Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH:30]=[N:29][CH:28]=[N:27]4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: c1nc[nH]n1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)Cn4cncn4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with 1H-[1,2,4]triazole. 1H-NMR (DMSO-D6) δ: 2.61 (s, 3H, CH3), 2.63 (s, 3H, CH3), 5.10 (s, 2H, CH2), 7.05 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.50 (d, 2H, J=8.3 Hz, pyrimidinyl-H), 7.69 (d, 2H, J=8.9 Hz, Ph-H), 7.98 (s, 1H, Aryl-H), 8.48 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 8.53 (s, 1H, Aryl-H), 9.62 (brs, 1H, NH), 10.30 (brs, 1H, NH). MS (ESI+) m/z 406.97 (C19H18N8OS requires 406.47).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=1[CH:13]=[CH:14][CH2:15][C:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:22](=[O:24])[CH3:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=1[CH:13]=[CH:14][CH2:15][C:16]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:22](=[O:24])[CH:23]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CC(=O)C(CC=Cc1ccccc1Cl)(CCC(=O)O)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(CC=Cc1ccccc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (2.81 g., 0.02 mole) in ethanol (10 ml.) is added to a solution of 4-(o-chlorocinnamyl)-4-phenyl-5-oxohexanoic acid (3.57 g., 0.01 mole) and sodium hydroxide (0.56 g., 0.014 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (250 ml.), and extracted with ether to remove the excess p-chlorobenzaldehyde. The aqueous phase is acidified with dilute hydrochloric acid (10 ml.), and the gum that separates out is extracted into ether. The ether extract is washed with brine solution, and dried over anhydrous Na2SO4. Filtration and removal of the ether in vacuo gives a viscous yellow residue, which upon trituration with petroleum ether (30°-60°C., 150 ml.) yields 4.3 g. of material, m.p. 90°-125°C. (cloudy). Recrystallization from n-butyl chloride, followed by ethanol, produces a material with m.p. 143°-146°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)[CH2:23][CH3:24])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:35]([OH:38])[C:36]#[CH:37]>>[CH2:23]([N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:37]#[C:36][CH2:35][OH:38])=[CH:3][CH:4]=3)=[N:9][S:10][C:11]=2[CH:16]=1)[CH3:24]
Reactant: C#CCO
Reactant: CCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCO[Si](C)(C)C(C)(C)C
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(C#CCO)cc3)nsc2c1

Procedure:
In analogy to example 36.1, {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amine and 2-Propyn-1-ol were converted to yield 3-[4-(6-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-benzo[d]isothiazol-3-yl)-phenyl]-prop-2-yn-1-ol as yellow oil, MS: 425 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=O)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[OH:1][C:2]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][C:5]([C:6](=[N:21][OH:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCCc1cc(C(=O)c2ccccc2F)ccc1O
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1cc(C(=NO)c2ccccc2F)ccc1O

Procedure:
A solution of 4-hydroxy-5-propyl-2′-fluorobenzophenone (Step A; 1.35 g, 5.23 mmol) in 15 mL of pyridine was treated with hydroxylamine hydrochloride (1.82 g, 26.15 mmol). The mixture was refluxed for 24 hours, cooled and the pyridine removed in vacuo. The residue was taken up in ethyl acetate and washed with 1N hydrochloric acid, water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified via flash chromatography on silica gel (20% ethyl acetate/hexane eluent) to yield the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CC(C)([O-])C.[K+].CS(O[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:29][CH2:28][C:27]3[CH:30]=[CH:31][S:32][C:26]=3[C:25](=[O:33])[C:24]=2[CH:34]=1)(=O)=O>C(O)C>[O:33]=[C:25]1[C:24]2[CH:34]=[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:3]([OH:4])[CH3:2])[CH:21]=[CH:22][C:23]=2[O:29][CH2:28][C:27]2[CH:30]=[CH:31][S:32][C:26]1=2
Reactant: CNO
Reactant: CS(=O)(=O)OCCCCc1ccc2c(c1)C(=O)c1sccc1CO2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CN(O)CCCCc1ccc2c(c1)C(=O)c1sccc1CO2
Temperature: 25 °C
Yield: 51.1 %

