Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[O:15]1[CH2:18][C:17](=O)[CH2:16]1.C([BH3-])#N.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH:17]3[CH2:18][O:15][CH2:16]3)[CH2:12][CH2:13]2)[CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: Clc1cc(C2CCNCC2)cc(Cl)n1
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(C2CCN(C3COC3)CC2)cc(Cl)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A solution of 2,6-dichloro-4-(piperidin-4-yl)pyridine (2 g, 8.7 mmol) and oxetan-3-one (6.26 g, 87 mmol) in THF (50 mL) was stirred at 70° C. for 30 min and then sodium cyanoborohydride (2.74 g, 43.5 mmol) was added to the mixture and the mixture solution was stirred at 70° C. for additional 30 min. The reaction solution was filtered and the filtrate was concentrated to give crude product which was purified by flash column chromatography on silica gel (30% ethyl acetate in petroleum ether) to afford 2,6-dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine. (2 g, 88.7% yield). LCMS (ESI) [MH]+=286.7.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([O:15]C)=[O:14])=[CH:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([OH:15])=[O:14])=[CH:3]1
Reactant: COC(=O)c1cc(-c2ccnn2C)n(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)cc1-c1ccnn1C
Yield: 95.6 %

Procedure:
A solution of methyl 1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylate (200 mg, 0.91 mmol) and sodium hydroxide (3.04 ml, 18.24 mmol) in tetrahydrofuran (4.561 ml) was stirred in a sealed tube for 12 h at 70° C. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification yielding 1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylic acid (187 mg, 0.87 mmol, 95% yield) as a white solid: LCMS (ES) m/e 206 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f37) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]2[C:26]2[C:27]([CH3:32])=[N:28][O:29][C:30]=2[CH3:31])=[CH:13][CH:12]=1>CN(C=O)C>[Br:8][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=2)[C:18]=1[C:26]1[C:27]([CH3:32])=[N:28][O:29][C:30]=1[CH3:31]
Reactant: COc1ccc(-n2c(-c3c(C)noc3C)cc3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(-c3c(C)noc3C)c(Br)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
NBS (59 mg, 0.33 mmol) was added to a cooled (0° C.) solution of 4-(1-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole (105 mg, 0.33 mmol) in 5 ml of DMF. The temperature was allowed to warm to RT and the mixture was stirred at RT for 30 min. DMF was evaporated. DCM and water were added and the phases were separated. After evaporation of the solvents, the residue was purified by flash chromatography with heptane/EtOAc 9:1 to provide 4-(3-bromo-1-(4-methoxyphenyl)-1H-indol-2-yl)-3,5-dimethylisoxazole in 98% yield. ES/MS m/z: 365.14 (M+H), 363.30 (M−H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:20]=[C:21]3[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=2)[NH:24][CH:23]=[C:22]3[CH:31]2[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]2)[CH:15]=[CH:16][C:17]=1[F:18])[CH3:9].[CH2:42](N)[CH3:43]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([NH:10][CH2:11][C:12]2[CH:13]=[C:14]([C:19]3[CH:20]=[C:21]4[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=3)[NH:24][CH:23]=[C:22]4[CH:31]3[CH2:32][CH2:33][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:35][CH2:36]3)[CH:15]=[CH:16][C:17]=2[F:18])[CH2:43][CH2:42][CH2:9]1
Reactant: CCNCc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)ccc1F
Reactant: CCN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(F)c(CNC5CCC5)c4)cc23)CC1
Yield: 42 %

Procedure:
The title compound was prepared according to the general procedure of 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting cyclobutanamine (39 mg, 0.46 mmol) for ethylamine to afford 20 mg of the title compound (42%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][C:12](SC)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[NH:18]([C:22]1[S:23][CH:24]=[C:25]([CH2:27][S:28][CH2:29][CH2:30][NH2:31])[N:26]=1)[C:19]([NH2:21])=[NH:20]>N1C=CC=CC=1>[NH:18]([C:22]1[S:23][CH:24]=[C:25]([CH2:27][S:28][CH2:29][CH2:30][NH:31][C:12]2[NH:11][C:10](=[O:17])[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:14][N:13]=2)[N:26]=1)[C:19]([NH2:21])=[NH:20]
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)cn1

Procedure:
Equimolar amounts of 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone and 2-(2-guanidino-4-thiazolylmethylthio)ethylamine are refluxed together with pyridine for 48 hours to give 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([OH:19])=O.C[N:21](C)C=O.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([NH2:21])=[O:19]
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cn1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 8.5 h

