Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>O=S(Cl)Cl.O>[Cl:1][C:2]1[C:10]2[N:9](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2c(c3cccc(Cl)c3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: C/C(=C\n1c2c(c3cccc(Cl)c31)CN(C)CC2)c1ccncc1
Temperature: 100 °C

Procedure:
1-(6-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (650 mg, 1.8 mmol) in SOCl2 (6.5 mL) was stirred at RT for 2 h. The progress of reaction was monitored by TLC and 1H NMR. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (3 mL), KOH (737 mg, 13.1 mmol) was added and the reaction mixture was heated at 100° C. for 2 h. After it was cooled to RT, the reaction mixture was diluted with water and extracted with EtOAc. Organic was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent 5% MeOH-DCM). 1H NMR (CD3OD, HCl salt) δ (ppm): 8.70 (d, 2H), 7.80 (d, 2H), 7.56 (s, 1H), 7.45 (d, 1H), 7.25 (d, 1H), 7.10 (t, 1H), 4.80 (m, 2H), 4.40 (m, 2H), 3.90 (m, 1H), 3.20 (m, 1H), 3.15 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](/[CH:12]=[C:13](\[CH2:17][CH2:18][CH3:19])/[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.F[B-](F)(F)F.[H][H]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CCC/C(=C\S(=O)(=O)c1ccc(OC)cc1)C(=O)O
Agent: F[B-](F)(F)F
Solvent: CO
Product: CCCC(CS(=O)(=O)c1ccc(OC)cc1)C(=O)O
Reaction time: 2 h
Yield: 99.2 %

