Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C(Cl)=CC(C2NC(C3C=CC(Cl)=CC=3)(C)C(C3C=CC(Cl)=CC=3)(C)N=2)=[C:7]([O:33]CC)C=1)(C)(C)C.Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:41])=[O:40]>>[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][N:48]([CH:7]=[O:33])[CH2:47][CH2:46]1)(=[O:40])=[O:41]
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CS(=O)(=O)CCCN1CCN(C=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the racemic rac-(4S*,5R*)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone. Chiral separation of the enantiomers by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C38H48N4O4SCl3 [(M+H)+] 761.2457, observed 761.2460.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH2:8][CH2:9][C:10]([O:12]C)=O.[C:21]1([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:14]([CH2:32][C:30]2[N:31]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:28][CH:29]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: COC(=O)CCC(N)c1ccccc1-c1ccccc1
Reactant: O=Cc1csc(-c2ccccc2)n1
Product: O=C1CCC(c2ccccc2-c2ccccc2)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-([1,1′-biphenyl]-2-yl)-4-aminobutanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.96 min.; [M+H]+: 410.81 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13](OCC)=[O:14]>C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:13](=[O:14])[CH2:12][Cl:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCl
Solvent: COC(C)(C)C
Product: CC(NC(=O)CCl)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
At 35° C., a solution of 6.3 g (0.04 mol) of racemic 1-(4-chloro-phenyl)-ethylamine in 45 ml of methyl tert-butyl ether is admixed successively with stirring with 4.9 g (0.04 mol) of ethyl chloroacetate and 0.5 g of Novozym 435® (=immobilized lipase from Candida antarctica; 7300 U/g). Stirring is continued at 35° C. and the progress of the reaction is monitored by gas chromatographic sample analysis. After 4 hours, a conversion of 54% is reached. At this stage, the reaction is terminated by filtering off the enzyme. In the filtrate that remains, the (S)-enantiomer of 1-(4-chloro-phenyl)ethylamine has an ee value of 96.2%, while the (R)-enantiomer of N-[1-(4-chlorophenyl)-ethyl]chloroacetamide is obtained with an ee value of 95.1%.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH3:24])=[C:8]([CH:21]=1)[C:9]([O:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])=[O:10]>C(OCC)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH3:24])=[C:8]([CH:21]=1)[C:9]([O:11][CH:12]([Br:1])[C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])=[O:10]
Reactant: CCOc1ccc(Cl)cc1C(=O)OCC(=O)c1ccccc1
Reactant: BrBr
Solvent: CCOCC
Product: CCOc1ccc(Cl)cc1C(=O)OC(Br)C(=O)c1ccccc1

Procedure:
Bromine (0.6 g, 3.7 mmol) is added dropwise to a solution of 5-chloro-2-(2-ethoxybenzoyloxy)-acetophenone (1.19 g, 3.7 mmol) in dry diethyl ether (30 ml) at room temperature. The mixture is stirred for an additional hour. The reaction mixture is washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound in pure form.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[O:23]1[C:27]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)=[CH:26][N:25]=[CH:24]1.C(N(C(C)C)C(C)C)C.C(OC([N:53]1[CH2:58][CH2:57][CH:56]([NH:59][CH:60]2[CH2:62][CH2:61]2)[CH2:55][CH2:54]1)=O)(C)(C)C.C>CN(C)C=O>[CH:60]1([N:59]([CH:56]2[CH2:57][CH2:58][NH:53][CH2:54][CH2:55]2)[C:32](=[O:34])[C:31]2[CH:30]=[CH:29][C:28]([C:27]3[O:23][CH:24]=[N:25][CH:26]=3)=[CH:36][CH:35]=2)[CH2:62][CH2:61]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1ccc(-c2cnco2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (6.10 g) is added to a solution of 4-oxazol-5-yl-benzoic acid (3.00 g) and ethyldiisopropylamine (5.56 mL) in N,N-dimethylformamide (50 mL) at room temperature. The solution is stirred for 10 min prior to the addition of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (4.57 g). The resulting mixture is kept at room temperature over night. The mixture is treated with activated charcoal and filtered through a pad of basic aluminum oxide. The pad is washed with N,N-dimethylformamide/methanol (9:1) and the combined filtrates are concentrated in vacuo. The residue is dissolved in 1,4-dioxane (35 mL), a 4 M solution of hydrogen chloride in 1,4-dioxane (20 mL) is added and the resulting mixture is stirred at room temperature for 2 h. The solvent is evaporated and the residue is taken up in water. The resulting mixture is washed with dichloromethane, basified with NaOH solution and extracted with dichloromethane.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](CN)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.[CH:32]([N:35](CC)C(C)C)(C)C>C(#N)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:32][NH:35][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH:28]=2)[CH:23]=[CH:22]1
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5cc[nH]c5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (100 mg, 0.35 mmol) and 1-(1H-indol-5-yl)-methylamine (139 mg, 0.95 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (0.4 mL, 2 mmol) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (30-60% acetonitrile-water [10 mM DEA]) to afford a light yellow solid.
Reaction SMILES: ClC1C(Cl)=CC=CC=1[NH2:4].N1C=CC=CC=1.O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:4])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1cccc(Cl)c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(N)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 175.8 %