Procedure:
To a suspension of 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (3.0 g) described in Reference Example 8 in toluene (37 ml) were added N,N-dimethylformamide (catalytic amount) and thionyl chloride (2.2 ml), stirred at 80° C. for 8.5 hours, and then the solvent was evaporated in vacuo. To a solution of the residue in pyridine (20 ml) was added a solution of 4-(5-aminopyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (2.8 g) in pyridine (17 ml), stirred at 80° C. for 5 hours, then additionally, 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid chloride (980 mg) described in Reference Example 180 was added thereto, and stirred at 80° C. for 2 hours. To the reaction solution was added triethylamine (4.2 ml), then water was added thereto, and the precipitated solid was washed with water and ethyl acetate to give N-[6-O-tert-butyloxycarbonylpiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (4.0 g) as a yellow solid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:27])([CH3:26])[C:19](=O)[CH2:20][C:21](OC)=[O:22])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:19]2[CH:20]=[C:21]([OH:22])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)([CH3:27])[CH3:26])=[CH:16][CH:17]=1
Reactant: COC(=O)CC(=O)C(C)(C)c1ccc(Cl)cc1
Reactant: N#Cc1ccnc(NN)c1
Product: CC(C)(c1ccc(Cl)cc1)c1cc(O)n(-c2cc(C#N)ccn2)n1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-(4-chlorophenyl)-4-methyl-3-oxopentanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:38])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].N[C@H:44]([C:52](O)=O)[CH2:45]C1C=CC=CC=1>>[C:1]([NH:24][CH:25]([CH2:39][C:40]1[CH:41]=[CH:52][CH:44]=[CH:45][CH:42]=1)[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([OH:38])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35])=[O:27])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(CC(C)C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(Cc1ccccc1)C(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanamido)-2-hydroxybenzoic acid was prepared in a similar fashion as 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoic acid, using the appropriate phenylalanine starting material. Mass calculated for C38H46N2O5=610.78; found: [M−H]+=609.3.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23]Br.O>CN(C)C=O.C(OCC)C>[CH3:20][O:21][C:22]([O:25][CH3:26])([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH3:23]
Reactant: COC(CBr)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COC(C)(OC)Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
4-Phenylphenol (1.70 g, 10 mmol) and cesium carbonate (3.91 g (12 mmol) were stirred at room temperature under a nitrogen atmosphere in 20 mL of dimethylformamide until it appeared that no more solid was dissolving. At that point, 1.42 mL (12 mmol) of bromoacetaldehyde dimethyl acetal (2.03 g, 12 mmol) were added to the mixture via syringe and the resulting brown suspension was stirred at room temperature overnight. The mixture was then heated under reflux for two hours and then stirred at room temperature overnight. At the end of this period, 100 mL of water and 200 mL of diethyl ether were added; the organics were extracted into the ether layer, which was separated, dried over anhydrous sodium sulfate and evaporated to yield 2.10 g (81% yield) of dimethoxy-2-(4-biphenyloxy)ethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](O)=[N:14][N:13]=[CH:12]3)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:15]1[C:16]2[C:11](=[CH:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:18][CH:17]=2)[CH:12]=[N:13][N:14]=1
Reactant: Oc1nncc2cc(Nc3ccc(F)cc3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(Nc2ccc3c(Cl)nncc3c2)cc1
Temperature: 105 °C

Procedure:
A mixture of 6-(4-fluorophenylamino)phthalazin-1-ol (0.650 g, 2.55 mmol) and phosphorus oxychloride (5.00 mL, 53.6 mmol) was heated at 105° C. in an oil bath for 2 h. The volatiles were removed by vacuum distillation. The residue was diluted with CH2Cl2 and treated with saturated aqueous solution of NaHCO3. The organic layer was collected and the aqueous layer was extracted with 25% i-PrOH/CHCl3 (2×). The combined organics were dried over Na2SO4, filtered through a pad of silica gel and eluted with EtOAc. The filtrate was concentrated to yield the title compound as a tan solid. MS (ESI, pos. ion) m/z: 274.0 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=1.O.[SH:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[NH:29][CH:30]=[N:31]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2
Reactant: COc1cc2nc(CCl)n(-c3ccccc3Cl)c(=O)c2cc1OC
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nc(CSc3ncnc4[nH]cnc34)n(-c3ccccc3Cl)c(=O)c2cc1OC
Yield: 65.5 %

