Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[OH-].[Na+].[C:12](Cl)([O:14][CH2:15][C:16]([Cl:19])([Cl:18])[Cl:17])=[O:13].O>CCOC(C)=O>[Cl:17][C:16]([Cl:19])([Cl:18])[CH2:15][O:14][C:12](=[O:13])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Cl)c1Cl)OCC(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of 2,3-dichloroaniline (0.200 g, 1.23 mmol) in EtOAc (5 mL) was added NaOH (1M, 2 mL, 2 mmol) and Troc-Cl (0.262 g, 1.23 mmol) and the resulting mixture was stirred overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×100 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 2,2,2-trichloroethyl-2,3-dichlorophenylcarbamate (408 mg, 98%) as a yellow foam. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J=6.4 Hz, 1H), 7.43 (brs, 1H), 7.25-7.22 (m, 2H), 4.86 (s, 2H); MS (EI) m/z: 335.8 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].N1C=CC=CC=1.[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[CH:29]([CH3:48])[C:30]([C:36]1[CH:47]=[CH:46][C:39]2[N:40]([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:38]=2[CH:37]=1)([OH:35])[C:31]([F:34])([F:33])[F:32]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([O:28][C:26]2[CH:25]=[CH:24][C:23]([CH:29]([CH3:48])[C:30]([C:36]3[CH:47]=[CH:46][C:39]4[N:40]([CH3:45])[C:41](=[O:44])[N:42]([CH3:43])[C:38]=4[CH:37]=3)([OH:35])[C:31]([F:32])([F:33])[F:34])=[C:22]([Cl:21])[CH:27]=2)=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)n(C)c(=O)n4C)C(F)(F)F)c(Cl)c2)cc1F
Reaction time: 96 h
Yield: 58.5 %

