Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH:36]=[O:37])[CH:34]=2)[CH:29]=[CH:28][CH:27]=1.[Li]C1C(Cl)=NC=CN=1>C1COCC1.CC(C)=O>[Cl:19][C:20]1[C:25]([CH:36]([C:33]2[CH:34]=[C:35]3[C:30]([CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:31][CH:32]=2)[OH:37])=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: O=Cc1ccc2cccnc2c1
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc2cccnc2c1)c1nccnc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (0.64 mL, 0.54 g, 3.8 mmol) in dry THF (10 mL), cooled by CO2(s)/acetone, was added nBuLi (2.5 M in hexanes; 1.6 mL, 4.0 mmol). The cooling bath was replaced with an ice/water bath for 15 min, and then the solution was re-cooled to −78° C. After 10 min, 2-chloropyrazine (0.29 mL, 0.37 g, 3.2 mmol) was added. A solution of quinoline-7-carbaldehyde (500 mg, 3.18 mmol) in dry THF (5 mL), cooled by CO2(s)/acetone, was transferred into the lithiochloropyrazine solution by cannula 30 min later, and the mixture was stirred at −78° C. for 2.5 h and at 0° C. for 0.5 h. The reaction was quenched by adding aq. HCl (2 mL of a 2 M solution) followed by aq. NH4Cl solution. The mixture was extracted with EtOAc (4×30 mL), combined EtOAc extracts were washed with water and brine and dried over MgSO4. The crude material was chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 2:1 (1-21)→1:1 (22-32)→1:4 (33-62)→EtOAc (63-66)], yielding the title compound as an orange foam; 1H NMR (CDCl3, 400 MHz) δ 4.87 (d, J=7.6 Hz, 1H), 6.26 (d, J=7.6 Hz, 1H), 7.41 (dd, J=4.4, 8.4 Hz, 1H), 7.60 (dd, J=1.6, 8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 8.02 (d, J=0.8 Hz, 1H), 8.14 (dd, J=0.8, 8.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 8.91 (dd, J=1.6, 4.4 Hz, 1H). MS (ES+): m/z 272.1/274.1 (100/38) [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[OH:12]>C(OC)(C)(C)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:11]([CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18]1)[OH:12]
Reactant: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Solvent: COC(C)(C)C
Product: COc1cccc([C@H](O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Temperature: 45 °C
Reaction time: 96 h

Procedure:
To a solution of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, butyrate ester (5a) (2.77 g, 6.2 mmol) in t-BuOMe (10 mL), Baker silica (8.3 g, 40μ) was added. After evaporation of the ether, the silica was transferred to 180 mL of 0.1M phosphate buffer (pH 7.0) and then 25 mL of the partially purified lipase (100 g crude=230 mL of a solution) was added. The suspension was stirred at 45° C. for 4 days. The reaction was stopped by filtering the reaction mixture. Both filtrate and silica were extracted with ethyl acetate (300 mL). The organic layer was dried over MgSO4, evaporated under vacuum to give a residue, which was purified by column chromatography (60 g Baker silica (40μ) EtOAc/heptane=3:1). (Rf 0.45 for (S)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, butyrate ester (5b) and 0.06 for (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3)). After the ester was eluted, the eluant was changed to MeOH/EtOAc=3:7 to recover (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) as a yellow oil (1.08 g, 46%, 98% ee). Recrystallization twice from EtOAc/heptane gave (R)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3) as a white crystalline compound (770 mg, 33%, 99% ee); m.p.=114-116° C.; [α]D=14.3 (c=1; CHCl3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[N:40][CH:39]=[C:38]([CH3:42])[N:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[N:40][CH:39]=[C:38]([CH3:42])[N:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Product: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) (290 mg, 1.0 mmol) and 3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K16) (312 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (400 mg, 76%).
Reaction SMILES: C1(S([O-])(=O)=O)C=CC=CC=1.[C:11](#[N:13])[CH3:12].[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17]>C(OCC)(=O)C>[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH:17][CH2:12][C:11]#[N:13]
Reactant: CC#N
Reactant: Cc1cccc(C)c1N
Agent: O=S(=O)([O-])c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1NCC#N