Procedure:
A solution of 2,3-dichloroaniline (162.0 g) in p-toluenesulfonyl chloride (190.7 g) is heated at 100° C. for one hour allowing the temperature to rise to 115° C. with the exotherm. The thick mixture is then cooled to 50° C. and pyridine (250 ml) is added carefully. The reaction mixture exotherms to 150° C. After stirring for one hour the mixture is cooled and poured into water (2.5 liter). The precipitated solid is collected and dried to yield 301 g of tosylamide, m.p. 112°-118° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=O)=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26]C(=O)CCl)=[CH:21][CH:20]=1)[CH3:18].Cl.[CH2:32]([OH:34])[CH3:33]>>[ClH:11].[CH2:32]([O:34][C:15](=[O:17])[CH2:14][O:13][C:7]1[CH:6]=[C:5]2[C:10](=[C:9]([Cl:11])[C:8]=1[Cl:12])[C:2](=[O:1])[C:3]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[CH:23][CH:24]=1)([CH3:18])[CH2:4]2)[CH3:33]
Reactant: CCO
Reactant: CC1(c2ccc(CNC(=O)CCl)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(CN)cc1)C2
Temperature: 5 °C

Procedure:
{1-Oxo-2-[4-(2-chloroacetamidomethyl)phenyl]-2-methyl-6,7-dichloro-5-indanyloxy}acetic acid (2.0 g., 0.004 mole), absolute ethanol (20 ml.) and 12 N hydrochloric acid (7 ml.) are combined and heated at reflux for 3 hours. On cooling to 5° C. 1.14 g. of ethyl[1-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetate hydrochloride precipitates and melts at 211°-213° C. after crystallization from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>C(OCC)C.CCCCCC.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc2ccccc2s1
Yield: 37.1 %

