Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 50.3 %

Procedure:
To a stirred solution of 4-bromophenol (10 g, 0.057 mol) and 2-(chloro methyl)quinoline (15.4 g, 0.063 mol) in AcN (25 mL) was added K2CO3 (24 g, 0.17 mol). The reaction mixture was refluxed for 3 h, filtered and the filtrate was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (2×200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain 2-((4-bromophenoxy)methyl)quinoline (9 g, 50%) as a solid.
Reaction SMILES: [C:1]([Cl:10])(=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CCOCC>[CH3:18][S:19]([O:9][N:8]=[C:1]([Cl:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: ON=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C(Cl)c1ccccc1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
The 9.4 g of recovered benzohydroximoyl chloride was dissolved in 100 ml of anhydrous ether and the solution was cooled to -20°. To the cold solution was rapidly added 12.3 g of triethylamine. To this mixture was slowly added (during 45 minutes) a solution of 6.95 g of methanesulfonyl chloride in 50 ml of anhydrous ether. The mixture was stirred at -30° for 1 hour, then at ambient temperature for about 16 hours. The mixture was filtered and the filtrate was conconcentrated under reduced pressure to give a yellow solid. The solid was recrystallized from a benzene-hexane mixture to give 5.2 g of N-(methanesulfonyloxy)benzimidoyl chloride, m.p. 106°-108°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][C:12]2=[N:17][C:18]2[CH:23]=[C:22]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[NH:27][CH2:28][CH3:29])=[CH:6][CH:5]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:42][N+:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[S:45][C:44]=1SC>>[C:24]([C:22]1[CH:21]=[CH:20][C:19]([NH:27][CH2:28][CH3:29])=[C:18]([N:17]=[C:12]2[N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:30])=[CH:5][CH:6]=3)[C:15](=[O:16])[C:14](=[C:44]3[N:43]([CH3:42])[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=4[S:45]3)[S:13]2)[CH:23]=1)(=[O:26])[CH3:25]
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccc(C(=O)OC)cc1
Reactant: CSc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared from intermediate 4-[2-(5-acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-ylmethyl]benzoic acid methyl ester and 3-methyl-2-(methylthio)benzothiazol-3-ium p-toluenesulfonate in a manner similar to Example 45. 1H-NMR (CDCl3): δ 8.03 (2H, d), 7.64-7.70 (2H, m), 7.49-7.55 (3H, m), 7.36 (1H, m), 7.20 (1H, m), 7.08 (1H, d), 6.51 (1H, d), 5.24 (2H, s), 4.15 (1H, br t), 3.91 (3H, s), 3.80 (3H, s), 3.04 (2H, m), 2.51 (3H, s), 1.01 (3H, s); MS(ESI): 573 (MH+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH2:18][CH2:19][OH:20])[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]([CH2:18][CH2:19][O:20][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:12]1[N:13]=[CH:14][CH:15]=[CH:16][N:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)c1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 4-fluorobenzaldehyde (12 ml) and 2-[N-methyl-N-(2-pyrimidinyl)amino]ethanol (10.05 g) in dry dimethyl sulphoxide (50 ml) containing anhydrous potassium carbonate (15 g) was stirred at 120° C. for 6 hours. The mixture was cooled to room temperature and added to water (200 ml). The aqueous solution was extracted with ethyl acetate (2×300 ml), the organic extracts washed with brine, dried (MgSO4) and evaporated. The title compound was obtained as an oil following chromatography on silica-gel in 2% methanol in dichloromethane.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13]>ClCCCl>[CH2:11]([N:14]([CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13]
Reactant: O=CC=Cc1ccccc1
Reactant: CCCNCCC
Solvent: ClCCCl
Product: CCCN(CC=Cc1ccccc1)CCC
Reaction time: 3 h

Procedure:
Cinnamaldehyde (0.504 cm3, 4.0 mmol), di-propylamine (0.548 cm3, 4.0 mmol) and [Ir(COD)(dppb)][PF6] (0.070 g, 2 mol %) were treated as stated above, with 1,2-dichloroethane as solvent, and at approx. 1 bar H2 for 3 hours. The yield of product (N,N-di-n-propylcinnamylamine) obtained was 80.9%.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:23]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([CH3:32])=[O:31])[CH:25]=2)=[C:22]([Cl:33])[CH:21]=[CH:20][C:9]=1[C:10]([O:12]C1N(CC)N=CC=1)=O.O>O1CCOCC1>[Cl:7][C:8]1[C:23]([C:24]2[N:28]([CH3:29])[N:27]=[C:26]([C:30]([CH3:32])=[O:31])[CH:25]=2)=[C:22]([Cl:33])[CH:21]=[CH:20][C:9]=1[C:10]([C:25]1[CH:26]=[N:27][N:28]([CH2:24][CH3:23])[C:1]=1[OH:4])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CCn1nccc1OC(=O)c1ccc(Cl)c(-c2cc(C(C)=O)nn2C)c1Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1ncc(C(=O)c2ccc(Cl)c(-c3cc(C(C)=O)nn3C)c2Cl)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 135.1 %

