Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[F:17])[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[F:17])[C:12]#[N:13])[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)c(Cc2cccc(Br)n2)c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)c(Cc2cccc(-c3ccc(F)cc3F)n2)c1
Temperature: 95 °C
Yield: 75.8 %

Procedure:
To a solution of 3-[(6-bromopyridin-2-yl)methyl]-4-fluorobenzonitrile (from Step B above, 8.34 g, 28.6 mmol) in toluene (300 mL) was added (2,4-difluorophenyl)boronic acid (8.15 g, 34.4 mmol), tetrakis(triphenylphosphine)palladium (1.65 g, 1.40 mmol), ethanol (30 mL), and 2M Na2CO3 (30 mL). The resulting mixture was heated to 95° C. for 2 hours. The reaction was cooled to room temperature and filtered through celite and concentrated in vacuo. The crude residue was dissolved in EtOAc, washed with H2O, brine (2×), dried over MgSO4, and concentrated. The crude material was purified via silica gel chromatography (hexanes/ethyl acetate) to give the title compound as a white solid (7.03 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-nitrobenzenesulfonyl chloride according to METHOD A, giving 8.66 g (46%) of product: MS (Ionspray, [M+H]+) m/z 372; Anal. Calcd. (found) for C13H13N3O6S2: C, 42.0 (42.5)%; H, 3.5 (3.3)%; N, 11.3 (11.4)%.
Reaction SMILES: C([S:4][CH:5]([CH2:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=O)C.O.S(=O)(=O)(O)O>O1CCOCC1>[SH:4][CH:5]([CH2:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)SC(CC(=O)c1ccc(Oc2ccccc2)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C(CC(S)C(=O)O)c1ccc(Oc2ccccc2)cc1
Yield: 38.4 %

Procedure:
3.44 g of 2-acetylthio-3-(4-phenoxybenzoyl)propionic acid were dissolved in 50 ml of dioxane, then 5 ml of distilled water and 2 ml of concentrated sulfuric acid were added, and the mixture was refluxed for 3 hours. The dioxane was removed by evaporation under reduced pressure. Diethyl ether was added to the residue, which was extracted with a saturated aqueous solution of sodium hydrogencarbonate. The extract was washed with diethyl ether, made slightly acidic by addition of dilute hydrochloric acid, and extracted with diethyl ether. The diethyl ether layer was washed with water and dried over magnesium sulfate. The diethyl ether was distilled off and the residue was purified by first by silica gel column chromatography, eluted with a mixture of hexane and dichloromethane, and then by recrystallization from a mixture of hexane and acetone to give 1.16 g of 2-mercapto-3-(4-phenoxybenzoyl)propionic acid.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([NH2:19])(=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC>C(O)C>[C:12]1([C:11]2[S:18][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)CC(=O)CBr
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)Cc1csc(-c2ccccc2)n1

Procedure:
Ethyl γ-bromoacetoacetate [2.62 g, 0.9-1.0 mole, described by A. Burger and G. E. Ullyot, J. Org. Chem., 12, 346 (1947)]is added in one portion to a suspension of thiobenzamide [117.5 g, 0.857 mole, described by A. Silberg et al., Ber., 94, 2887 (1961)] in ethanol. The clear solution is refluxed on a steam bath for 2 hr, cooled and slowly added with stirring to ether (3500 ml). The white crystalline precipitate is collected, washed with ether and partitioned between water and ether. Sodium bicarbonate is added in portions until the mixture is alkaline. The mixture is extracted with ether, the ether solution is washed with saturated sodium chloride solution, dried, and evaporated to give ethyl 2-phenylthiazole-4-acetate (VII; R1 = H, R9 = CH2CH3), γmaxCHCl3 1725 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5](=[CH:10][C:11]=1[Cl:12])[C:6]([O:8][CH3:9])=[O:7].[CH2:14](Br)[CH:15]=[CH2:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:16]([O:13][C:4]1[CH:3]=[C:2]([NH2:1])[C:11]([Cl:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH:15]=[CH2:14]
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of methyl 4-amino-5-chlorosalicylate (5 g), allyl bromide (12.6 g), ground K2CO3 (30 g) and acetone (120 ml) is stirred at reflux for 5 hours and cooled to 25° C. The mixture is partitioned between methylene chloride and H2O, the organic layer is separated, dried (MgSO4), filtered and evaporated. The residue is recrystallized from hexanechloroform affording the desired product as a crystalline solid (M.P. 107°-109° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][CH2:17]2)[CH:7]=1
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(F)(F)F)ccn2)CC1
Yield: 70.8 %