Procedure:
A solution of 158.5 g (0.804 mol) of benzenesulphonate-acetonitrile in 200 ml of ethyl acetate is run dropwise into a solution of 193.6 g (1.608 mols) of 2,6-dimethyl-aniline in 400 ml of ethyl acetate. The mixture is heated under reflux for 3 hours, cooled and the excess aniline benzenesulphonate is filtered off. The filtrate is evaporated to dryness. The residue is taken up in ether. Insoluble material is again filtered off and discarded. The ether is evaporated to dryness. The residue is taken up in a mixture of petroleum ether/benzene (3:4 v/v). The crystals which form are filtered off.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][S:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[CH3:9][S:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[NH:8])=[CH:13][CH:12]=1
Reactant: CSc1ccc(N)cc1
Reactant: N#Cc1ccccc1
Product: CSc1ccc(NC(=N)c2ccccc2)cc1

Procedure:
The title compound was prepared from benzonitrile (3.705 g, 35.97 mmol) and 4-methylthioaniline (5.0 g, 35.97 mmol) by following the procedure described in preparation 1, (3.66 g, 42.1%, purity 99.8% by HPLC), mp 129-131° C. 1H-NMR (CDCl3):δ 2.49 (s, 3H), 4.84 (bs, 2H), 6.94-6.96 (d, 2H), 7.26-7.31 (m, 2H), 7.45-7.49 (m, 3H), 7.87-7.88 (d, 2H). MS m/z:243.2 (M+)
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:4]=1[NH:10][S:11]([NH2:14])(=[O:13])=[O:12])#[N:2].[CH:15](/B(O)O)=[CH:16]\[CH3:17]>>[C:1]([C:3]1[CH:8]=[C:7](/[CH:15]=[CH:16]/[CH3:17])[CH:6]=[CH:5][C:4]=1[NH:10][S:11]([NH2:14])(=[O:13])=[O:12])#[N:2]
Reactant: C/C=C/B(O)O
Reactant: N#Cc1cc(Br)ccc1NS(N)(=O)=O
Product: C/C=C/c1ccc(NS(N)(=O)=O)c(C#N)c1