Procedure:
The title compound (1.2 g) after column chromatography (silica gel, 5% diethyl ether/hexane-diethyl ether eluant) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and 2-chlorobenzothiazole (1.58 g) according to the method of D2.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6](I)=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[CH3:1][NH:2][C:3]([C:5]1[C:6]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Cl:26])=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)c1cnc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)cc1I
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)c1cnc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)cc1-c1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A mixture of 480 mg (1.01 mmol) 4-(tert-butyl-dimethyl-silanyloxy)-4′-iodo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid methylamide, 174 mg (1.11 mmol) 2-chlorophenylboronic acid, 6 ml dimethoxyethane and 1 ml of a 2 M aqueous solution of sodium carbonate was deoxygenated by three freeze-thaw cycles. After addition of 60 mg (0.052 mmol) tetrakis(triphenylphosphine)palladium(0) the reaction mixture was stirred at 90° C. for 3 h. Cooling to room temperature was followed by dilution with water and extraction with ethyl acetate. The organic extract was washed with saturated aqueous sodium carbonate and sodium chloride solutions, dried with sodium sulfate and concentrated. Column chromatography afforded 425 mg (91.5%) of the title compound as an off-white solid. MS m/e (%):460 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]([N:10]2[CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])[CH2:13][C:12]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:11]2)=[O:9])=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[N:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[C:54](O)=[O:55]>C(Cl)Cl.O>[OH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:14]1[N:10]([C:8]([C:6]2[S:7][C:3]([CH2:2][NH:1][C:54]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][N:48]=3)=[O:55])=[CH:4][CH:5]=2)=[O:9])[N:11]=[C:12]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:13]1
Reactant: O=C(O)c1ccccn1
Reactant: NCc1ccc(C(=O)N2N=C(c3cccnc3)CC2c2ccccc2O)s1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(C(=O)N2N=C(c3cccnc3)CC2c2ccccc2O)s1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
A mixture of 2-(1-{[5-(aminomethyl)-2-thienyl]carbonyl}-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (0.080 g, 0.21 mmol), EDCI (0.070 g, 0.36 mmol), DIPEA (0.150 mL, 0.86 mmol), and picolinic acid (0.31 g. 0.25 mmol) in DCM (4 mL) was allowed to stir at rt overnight. The reaction mixture was diluted with water and extracted with DCM. The organic solutions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give N-[(5-{[5-(2-hydroxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}-2-thienyl)methyl]pyridine-2-carboxamide (I-136) (0.033 g) as a clear oil. LCMS: (FA) ES+ 484.2. 1H NMR (400 MHz, d6-DMSO) δ: 9.53-9.59 (m, 1H), 9.05-9.09 (m, 1H), 8.72-8.76 (m, 1H), 8.65-8.69 (m, 1H), 8.36-8.41 (m, 1H), 8.06-8.11 (m, 1H), 7.98-8.05 (m, 1H), 7.88 (d, 1H), 7.60-7.67 (m, 2H), 7.02-7.12 (m, 2H), 6.86-6.91 (m, 1H), 6.82 (d, 1H), 6.69 (t, 1H), 5.82 (dd, 1H), 4.70 (d, 2H), 3.82-3.92 (m, 1H), and 3.17 (dd, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH:10]([CH3:13])[CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[NH:15]([CH2:17]C(O)=O)[CH3:16]>C1(C)C=CC=CC=1>[CH3:16][N:15]1[CH2:17][CH2:3][CH:2]2[CH:11]1[CH:10]([CH3:13])[N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2
Reactant: CNCC(=O)O
Reactant: C=CCN(C(=O)OCC)C(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN(C)C2C1C

Procedure:
18.5 g (0.1 mol) of ethyl N-allyl-N-(1-oxoprop-2-yl)-carbamate are heated under reflux overnight in a water separator with 9 g (0.1 mol) of sarcosine in 300 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[C:19]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)(=[O:23])=[O:22])[CH:18]=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[Cl:30][C:26]1[CH:25]=[C:24]([S:21]([C:19]2[CH:18]=[CH:17][C:15]3[O:16][CH:10]4[CH2:9][NH:8][CH2:13][CH2:12][CH:11]4[C:14]=3[CH:20]=2)(=[O:22])=[O:23])[CH:29]=[CH:28][CH:27]=1.[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCC2c3cc(S(=O)(=O)c4cccc(Cl)c4)ccc3OC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1cccc(Cl)c1)c1ccc2c(c1)C1CCNCC1O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(3-Chloro-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (0.20 mmol, 1.0 eq) was dissolved into 20% TFA in DCM and shaken at room temperature for 3 h. The reaction solution was then concentrated and the crude product purified by preparative LC/MS to afford 6-[(3-chlorophenyl)sulfonyl]-1,2,3,4,4a,9a-hexahydro[1]benzofuro[2,3-c]pyridine as a trifluoroacetic acid salt. MS m/z 350 [M+H]+
Reaction SMILES: [O:1]([C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:25](Cl)(=[O:34])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>C1COCC1>[O:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:25](=[O:34])[CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C(Oc2ccccc2)CCC1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)C1CCC(Oc2ccccc2)=CC1=O
Reaction time: 0.25 h
Yield: 43.2 %

