Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:15]=1[OH:21].[N:22]1([C:28]2[N:29]=[C:30]([CH2:35][C:36]([O-])=[O:37])[NH:31][C:32](=[O:34])[CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[Na+]>N1C=CC=CC=1>[Br:20][C:16]1[C:15]([OH:21])=[C:14]([NH:13][C:36](=[O:37])[CH2:35][C:30]2[NH:31][C:32](=[O:34])[CH:33]=[C:28]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:29]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(Br)c1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.3 %

Procedure:
600 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 550 mg of 2-amino-6-bromophenol are added to a solution of 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 4 ml of pyridine. The reaction mixture is stirred at ambient temperature for 20 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 543 mg of N-(3-bromo-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].C(Cl)CCl.[CH:11]1[CH:12]=[CH:13][C:14]2[N:19](O)N=[N:17][C:15]=2[CH:16]=1.NCC1C=CC=CN=1>C1COCC1>[N:17]1[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=1[CH2:14][NH:19][C:1](=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: On1nnc2ccccc21
Agent: NCc1ccccn1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCCC(=O)NCc1ccccn1
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a solution of butyric acid (4.5 mL, 48.7 mmol) in THF (50 mL) was added EDC (11.2 g, 58.4 mmol) and HOBt (7.88 g, 58.4 mmol). The mixture was stirred for 10 min. then 2-(aminomethyl)pyridine (4.7 mL, 46.3 mmol) was added. The solution was allowed to stir for 3 h then quenched with water (100 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield N-pyridin-2-ylmethyl-butyramide (5.82 g, 67%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([O:11]C(=O)C2C=CC=CC=2)=[C:9]([OH:20])[N:8]=[C:7]([C:21]2([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:6]=1)=O.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[C:38]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:37]=1>CO>[C:31]([O:30][C:28](=[O:29])[NH:27][C:21]1([C:7]2[N:6]=[C:5]([C:3]([NH:41][CH2:40][C:39]3[CH:42]=[CH:43][C:36]([F:35])=[CH:37][C:38]=3[S:44]([CH3:47])(=[O:46])=[O:45])=[O:2])[C:10]([OH:11])=[C:9]([OH:20])[N:8]=2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)([CH3:33])([CH3:32])[CH3:34]
Reactant: CS(=O)(=O)c1cc(F)ccc1CN
Reactant: COC(=O)c1nc(C2(NC(=O)OC(C)(C)C)CCOCC2)nc(O)c1OC(=O)c1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2nc(O)c(O)c(C(=O)NCc3ccc(F)cc3S(C)(=O)=O)n2)CCOCC1

Procedure:
Methyl-5-(benzoyloxy)-2-{4[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-yl}-6-hydroxypyrimidine-4-carboxylate (C-30) in dry MeOH was treated with 4-fluoro-2-(methylsulfonyl)benzylamine (2.5 eq.) at reflux for 2 hours. Solvent was removed in vacuo and the residue was taken up in ethyl acetate, washed with HCl 1N, brine, dried over Na2SO4. The filtrate was concentrated in vacuo and triturated with ethyl ether to obtain the crude title compound (C-31).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[CH2:15]([O:12][C:4]1[CH:3]=[C:2]([Br:1])[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cc(Br)c2ccccc2c1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cc(OCc2ccccc2)cc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-Bromo-naphthalen-2-ol (5.0 g, 22.41 mmol) is dissolved in dry DMF (50 ml) under an atmosphere of argon. Sodium hydride (986 mg of a 60% suspension in mineral oil, 592 mg, 24.65 mmol) is added and the mixture is stirred at 50° C. for 1 h. After re-cooling to RT, benzyl bromide (3.46 ml, 4.98 g, 29.14 mmol) and tetrabutyl ammoniumiodide (828 mg, 2.24 mmol) are added. After 16 h at RT, the reaction mixture is diluted with EtOAc. The solution is washed twice with semi-concentrated brine (back extracted). The combined organic layers are dried over Na2SO4, the solvent is removed, and the residue is purified by FCC (hexane/EtOAc 100:0 to 95:5 to 90:10) to yield the title compound. 1H NMR (CDCl3, 400 MHz) δ 5.22 (s, 2H), 7.25 (d, J=1.5 Hz, 1H), 7.45 (m, 7H), 7.64 (d, J=2.4, 1H), 7.75 (d, J=7.8, 1H), 8.17 (d, J=7.8, 1H); ES-MS: 312 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(I)cc4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 606.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6](O)=[O:7].B.CO>O1CCCC1>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:5][CH2:6][OH:7]
Reactant: COC(=O)[C@H](CC(=O)O)CC1CCCCC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCO)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A mixture of (S)-2-cyclohexylmethyl-succinic acid 1-methyl ester (484 mg, 2.12 mmol) and tetrahydrofuran 10 mL) was stirred at room temperature and then cooled to 0° C. To the reaction mixture was added 1.0 M borane in tetrahydrofuran (4.2 mL) dropwise over 5 min. After 2 h, MeOH was added drop-wise to quench the reaction. The reaction mixture was stirred for 30 min at room temperature and then concentrated to dryness. The crude residue was suspended in MeOH, concentrated to dryness, and purified on SiO2 (40 g) using 5-10% MeOH/DCM as eluent to provide the title compound (0.32 g) as a clear oil: 1H NMR (CDCl3, 400 mHz) δ (ppm): 3.69-3.65 (m, 5H), 2.65 (m, 1H), 1.85-1.59 (m, 8H), 1.32-1.12 (m, 5H), 0.87 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[NH:14][C:13](=O)[C:12]=2[CH2:11][CH2:10]1>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:24])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:9][CH2:4][CH2:3][OH:2])[C:12]=2[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCc2c1c1cccc(OC(F)(F)F)c1[nH]c2=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccccc1N1CCc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 160.9 %

