Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH:14]=[O:15])[CH:8]=1)C.[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[CH:14]([C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([CH3:13])[CH:10]=1)[O:6][CH2:5][C:4]([OH:16])=[O:3])=[O:15]
Reactant: CCOC(=O)COc1cc(C)cc(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C=O)cc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 2-(3-formyl-5-methyl-phenoxy)-acetic acid ethyl ester (0.79 g) in methanol (4 ml) at 5° C. was treated with a 2M sodium hydroxide solution (3.6 ml). After 15 min the mixture was allowed to warm to room temperature. After a further 2 h the stirred solution was again cooled to 5° C. and covered with ethyl acetate and the aqueous layer was adjusted to acidic pH with 2M hydrochloric acid. The layers were separated and the aqueous phase was extracted with more ethyl acetate. The combined organic phase was washed with water and brine and dried with magnesium sulphate. Concentration gave a gummy solid which was triturated with diethyl ether giving, after drying, the title compound (0.47 g) as a pale yellow solid. Hplc system 1 (λ=254 nm) Rt 5.2 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]12[CH2:14][CH2:13]1.[CH3:15][N:16]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[C:17]1B(O)O.[F-].[K+]>>[F:11][C:9]1[CH:10]=[C:2]([C:17]2[N:16]([CH3:15])[C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:12])[C:5]12[CH2:14][CH2:13]1
Reactant: O=C1Nc2c(F)cc(Br)cc2C12CC2
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [F-]
Agent: [K+]
Product: Cn1c(C#N)ccc1-c1cc(F)c2c(c1)C1(CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.9 %

Procedure:
5′-Bromo-7′-fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one (0.60 g, 2.3 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (0.63 g, 4.2 mmol), KF (0.44 g, 7.6 mmol), and Pd2(dba)3 monochloroform adduct (60 mg, 0.058 mmol) were added to a vial and then purged with nitrogen. THF (5.5 mL) was added and the mixture was purged with nitrogen for 5 min. A solution of tri-t-butylphosphine (10% wt in hexanes) (0.342 mL, 0.115 mmol) was added via syringe and the mixture was stirred vigorously at 25° C. for 2.5 h. The mixture was diluted with 100 mL of EtOAc and filtered through a plug of silica gel and concentrated. Purification by flash chromatography (25% acetone/hexane) afforded the title compound (0.53 g, 83%) as a white solid. MP 228-231° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>ClC(Cl)C>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]1)=[O:32]
Reactant: CC(C)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](C(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
D-Phenylalanine methyl ester hydrochloride (20 g, 0.092 mol) was suspended in a solution of triethylamine (66 mL) in dichloroethane (100 mL) and the mixture was stirred for 1 hour at room temperature. The organic layer was separated after washing with water and dried over anhydrous sodium sulphate. Trans-4-isopropylcyclohexane carboxylic acid (15.8 g, 0.092 mol) was added to the organic layer followed by LiOH—Al2O3 (5.5 g of LiOH adsorbed on 40.5 g aluminum oxide) and the resulting mixture heated at for 24 hours. The reaction mixture was filtered through a celite bed and washed with 1.5 N HCl, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to yield 15.5 g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25](Br)=[CH:24][C:23]([Cl:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37](C)C(=O)C>C(OCC)(=O)C.[Zn].[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25]([C:36]#[N:37])=[CH:24][C:23]([Cl:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)cc(Cl)cn4c3-c3ccccc3)cc2)CCC1
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(C#N)cc(Cl)cn4c3-c3ccccc3)cc2)CCC1
Reaction time: 1 h

Procedure:
300 mg (0.54 mmol) {1-[4-(8-Bromo-6-chloro-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, intermediate example Int-400-12, 3.5 mg (0.054 mmol) zinc, 44.3 mg (0.054 mmol) 1,1 bis(diphenylphosphino)-ferrocenedichloropalladium(II) and 127.4 mg (1.08 mmol) zinc cyanide in 4.5 mL N,N-dimethylacetamide (degassed) were heated in the microwave at 110° C. for three hours. Due to an incomplete reaction additional zinc, catalyst and zinc cyanide were added, and stirring was continued at 150° C. for one hour. The reaction mixture was diluted with ethyl acetate and washed with water/saturated ammonium chloride. The organic phase was separated, dried (sodium sulfate), filtrated and the solvent was removed. The crude product (530 mg >100%) was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH:11]3[CH2:16][CH2:15][CH:14]([C:17]([O:19]CC)=[O:18])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Li+]>CO.O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH:11]3[CH2:12][CH2:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)C1CCC(Oc2ccc3[nH]ncc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 2 h
Yield: 57.9 %