Procedure:
A solution of 3-phenoxy-cyclohex-2-enone (301 mg, 1.6 mmol) in 1 mL of THF was added to a stirred solution of 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (3.2 mL) at −78° C. After 15 min, cinnamoyl chloride (266 mg, 1.6 mmol) was added all at once. After 15 min. the reaction mixture was poured into 0.5 N HCl and extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), filtered, and concentrated under reduced pressure. Chromatography of the residue with 4:1 hexanes/ethyl acetate as eluant provided 220 mg (43%) of 3-phenoxy-6-(3-phenyl-acryloyl)cyclohex-2-enone as a yellow solid (220 mg, 43%): 1H NMR (CDCl3) (enol form) δ 2.66 (t, 2H, J=7.2 Hz), 2.84 (t, 2H, J=7.1 Hz), 5.11 (s, 1H), 6.86 (d, 1H, J=15.6 Hz), 7.02 (d, 2H, J=8.1 Hz), 7.20 (m, 2H), 7.28-7.38 (m, 3H). HRMS M+H+ calc: 319.1334, found 319.1340.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([CH:17]3[CH2:19][CH2:18]3)[C:12]([C:14](=[O:16])[CH3:15])=[CH:13][C:8]=2[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23](OC2C=CC=CC=2)=[CH:22][CH:21]=1)=[O:4].[F:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.CN.[CH3:43][Mg]Br>>[CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([CH:17]3[CH2:18][CH2:19]3)[C:12]([C:14]([OH:16])([CH3:15])[CH3:43])=[CH:13][C:8]=2[O:7][C:6]=1[C:20]1[CH:21]=[CH:22][C:23]([O:40][C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[CH:24][CH:25]=1)=[O:4]
Reactant: Oc1ccc(F)cc1
Reactant: C[Mg]Br
Reactant: CNC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)oc2cc(C(C)=O)c(C3CC3)cc12
Agent: CN
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)oc2cc(C(C)(C)O)c(C3CC3)cc12

Procedure:
I-86 is prepared analogously except the starting material was 6-acetyl-5-cyclopropyl-2-(4-phenoxy-phenyl)-benzofuran-3-carboxylic acid methylamide. I-103 and I-104 can be prepared from A-2c by introduction of the p-fluorophenyl by Suzuki coupling with p-fluoro-phenol (see step 5 of example 3), Freidel-Crafts acylation, hydrolysis of the ethyl ester and coupling with methylamine and addition of methyl magnesium bromide as carried described in the current example.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:7]2[CH:17]([CH2:21][C:22]([O:24]CC3C=CC=CC=3)=[O:23])[CH2:18][CH2:19][CH2:20][C:6]=2[N:5]=1)[CH3:3].[OH-].[Na+].Cl>CO.C(#N)C.O>[NH3:5].[CH3:3][CH:2]([C:4]1[N:8]([C@@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:7]2[CH:17]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:19][CH2:20][C:6]=2[N:5]=1)[CH3:1]
Reactant: CC(C)c1nc2c(n1[C@H](C)c1ccccc1)C(CC(=O)OCc1ccccc1)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: CC(C)c1nc2c(n1[C@H](C)c1ccccc1)C(CC(=O)O)CCC2
Product: N
Reaction time: 8 h
Yield: 91 %

Procedure:
Intermediate 67 (224 mg) was dissolved in methanol (4 mL). NaOH (2 mL, 6.60 mmol) was added to the stirred reaction mixture as a 3.3 N aqueous soln. After stirring overnight the reaction mixture was conc in vacuo and taken up in acetonitrile/water. The soln was taken to pH4-5 by the addition of 2 M aqueous HCl and loaded onto an SCX column. After washing with water and acetonitrile, the product was eluted with 2 M ammonia soln in methanol. The washing were conc in vacuo to afford the ammonium salt of the desired product (84 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(=O)([O-])[O-].[K+].[K+].[C:17]([C:24](OCC)=[O:25])#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C(O)C.O>[CH2:22]([O:21][C:19]([C:18]1[CH:17]=[C:24]([OH:25])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[N:10]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NNc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(O)n(-c2ccccc2Cl)n1