Procedure:
Copper(II)acetate (657 mg), 3-fluoro-4-methoxycarbonylphenylboronic acid (CAS Reg. 505083-04-5, 716 mg), and pyridine (0.3 ml) were added to a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 500 mg) in DCM (20 ml). The mixture was stirred with molecular sieves under air atmosphere for 4 days and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 2:1 EtOAc/heptane) to give the title compound (400 mg) as a light yellow oil. MS (m/e)=567.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Fe]>[Br:12][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(F)c1
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: Cc1cc(F)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2-Fluoro-4-methylbenzoic acid (244 mg) was added in portions to a mixture of bromine (1 ml) and iron powder (60 mg) and the reaction stirred in a sealed vial at room temperature for 25 minutes. The reaction was poured into aqueous sodium thiosulphate and extracted with ethyl acetate (x2). The combined extracts were washed with brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was recrystallised from cyclohexane to give 5-bromo-2-fluoro-4-methylbenzoic acid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][C@@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][C@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7]
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reactant: C[C@@H](N)C(=O)O
Product: C[C@@H](NC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-63 g) by reacting 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester with D-alanine. MS-(−)-ion: M−1=367.1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=O)[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]1[CH:29]2[CH2:30][CH:31]([NH2:32])[CH:27]([CH2:28]2)[CH2:26]1>>[CH:27]12[CH2:28][CH:29]([CH2:25][CH2:26]1)[CH2:30][CH:31]2[NH:32][CH2:23][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=2)[C:8]=1[OH:22]
Reactant: NC1CC2CCC1C2
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(CNC2CC3CCC2C3)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
3-((Bicyclo[2.2.1]heptan-2-ylamino)methyl)-5-(tert-butyl)-4′-(trifluoromethoxy)-[1,1′-biphenyl]-2-ol was prepared as a white solid using the procedure described in Example 5 from 5-(tert-butyl)-2-hydroxy-4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-carbaldehyde (Intermediate 5) and exo-2-aminonorbornane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Cl)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 537.3 (M+H)+.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:43])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]=3[C:19]3[CH:39]=[CH:40][CH:41]=[CH:42][C:18]2=3)[CH3:14])=CC=1)([O-])=O.Cl.[F:46][CH2:47][CH2:48][NH2:49]>N1C=CC=CC=1>[CH2:28]([O:27][CH2:26][CH2:25][N:22]1[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:49][CH2:48][CH2:47][F:46])[CH3:14])=[O:43])[C:18]2[CH:42]=[CH:41][CH:40]=[CH:39][C:19]=2[C:20]2[CH:38]=[CH:37][CH:36]=[CH:35][C:21]1=2)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCCF
Agent: Cl
Solvent: c1ccncc1
Product: C[C@H](OC(=O)NCCF)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Carbonic acid (S)-1-[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester 4-nitro-phenyl ester (80 mg, 0.13 mmol), 2-fluoroethylamine hydrochloride (40 mg, 0.40 mmol) and pyridine (2 ml) were stirred in a sealed tube for 18 h at ambient temperature. After evaporation of the volatile components under reduced pressure, the residue was taken up in water/ethyl acetate, the phases separated and the organic layer extracted 5-times with saturated aqueous sodium carbonate, twice with 10% citric acid and once with saturated aqueous sodium chloride. After drying over magnesium sulphate and evaporation of the solvent, the title compound is obtained as white solid (>98%). MS: n/e=520(M+H+).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](O)=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:27]>ClCCl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([F:27])=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
To a mixture of 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (I-5D, 197 mg, 0.766 mmol) and pyridine (0.074 mL, 0.919 mmol) in dichloromethane (5 mL) at room temperature was added cyanuric fluoride (0.078 mL, 0.919 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with dichloromethane (40 mL) and washed with an ice-cold 0.5N aqueous solution of hydrochloric acid (20 mL). The aqueous layer was extracted with dichloromethane (20 mL), and the combined organic layers were washed with ice-cold water (20 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded 5-phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (199 mg, 0.768 mmol, 100% yield) as a pale yellow oil. The compound had an HPLC retention time=2.53 min. (methyl ester)-Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [CH2:1]([CH:8]1[NH:14][CH2:13][CH2:12][S:11][C:10]2[C:15](=[O:20])[N:16]([CH3:19])[N:17]=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:22].[Na+]>C(O)(=O)C.O>[CH2:1]([CH:8]1[NH:14][CH2:13][CH2:12][S:11](=[O:22])[C:10]2[C:15](=[O:20])[N:16]([CH3:19])[N:17]=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cn1ncc2c(c1=O)SCCNC2Cc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1ncc2c(c1=O)S(=O)CCNC2Cc1ccccc1
Temperature: 0 °C
Yield: 63.2 %

Procedure:
To a solution of 0.84 g (2.92 mmol) of 5-benzyl-8-methyl-2,3,4,5-tetrahydro-9(8H)-pyridazino[4,5-b][1,5]thiazepinone in 7.5 ml of glacial acetic acid the solution of 0.75 g (3.6 mmol) of sodium metaperiodate in 6 ml of water are added dropwise while stirring and cooling with ice-water. The reaction mixture is stirred for 3 hours while cooling with ice-water. The obtained suspension is filtered and washed with a small amount of water. The aqueous phase is extracted with 3×20 ml of dichloromethane. The organic phase is washed with 2×5 ml of 10% aqueous sodium carbonate solution and then with 2×10 ml of water. The organic phase is dried and evaporated in vacuum. The residue is crystallized from a 9:1 mixture of ethyl acetate and methanol. In this way 0.56 g (63%) of the title compound is obtained with a melting point of 162-163° C.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]1C(=O)C2C(=CC=CC=2)C1=O)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[C:24]([O:29][CH3:30])[C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.O.NN>C(O)C>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[C:24]([O:29][CH3:30])[C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]
Reactant: COc1ccnc2c1CCCC2N(CCCCN1C(=O)c2ccccc2C1=O)Cc1nc2ccccc2n1C(=O)OC(C)(C)C
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccnc2c1CCCC2N(CCCCN)Cc1nc2ccccc2[nH]1
Yield: 67.1 %