Procedure:
Prepared as in Example 77a from N-(2-cyano-4-bromophenyl)sulfamide (Example 83b) and (E)-prop-1-enylboronic acid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.C(N(CC)CC)C.Cl>O1CCCC1>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:22][CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)([O-:14])=[O:13]
Reactant: NCC1CCOCC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.18 g), 1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) in tetrahydrofuran (30 mL) were stirred overnight, neutralized with concentrated HCl and concentrated. The residue was suspended in ethyl acetate and the precipitates were collected, washed with water and dried to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[N:7]([CH:8]([CH3:11])[CH2:9][OH:10])[C:6]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:5]=2[N:4]=1.[Cr](O)(O)(=O)=[O:33].S(=O)(=O)(O)O>CC(C)=O.O.[O-2].[O-2].[O-2].[Cr+6]>[F:31][C:2]([F:1])([F:30])[C:3]1[N:7]([CH:8]([CH3:11])[C:9]([OH:33])=[O:10])[C:6]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:5]=2[N:4]=1
Reactant: O=[Cr](=O)(O)O
Reactant: CC(CO)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CC(C(=O)O)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, 4.3 grams (0.010 mole) of 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl) benzimidazol-1-yl]propan-1-ol in 120 mL of acetone was stirred, and 16 mL chromic acid (prepared by dissolving about five grams of chromium trioxide in 12 mL of water, then adding five mL of concentrated sulfuric acid), was added dropwise during a one hour period. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction was quenched with about three mL of 1-methylethanol, and the mixture was made basic with an aqueous solution saturated with sodium bicarbonate. The mixture was filtered to remove chromium salts, and the filtrate was extracted with ethyl acetate. The combined extracts were then washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.0 grams of 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl)benzimidazol-1-yl]propanoic acid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6](=[O:28])[CH:7]([OH:27])[CH:8]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.FC(F)(F)C(O)=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6](=[O:28])[C:7](=[O:27])[CH:8]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)C(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)CC(=O)C(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
A solution of 4-hydroxy-6-phenyl-5-[((phenylmethoxy)carbonyl)amino]-3-oxohexanoic acid ethyl ester (397 mg, 1.0 mmol) is dissolved in acetonitrile (15 ml) and the Dess-Martin periodinane (1.27 g, 3.0 mmol)) is added. To the mixture trifluoroacetic acid (342 mg, 3.0 mmol) is added and the mixture is stirred for 48 h. The solvent is removed in vacuo and EtOAc (100 ml) is added, followed by the addition of a solution of NaHCO3 (0.80 g) and Na2S2O3 (1.41 g) in H2O (25 ml). The organic layer is separated and the aqueous phase extracted with ethyl acetate. The combined extracts are dried over Na2S2O3 and the solvent is removed in vacuo. The product is purified by flash chromatography on silica gel.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)#[CH:29]>O1CCOCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:19]=[C:14]1[C:13]2[NH:20][CH:21]=[CH:22][C:12]=2[C:11]2[CH:10]=[C:9]([C:29]#[C:28][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:18]=[CH:17][C:16]=2[NH:15]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Reactant: C#Cc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C#Cc3ccccn3)cc2c2cc[nH]c12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
20 mg (0.11 mmol) of copper iodide, 28 mg (0.27 mmol) of triethylamine and 14 mg (0.02 mmol) of dichlorobis(triphenylphosphine)-palladium (II) are added to a suspension of 80 mg (0.21 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 2.4 ml of anhydrous dioxan, then this mixture is degassed under argon. After 15 minutes, 32 mg (0.31 mmol) of 2-ethynyl-pyridine are added, then the mixture is heated at 100° C. for 3 hours. The raw reaction product is then filtered on celite, the filtrate is evaporated to dryness and the residue is purified by chromatography on silica (eluent ethyl acetate) to give 34 mg (46%) of 4-oxo-8-pyridin-2-ylethynyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[O:49][C:48]([NH2:51])=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[C:50]3[O:49][C:48]([NH:51][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][N:10]=[C:2]([CH3:1])[CH:3]=4)=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 378 (M+H+, 100).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]3[S:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.BrB(Br)Br>C(Cl)Cl>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[C:13]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[N:10][NH:11][CH:12]=1
Reactant: COc1ccc(-c2n[nH]cc2-c2nc3ccccc3s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2n[nH]cc2-c2nc3ccccc3s2)cc1
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a suspension of 2-[3-(4-methoxyphenyl)-1H-pyrazol-4-yl]benzothiazole (100 mg, 0.33 mmol) was slowly added tribromoborane (3.3 mL of a 1 M solution in CH2Cl2, 3.3 mmol). The mixture was stirred overnight. The reaction was then quenched by the addition of methanol. The mixture was neutralized with sodium carbonate solution and extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and evaporated. The crude material was recrystallized from ethyl acetate to yield 64 mg (66%) of the title compound as a yellow solid. MS (m/z, ES+): 294 (M+1, 100%). 1H NMR (400 MHz, ppm, DMSO-d6): δ 13.5 (br s, 1H), 9.80 (br s, 1H), 8.22 (br s, 1H), 7.98 (d, 3J=8.1 Hz, 1H), 7.91 (d, 3J=8.0 Hz, 1H), 7.47 (d, 3J=8.0 Hz, 2H), 7.45 (dd, 3J=7.4 Hz, 3J=8.1 Hz, 1H), 7.34 (dd, 3J=7.4 Hz, 3J=8.0 Hz, 1H), 6.89 (d, 3J=8.0 Hz, 2H).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C)=O)=[CH:14][CH:13]=2)[CH2:8]C1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[CH3:24]COCC>>[OH:21][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH:9]([CH3:8])[CH2:10][CH2:11][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:24]2)=[CH:17][CH:16]=1
Reactant: CCOCC
Reactant: CCCCCC1CCC(c2ccc(CC(=O)OC)cc2)CC1
Agent: Cl
Product: CC(CCCC1CCCCC1)c1ccc(CCO)cc1