Procedure:
Prepared according to Procedure C using Intermediate 2a (200 mg, 0.546 mmol), 6-mercapto-purine monohydrate (102 mg, 0.601 mmol), K2CO3 (83 mg, 0.601 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 172 mg of an off-white solid (65%), mp 160-180° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 13.55 (br s, 1H); 8.49 (s, 1H); 8.44 (s, 1H); 7.72 (d, J=6.9 Hz, 1H); 7.66 (d, J=6.9 Hz, 1H) 7.38-7.54 (m, 3H); 7.22 (s, 1H); 4.36-4.52 (m, 2H); 3.94 (s, 3H); 3.89 (s, 3H). 13C NMR (DMSO-d6) ppm: 160.1, 155.4, 151.5, 151.1, 149.4, 143.2, 134.6, 132.3, 131.6, 131.5, 130.4, 128.7, 113.6, 108.4, 105.8, 56.5, 56.1, 32.0. MS (ES): m/z 481.1 (M+). Anal. calcd. for C22H37ClN6O3S.0.5C2H6O.0.05KCl: C, 54.41; H, 3.97; Cl, 7.33; N, 16.55; S, 6.32. Found: C, 54.43; H, 3.94; Cl, 7.69; N, 16.69; S, 6.52.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]2[N:32]=[N:33][N:34]([CH3:36])[N:35]=2)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COc1ccc(NCc2nnn(C)n2)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COc1ccc(N(Cc2nnn(C)n2)[C@H]2c3cc([N+](=O)[O-])ccc3O[C@](C)(C(OC)OC)[C@@H]2O)cc1
Yield: 78 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.07 mmol) obtained in step 1 of example 2 and N-(4-methoxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (417 mg, yield: 78%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=[O:8])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Cl:19])[CH:13]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
400 mg (1.10 mmol) of the compound from Example 4A are provided in 19 ml of tetrahydrofuran, and 263 mg (11.0 mmol) of lithium hydroxide and 19 ml of water are added at room temperature. The mixture is stirred at room temperature overnight, a 1N aqueous hydrogen chloride solution is then added until an acidic pH is achieved, the mixture is extracted with ethyl acetate and the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. 190 mg of the title compound having a purity of 86% (44% of theory) are obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([O:11][CH3:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].N1C=CN=C1.Cl[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([O:11][CH3:12])[C:5]=1[O:13][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:2]=[CH2:3]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=CCc1cc(Br)cc(OC)c1O
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1cc(Br)cc(OC)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
After dissolving 3 g of 2-allyl-4-bromo-6-methoxy-phenol [CAS No. 352019-92-2] in 10 ml of DMF, 1.3 g of imidazole and 2 g of chlorotriisopropylsilane were added and the mixture was stirred at 50° C. for 4 hours. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give (2-allyl-4-bromo-6-methoxyphenoxy)triisopropylsilane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[S:9]([C:13]1[CH:19]=[CH:18][C:16](C)=[CH:15][CH:14]=1)(O)(=O)=O.OCCC1SC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:19][CH2:18][C:16]2[S:9][CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: OCCc1cccs1
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CCc1cccs1
Temperature: 90 °C
Yield: 38.9 %

Procedure:
A stirred suspension of 5-chloropyrimidin-2-one (131 mg), 2-(2-hydroxyethyl)thiophene tosylate (424 mg), anhydrous sodium carbonate (265 mg) and benzyltrimethylammonium chloride (4 mg) in dry N,N-dimethylformamide (5 ml) was heated at 90° C. After 41/2 h the reaction mixture was evaporated to dryness and the residue was suspended in ethyl acetate (50 ml) and washed with water (3×15 ml), dried (MgSO4) and evaporated to a solid. The solid was subjected to p.l.c. on silica developing with chloroform-ethanol, 19:1. The more polar band was eluted with ethyl acetate and crystallised twice from acetone to give white crystals of the title pyrimidinone (94 mg), m.p. 182°-183° C., λmax (EtOH) 230 nm (ε 17,190), 335 nm (ε 3,470).
Reaction SMILES: [NH2-].[Na+].[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12]1[CH:13]=[C:14]([CH3:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].CO>O1CCCC1>[CH2:3]([NH:10][C:15]1[CH:16]=[C:17]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C)cc1Br
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C)c(NCc2ccccc2)c1
Temperature: 60 °C