Procedure:
To a solution of 2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(4-methoxy-5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (0.133 g, 0.22 mmol) in ethanol (4 mL) was added hydrazine monohydrate (0.20 mL, 4.12 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was filtered through filter paper and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2—CH3OH—NH4OH) provided 56 mg (68%) of the free base of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[OH:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[S:23]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH2:29][CH2:28][CH2:27]1)(=[O:25])=[O:24]>>[CH3:1][O:2][C:3](=[O:13])[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:36]([C:33]2[CH:34]=[C:35]3[C:30]([CH2:29][CH2:28][CH2:27][N:26]3[S:23]([C:17]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=3[O:15][CH3:14])(=[O:25])=[O:24])=[CH:31][CH:32]=2)=[O:37])=[CH:8][CH:7]=1
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Reactant: COC(=O)C(O)c1ccc(N)cc1
Product: COC(=O)C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)cc1

Procedure:
1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using (4-amino-phenyl)-hydroxy-acetic acid methyl ester and 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid and yielded hydroxy-(4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-phenyl)-acetic acid methyl ester, which was hydrolyzed to hydroxy-(4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-phenyl)-acetic acid in step 4, MS (ISP): m/e=509.5 (M−H).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.I[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I>[CH:1]1([C:4]#[C:5][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(I)cc1
Reactant: C#CC1CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C#CC2CC2)cc1
Reaction time: 4 h
Yield: 66.9 %

Procedure:
Cyclopropylethyne (15 g, 0.22 mol) was slowly added to a mixture of 4-iodoanisole (30. g, 0.13 mol), copper (I) iodide (1.2 g, 0.0063 mol), and triethylamine (30. g, 0.30 mol) in tetrahydrofuran (THF, 400 mL). After being stirred for 4 hours, the resulting precipitate was filtered and washed with THF. The combined filtrate was evaporated to dryness and the residue was purified by column chromatography to afford 1-cyclopropylethynyl-4-methoxy-benzene as a yellow oil (15 g, 0.087 mol, 67%). 1H NMR (CDCl3): δ 7.31 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 3.79 (s, 3H), 1.43 (m, 1H), 0.85 (m, 2H), 0.78 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[S:12]1(=[O:18])(=[O:17])[CH2:16][CH2:15][CH2:14][NH:13]1.[H-].[Na+].O>CN(C)C=O>[O:17]=[S:12]1(=[O:18])[CH2:16][CH2:15][CH2:14][N:13]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: O=S1(=O)CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(N2CCCS2(=O)=O)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
Methyl 2-chloropyrimidine-5-carboxylate (173 mg) and isothiazolidine 1,1-dioxide (145 mg) were dissolved in N,N-dimethylformamide (1 mL), and sodium hydride (48 mg, 60% in oil) was added under ice-cooling. After stirring at room temperature for 6 hr, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated, diisopropyl ether and ethyl acetate were added, and the precipitated solid was collected by filtration to give the title compound (185 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9](O)(=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:3]1([CH2:2][NH:1][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NCC1CCCCC1
Reactant: CCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCC(=O)NCC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of aminomethylcyclohexane (0.34 g, 3.0 mmol) in methylene chloride (30 mL) was added heptanoic acid (0.39 g, 3 mmol) and DMAP(0.37 g, 3.0 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.57 g, 3.0 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (100 mL), and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL) and brine (75 mL), and dried over Na2SO4. Concentration in vacuo afforded 0.62 g (92%) of an oil, which then crystallised.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>CN(C=O)C>[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:36]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1cccc(C)c1