Procedure:
Next, 400 ml of (C2H5)2O was added to 6 g of Li[AlH4 ], and the resulting mixture was stirred. Thereto was very gradually added dropwise a (C2H5)2O solution including 36 g of the aforesaid methyl p-(4-pentylcyclohexyl)phenylacetate, and after completion of the addition, the thus obtained mixture was stirred at 30° C. or lower continuously for 3 hours. The mixture was then poured into dilute hydrochloric acid and extracted with (C2H5)2O was distilled off, the residue was recrystallized from n--C6H14 to obtain 4-[p-(2-hydroxyethyl)phenyl]pentylcyclohexane. The melting point of this compound was 44° to 46° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([F:13])[CH2:10][CH:9]1[CH2:14][O:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=1[O:27][CH3:28])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:13][CH:11]1[CH2:12][NH:8][CH:9]([CH2:14][O:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10]1
Reactant: CCOC(=O)c1ccc(OCC2CC(F)CN2C(=O)OC(C)(C)C)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCC2CC(F)CN2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a stirred solution of ethyl 4-[1-(tert-butoxycarbonyl)4-fluoro-2-pyrrolidinyl]methoxy-3-methoxybenzoate (482.2 mg, 1.213 mmol) in CH2Cl2 (10.0 mL) was added TFA (1.9 mL) at 0° C., and the mixture was stirred at room temp for 2 hr. The solvent was removed under a reduced pressure and the residue was made basic by the addition of 1 N NaOH and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and concentrated under a reduced pressure to afford 348.7 mg (97%) ethyl 4-(4-fluoro-2-pyrrolidinyl)methoxy-3-methoxybenzoate as a brownish oil. 1H-NMR (400 MHz, CDCl3) δ 1.39 (t, J=6.8 Hz, 3H), 1.97 (ddt, J=1.5, 5.4, 14.7 Hz, 1H), 2.27 (dddd, J=5.9, 8.8, 14.7, 32.7 Hz, 1H), 3.02 (ddd, J=3.9, 13.1, 35.2 Hz, 1H), 3.36 (dd, J=12.7, 21.5 Hz, 1H), 3.65 (m, 1H), 3.90 (s, 3H), 4.09 (m, 1H), 4.35 (q, J=6.8 Hz, 2H), 5.17, 5.31 (br m each, 1H), 6.90 (d, J=8.3 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.65 (dd, J=2.0, 8.3 Hz, 1H); MS (FAB) m/z 298 (M++1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1([CH2:15][CH2:16][OH:17])[CH2:14][CH2:13]1>N1C=CC=CC=1.ClCCl.CCOCC>[CH:12]1([CH2:15][CH2:16][O:17][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1CC1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
p-Toluenesulfonyl chloride (7.20 g, 37.8 mmol) was added to a cooled (0° C.) solution of 2-cyclopropylethanol (4.00 g, 46.4 mmol) in pyridine (10 mL) and dichloromethane (60 mL). The reaction mixture was stirred at ambient temperature overnight, then diluted with ether (200 mL) and washed sequentially with water, 10% HCl, water and brine and then dried over anhydrous Na2SO4. Toluene-4-sulfonic acid 2-cyclopropylethyl ester (8.1 g, 89%) was obtained after removal of solvent and used for next step reaction without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].O.CCCCC>CN(C=O)C>[C:5]1([C:3](=[CH2:4])[CH2:2][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=C(CCl)c1ccccc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Solvent: CN(C)C=O
Product: C=C(CS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 70 °C
Yield: 76 %

Procedure:
This mixture (17 g, 0.05 molar as 1-chloro-2-phenyl-2-propene) is dissolved in DMF (100 cc). Sodium benzenesulphinate (8.2 g, 0.05 mole) is added and the mixture is heated to 70° C. for 2 h. The reaction mixture is poured into water and ice (350 g). It is stirred energetically with pentane (150 cc) to extract the 1-chloro-2-phenyl-1-propene and the 1-chloro-2-phenyl-2-propanol which have not reacted, for 15 to 30 min until crystallization is complete. The crystals formed are filtered off, are washed with pentane (50 cc) and with diisopropyl ether (50 cc) and are thoroughly drained and dried. 2-Phenyl-1-phenylsulphonyl-2-propene (9.8 g, 76%) is obtained. Mp=105° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:3][C:2]1[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:18]([C:19]([OH:21])=[O:20])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:1]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Product: O=C(O)c1c(-c2ccccc2)c(O)nc2ccccc12

Procedure:
As shown in Scheme 1, reaction of isatin (1) and phenylacetic acid (2) gives 2-hydroxy-3-phenylquinoline-4-carboxylic acid (3), which may be treated with POCl3 to yield 6-chloro-11H-indeno[1,2-c]quinolin-11-one (4). Reaction of a compound 4 with a compound of formula R9AH, such as piperazine, yields a compound 5, such as 6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one (compd. 5x in Synthesis Ex. 9, infra), which may be reacted either with NH2OH, optionally followed by alkylation with an alkyl halide of formula R10X, or with NH2OR10 directly, to give a corresponding compound of formula (I).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14](F)(F)[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=[O:20].[Cs+].[Cs+]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14](=[O:20])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Agent: [Cs+]
Product: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Yield: 23.9 %

Procedure:
According to a similar synthesis of compound 344, compound 5 (100 mg, 0.26 mmol) was alkylated with compound 2 (159 mg, 1.04 mmol) in the presence of Cs2CO3 (339 mg, 1.04 mmol) to give compound 4 (73 mg, 53%).