Procedure:
To a stirred solution of 2-chlorophenylhydrazine hydrochloride (22.4 g) and potassium carbonate (34.5 g) in ethanol (250 ml) was added diethyl acetylenedicarboxylate (20 ml) and the resulting mixture was heated at reflux for 18 hours. The reaction mixture was cooled, 6 N hydrochloric acid (75 ml) and water (500 ml) were added sequentially. The reaction mixture was extracted with ethyl acetate, the organic layer washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The resulting gum was stirred with isopropyl ether (250 ml) to afford the title compound (I-1a) as a tan solid, (23 g) after filtering and drying in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH3:18])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-].P(Br)(Br)Br>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[CH:5]=[C:4]([O:16][CH2:17][CH3:18])[CH:3]=1
Reactant: CCOc1cc(C)[n+]([O-])c(-c2cccc(C)n2)c1
Agent: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CCOc1cc(C)nc(-c2cccc(C)n2)c1
Yield: 69 %

Procedure:
6,6'-Dimethyl-4-ethoxy-2,2'-bipyridine-N-oxide (21) (0.96 g, 3.93 mmoles) was dissolved in chloroform (34 ml). After addition of phosphorus tribromide (3.0 ml) the mixture was refluxed for 1.5 hours. The solution was poured on ice, some chloroform was added and the phases were separated. The chloroform phase was extracted with water. The aqueous phases were combined, made alkaline with sodium hydroxide solution, and extracted with chloroform. Evaporation of the organic phase followed by silica gel chromatography yielded pure title product. Yield: 69%
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][C:4](=O)[CH2:3]1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].[Cl-].[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[C:9](/[C:11](=[C:4]1\[CH2:3][C:2]([CH3:8])([CH3:1])[CH2:6][CH2:5]\1)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CC1(C)CCC(=O)C1
Reactant: CCOC(=O)CC#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C#N)=C1\CCC(C)(C)C1
Temperature: 25 °C

Procedure:
To a round bottomed flask equipped with a stir bar, reflux condenser, and Dean Stark trap were added 3,3-dimethylcyclopentanone (3.4 g, 30 mmol), toluene (50 mL), and ethyl 2-cyanoacetate (3.4 g, 30 mmol), ammonium chloride (231 mg, 3 mmol) and acetic acid (0.36 mL, 6 mmol). The reaction mixture was refluxed for 24 h. The reaction was cooled to RT and concentrated to dryness. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phases were dried with Na2SO4, concentrated to dryness subjected to FCC to afford the title compound as colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[C:6]1=[O:7])=[O:4].C1CCN2C(=NCCC2)CC1.[NH2:27][C:28]([NH2:30])=[O:29]>O1CCCC1>[CH3:1][N:2]1[C:8]([OH:9])([C:6]([NH:27][C:28]([NH2:30])=[O:29])=[O:7])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:5][C:3]1=[O:4]
Reactant: CNC(=O)N1C(=O)C(=O)c2ccccc21
Reactant: NC(N)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CN1C(=O)Nc2ccccc2C1(O)C(=O)NC(N)=O

Procedure:
1-Methylcarbamoylisatin (10.2 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.3 g) are dissolved in tetrahydrofuran (100 ml), and thereto is added urea (4.5 g), and the mixture is refluxed for 10 hours. After cooling, the precipitates are taken by filtration, washed with water and methanol and recrystallized from a mixture of dimethylsulfoxide and ethanol to give 3-methyl-4-hydroxy-4-ureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline, M.p.>280° C.,
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[CH:4][C:3]=1[CH3:17].C1(C2(CC(O)(C)C)OC(=O)N([C@H](C3C=CC(C4C=CN(C)C(=O)C=4)=CC=3)C)CC2)CC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[CH:4][C:3]=1[CH3:17]
Reactant: CC(=N[S@](=O)C(C)(C)C)c1ccc(Br)c(C)c1
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Product: Cc1cc([C@H](C)N[S@](=O)C(C)(C)C)ccc1Br

Procedure:
The title compound was prepared from (R)-2-methyl-propane-2-sulfinic acid [1-(4-bromo-3-methyl-phenyl)ethylidene]-amide following a procedure analogous to that described in Step 2 of Intermediate 1. LC-MS (Method 5): tR=4.04 min; Mass spectrum (ESI+): m/z=318/320 (Br) [M+H]+.