Procedure:
1-(2-Methoxyphenyl)-4-oxo-6-trifluoromethoxy-2,3,4,5-tetrahydro-pyrrolo[3,2-c]quinoline(3.0 g, 8.0 mmol) was dissolved in phosphoryl chloride(10 ml), then reaction mixture was refluxed for 2 hours. After removing the excess phosphoryl chloride by simple distillation, the residue was poured into iced water, neutralized with aqueous solution of sodium hydroxide(1N), stirred at room temperature for 30 minutes, and extracted with dichloromethane(20 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 2.7 g of desired compound as solid in 85% of yield.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:24])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH3:23])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:25]#[C:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:25]([C:2]1[N:3]=[C:4]([NH2:24])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH3:23])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[C:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: C#CCCCC
Reactant: CCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CCCCC#Cc1nc(N)c2nc(NCCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-propylaminoadenosine (9, 68 mg, 0.15 mmol) and 1-hexyn (0.73 mmol). The mixture was purified by column chromatography (EtOAc-10% MeOH in EtOAc). Yield 49 mg (0.12 mmol, 80%), mp 184–186÷C; Rƒ 0.60 (10% MeOH in EtOAc); 1H NMR (DMSO-d6) δ 6.98 (t, 1H, J=5.15 Hz, NH), 6.54 (bs, 2H, NH2), 5.87 (d, 1H, J=7.55 Hz, H-1′), 5.75 (t, 1H, J=4.46 Hz, OH-2′), 5.26 (d, 1H, J=6.86 Hz, OH-5′), 5.15 (d, 1H, J=4.12 Hz, OH-3′), 4.55 (q, 1H, J=6.86 Hz, H-2′), 4.06 (m, 1H, H-3′), 3.96 (bs, 1H, H4′), 3.61 (bs, 2H, H-5′), 2.49 (m, 2H, NHCH2), 2.36 (m, 2H, ≡CCH2), 1.60–1.42 (m, 6H, NHCH2CH2CH3, CH2CH2), 0.89 (t, 6H, J=7.55 Hz, 2×CH3); MS m/z 405 (M+H)+; Anal. (C19H28N6O4) C, H, N.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.S(=O)(=O)(O)O.[CH3:14]O>>[CH3:14][O:7][C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8]
Reactant: O=C(O)c1ccsc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccsc1
Yield: 81 %

Procedure:
To a solution of 3-thiophene carboxylic acid (2.0 g, 15.60 mmol) in methanol (30 ml) was added a catalytic amount of sulphuric acid (0.5 ml) and the reaction mixture was heated to reflux for 2 hr. The solvent was removed under reduced pressure and the residue was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, concentrated and dried to give 3-thiophene carboxylic acid methyl ester (1.8 g, 81%).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]([CH2:29][CH2:30][OH:31])[CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]([CH2:29][CH2:30][OH:31])[CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:25])[F:26])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N(CCO)CC(O)c2csc(C(F)(F)F)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)N(CCO)CC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 16 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in methanol with 1N sodium hydroxide solution. After the mixture has been neutralised with 1N hydrochloric acid it is evaporated to dryness, treated with 10 ml of ethanol, and the inorganic residues are removed by filtration. The ethanol phase is diluted with 60 ml of methylene chloride and again filtered. The mother liquor is evaporated to dryness, and the residue is triturated with ether and filtered off with suction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC1(C)C(C)(C)OB([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH2:27])O1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[C:28]1([C:26]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH2:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccccc1
Reactant: COC(=O)c1cc(Br)cc(-c2ccccn2)c1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: C=C(c1ccccc1)c1cc(C(=O)OC)cc(-c2ccccn2)c1