Procedure:
To a stirring solution of 4.77 g of N-methylhydroxylamine hydrochloride in 100 ml of absolute ethanol was added 6.38 g of potassium tert-butoxide. To the resulting suspension was added 6.98 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)butanol methanesulfonate, and an additional 150 ml of absolute ethanol. The suspension was allowed to reflux for 24 hours and was then cooled to room temperature. The suspension was filtered to remove potassium chloride and the filter cake was washed with absolute ethanol. The resulting solution was concentrated in vacuo to a waxy solid. The solid was dissolved in 300 ml of methylene chloride and partitioned against 200 ml of water. The organic phase was dried with 200 ml of saturated aqueous sodium chloride, collected, dried again (Na2SO4), filtered, and concentrated in vacuo to an oil. The oil solidified upon standing, and was recrystallized from isopropanol to give 3.09 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)-N-hydroxy-N-methyl-1-butylamine, m.p. 107-108° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[K+].[CH:12](=[O:15])[CH2:13][CH3:14].C(O)(=O)C>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([CH3:14])[CH:12]=[O:15])=[CH:4][CH:3]=1
Reactant: CCC=O
Reactant: O=Cc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C=O)=Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 124 g (1 mole) of 4-fluorobenzaldehyde and 8 g (0.143 mole) of potassium hydroxide in 500 ml ethanol at room temperature was added dropwise a solution of 52.2 g (0.9 mole) of propionaldehyde in 100 ml ethanol. After stirring for 0.5 hour, the mixture was acidified with acetic acid and concentrated by rotary evaporation. The residue was partitioned between methylene chloride and water. The aqueous layer was extracted three times with additional methylene chloride. The combined organic layers were dried and concentrated. Distillation through a 12-inch vacuum jacketed column gave 113.5 g (77%) of pale yellow low-melting crystalline product, b.p. 70°-72° C. (0.4-0.7 mm).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH2:7][CH2:6]1.[Cl:18]CCl.S(Cl)(Cl)=O>O1CCCC1>[Cl:18][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=2)[CH2:7][CH2:6]1
Reactant: O=c1ccc(N2CCC(CCCO)CC2)n[nH]1
Reactant: ClCCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=c1ccc(N2CCC(CCCCl)CC2)n[nH]1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice bath) mixture of 2.8 parts of 6-[4-(3-hydroxypropyl)-1-piperidinyl]-3(2H)-pyridazinone, 65 parts of dichloromethane and 45 parts of tetrahydrofuran were added dropwise 2.8 parts of thionyl chloride. Upon complete addition, stirring was continued overnight at room temperature. The whole was evaporated and the residue was taken up in methylbenzene. The organic layer was evaporated again, yielding 3 parts (100%) of 6-[4-(3-chloropropyl)-1-piperidinyl]-3(2H)-pyridazinone as a residue (int. 100).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Br:24][C:25]1[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=1>ClCCl.N1C=CC=CC=1>[Br:24][C:25]1[S:29][C:28]([S:30]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:32])=[O:31])=[CH:27][CH:26]=1
Reactant: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(N)c2)C[C@H](C)N1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(NS(=O)(=O)c3ccc(Br)s3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-[(phenylmethyl)oxy]aniline (D39) (300 mg, 0.96 mmol) in dichloromethane (5 ml) and pyridine (5 ml) was added 5-bromo-2-thiophenesulfonyl chloride (505 mg, 1.93 mmol) and the mixture stirred at room temperature for 4 hours. The mixture was then reduced in vacuo and the residue purified by SCX (eluting with methanol then ammonia 2M in methanol). The appropriate fractions were combined and reduced and the residue purified by trituaration with methanol to afford the title compound (D42). MS (ES+) m/e 536/538 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:35]4[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][OH:29])[CH2:33][CH2:34]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: OCCN1CCNCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCN(CCO)CC4)cn3)nc2n1C1CCCC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.396 mmol) and N-(2-hydroxyethyl)piperazine (57 mg, 0.436 mmol) gave 7-cyclopentyl-2-{5-[4-(2-hydroxy-ethyl)-piperazin-1-ylmethyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as an off white solid (78 mg, 40%) [following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/DCM]. MS (ESI) m/z 493.3 (M+H)+ (method A).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:44])[NH:13][C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=2)=[O:31])=[CH:25][CH:24]=1)=O)(C)(C)C>C(OC(=O)C)C.Cl>[ClH:39].[CH3:6][NH:8][CH2:9][CH2:10][O:11][C:12](=[O:44])[NH:13][C:14]1[N:22]=[CH:21][N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:41])([F:42])[F:43])[CH:34]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 2 mL of a 4N hydrogen chloride ethyl acetate solution, 13 mg (0.02 mmol) of (9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl]carbamic acid 2-(tert-butoxycarbonylamino)ethyl ester was dissolved and the solution was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, and then the residue was triturated with n-hexane:ethyl acetate=1:1, collected by filtration and vacuum dried to obtain 1.7 mg (16%) of (9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-ylcarbamic acid 2-(methylamino)ethyl ester hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][OH:13])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]([C:23]2[C:31]3[CH:30]=[N:29][CH:28]=[N:27][C:26]=3[N:25]([CH:32]([CH3:34])[CH3:33])[CH:24]=2)=[O:22])[CH:18]=[N:19][CH:20]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][OH:13])[C:9]([NH:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]([C:23]3[C:31]4[CH:30]=[N:29][CH:28]=[N:27][C:26]=4[N:25]([CH:32]([CH3:34])[CH3:33])[CH:24]=3)=[O:22])[CH:16]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)C(CO)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(CO)c3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 3 %