Procedure:
0.076 g (0.6 mmol) of potassium carbonate was added to 0.16 g (0.4 mmol) of (1-ethylpyrazol-5-yl) 2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoate in 3 ml of dioxane and the mixture was heated under reflux for 3 hours and then stirred at room temperature for 12 hours. 50 ml of water were added, the solution was washed with methylene chloride and methyl t-butyl ether, nitrogen was passed through and the pH was adjusted to 1 using 10% strength hydrochloric acid. The precipitate that had formed was filtered off with suction, washed with water and taken up in ethyl acetate. After drying, this organic phase was concentrated. 0.11 g (69% of theory) of 4-[2,4-dichloro-3-(1-methyl-3-methylcarbonyl-1H-pyrazol-5-yl)benzoyl]-1-ethyl-5-hydroxy-1H-pyrazole was obtained.
Reaction SMILES: [CH:1]1([C:6]2[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([NH:17][CH2:18][CH2:19][CH:20]=[O:21])[CH2:15][CH3:16]>C1C=CC=CC=1>[CH2:14]([N:17]([CH2:18][CH2:19][CH:20]=[O:21])[C:12]([NH:11][C:9]1[S:10][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:7][N:8]=1)=[O:13])[CH2:15][CH3:16]
Reactant: O=C=Nc1nnc(C2CCCC2)s1
Reactant: CCCNCCC=O
Solvent: c1ccccc1
Product: CCCN(CCC=O)C(=O)Nc1nnc(C2CCCC2)s1

Procedure:
A mixture of 5-cyclopentyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-propylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-propyl-3-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:23][CH3:24].[H-].[Na+].[F:27][C:28]([F:41])([O:32][C:33]1[CH:34]=[C:35]([CH2:39]Br)[CH:36]=[CH:37][CH:38]=1)[CH:29]([F:31])[F:30].O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:22])[CH:16]([CH2:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:28]([F:27])([F:41])[CH:29]([F:30])[F:31])[CH:34]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[CH2:23][CH3:24]
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)CC(=O)c1ccc(Oc2ccc(Cl)c(CC)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(Oc2ccc(Cl)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (6.0 g, 28.8 mmol) in carbon tetrachloride (60 ml) were added N-bromosuccinimide (5.65 g, 31.7 mmol) and 2,2′-azobis(isobutyronitrile) (237 mg, 1.44 mmol), and the mixture was heated under reflux for 6 hrs. After cooling, the reaction solution was filtered, and the filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxopropionate (10 g, 28.8 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 1.15 g, 28.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (10 ml), and the reaction solution was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxo-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate (9.26 g, 58%) as a colorless oil.
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].Cl.C(N(CC)CC)C.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[N:15]1([CH:3]=[CH:4][C:5]#[N:6])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#CC=CO
Reactant: C1CCNCC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CC=CN1CCCCC1
Temperature: 25 °C
Yield: 79 %

Procedure:
30.3 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 75%) is added to a suspension of 41.3 g (0.3 mol) of triethylamine hydrochloride and 21.3 g (0.25 mol) of piperidine in 200 ml of ethanol and maintained for 24 h at 25° C. After working up as in Example 56, 26.9 g of 3-piperidinoacrylonitrile is obtained (79.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])[CH3:19]>>[CH2:18]([N:20]([CH2:24][CH3:25])[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22])[CH3:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 87.3 %

Procedure:
Beginning with 13.0 mg (0.056 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 8.0 mg (0.062 mMol) diethyl carbamoyl chloride, 16.05 mg (86%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH2:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)[CH3:34]>COCCOC>[CH2:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH3:34]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1cc(F)c(F)cc1Br
Reactant: CCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1ccccc1-c1cc(F)c(F)cc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 72.7 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4,5-difluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/2M Na2CO3 (0.435 ml, 0.864 mmol) was treated with 2-ethylphenylboronic acid (70 mg, 0.468 mmol) and Pd[PPh3]4 (27 mg, 0.0234 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate in hexanes gradient to afford the product as a white solid (77 mg, 73%). MS m/e 453.30 (M+H+)
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15](C(OC)=O)[CH2:14][CH2:13]1>C(O)C.Cl>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: COC(=O)N1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Yield: 88.3 %