Procedure:
A solution of 2-bromo-4-trifluoromethylpyridine (1.00 g, 4.42 mmol), tert-butyl piperidine-4-ylcarbamate (0.93 g, 4.65 mmol) and TEA (0.67 mL, 4.86 mmol) in DMSO (5 L) was heated at 120° C. for 17 h. The reaction mixture was evaporated to dryness, Et2O was added, and the organic phase was washed with water, brine and evaporated to dryness. The residue was purified using the Biotage Horizon HPFC system eluting with 22% EtOAc in petroleum ether (40-60° C.) to give the title compound (1.08 g, 71%) as a solid. 1H NMR (500 MHz, CDCl3): 8.30 (d, 1H), 6.82 (s, 1H), 6.77 (d, 1H), 4.49 (bs, 1H), 4.36-4.22 (m, 2H), 3.74 (bs, 1H), 3.06 (td, 2H), 2.10-2.04 (m, 2H), 1.56-1.38 (m, 11H); 13C NMR (CDCl3): 159.4, 155.4, 149.5, 140.1, 139.9, 124.5, 122.4, 108.1, 102.7, 79.8, 48.3, 44.4, 32.3, 28.6; Mass Spectrum: M+H 346.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][C:14]=1B(O)O>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].C(Cl)Cl>[F:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[C:18]1[CH:17]=[C:16]([O:19][CH2:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[F:12]
Reactant: CCCOc1ccc(F)c(B(O)O)c1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CCCOc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2-fluoro-5-propoxyphenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 5-fluoro-6-(2-fluoro-5-propoxyphenyl)picolinic acid. LC/MS=294.2 (M+H), Rt=0.95 min.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[C:20]1([CH3:37])[CH:25]=[CH:24][C:23](S(OCC2CCCCC2)(=O)=O)=[CH:22][CH:21]=1>>[CH:20]1([CH2:37][N:7]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(CC2CCCCC2)c(=O)[nH]c1=O
Yield: 52.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (195 mg, yield: 52.3%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:51]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.[C:52]1([CH2:58][C:59](Cl)=[O:60])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:51]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][CH:45]1[CH2:46][CH2:47][N:48]([C:59](=[O:60])[CH2:58][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:49][CH2:50]1
Reactant: Clc1cnc2nc1Nc1ccc(NC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)N1CCC(Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 29 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-piperidin-4-yl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) and benzeneacetyl chloride as the starting materials in 29% yield. LCMS for C30H31ClN7O (M+H)+: m/z=540.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([CH3:18])([CH3:17])[CH3:16])\[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([CH3:18])([CH3:17])[CH3:16])\[CH2:7][Br:20])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1C(C)(C)C
Yield: 51.3 %

Procedure:
To a stirred mixture of (E)-3-(2-t-butyl-phenoxy)-but-2-enoic acid ethyl ester (3.20 g, 0.012 mol) in carbon tetrachloride (20 mL) under a nitrogen atmosphere was added N-bromosuccinimide (3.26 g, 0.018 mol) and benzoyl peroxide (295 mg, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2-t-butyl-phenoxy)-but-2-enoic acid ethyl ester (2.10 g, 50%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:10][C:11]1[N:12]=[C:13]([Sn](CCCC)(CCCC)CCCC)[S:14][CH:15]=1>>[CH3:10][C:11]1[N:12]=[C:13]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[N+:7]([O-:9])=[O:8])[S:14][CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Reactant: O=[N+]([O-])c1ccsc1Cl
Product: Cc1csc(-c2sccc2[N+](=O)[O-])n1