Procedure:
(E)-3-(4-Methoxybenzenesulfonyl)-2-propylacrylic acid (1.0 g, 3.52 mmol) was dissolved in degassed methanol (15 ml) and [(S,S)-MeDuPHOS Rh (COD)]BF4 (22 mg, 3.52×10−2 mmol) was added under a stream of nitrogen. This solution was injected into the pressure vessel under nitrogen, and then the bomb was charged with hydrogen. The mixture was hydrogenated at 1035 kPa (150 psi) for 2 hour at room temperature. The methanol was removed under reduced pressure to give the title compound (1.0 g, 99% yield). E.e. was determined by chiral HPLC to be 96% [Chirocel OD; 20% IPA-80% heptane; 1 ml/min; 254 nm; major enantiomer Rf 10.91 min., minor enantiomer Rf 9.71 min.]
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C1([NH2+]C2CCCCC2)CCCCC1.C(OCC)(=O)C.[CH3:57][N:58]([CH2:60][CH2:61]Cl)[CH3:59]>C1C=CC=CC=1>[CH3:57][N:58]([CH2:60][CH2:61][O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:59]
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Reactant: CN(C)CCCl
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CN(C)CCOC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
To 1.88 g N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl ammonium salt, 24 ml ethyl acetate and 3.3 ml solution of dimethylaminoethylchloride in the amount of 0.78 g, stoichiometrically corresponds to two times the molar volume, in benzene were added to be subjected to reflux in oil bath at 90° C. for 16 hrs. After cooling down to a room temperature, precipitated dicyclohexyl ammonium chloride was filtered off and ethyl acetate phase in the filtrate was washed with diluted hydrochloride to remove excessive dimethylaminoethylchloride contained therein. The filtrate was further washed with 10% aqueous solution of hydrogen sodium bicarbonate so as to remove unreacted starting meterial, N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl-ammonium salt and then with saturated brine to be neutral, which was then treated with sulfuric sodium anhydride for dehydration and subjected to reduced pressure distillation so as to distill off ethyl acetate and obtain Intermediate I, N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dimethylamino-ethyl ester in the amount of 1.43 g (yield; 96.6% by weight).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:17][CH2:16][CH2:15][CH2:14][C:11]21[CH2:13][CH2:12]2)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O>[CH2:12]1[C:11]2([CH2:14][CH2:15][CH2:16][CH2:17][CH:10]2[CH2:9][OH:8])[CH2:13]1
Reactant: [H][H]
Reactant: c1ccc(COCC2CCCCC23CC3)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: OCC1CCCCC12CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((benzyloxy)methyl)spiro[2,5]-octane (0.42 g, 1.8 mmol) in a 5:1 MeOH-EtOAc (12 mL) Pd/C (0.05 g, 5 wt %, 50% wet Degussa type) was added. The flask was fitted with a balloon of hydrogen, and the heterogeneous reaction mixture was stirred for 2 hours under a hydrogen atmosphere at rt. The catalyst solids were filtered off and the filtrate was concentrated under vacuum to give the desired product spyri[2.5]octan-4-ylmethanol as clear oil. 1H NMR (400 MHz, CDCl3) δ 3.74-3.62 (m, 2H), 3.48 (d, J=5.2 Hz, 2H), 1.65-1.59 (m, 2H), 1.51-1.43 (m, 3H), 1.27-1.24 (m, 1H), 1.12-1.11 (m, 1H), 0.96-0.95 (m, 1H), 0.41-0.37 (m, 1H), 0.29-0.17 (m, 3H). MS m/z 123.1 (M−17+1).
Reaction SMILES: [CH2:1]([S:3][CH:4]=[CH:5][C:6]([OH:8])=O)[CH3:2].S(Cl)(Cl)=O.C[N:14]([CH:16]=O)C.[C:18]1(C)[CH:23]=[CH:22]C=[CH:20][CH:19]=1>>[CH2:1]([S:3][CH:4]=[CH:5][C:6]([NH:14][C:16]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1)=[O:8])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CCSC=CC(=O)O
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCSC=CC(=O)Nc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(ethylthio)acrylic acid (5.67 g) in toluene (50 mL) were added thionyl chloride (3.48 mL) and DMF (catalytic amount) at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added acetonitrile (50 mL), and then was added dropwise a solution of aniline (8.78 g) in acetonitrile (10 mL) under ice-cooling. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 3 hours, and then concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (50 mL), and the mixture was stirred at room temperature for 0.5 hour. The formed crystals were collected by filtration, washed with water, filtered, and then dried to obtain 3-(ethylthio)-N-(phenyl)acrylamide (8.03 g) as a white crystal.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:8]([N:10]2[C@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.CCN(C(C)C)C(C)C.[N:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[C:66]1[CH:71]=[CH:70][N:69]=[C:68]([NH2:72])[N:67]=1>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:8]([N:10]2[C@H:14]([C:15]([NH:72][C:68]3[N:67]=[C:66]([C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][N:60]=4)[CH:71]=[CH:70][N:69]=3)=[O:17])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OC1CCCCO1
Reactant: Nc1nccc(-c2ccccn2)n1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2nccc(-c3ccccn3)n2)CCN1C(=O)OCc1ccccc1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
To a solution of (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (800 mg, 1.5 mmol) in THF (10 mL) under N2 was added 2,4,6-trichlorobenzoyl chloride (477 mg, 2 mmol) and DIPEA (1.3 mL, 7.5 mmol). The mixture was stirred at rt for 2 h. THF was removed under vacuum and toluene (10 mL) was added. To this mixture was added 4-(2-pyridinyl)-2-pyrimidinamine (337 mg, 2 mmol) and DMAP (37 mg, 0.3 mmol). After being stirred at rt overnight, the mixture was diluted with EtOAc (50 mL) and washed with 5% citric acid and sat. NaHCO3. The organic solution was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography to provide the title compound (400 mg, 39%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5]CN.[NH2:14][C:15]1[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=1.Cl.[CH3:27][N:28]1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[NH2:14][C:15]1[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([N:28]([CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:3]=2[O:2][CH3:1])[CH3:27])=[O:25])=[CH:17][CH:16]=1
Reactant: COc1cccc(CCN)c1OC
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: COc1cccc(CN(C)C(=O)/C=C/c2ccc(N)nc2)c1OC