Procedure:
20.3 g (0.520 mol) of sodium amide was added to 140 g (1.31 mol) of benzylamine under an argon atmosphere. After stirring under cooling with ice for 20 minutes, a solution of 34.84 g (0.129 mol) of 3-bromo-4-methoxytoluene dissolved in 220 ml of tetrahydrofuran was added dropwise over 90 minutes. The reaction mixture was heated to 60° C. and stirred for 60 minutes. Methanol was added under cooling with ice, followed by further addition of ice water. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized (chloroform-n-hexane) to obtain 26.96 g (yield, 68.4%) of colorless needles of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.[NH2-].[Na+].Br[CH:21](Br)[C:22]([O-:24])=[O:23].[K+].O>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH:21]([C:22]([OH:24])=[O:23])[O:9][C:8]([CH3:16])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: CC(O)(c1ccccc1)c1cc(Cl)ccc1O
Reactant: O=C([O-])C(Br)Br
Agent: [K+]
Agent: [NH2-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccccc2)OC(C(=O)O)Oc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of 9.95 g of 5-chloro-2-hydroxy-α-methyl-α-phenyl-benzene-methanol in 150 ml of anhydrous toluene was added dropwise at room temperature to a mixture of 4 g of sodium amide and 50 ml of anhydrous toluene and the mixture was refluxed for 6 hours and cooled to room temperature. 10.25 g of potassium dibromoacetate were added thereto and the mixture was refluxed for another 6 hours and cooled. 200 ml of water were added thereto and the organic phase was decanted and extracted twice with 80 ml of water. The aqueous phase was washed twice with 80 ml of ether and was acidified with 40 ml of 2 N hydrochloric acid. The resulting precipitate was extracted 3 times with 100 ml of ether and the ether extracts were washed twice with 80 ml of water and extracted with 50% of an aqueous 5% sodium bicarbonate solution. The aqueous phase was washed 3 times with 80 ml of ether and acidified with 90 ml of 2 N hydrochloric acid solution. The mixture was extracted 4 times with 100 ml of ether and the combined ether extracts were washed with water, dried over magnesium sulfate, treated with activated carbon and evaporated to dryness under reduced pressure to obtain 7.85 g of raw product. The latter was taken up in hexane and vacuum filtered and the recovered crystals were dried to obtain 6 g of 6-chloro-4-methyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two racemates diastereoisomers) melting at 144° C.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[CH:3]=[CH:2]1.C([Li])(C)(C)C.[I:18]I.C(Cl)Cl.CO>C(OCC)C>[I:18][C:2]1[O:1][C:5]2[C:4](=[C:9]([C:10]([OH:12])=[O:11])[CH:8]=[CH:7][CH:6]=2)[CH:3]=1
Reactant: II
Reactant: O=C(O)c1cccc2occc12
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1cccc2oc(I)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a cold (−78° C.) solution of benzofuran-4-carboxylic acid (100 mg) in dry diethyl ether (1.2 mL), was added dropwise tert-butyl lithium (1.7 M in pentane, 0.8 mL, 2.2 eq). The reaction mixture was stirred at −78° C. for 30 min. under nitrogen, then a solution of iodine (172.2 mg, 1.2 eq) in ether (1.9 mL) was added dropwise. The reaction was stirred at −78° C. for 30 min. and allowed to warm to rt. The reaction mixture was partitioned between sat. NH4Cl and diethyl ether, the aqueous phase was extracted once again with diethyl ether. The combined organic extracts were washed with sat. sodium thiosulfate, water, dried (Na2SO4), filtered and concentrated to yield a crude brown solid. FC (DCM/MeOH: 99/1 to 97/3) afforded the title compound as a pink solid (40 mg, 23%). LC-MS: tR=0.89 min; [m+H]+=288.99. b) 2-Iodo-benzofuran-4-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-thiazolidin-4-ylmethyl]-amide A solution of 2-iodo-benzofuran-4-carboxylic acid (29.5 mg), TBTU (34 mg 1 eq), DIPEA (0.087 mL, 5 eq) in dry DMF (0.325 mL) was stirred at rt for 15 min. Then, was added (4-Aminomethyl-thiazolidin-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone (34 mg, 1.0 eq.) in dry DMF (0.325 mL). Stirring was continued over night. The reaction mixture was partitioned between sat. aq. NaHCO3 solution/EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give 2-iodo-benzofuran-4-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-thiazolidin-4-ylmethyl]-amide (57 mg, 93%) which was used for the next step without further purification. LC-MS: tR=0.89 min; [m+H]+=288.99. c) 2-Trifluoromethyl-benzofuran-4-carboxylic acid [3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-thiazolidin-4-ylmethyl]-amide