Procedure:
Methyl 3-bromo-5-(pyridin-2-yl)benzoate (137 mg, 0.47 mmol), 4,4,5,5-tetramethyl-2-(1-phenylvinyl)-1,3,2-dioxaborolane (162 mg, 0.70 mmol), Pd(PPh3)4 (19 mg, 0.023 mmol) and K2CO3 (195 mg, 1.41 mmol) were taken up in DME (5 mL) and water (1 mL) and heated to about 80° C. overnight. The reaction mixture was combined with water and the product was extracted into EtOAc (3×10 mL). The combined organic extracts were washed with water (1×10 mL), brine (1×10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified via automated flash chromatography (silica gel; 0 to 25% EtOAc in hexanes) to afford methyl 3-(1-phenylvinyl)-5-(pyridin-2-yl)benzoate. MS m/z=316 [M+1]+. Calc'd for C21H17NO2: 315.
Reaction SMILES: [Na+].[Na+].[NH:3]=[CH:4][C:5]([O-:7])=[O:6].N=[CH:9][C:10]([O-:12])=[O:11].O.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCOCC1.C(Cl)Cl>[C:5]([CH2:4][N:3]([CH2:9][C:10]([OH:12])=[O:11])[S:29]([C:26]1[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=1)(=[O:31])=[O:30])([OH:7])=[O:6]
Reactant: N=CC(=O)[O-]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of iminoacetic acid disodium salt monhydrate (5.0 grams, 25.6 mmol) in dioxane (50 ml) and water (50 ml) was added triethylamine (5.3 ml, 38 mmol) followed by 4-methoxybenzenesulfonyl chloride 95.8 grams, 28.0 mmol). The mixture was stirred overnight at room temperature and diluted with methylene chloride. The solution was washed with 1 N hydrochloric acid solution, water and brine, dried over magnesium sulfate and concentrated under vacuum leaving [carboxymethyl(4-methoxybenzenesulfonyl)amino]acetic acid as a white solid, 3.83 grams (49%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([CH3:33])=[C:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C@H:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:22][CH2:21]4)[N:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCO.[Li+].[OH-]>C1COCC1.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]([CH3:33])=[C:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C@H:23]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21]4)[N:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C(C)C)cc4)sc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1sc(-c2ccc(C(C)C)cc2)nc1CCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of Example 27 (305 mg, 0.657 mmol) in a mixture of THF (8 mL), water (8 mL), and EtOH (4 mL), was added LiOH (63 mg, 2.63 mmol). The reaction mixture was vigorously stirred for 24 h, diluted with water (20 mL), and washed with Et2O (10 mL). The aqueous phase was then acidified to pH ˜1 using 1N HCl, and then extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to afford product (189 mg, 66%) as a white solid. (C26H29NO3S): LC-MS, RT 3.95 min, M+H 436.4; 1H NMR (CDCl3): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.70-1.82 (m, 1H), 2.32-2.43 (m, 2H), 2.45 (s, 3H), 2.74-2.98 (m, 4H), 3.18 (t, 2H), 3.47-3.54 (m, 1H), 4.28 (t, 2H), 6.72 (dd, 1H), 6.78 (s, 1H), 7.08 (d, 1H), 7.51 (AB quartet, 4H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:8][C:7]=1[Cl:17])(=[O:3])[CH3:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CC#N>[C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([S:13](=[O:15])(=[O:16])[N:14]=[CH:20][N:21]([CH3:23])[CH3:22])=[CH:8][C:7]=1[Cl:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)cc(S(N)(=O)=O)cc1Cl
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CC(=O)OCc1c(F)cc(S(=O)(=O)N=CN(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of 2-chloro-6-fluoro-4-sulfamoylbenzyl acetate (1 g, 3.6 mmol) in CH3CN (20 mL2) at 0° C. under N2 was added 1,1-dimethoxy-N,N-dimethylmethanamine (0.7 ml, 5.4 mmol). The resulting solution was stirred at room temperature 1 h, concentrated under reduced pressure, and purified by column chromatography (DCM/EtOAc=9:1) to afford 2-chloro-4-(N-((dimethylamino)methylene)sulfamoyl)-6-fluorobenzyl acetate (850 mg, 76%) as ivory solid. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.76 (s, 1H), 7.55 (d, 1H), 5.26 (s, 2H), 3.18 (s, 3H), 3.05 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [C:1]1([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].[H][H]>C(O)(=O)C.O=[Pt]=O>[C:1]1([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]2)[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1cccc(C)c1OCc1ccccn1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1cccc(C)c1OCC1CCCCN1