Procedure:
According to the procedure of Example 1 (a), except substituting (2,3-dimethoxy-benzyl)methyl-amine for the methyl-1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound was prepared as a pale yellow solid (434 mg, 53%): 1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J=11.3 Hz, 1H), 7.89-7.77 (m, 1H), 7.44-7.39 (m, 1H), 7.05-6.94 (m, 3H), 6.68-6.45 (m, 4H), 4.74-4.61 (m, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.07-2.86 (m, 3H); MS (ESI) m/e 328 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)C.O>C(Cl)Cl>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:4](=[O:19])[CH2:5][CH:6]3[CH2:10][CH2:9][CH2:8][CH:7]32)=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC1CCCC1c1cccc(OC)c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)C1CCCC1CC2=O
Yield: 80.9 %

Procedure:
Heat a solution of [2-(3-methoxyphenyl)-cyclopentyl]-acetic acid ethyl ester (4.2 g, 16.0 mmoles) in polyphosphoric acid (27 g) at 100° C. for 3.5 hours. Cool the reaction to r.t. and add ice, water and methylene chloride cautiously. Extract the aqueous layer was 2× with additional methylene chloride, combine the organic layers and dry over anhydrous sodium sulfate. Concentrate in vacuo at 40° C. Chromatograph the crude product on silica with 11-17% ethyl acetate/hexanes to yield the titled compound (2.8 g, 81%) as a neat crystalline solid. 1H NMR (CDCl3): 7.95 (d, J=8.8 Hz, 1H), 6.8 (dd, J=2.8 Hz, 6.4 Hz, 1H), 6.73(m, 1H), 3.86 (s, 3H), 3.19 (m, 1H), 2.72 (m, 1H), 2.53 (m, 2H), 2.18 (m, 1H), 2.0-1.75 (m, 5H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:6]([NH:8][CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][S:19]([C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][C:6]=1[NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)(=[O:21])=[O:20]
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1ccc(F)cc1NC1CCCc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1NC1CCCc2ccccc21
Yield: 119.4 %

Procedure:
A solution of N-(5-fluoro-2-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-amine (720 mg, 2.26 mmol), piperazine (583 mg, 6.77 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.77 mmol) in acetonitrile (10 mL) was stirred at reflux for 16 h. The reaction mixture was cooled down and concentrated under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried and concentrated in vacuo to yield 1.04 g of the crude aniline. The crude product was purified by PTLC (20% ethyl acetate in hexanes) to yield 257 mg (30%) of 1,2,3,4-tetrahydro-N-(2-(methylsulfonyl)-5-(piperazin-1-yl)phenyl)naphthalen-1-amine: 1H NMR (400 MHz, CD3OD): δ 7.60 (d, 1H), 7.30 (d, 1H), 7.20-7.10 (m, 2H), 6.32-6.26 (m, 2H), 6.23 (br s, 1H), 4.67 (dd, 1H), 3.26 (br t, 4H), 2.98 (br t, 4H), 2.92 (s, 3H), 2.90-2.72 (m, 2H), 2.02-1.80 (m, 4H). MS (ESI) m/z: Calculated: 385.52; Observed: 386.2 (M++1).
Reaction SMILES: [OH:1][PH2:2]=[O:3].[OH2:4].[OH2:5].O.O.O.O.[N+]([O-])([O-])=O.[Zn+2:14].[N+]([O-])([O-])=O.[Zn]>O>[P:2]([O-:5])([O-:4])([O-:1])=[O:3].[Zn+2:14].[P:2]([O-:5])([O-:4])([O-:1])=[O:3].[Zn+2:14].[Zn+2:14]
Reactant: O=[PH2]O
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [Zn+2]
Agent: [Zn]
Product: O=P([O-])([O-])[O-]