Procedure:
4-Methyl-2-(3-nitrothiophen-2-yl)thiazole was prepared from 2-chloro-3-nitrothiophene (219 mg, 1.34 mmol) and 4-methyl-2-(tributylstannyl)thiazole (520 mg, 1.34 mmol) according to protocol E. Retention time (min)=2.462, method [1], MS(ESI) 227.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:19][O:20][CH2:21][CH2:22][N:23]=[C:24]=S>>[Cl:18][C:3]1[C:2]2[N:1]=[C:24]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[N:12]([CH2:13][C:14]([CH3:15])([OH:16])[CH3:17])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Reactant: COCCN=C=S
Product: COCCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Yield: 65.7 %

Procedure:
The method described in Part A of Example 7 was used to treat 1-[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (3.00 g, 11.3 mmol) with 2-methoxyethyl isothiocyanate (1.59 g, 13.6 mmol) to provide 2.59 g of 1-{4-chloro-2-[(2-methoxyethyl)amino]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol after chromatographic purification.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][C:20]=1[F:21].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:24][CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][C:20]([F:21])=[C:15]([Cl:14])[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
4.54 ml of 4-tert-butylbenzaldehyde (27.13 mmol), 3.8 g 2-(3-chloro-4-fluoro-phenyl)-ethylamine hydrochloride (18.1 mmol) and 2.5 g potassium carbonate (18.1 mmol) were suspended in 55 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 1.03 (27.13 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 5 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; EtOAc/heptane 1:4) to give 4.66 g light yellow oil (80%). MS (ISP) 320.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH:21]([O:24]C5CCCCO5)[CH2:20]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:31])=[N:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:31])=[N:4][CH:3]=1
Reactant: Cc1ncc(C)n2nc(CCc3nc(N4CCC(OC5CCCCO5)C4)nn3C)nc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3nc(N4CCC(O)C4)nn3C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
To a solution of 5,8-dimethyl-2-(2-(1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)ethyl)-[1,2,4]triazolo[1,5-a]pyrazine (30 mg, 70.3 μmol, Eq: 1.00) in methanol (3 ml) was added p-toluenesulfonic acid monohydrate (669 μg, 3.52 μmol, Eq: 0.05), the resulting mixture was stirred for 2 hours at 25° C. under nitrogen atmosphere→nearly no reaction, another portion of p-toluenesulfonic acid monohydrate (13.4 mg, 70.3 μmol, Eq: 1.00) was added, stirring at 25° C. was continued overnight. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with sat. sodium hydrogen carbonate. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. Purification by HPLC separation afforded 1-{5-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-pyrrolidin-3-ol (2.05 mg, 8.51%) as a light yellow viscous oil. MS: m/z=323.5 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:12]([O:14]CC2C=CC(OC)=CC=2)=[O:13])=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:12]([OH:14])=[O:13])=[CH:37][CH:38]=1
Reactant: COc1ccc(COC(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(COc2ccc(C(=O)O)cc2OCc2ccc(OC)cc2)cc1
Temperature: 60 °C
Yield: 85 %