Procedure:
Twenty-nine (29) g of 2-[(2,6-xyloxy)methyl]pyridine were hydrogenated in 250 mls of concentrated acetic acid using hydrogen in the presence of 1.0 g of PtO2. The hydrogenation took place by introducing hydrogen to theoretical volume at 70°-80° C. in an autoclave at a pressure of 5-10 atmospheres. The catalyst was filtered off, and the acetic acid evaporated. Twenty-four (24) g of 2-[(2,6-xyloxy)methyl]piperidine were obtained. The acetic acid salt produced was dissolved in 300 mls of water and was purified with active carbon, whereupon the product was precipitated as the base using ammonia. The base product was dried and dissolved in 150 mls of methyl ethyl ketone, whereupon the hydrochloride was obtained by neutralizing with dry HCl. The hydrochloride of 2-[(2,6-xylyoxy)methyl]piperidine melted at 227°-229° C.
Reaction SMILES: C([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)C.[CH:37]1(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)[CH2:39][CH2:38]1.ClC1N=C(N2CCOC[C@@H]2C)C2CCN(C(OC(C)(C)C)=O)CC=2N=1>>[CH:37]1([NH:3][C:4]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]4[CH3:35])[C:15]4[CH2:21][CH2:20][NH:19][CH2:18][C:16]=4[N:17]=3)=[CH:10][CH:11]=2)=[O:36])[CH2:39][CH2:38]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C(=O)OC(C)(C)C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCNC2

Procedure:
Method as described for intermediate 5 using 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea and intermediate 4 as starting materials. Followed by method as described for example 3 step 2.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[Cl:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[N:27][C:28]=1[Cl:29]>C(OCC)(=O)C>[Cl:29][C:28]1[C:23]([Cl:22])=[CH:24][C:25]([O:30][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[CH:26][N:27]=1
Reactant: Oc1cnc(Cl)c(Cl)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(COc1cnc(Cl)c(Cl)c1)OCC
Temperature: 100 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
Bromoacetaldehyde diethyl acetal (2.74 ml, 18.3 mmol) and cesium carbonate (9.93 g, 30.5 mmol) were added to an N,N-dimethylacetamide solution (10 ml) of 5,6-dichloropyridin-3-ol (1.0 g, 6.10 mmol), and stirred under a nitrogen atmosphere at 100° C. for 16 hours. Saline solution and ethyl acetate were added to the reaction solution, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=11:1 to 9:1) to obtain 2,3-dichloro-5-(2,2-diethoxyethoxy)pyridine (1.51 g, yield: 88%) as an orange oil.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.ClC1SC2C=[C:37]([O:39]C)C=CC=2N=1>>[CH3:37][O:39][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: COc1ccc2nc(Cl)sc2c1
Product: COc1ccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc2c1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-6-methoxy-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.30 (m, 4H), 3.04-3.17 (m, 2H), 3.41 (d, J=12.8 Hz, 2H), 3.89 (s, 3H), 4.48-4.59 (m, 1H), 7.20 (dd, J=9.1, 2.5 Hz, 1H), 7.78 (d, J=2.5 Hz, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.08 (s, 1H), 8.38-8.45 (m, 2H), 8.50 (d, J=2.0 Hz, 1H). MS (ES+): m/z=407.12 [MH+]. HPLC: tR=2.13 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:13])(=[O:12])[N:4]=1.[CH3:14][N:15]([CH2:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23]O)[N:22]=1)[CH3:16]>Cl>[CH3:14][N:15]([CH2:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:13])(=[O:12])[N:6]=2)[N:22]=1)[CH3:16]
Reactant: CN(C)Cc1nc(CO)cs1
Reactant: CNC1=NS(=O)(=O)N=C1NCCS
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
Reaction of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1,1-dioxide [prepared in Example 25, Step A] with about one equivalent of 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example 34, Step D] in concentrated hydrochloric acid, and then made basic and worked up, produces the title compound which is identical to the product prepared in Example 33.