Procedure:
An aqueous solution of 13.67 g 50 wt % H3PO2 was combined with 5.00 g deionized water to form a clear, colorless solution contained in a 250 ml Pyrex beaker. To this solution was added 46.23 g zinc nitrate hexahydrate salt, Zn(NO3)2.6H2O (Aldrich Chemical Co., Inc. #22,873-7, CAS #10196-18-6), equivalent to 21.97 wt. % Zn. The molar ratio of [Zn]2+/[PO4]−3 in this mixture was 3/2 and the equivalent solids level [as Zn3(PO4)2] was 27.5 wt. %.
Reaction SMILES: [C:1]([C:3](=[C:9]([CH3:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CCOCC>[C:1]([CH:3]([C:9]([CH3:10])([CH3:11])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C(C)C
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C(C)(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To a solution of ethyl 2-cyano-3-methylbut-2-enoate (0.91 mL, 6 mmol) in ether (4 mL) under N2 was added 1.0 M benzylmagnesium chloride in ether (9 mL, 9 mmol) dropwise to give a pale yellow solution. The reaction was stirred at room temperature for 3 h, and was then cooled to 0° C. and acidified with 10% HCl (10 mL). The organic layer was isolated, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give bright yellow oil. Purification by flash column chromatography (10% ethyl acetate in hexanes, Rf=0.26) gave the title compound as a pale yellow oil (1.08 g, 73.5%). 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J=7.6 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.22 (d, J=7.6 Hz, 2H), 4.22 (m, 2H), 3.44 (s, 1H), 3.07 (d, J=16.5 Hz, 1H), 2.83 (d, J=16.5 Hz, 1H), 1.28 (t, J=7.1 Hz, 2H), 1.18 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=O)[CH2:19][C:20](=O)[CH3:21])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2)[C:8](=[O:10])[CH3:9].O.[NH2:39][NH2:40].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CO.O>[F:36][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[C:20]([CH3:21])[NH:40][N:39]=2)[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: NN
Reactant: CC(=O)CC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2ccc(Cl)cc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CO
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(c2cc(C)[nH]n2)c2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a mixture of N-(3,5-Bis-trifluoromethyl-benzyl)-N-[8-chloro-1-(3-oxo-butyryl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-acetamide (0.13 mmol, 72 mg), hydrazine hydrate (1.3 mmol, 40.0 μL) in MeOH (2 mL) was added P4O10 (0.5 g) at room temperature. The resulting suspension was stirred vigorously at 70° C. for 12 h. After completion, the mixture was diluted with water (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated to dryness. Flash chromatography (EtOAc-Hexane as eluent 1:1) afforded the title compound as viscous foam; Rf 0.28 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 545 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[C:7]([CH3:11])[C:8]=1[N:9]=O)[CH3:2].C.[H][H]>O1CCCC1.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[C:7]([CH3:11])[C:8]=1[NH2:9])[CH3:2]
Reactant: [H][H]
Reactant: CCc1cc(O)cc(C)c1N=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1cc(O)cc(C)c1N

Procedure:
88.7 g (537.6 mmol) of the 3-ethyl-4-nitroso-5-methylphenol prepared in stage 1 are catalytically hydrogenated in 1 liter of tetrahydrofuran (THF) with molecular hydrogen under 5 bar at 20°-25° C. 10 g of 5% palladium on active charcoal (Pd-C) are used as catalyst. The hydrogen uptake is 77% of theory. The catalyst is filtered off, the filtrate is evaporated and the residue is recrystallised from methanol. Yield 51.2 g (63.2% of theory); melting point 167°-170° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:10]2[S:26][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:28][C:9]1=2)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:33])[C:9]3=[CH:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[S:26][C:10]3=[C:11]2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1C=C2C(=C(C3CCCCC3)C(c3ccccc3)(c3ccc(Cl)cc3)N2CC(=O)O)S1
Yield: 94 %