Procedure:
The ethyl 4-(1H-indazol-5-yloxy)cyclo-hexanecarboxylate (728.4 mg, 2.53 mmol) obtained in Example 367 was dissolved in a mixture of methanol (2.5 ml) and tetrahydrofuran (2.5 ml), and a 2M-aqueous lithium hydroxide solution (2.53 ml, 5.05 mmol) was added dropwise thereto. After 2 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water (5 ml). The resulting aqueous solution was adjusted to pH 4 with a 0.5M-aqueous potassium hydrogensulfate solution. The crystals formed were filtered under reduced pressure and then dried to obtain 4-(1H-indazol-5-yloxy)cyclohexanecarboxylic acid (381 mg, 58%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][NH:7][CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45].[OH-].[Na+]>ClCCl.Cl>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:6][N:7]([CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)[C:44](=[O:46])[CH3:45]
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (+/−) (3,5-Bis-trifluoromethyl-benzyl)-[1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-amine (149 mg, 0.27 mmol) and pyridine (0.33 ml, 4 mmol) in dichloromethane (1.5 ml) at room temperature is added acetic anhydride (0.38 ml, 4.1 mmol) via dropwise addition over 2 minutes. The mixture is stirred at room temperature for 20 hours. The mixture is treated with 1N aqueous NaOH (4 ml) and stirred for 10 minutes, then diluted with 1N HCl (15 ml) and dichloromethane (15 ml). The organic layer is washed with water, dried (Na2SO4), and concentrated to a solid. Purification by silica gel column chromatography (eluent, 35% ethyl acetate in hexanes) gives the title compound as a solid. Mass spectrum (ES+): 585 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1C(C)CCN>>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][CH2:12][CH2:11][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)=[CH:15]1
Reactant: ClCCOc1cccc2[nH]ccc12
Reactant: CC(CCN)c1cc2ccccc2[nH]1
Product: CC(CCNCCOc1cccc2[nH]ccc12)c1c[nH]c2ccccc12
Yield: 43 %

Procedure:
This compound was prepared in the manner described above for Example 5 using 2-(1H-indol-4-yloxy)ethylchloride and 3-indolyl-butylamine in 43% yield as an off-white solid: mp 70-73° C.
Reaction SMILES: [OH:1][CH:2]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C@H:5]([CH3:17])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1.[ClH:26].[C:27](O)(=[O:29])[CH3:28]>>[ClH:26].[C:27]([O:1][CH:2]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:3][NH:4][C@H:5]([CH3:17])[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: C[C@H](CCc1ccc(C(N)=O)cc1)NCC(O)COc1ccccc1
Agent: Cl
Product: CC(=O)OC(CN[C@H](C)CCc1ccc(C(N)=O)cc1)COc1ccccc1

Procedure:
0.5 g of p-[(R)-3-[[(RS)-2-hydroxy-3-phenoxypropyl]-amino]butyl]benzamide was warmed to 40° for 24 hours in 25 ml of acetic acid saturated with hydrochloric acid gas. Thereupon, the solvent was removed in vacuo and the crystalline residue was recrystallized from acetonitrile, and there was obtained p-[(R)-3-[[(RS)-2-acetoxy-3-phenoxypropyl]amino]butyl]-benzamide hydrochloride of m.p. 83°-85°, [α]D20 =-10° (c=0.6 in methanol), ε222 =15020, ε234 =13590.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]2=[O:13].[F:25][C:26]1[CH:27]=[C:28]([CH2:36][C:37](O)=[O:38])[CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33].C(N(CC)C(C)C)(C)C.CN(C)C=O>>[F:25][C:26]1[CH:27]=[C:28]([CH2:36][C:37]([NH:1][C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:7]3=[O:13])=[O:38])[CH:29]=[CH:30][C:31]=1[C:32]([F:34])([F:35])[F:33]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A reaction vial was charged with tert-butyl 2-(5-amino-6-methyl-1-oxoisoquinolin-2(1H)-yl)ethyl(methyl)carbamate (150 mg, 0.00041 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (200 mg, 0.0009 mol), N,N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (700 mg, 0.002 mol), N,N-diisopropylethylamine (0.3 mL, 0.002 mol), N,N-dimethylformamide (4 mL, 0.05 mol) and the reaction was stirred at 45° C. overnight. The reaction was then quenched with water, extracted with warm ethyl acetate, and the solvent removed under reduced pressure. The residue was purified by flash chromatography and then by reversed phase preparative HPLC to afford the product as an off white solid.
Reaction SMILES: [C@]12(C)C(C)(C)C(CC1)CC2C([O:12][C@H:13]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([I:26])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[C:14]([CH3:17])([CH3:16])[CH3:15])=O.C([O-])([O-])=O.[K+].[K+]>CO>[I:26][C:21]1[C:22]([O:24][CH3:25])=[CH:23][C:18]([C@@H:13]([OH:12])[C:14]([CH3:17])([CH3:16])[CH3:15])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=1
Reactant: COc1cc([C@@H](OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c([N+](=O)[O-])cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc([C@@H](O)C(C)(C)C)c([N+](=O)[O-])cc1I
Yield: 98.6 %