Procedure:
1-(3-Methylbenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 3-methylbenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([N:24]([CH:26]1[CH:30]([CH3:31])[CH2:29][NH:28][CH2:27]1)[CH3:25])(=[O:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([N:24]([CH:26]1[CH:30]([CH3:31])[CH2:29][N:28]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:27]1)[CH3:25])(=[O:23])[CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(=O)N(C)C1CNCC1C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(=O)N(C)C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-(N-acetyl-N-methylamino)-4-methylpyrrolidine (0.42 g) and DBU (0.27 g) was refluxed for an hour and allowed to stand overnight. The resulting precipitate was collected by filtration and washed with acetonitrile-ether to give the title compound (0.56 g) as pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[CH:6]2[O:11][CH3:12].[Li]CCCC.[CH2:19]1[O:21][CH2:20]1.O>C1COCC1>[CH3:12][O:11][CH:6]1[C:7]2[C:3](=[C:2]([CH2:19][CH2:20][OH:21])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH:5]1[CH3:13]
Reactant: C1CO1
Reactant: COC1c2cccc(Br)c2CC1C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COC1c2cccc(CCO)c2CC1C
Temperature: -110 °C
Reaction time: 0.67 h

Procedure:
To a solution of 20.0 g (82.9 mmol) of 4-bromo-2-methyl-methoxyindane in 200 ml of THF 33.2 ml of 2.5 M (83.0 mmol) n-BuLi in hexanes was added for 20 min at −80° C. This mixture was stirred for 40 min at this temperature, cooled to −110° C., and 4.38 g (99.4 mmol) of ethylene oxide was added by one portion at vigorous stirring. The resulting mixture was stirred for 12 h at room temperature, and then 10 ml of water was added. The organic layer was separated and evaporated to dryness. To the residue 200 ml of water was added, and the crude product was extracted with 3×100 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography using short column with Silica Gel 60 (40-63 um, d 110 mm, 190 mm; eluent: hexanes/ether=20/1). Yield 12.7 g (74%) of a ca. 1 to 1.2 mixture of two diastereomers.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:6](=[C:19](OCC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:29])(=O)C.[N:30]1([CH2:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH:41]/[C:19](=[C:6]3\[C:5](=[O:29])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=4)/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:42][CH:43]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Product: O=C1Nc2cc(-c3ccccc3)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14]([C:22]3[CH:26]=[CH:25][O:24][C:23]=3[CH:27]=[CH2:28])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.O.C(OCC)(=[O:34])C>C1COCC1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14]([C:22]3[CH:26]=[CH:25][O:24][C:23]=3[CH2:27][CH2:28][OH:34])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1occc1-c1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1O
Reactant: CCOC(C)=O
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2CCO)c1O
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A solution of 9-borobicyclononane (0.5M in THF, 12.6 mL) was added to methyl 6-(benzenesulfonylmethyl)-2-hydroxy-3-(2-vinylfuran-3-yl)-benzoate (Intermediate 24, 1.0 g) in THF (20 mL) at 50° C. and the resultant mixture was stirred and heated at 50° C. for 75 minutes. After cooling to room temperature, 35% hydrogen peroxide (2 mL) was added and the mixture was stirred for 1.5 hours. Water and ethyl acetate were added to the mixture and the organic layer was separated, washed with water, sodium metabisulfite and brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 30-70%. The product was triturated with diethyl ether and the solid was collected by filtration and dried in vacuo to give methyl 6-(benzenesulfonylmethyl)-2-hydroxy-3-[2-(2-hydroxyethyl)-furan-3-yl]-benzoate (0.4 g).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13](=[O:24])[CH:14]=[C:15]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16][C:11]=2[C:10]=1[CH2:27][CH2:28][CH3:29])C1C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[C:13](=[O:24])[CH:14]=[C:15]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16][C:11]=2[C:10]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(CCC(=O)OCC)oc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCCc1c(O)ccc2c(=O)cc(CCC(=O)OCC)oc12
Reaction time: 0.33 h

Procedure:
By a process analogous to that of Example 3(a) was prepared ethyl 3-[7-benzyloxy-4-oxo-8-propyl-4H-1-benzopyran-2-yl]propionate. This compound (1.0 g) in dry dichloromethane (30 ml) at -78° C. was treated with boron trichloride (2 ml). After 20 minutes, the mixture was poured onto ice and extracted with 10% aqueous sodium carbonate. Acidification gave a solid which crystallised from ethyl acetate to give the desired product (0.35 g), mp 127°-128° C.