Procedure:
To a solution of methyl 4-[2-fluoro-3-(methylsulfonyl)-phenyl]piperidine-1-carboxylate (0.7 g, 2.2 mmol) in ethanol (4 ml), hydrochloric acid (3 M, 10 ml) was added and the mixture was heated at reflux for 24 h. The ethanol was evaporated and the aqueous residue was basified with sodium hydroxide (5 M) and extracted with ethylacetate (3×50 ml). The combined organic phases was washed with brine (50 ml), dried (MgSO4) and evaporated to dryness to give the title compound (0.5 g, 91%). MS m/z (relative intensity, 70 eV) 257 (M+, 6), 237 (95), 208 (83), 173 (bp) 130 (69).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+]>C(#N)C>[F:15][CH:11]([F:16])[O:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(O)n1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1cccc(OC(F)F)n1
Temperature: 70 °C
Yield: 42.7 %

Procedure:
To a solution of 6-hydroxypicolinaldehyde (2 g, 16.24 mmol) in acetonitrile (20 mL) was added sodium 2-chloro-2,2-difluoroacetate (4.46 g, 29.24 mmol) at room temperature. The reaction mixture was heated at 70° C. for 18 h. The reaction mixture was cooled to room temperature and the solid was filtered off. Then the crude material was purified via flash chromatography (100-200 mesh silica gel, 10% ethyl acetate in hexane) to afford the title compound (1.2 g, 42.85%). MS (ES+) (M+H) 174.10
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4](S)[N:3]=1.Br[CH2:23][C:24]([NH2:26])=[O:25].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:19]([C:5]1[C:4]([CH2:23][C:24](=[O:25])[NH2:26])=[N:3][C:2]([NH2:1])=[C:7]([C:8]#[N:9])[C:6]=1[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=1)#[N:20]
Reactant: NC(=O)CBr
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(CC(N)=O)c(C#N)c1-c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
337.2 mg (1 mmol) of 2-amino-4-(3,5-dichloro-4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile and 207 mg (1.5 mmol) of bromoacetamide are dissolved in 4 ml of DMF, 336 mg (4 mmol) of NaHCO3 are added and the mixture is stirred at RT for 8 hours. The mixture is diluted with water and washed with ethyl acetate. The aqueous phase is acidified with 1N HCl and the resulting crystals are filtered off with suction and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]#[N:11].B>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: N#CCCc1ccccc1Br
Agent: B
Solvent: C1CCOC1
Product: NCCCc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed a solution of 3-(2-bromophenyl)propanenitrile (2.1 g, 10.00 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). This was followed by the addition of borane (1 mol/L in THF, 50 mL, 5.00 equiv) dropwise with stiffing at 0° C. The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 50 mL of water at 0° C. and extracted with 3×50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 30 mL of 6N aqueous hydrogen chloride. The aqueous solution was extracted with 30 mL of ethyl acetate and the aqueous layers were combined. The pH value of the aqueous solution was adjusted to 10 with 10% aqueous sodium hydroxide. The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, concentrated under vacuum. This resulted in 1.3 g (58%) of 3-(2-bromophenyl)propan-1-amine as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(N(CC)C(C)C)(C)C.Cl.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([C:30]([Cl:32])=[O:31])[CH2:23]2>CN(C=O)C>[ClH:32].[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:30]([CH:24]3[CH:25]4[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]4)[CH2:23]3)=[O:31])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CN2CCC1CC2
Reactant: Nc1ccc2ncccc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2ncccc2c1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
172 mg (1.19 mmol) of 6-aminoquinoline are mixed with 461 mg (3.57 mmol) of N,N-diisopropylethylamine in 3 ml of DMF under argon at 0° C. 250 mg (2.57 mmol) of 3-quinuclidinecarbonyl chloride hydrochloride are dissolved in a little dry DMF and added dropwise to the reaction mixture at 0° C. It is then stirred at room temperature overnight. It is worked up by concentrating and taking up in dichloromethane. The crude product is chromatographed on silica gel 60 (mobile phase: dichloromethane/ethyl acetate 10:1, then dichloromethane/methanol 10:1, 3:1). The product fractions are combined and finally purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water, gradient 1:99→30:70).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])=[N:24][CH:25]=1>>[OH:29][CH2:28][C:27]([NH:26][C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1)([CH3:30])[CH3:31]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(CO)Nc1ccc(N)cn1
Product: CC(C)(CO)Nc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-hydroxy-1,1-dimethyl-ethylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 2-(5-Amino-pyridin-2-ylamino)-2-methyl-propan-1-ol. LCMS calcd for C20H19F3N4O3 (m/e) 420, obsd 421 (M+H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)N.[CH3:13][CH:14]([C:23](=O)[CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20]>C(O)(=O)C>[CH3:24][C:23]1[C:14]([CH3:13])([CH2:15][CH2:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:7]=2)[N:1]=1
Reactant: CC(=O)C(C)CCCCS(=O)(=O)O
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCS(=O)(=O)O