Procedure:
A mixture of (S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate (1.1 g, 2.0 mmol) and K2CO3 (552 mg, 4.0 mmol) in methanol (50 mL) was heated to reflux for one hour, then cooled down, concentrated in vacuo, and diluted with CH2Cl2 (50 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield enantiopure (S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (720 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H, Ph-H), 7.17 (s, 1H, Ph-H), 5.60 (d, 1H, J=4.0 Hz, PhCH), 3.98 (s, 3H, OCH3), 2.12 (d, 1H, J=4.0 Hz, OH), 0.89 (s, 9H, C(CH3)3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH3:30])[CH2:24]2)[CH:3]=1.[NH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:31])=[O:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([O:29][CH3:30])[CH2:24]2)[CH:3]=1
Reactant: N
Reactant: CO[C@@H]1CCC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Product: CO[C@@H]1CCC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1

Procedure:
Prepared analogously to example 1.4 from 0.3 g racemic 4-[4-Fluoro-2-((cis)-3-methoxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (0.5 M in dioxan).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][N:13]3[CH2:19][CH2:18][C:17]4[C:20](Cl)=[N:21][CH:22]=[N:23][C:16]=4[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:26][O-:27].[Na+]>CO>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][N:13]3[CH2:19][CH2:18][C:17]4[C:20]([O:27][CH3:26])=[N:21][CH:22]=[N:23][C:16]=4[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CN1CCc2ncnc(Cl)c2CC1)N1CCN(C2CCC2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncnc2c1CCN(CC(=O)N1CCN(C3CCC3)CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (52 mg, 0.14 mmol) in MeOH, a solution of NaOMe in MeOH (0.3 ml, 25% in MeOH) is added. The mixture is stirred at rt overnight. The solvent is removed and water is added to the residue. The mixture is extracted with DCM. The organic layer is washed with brine, dried and solvent evaporated to give the crude product, which is purified by PTLC (5% TEA in EtOAc) to afford the title compound. 1H NMR (CDCl3) δ 8.49 (s, 1H), 3.94 (s, 3H), 3.62 (m, 4H), 3.30 (s, 2H), 3.04 (m, 2H), 2.88 (m, 2H), 2.74-2.62 (m, 5H), 2.31 (m, 4H), 2.04 (m, 2H), 1.88 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].[OH-].[K+]>CO>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a mixture of p-hydroxyacetophenone (50.7 g, 0.37 mol) and 1-bromo-3-chloropropane (160 ml, 1.5 mol) in methanol (250 mL) was added portionwise potassium hydroxide (63 g, 1.12 mol). The mixture was stirred at reflux for 24 hours, cooled to room temperature, filtered through Celite and evaporated in vacuo. The residual semi-solid was diluted with diethyl ether (500 ml) and washed with H2O (2×300 mL). The ether solution was dried over MgSO4, filtered and evaporated in vacuo to give p-chloropropoxy acetophenone as a liquid in 68% yield (53.38 g). 1H NMR (CDCl3): δ7.98-7.89 (d, J=8.9 Hz, 2H), 7.02-6.92 (d, J=8.9 Hz, 2H), 4.16 (t, J=5.9 Hz, 2H), 3.75 (t, J=6.4 Hz, 2H),2.52 (s, 3H), 2.34-2.16 (m, 2H).
Reaction SMILES: C1(S([C:10]2(SC)[CH2:15][C@@H:14]3[C@@:12]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=4)([CH2:13]3)[CH2:11]2)(=O)=O)C=CC=CC=1.C[OH:27].Cl>C(OCC)(=O)C.CCCCCC>[Cl:23][C:18]1[CH:17]=[C:16]([C@@:12]23[CH2:13][C@@H:14]2[CH2:15][C:10](=[O:27])[CH2:11]3)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CO
Reactant: CSC1(S(=O)(=O)c2ccccc2)C[C@H]2C[C@@]2(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1C[C@H]2C[C@@]2(c2ccc(Cl)c(Cl)c2)C1
Yield: 99 %