Procedure:
2-(4-Chloro-phenyl)-3-hydroxy-propionic acid (570 mg, 2.84 mmol) (Preparation 244) was added to a solution of (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (200 mg, 0.71 mmol) (Preparation 95) in THF (5 mL). Di-isopropyl ethylamine (0.64 mL, 3.56 mmol), EDCI.HCl (273 mg, 1.42 mmol) and HOBT (193 mg, 1.42 mmol) were added and the mixture was stirred at 25° C. for 48 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with water (5 mL), brine (5 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by preparative TLC (dichloromethane:methanol 93:7) to afford the title compound as a yellow solid in 3% yield, 10 mg.
Reaction SMILES: Br[C:2]1[C:3]2[C:28]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:27](=[O:35])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.[CH3:36][NH2:37]>C1COCC1>[CH3:34][C:28]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:3]2[C:2]([NH:37][CH3:36])=[N:7][C:6]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][C:19]([F:24])([F:25])[C:20]([F:23])([F:22])[F:21])[N:9]=3)=[N:5][C:4]=2[NH:26][C:27]1=[O:35]
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(Br)c21
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(NC)c21

Procedure:
The intermediate from Step A above (190 mg, 0.337 mmol), methylamine (2M in THF) (0.843 mL, 1.687 mmol) and THF (2 mL) were sealed in a microwave tube and subjected to microwave irradiation at 150° C. for 3 h. The reaction mixture was partitioned between brine and EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford a dark solid. The residue was purified by reverse phase preparative HPLC to give the title product, as a solid. 1H NMR (500 MHz, DMSO-d6): δ 11.35 (s, 1H); 8.87 (d, J=8.1 Hz, 1H); 8.64-8.62 (m, 1H); 7.39 (dd, J=8.1, 4.5 Hz, 1H); 6.61 (d, J=4.9 Hz, 1H); 4.88 (t, J=6.8 Hz, 2H); 4.12-4.07 (m, 2H); 3.04-2.90 (m, 5H); 1.61 (s, 3H); 1.09 (t, J=7.1 Hz, 3H). m/z=514.1 (M+H).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[S:39]([CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:26][CH2:27][N:28]([S:39]([CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])(=[O:41])=[O:40])[CH2:29][CH:30]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)n1
Reactant: COC(=O)CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5nc(C(C)C)no5)CC4)sc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a solution of 3-isopropyl-5-(4-(6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazol-2-yloxy)piperidin-1-yl)-1,2,4-oxadiazole (Compound 43E, 95 mg, 0.223 mmol) and triethylamine (0.08 mL, 0.56 mmol) in CH2Cl2 (2 mL) at 0° C. was added methyl 3-(chlorosulfonyl)propanoate (62.5 mg, 0.335 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt overnight. The reaction mixture was quenched with sat. aq. NaHCO3 (2 mL) and extracted with CH2Cl2 (3×3 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 60% EtOAc) to afford methyl 3-(4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)propanoate (75 mg, 0.13 mmol, 58% yield) as an off white solid. LCMS (m/z)=576 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C(=O)N[C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH-].[Na+]>>[C:11]1([CH:2]2[O:1][C:5](=[O:9])[NH:4][C:3]2=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1NC(=O)C(O)(c2ccccc2)C(=O)N1
Agent: [Na+]
Agent: [OH-]
Product: O=C1NC(=O)C(c2ccccc2)O1

