: 92.9 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with 3,5-dichlorobenzoyl chloride (120 mg, 0.57 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave 3,5-dichloro-N-(2-thiophen-2-yl-ethyl)-benzamide (118 mg, 0.39 mmol, 92% yield) as a white powder after purification by chromatography on silica gel (eluent: EtOAc/hexane 2/8).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.C([Li])CCC.Cl[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][N:15]=1.CCOC(C)=O>C1COCC1.CCOCC.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:2]2[S:3][C:4]([CH3:7])=[CH:5][N:6]=2)[CH:19]=1
Reactant: Cc1cnc(Br)s1
Reactant: Fc1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cnc(-c2cc(F)ccn2)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
To a dry 10 mL Schlenk flask equipped with a stir bar and placed under N2 atmosphere was added 2-bromo-5-methylthiazole (244 mg, 1.37 mmol) in THF (5 mL). The flask was cooled to −78° C. To the solution was added n-butyllithium in hexanes (0.55 mL, 1.37 mmol). The solution was stirred for 15 minutes. To the solution was added zinc(II) chloride in THF (2.74 mL, 1.37 mmol). The solution was immediately allowed to warm to r.t. (using a r.t. water bath) with stirring for 30 min. To the solution was added 2-chloro-4-fluoropyridine (150 mg, 1.14 mmol), then Pd(dppf)Cl2 (42 mg, 0.057 mmol). The vial was placed in a 60° C. heating block with stirring for 2.25 h. The reaction solution was transfered to a 125 mL separatory funnel and was diluted with Et2O (20 mL). The solution was washed with sat. aq. NaHCO3 (20 mL). The aq. phase was extracted with EtOAc (25 mL). The combined organics were washed with brine (20 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford an orange residue. This material was subjected to silica gel chromatography (hexanes:EtOAc, 100:0 to 80:20) to afford 2-(4-fluoropyridin-2-yl)-5-methylthiazole as a white solid (54 mg, 24%). 1H-NMR (400 MHz, CDCl3) δ 8.55 (dd, J=8.2, 5.4 Hz, 1H), 7.91-7.82 (m, 1H), 7.62-7.56 (m, 1H), 7.02 (ddd, J=8.2, 5.6, 2.5 Hz, 1H), 2.55 (d, J=1.3 Hz, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl[C:40]1[N:47]=[CH:46][CH:45]=[CH:44][C:41]=1[C:42]#[N:43].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+].Cl>C(COC)OC.O.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[N:47]=[CH:46][CH:45]=[CH:44][C:41]=5[C:42]#[N:43])=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: N#Cc1cccnc1Cl
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ncccc5C#N)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-chloronicotinonitrile (290 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was partially purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient). A solution of this partially purified product (444 mg, 0.83 mmol) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (286 mg, 82%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]([C:12]([O:14][CH3:15])=[O:13])[C:7](=[O:16])[C:6]=2[CH:5]=[N:4][CH:3]=1.[H-].[Na+].[CH3:19]I>CN(C=O)C.C1COCC1.O>[CH3:15][O:14][C:12]([C:8]1([CH3:19])[C:7](=[O:16])[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[C:11]=2[CH2:10][CH2:9]1)=[O:13]
Reactant: COC(=O)C1CCc2c(Br)cncc2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(C)CCc2c(Br)cncc2C1=O
Temperature: 25 °C
Yield: 90 %

Procedure:
To a stirred solution of (rac)-methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (3.5 g, 12.3 mmol) (intermediate A-1[B]) in DMF (10 mL) and THF (50 mL) was added 60% NaH (750 mg, 18.5 mmol) in portions at 0° C. The reaction mixture was stirred at 0° C. for 15 min before methyl iodide (1.6 mL, 24.6 mmol) was added and the resulting reaction mixture was allowed to warm up to room temperature and stirred over night. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (2×). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtOAc-heptane gradient to give the title compound (3.3 g, 90% yield) as a light yellow solid. MS: 297.9 & 299.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])[CH:14]=3)[C:9]2=[O:23])=[CH:5][CH:4]=1.C(O)C.[BH4-].[Na+]>C1COCC1>[OH:20][CH2:19][C:18]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:23])[N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=1)[CH2:17][CH2:16]2)([CH3:21])[CH3:22]
Reactant: COc1ccc(CN2CCc3cc(C(C)(C)C=O)ccc3C2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CN2CCc3cc(C(C)(C)CO)ccc3C2=O)cc1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
180 mg 2-[2-(4-Methoxy-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionaldehyde (0.54 mmol, 1 eq) was cooled to zero° C. in 20 ml of a 1:1 mixture of ethanol and THF. 20 mg sodium borohydride (0.54 mmol, 1 eq) was added and the mixture was stirred at 0°° C. for 1 hour. Quenched with water, then 2 drops glacial acetic acid, stirred for 5 minutes, and the mixture concentrated under vacuum to remove the majority of solvents, added saturated bicarb solution, extracted ethyl acetate 2×, dried ethyl acetate over MgSO4, and concentrated to give 180 mg 6-(2-Hydroxy-1,1-dimethyl-ethyl)-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-1-one (M+H=340) which was used directly in the next reaction with no purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>ClCCl>[Cl:15][S:16]([C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:18])=[O:17]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1cc(OC)ccc1C(=O)O
Solvent: ClCCl
Product: CCOc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 25 °C
Yield: 94 %

Procedure:
2-Ethoxy-4-methoxybenzoic acid (9.5 g, 48.5 mmol) was added in portions to cold chlorosulfonic acid (60 mL, Aldrich) stirring at −3 to 0° C. (ice-acetone bath) over 15 min and warmed slowly to room temperature and heated to 60-65° C. for 40 min. The resulting dark solution was carefully poured with stirring into a large excess of ice and then 500 mL of dichloromethane was added. After stirring for 15 min, the layers were separated and the aqueous layer was extracted with dichloromethane (3×250 mL). The organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was evaporated to a low volume. This was triturated with ether/hexane and filtered to give 5-chlorosulfonyl-2-ethoxy-4-methoxybenzoic acid as a colorless solid (13.4 g, 94%).