Procedure:
A solution (0.04 M) of methyl 4-(2-tert-butoxy-2-oxoethyl)-6-cyclohexyl-5-(4-chlorophenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in DCM/TFA (1:1) was stirred at RT for 3 h. Evaporation of the solvent gave the title compound (94%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[I-].[K+].Cl[CH:12]1[C:21]2[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>CN(C=O)C>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH2:4][CH2:3]1
Reactant: ClC1CCCc2cc(Br)ccc21
Reactant: CN1CCCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCN(C2CCCc3cc(Br)ccc32)CC1

Procedure:
N-Methylhomopiperazine (2.31 g; 20.2 mmol) and potassium iodide (0.35 g; 2.2 mmol) in DMF (13 ml) were reacted with 1-chloro-6-bromo-1,2,3,4-tetrahydronapthalene (2.48 g; 10.1 mmol) in DMF (8 ml) as in Example 15. The yellow oil was kugelrohr distilled to give the title compound, 1.47 g, bp (air bath temperature) 152°-165° C. at 0.10 torr; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H, NCH3), 3.81 (t, 1H, ArCHN), 7.19 (s, 1H), 7.25 (d, 1H), 7.64 (d, 1H). Anal: Calcd. for C16H23BrN2: C, 59.45; H, 7.17; N, 8.67. Found: C, 59.40; H, 7.02; N, 8.30. 1-Chloro-6-bromo-1,2,3,4-tetrahydronaphthalene was prepared as follows:
Reaction SMILES: [CH3:1][N:2]([S:6][C:7]([CH2:10][Cl:11])([CH3:9])[CH3:8])[C:3](Cl)=[O:4].[N:12](=[C:14]1[CH2:19][S:18][CH2:17][CH2:16][S:15]1)[OH:13].C(N(CC)CC)C>O1CCOCC1.O>[CH3:1][N:2]([S:6][C:7]([CH2:10][Cl:11])([CH3:9])[CH3:8])[C:3]([O:13][N:12]=[C:14]1[CH2:19][S:18][CH2:17][CH2:16][S:15]1)=[O:4]
Reactant: CN(SC(C)(C)CCl)C(=O)Cl
Reactant: ON=C1CSCCS1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(SC(C)(C)CCl)C(=O)ON=C1CSCCS1
Reaction time: 16 h

Procedure:
To a solution of 1.4 g of N-methyl-N-(2-chloromethyl-2-propanesulfenyl)carbamoyl chloride and 0.966 g of 2-oximino-1,4-dithiane in 50 ml of dioxane, was added dropwise with stirring 0.76 g of triethylamine. After allowing the reaction mixture to stand at ambient temperature for 16 hours it was diluted with water and extracted into ethylacetate. The organic extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The product was crystallized from isopropyl ether-methylene chloride solution. The weight of first crop was 1.0 g. m.p. 116°-117° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:5]1[C:13](=[O:21])[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:22])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)c1cccc(C)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(C)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.5 %

Procedure:
2-(3-Methylbenzoyl)-3-phenylacrylate ethyl ester (1 g, 3.39 mmol) was dissolved in dichloromethane. Methanesulfonic acid (5.22 g, 54.35 mmol) was added thereto and the mixture was stirred for 3 hours at room temperature. After the reaction was completed, the mixture was cooled to 0° C. followed by neutralizing with sodium bicarbonate. Then, the separated organic layer extracted with dichloromethane was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography (ethyl acetate:hexane=1:9) to obtain 5-methyl-3-oxo-1-phenyl-indene-2-carboxylate ethyl ester (273 mg, yield 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1Cl
Reaction time: 0.05 h
Yield: 53.8 %

Procedure:
40% Methanolic Triton B (0.15 mL, 0.34 mM) was added to a solution of the 9-[(2-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.23 mM) in 5 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (182 mg, 0.91 mM) was added and the resultant mixture stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 57 mg (53%) of the {9-[(2-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.5-6.9 (m, 9H), 6.55 (d, 1H, J=8 Hz), 6.35 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.75 (s, 2H), and 1.45 (s, 9H). IR (KBr, cm−1) 1753 and 1678. MS (FD) m/e 464.