Procedure:
4-Hydrazinobenzenesulfonic acid (1.88 g), 5-methyl-6-oxoheptanesulfonic acid (2.5 g) and acetic acid (50 ml) were mixed and heated under reflux for 6 hrs. The solvent was evaporated under vacuum, then the residue was triturated with 2-propanol to yield the crude product as a yellow solid. This was purified by HPLC as required (RPC18. Water+0.1% TFA). 1H-nmr (D2O) δ0.8-1.0 (2H, m), 1.55-1.65 (5H,=3H, s+2H, m), 2.16 (1H, ddd), 2.29 (1H, ddd), 2.75 (2H, m), 2.81 (partially d-exchanged methyl singlet), 7.71 (1H, d), 7.94 (1H, d) and 8.01 (1H, d). UV/Vis (Water+0.1% TFA): 269, 229 nm. MS (LCMS): MH+362. Acc. Mass: Found, 362.0729. MH+=C14H20NO6S2 requires 362.0732 (−0.8 ppm).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20]C(OCC3C=CC=CC=3)=O)[CH:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO.[Pd]>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH2:20])[CH:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(NC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 80 %

Procedure:
A solution of 200 mg of 1-(SR)-(3,5-bis(trifluoromethyl)phenyl)methoxy-2-(SR)-phenyl-3-(RS)-(benzyloxycarbonylamino)cyclopentane prepared in Example 4, Step B in 5 mL of methanol was hydrogenated over 50 mg of 10% Pd/C for 2 hours. The reaction was filtered and concentrated. The residue was purified on a 1 mm preparative silica gel plate eluted with 10% MeOH in ethyl acetate to obtain 120 mg of title compound. Mass spec (NH3/CI): 404 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>>[Cl:29][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1CCc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1CCc1ccccc1
Yield: 100 %

Procedure:
3-(4-Chlorophenyl)-3-hydroxy-2-phenethylisoindolin-1-one (250 mg, 0.687 mmol.) was reacted with thionyl chloride (0.055 mL, 0.756 mmol.) and a catalytic amount of DMF as for general procedure B, and the solvent removed to give a colourless oil of the crude 3-chloro-3-(4-chlorophenyl)-2-phenethylisoindolin-1-one (256 mg, 0.687 mmol., 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:11]([C:24](OCC)=[O:25])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:3]=1.[BH4-].[Li+].O>C(O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH:11]([CH2:24][OH:25])[C:10]=3[C:6]=2[CH:5]=[C:4]([S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:3]=1
Reactant: CCOC(=O)C1c2c(oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc23)CCN1Cc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN2CCc3oc4c(Cl)cc(S(=O)(=O)c5ccccc5)cc4c3C2CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
The product obtained from step A (269 mg, 0.50 mmol) was dissolved in ethanol (10 mL) at 0° C. Lithium borohydride (220 mg, 10.0 mmol) was added slowly and the reaction mixture was stirred at ambient temperature for 2 h. Water (10 mL) was added and the mixture was extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over MgSO4, filtered, and the filtrate concentrated in vacuo. Purification by flash column chromatography (SiO2, 9:1 to 7:3 hexanes/ethyl acetate) afforded (6-chloro-2-(4-methoxybenzyl)-8-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-1-yl)methanol (149 mg, 60%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.05-7.94 (m, 3H), 7.86-7.83 (m, 1H), 7.57-7.48 (m, 3H), 7.26-7.21 (m, 3H), 6.92-6.87 (m, 2H), 4.02-3.98 (m, 1H), 3.82 (s, 3H), 3.83-3.80 (m, 1H), 3.72 (s, 2H), 3.64-3.57 (m, 1H), 3.29-3.19 (m, 1H), 3.12-2.98 (m, 2H), 2.68-2.60 (m, 1H).