Procedure:
4-Methoxybenzyl 3,4-bis(4-methoxybenzyloxy)benzoate (6.48 g, 0.013 mol) was suspended in ethanol and treated with 2.5N aqueous sodium hydroxide solution (7.6 ml, 0.015 mol). The mixture was warmed to 60° C. for 4 h. The mixture was evaporated to low volume and then partitioned between water and ethyl acetate. The aqueous layer was washed again with ethyl acetate and then acidified and extracted into ethyl acetate. As the ethyl acetate solution was concentrated the product precipitated from solution and was filtered off to give the title compound (4.36 g, 87%).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:7]=1[NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12]>[Fe].C(OCC)(=O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:6]([F:5])=[C:7]([CH:14]=1)[NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12]
Reactant: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1cc(N)ccc1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A mixture of 39.4 g (706 mmol) of iron powder and 75 ml of an aqueous solution of 5% acetic acid was heated to 80° C., and a mixed solution of 16.1 g (70.6 mmol) of ethyl 2-fluoro-5-nitrocarbanilate, 72 ml of acetic acid and 72 ml of ethyl acetate was slowly added dropwise to the mixture. After the reaction was continued for 3 hours, the insolubles were filtered out and washed with ethyl acetate. Thereafter the filtrate was distilled to remove the solvent, and the resultant product was dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate, water and saturated saline solution. The solution was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to obtain the crude product (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 12.8 g of the objective product (yield: 91%) in the form of light yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C[O-].[Na+].Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[CH:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Oc1cccc2cnccc12
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2cnccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of 29.0 g of 5-hydroxyisoquinoline in 300 ml of DMF, 11.0 g of sodium methylate was added portionwise. After stirring for 30 min, 17.9 ml of methyl chloroacetate was added dropwise, and the resultant mixture was stirred at room temperature overnight and concentrated under reduced pressure. To the residue, 300 ml of toluene and 300 ml of water were added, and the whole mixture was filtered. The aqueous layer was extracted with 50 ml of toluene, and the combined toluene solution was treated with 2 g of charcoal and evaporated to give methyl 5-isoquinolyloxyacetate. The ester was dissolved in 100 ml of methanol, reacted with 80 ml of 3 N sodium hydroxide aqueous solution for 30 min. The reaction mixture was concentrated under reduced pressure, diluted with 80 ml of water and 160 ml of acetone, and neutralized with 20 ml of concentrated hydrochloric acid. The precipitates formed were filtered, washed with 80 ml of 50% aqueous acetone, and dried to give 34.5 g (85% yield) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:8]([CH2:22][CH2:23][N:24]=3)[C:9]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)=[N:10][C:11]=2[CH:12]=1.[S-2].[Na+].[Na+]>CN1CCCC1=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:8]([CH2:22][CH2:23][N:24]=3)[C:9]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)=[N:10][C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)N=C(NC(=O)c1cccnc1)N1CCN=C21
Agent: [Na+]
Agent: [S-2]
Solvent: CN1CCCC1=O
Product: O=C(NC1=Nc2cc(O)ccc2C2=NCCN12)c1cccnc1
Temperature: 160 °C
Yield: 69.9 %

Procedure:
A suspension of N-(8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (example 2-22) 3.50 g (10.9 mmol) and sodium sulfide 4.25 g (54.5 mmol) in 1-methyl-2-pyrrolidinone 10 mL was heated to 160° C. for 4 hours (LC-MS indicated complete consumption of the starting material). The mixture was cooled to room temperature and volatile sideproducts were evaporated. The mixture was partitioned between chloroform and 0.5N NaOH solution. The aqueous layer was neutralized and the formed precipitate was collected to give the title compound 2.34 g as off-white solid. Yield 69.9%.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:31])=[O:30])=[CH:25][C:24]=2[C:38]#[N:39])=[C:18]([C:40]2[N:44]([CH3:45])[N:43]=[CH:42][CH:41]=2)[CH:17]=1)C)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[C:38]([C:24]1[CH:25]=[C:26]([S:29]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)(=[O:30])=[O:31])[CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][NH:7][CH3:6])=[CH:17][C:18]=1[C:40]1[N:44]([CH3:45])[N:43]=[CH:42][CH:41]=1)#[N:39]
Reactant: CN(Cc1ccccc1-c1ccc(Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)c(-c2ccnn2C)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccccc1-c1ccc(Oc2ccc(S(=O)(=O)Nc3nccs3)cc2C#N)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
tert-Butyl-{[4′-{2-cyano-4-[(1,3-thiazol-2-ylamino)sulfonyl]phenoxy}-3′(1-methyl-1H-pyrazol-5-yl)biphenyl-2-yl]methyl}methylcarbamate (Preparation 65, 64 mg, 0.01 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (0.2 mL) was added and the reaction was stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC to afford the title compound (22 mg, 37%) as a white solid as the trifluoroacetate salt.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14]>>[OH:12][CH:7]1[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: OC1CCCc2c(Br)cncc21
Product: N#Cc1ccc(-c2cncc3c2CCCC3O)cc1
Yield: 83 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-ol (intermediate A-2) was reacted with 4-cyanophenylboronic acid to give the title compound as light brown powder in 83% yield. MS: 251.1 (M+H+).