Procedure:
5-Hydroxy-5-phenyl-2,4,6(1H,3H,5H)pyrimidinetrione (0.7 g.) is dissolved in 15 ml. of 1N sodium hydroxide, stirred at room temperature for 15 minutes, extracted with ethyl acetate, made slightly acidic with about 1 ml. of glacial acetic acid, and extracted with 25 ml. of ethyl acetate. The latter ethyl acetate extract is back washed with about 6.5 ml. of water, filtered over a bed of anhydrous magnesium sulfate and evaporated to yield 5-phenyloxazolidine-2,4-dione.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[C:26]([F:34])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(O)C>[F:34][C:26]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[CH:29]=[CH:28][C:27]=1[S:30]([NH2:33])(=[O:31])=[O:32]
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: NS(=O)(=O)c1ccc(Br)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
Product: C[C@H](Oc1ccc(-c2ccc(S(N)(=O)=O)c(F)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 38.5 %

Procedure:
Prepared according to the method described in Example 12b) from 4-[(2S,3R)-5-(pyridin-3-yl)-3-hydroxypent-2-yloxy]benzeneboronic acid (0.20 g, Example 33), 4-bromo-2-fluorophenylsulfonic acid amide (0.20 g), ethanol (3 ml), 2M aqueous sodium carbonate (1.0 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) with heating at 90° C. for 3 hours. After work-up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane, followed by recrystalisation from aqueous ethanol, to give the title compound as a solid (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][SH:10])=[CH:4][CH:3]=1.Br[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: SCCc1ccc(Cl)cc1
Product: O=Cc1ccc(SCCc2ccc(Cl)cc2)cc1

Procedure:
Title product was prepared from 2-(4-chlorophenyl)ethyl mercaptan and 4-bromobenzaldehyde according to the method of Preparation 7.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:7][C:8]1[C:9]([CH2:20][CH3:21])=[N:10][N:11]([CH2:15][C:16]([O:18]C)=[O:17])[C:12]=1[CH2:13][CH3:14]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:7][C:8]1[C:9]([CH2:20][CH3:21])=[N:10][N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]=1[CH2:13][CH3:14]
Reactant: CCc1nn(CC(=O)OC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nn(CC(=O)O)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 78 %

Procedure:
Aqueous sodium hydroxide solution (1N, 6.2 ml, 6.2 mmol) was added dropwise to a stirred solution of the ester (2 g, 5.6 mmol) of Example 9 in tetrahydrofuran (20 ml) at 0° C. After 1 hour the solvent was removed under reduced pressure and aqueous hydrochloric acid (20 ml) was added with vigorous stirring. The resulting white precipitate was collected by filtration, washed with ether (3×30 ml) and dried in a vacuum pistol at 60° C./10 mmHg to afford the title compound as a white solid (1.5 g), m.p. 157-158° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3cccc(C(F)(F)F)c3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.8 %

Procedure:
To methyl 4-{[2-(1-{4-hydroxy-1-methyl-5-[3-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}ethylidene)hydrazino]carbonyl}benzoate (0.072 mmol, 33.1 mg), methanol (2 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.360 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to 0° C., and 1 M hydrochloric acid (5 eq., 0.360 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (17.6 mg, yield 55%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][NH2:21]>C1COCC1.C1(C)C=CC=CC=1>[NH:21]1[C:2]2=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]2[CH2:18][CH2:19][CH2:20]1
Reactant: NCCCBr
Reactant: COC(=O)c1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1c2n(c3ccccc13)CCCN2
Reaction time: 0.33 h

Procedure:
A solution of methyl 2-chloroindole-3-carboxylate (D11a, 1.5 g, 0.0071 mole) in THF (30 ml) under argon was treated with sodium hydride (215 mg of 80% oil dispersion, 0.0071 mole) and stirred for 20 minutes. The resulting solution was treated with a solution of 3-bromopropylamine (0.0093 mole) in toluene (15 ml) and a white gelatinous precipitate formed. This mixture was diluted with more THF (30 ml) and heated under reflux for 18 h, then concentrated in vacuo and the residue shaken well with ethyl acetate (40 ml) and 10% Na2CO3 solution (30 ml). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a beige solid. This was chromatographed on silica gel eluting with ether/60-80 petrol (1:1) to afford unreacted starting material (600 mg) and the title compound (D18) as a white solid (110 mg, 6%).