Procedure:
(1R,5R)-3-Benzenesulfonyl-1-(3,4-dichlorophenyl)-3-methylsulfanyl-bicyclo[3.1.0]hexane (1.4 g, 3.3 mmol), methanol (6 mL) and concentrated hydrochloric acid (1.5 mL) were heated to reflux for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (20:80)). The reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the reaction mass was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous layer was extracted with diethyl ether (100 mL). The organic layer was washed with water, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 1.1 g of crude oil, which was purified by preparative HPLC to yield 560 mg (70%) of 99% pure product. 1H NMR δ(300 MHz,CDCl3) 0.67-0.70 (1H,t, J=4 Hz), 1.25-1.35 (1H,m), 1.94-2.15 (1H,m), 2.36-2.42 (1H,d ,J=18 Hz), 2.59-2.65 (1H,d,J=18 Hz), 2.83-2.89 (2H,m),6.99-7.03 (1H,dd,J=9.3 Hz), 7.25-7.26 (1H,d,J=3 Hz),7.36-7.39 (1H,d,J=9 Hz). 13CNMR(CDCl3) δ: 215.25, 143.49, 132.55, 130.39, 130.06, 128.07, 125.40, 45.34, 42.08, 27.18, 23.32, 22.24.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:28][CH:29]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)c2ccc(C(F)(F)F)cc2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Trifluoromethylbenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-trifluoromethylbenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: C([O:5][C:6](=[O:22])[NH:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[CH:9]([CH:11]1[CH2:13][CH2:12]1)O)(C)(C)C.[H-].[Na+].O>C1COCC1>[CH:11]1([CH:9]2[O:22][C:6](=[O:5])[NH:7][CH:8]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC(c1ccc(F)c(F)c1)C(O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(c2ccc(F)c(F)c2)C(C2CC2)O1
Temperature: 35 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
To a well stirred solution of [2-cyclopropyl-1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (1.7 g, 5.4 mmol) in THF (20 mL) was added 95% NaH (0.4 g, 16.2 mmol) at room temperature. The resulting suspension was stirred for 3 h at about 35° C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo to yield 5-cyclopropyl-4-(3,4-difluorophenyl)-oxazolidin-2-one (1.3 g, 93% yield) as a 3:1 mixture of the trans:cis diastereomers. The diastereomers were separated by column chromatography over silica gel with 7:3 cyclohexane/ethyl acetate as the eluting system. The trans isomer eluted first (Rf=2.5, 0.65 g) followed by the cis isomer (Rf =2.0, 0.2 g). The relative streochemistry was assigned by comparing the 1H NMR of the two isomers of 5-cyclopropyl-4-(3,4-difluorophenyl)-oxazolidin-2-one to the corresponding isomers of 4-(3,4-difluorophenyl)-5-methyl-oxazolidin-2-one as described in Example 19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8].[N:33]1([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:36]2[CH2:37][CH2:38][N:33]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)[CH2:34][CH2:35]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)c(OC)c1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4ccc5ccccc5n4)CC3)c3ccccc3-c3ccccc32)c(OC)c1

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-2,4-dimethoxy-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][CH2:42][CH2:43][OH:44]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([NH:40][CH2:41][CH2:42][CH2:43][OH:44])=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCO
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCC(=O)NCCCO)cc2)cc1

Procedure:
The product from Example 104A and 3-amino-1-propanol were processed as described in Example 147 to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.95 (s, 1 H), 7.75 (t, 1 H), 7.26 (m, 6 H), 7.19 (m, 3 H), 7.04 (t, 1 H), 6.96 (m, 2 H), 6.87 (m, 4 H), 4.05 (s, 2 H), 4.01 (s, 2 H), 3.35 (m, 2 H), 3.07 (dd, 2 H), 2.91 (s, 3 H), 2.78 (t, 2 H), 2.39 (s, 3 H), 2.34 (t, 2 H), 1.50 (m, 2 H); MS (ESI+) m/z 602 (M+H)+.