Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:21](O)=[O:22])[NH:19][CH:20]=3)[NH:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.N1C=CC=CC=1.O>[C:1]([C:9]1[CH:25]=[CH:24][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:21]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:22])[NH:19][CH:20]=3)[NH:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(-c3c[nH]c(C(=O)O)c3)[nH]c2c1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc2nc(-c3c[nH]c(C(=O)N4CCCC4)c3)[nH]c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
The 4-(5-benzoylbenzimidazol-2-yl)-pyrrole-2-carboxylic acid (130 mg) obtained in Example 5 was dissolved in N,N-dimethylformamide (2 ml) and pyridine (2 ml). Pyrrolidine (56 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (112 mg), and 1-hydroxybenzotriazole monohydrate (80 mg) were added and stirred overnight at 80° C. After the starting material was disappeared, the reaction mixture was allowed to cool to room temperature, and then added dropwise to water. The precipitate was collected by filtration, and dried in vacuo to afford ((4-(5-benzoylbenzimidazol-2-yl)-pyrrol-2-yl)-carbonyl)pyrrolidine (118 mg, 78%) as a red solid.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][CH:12]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH3:26])[CH2:13][CH:14]([OH:20])[C:15]#[C:16][CH:17]([OH:19])[CH3:18]>C(O)C.[Pd]>[CH3:11][CH:12]([CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH3:26])[CH2:13][CH:14]([OH:20])[CH2:15][CH2:16][CH:17]([OH:19])[CH3:18]
Reactant: CCC/C=C\CC(C)CC(O)C#CC(C)O
Agent: [Pd]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CCC/C=C\CC(C)CC(O)CCC(C)O
Reaction time: 2 h
Yield: 79.4 %

Procedure:
At room temp., 550 mg (0.516 mmol) of 10% palladium on barium sulphate and 200 mg (1.55 mmol) of quinoline were added to a stirred solution of 7.60 g (33.9 mmol) of this (9Z)-7-methyltridec-9-en-3-yne-2,5-diol in 170 mL of ethanol. The flask was evacuated and flushed with nitrogen three times, and three times evacuated and flushed with hydrogen. The resulting reaction mixture was then stirred for 2 h under an atmosphere of hydrogen at ambient pressure and temperature, prior to evacuation and ventilation with nitrogen. The reaction flask was opened to air, and the catalyst filtered off by suction over a pad of Celite. After removal of the solvent in a rotary evaporator under reduced pressure, the resulting crude product (6.87 g) was purified by flash chromatography (100 g of silica gel, pentane/ether, 1:1, Rf=0.10) to afford 6.15 g (80%) of (9Z)-7-methyltrideca-9-ene-2,5-diol as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]2[C:12]([O:22][CH2:23][C:24]3[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:41]=[CH:40][C:39]([CH2:42][C:43]([O:45]CC)=[O:44])=[CH:38][CH:37]=5)[O:33][C:34]=4[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=3)=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH:1]([C:4]1[O:5][CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]2[C:12]([O:22][CH2:23][C:24]3[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]4[N:31]=[C:32]([C:36]5[CH:37]=[CH:38][C:39]([CH2:42][C:43]([OH:45])=[O:44])=[CH:40][CH:41]=5)[O:33][C:34]=4[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=3)=[N:13][N:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:15]=2)[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(C(C)C)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2coc(C(C)C)n2)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (180 mg), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (0.8 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate. The residue was recrystallized from ethyl acetate-hexane and the precipitated crystals were collected by filtration to give {4-[4-({4-[({4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid (47 mg, yield 27%) as colorless crystals. melting point: 116-118° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:14]([CH3:22])=[CH:15][CH:16]=[C:17]([O:20]C)[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.B(Br)(Br)Br>[CH2:1]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:14]([CH3:22])=[CH:15][CH:16]=[C:17]([OH:20])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C)c2c1C[C@@H]1CN(Cc3ccccc3)CCN1C2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(O)c2c1C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of (R)-2-benzyl-7-methyl-10-methoxy-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (210 mg, 0.625 mmol) in dry dichloromethane (7 mL), 1M BBr3 in dichloromethane (3.1 mL, 3.1 mmol) was added at −78° C. The reaction was stirred for 2.5 h at RT under Argon. Slowly quenched with MeOH (5 mL) and conc in vacuo to give light brownish residue. MS (ESI) 323 (M+H).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C[O-].[Cu+2:11].C[O-]>C1(C)C=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Cu+2:11]
Reactant: Oc1ccccc1O
Agent: [Cu+2]
Agent: C[O-]
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1[O-]
Temperature: 100 °C

Procedure:
A solution of catechol (2.20 g, 20 mmol) and toluene (45 ml) was dehydrated by distilling 5 mL of the solution. Thereafter, 2.50 g (20 mmol) of copper(II) methoxide was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (catechol-copper complex) was purple in color. The yield amount was 3.30 g (19.2 mmol), and the yield percentage was 96%. Catechol-copper complex was dissolved into acetylacetone until saturated, and then filtered to be used as a coating liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=S)[CH2:25][C:26](=O)[CH3:27])=[O:4].[Cl:30][C:31]1[CH:36]=[C:35]([NH:37][NH2:38])[CH:34]=[CH:33][N:32]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]1[N:37]([C:35]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:30])[CH:36]=2)[N:38]=[C:26]([CH3:27])[CH:25]=1)=[O:4]
Reactant: NNc1ccnc(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1-c1ccnc(Cl)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with (2-chloro-pyridin-4-yl)-hydrazine (CAS Reg. No. 700811-29-6) to give the title compound as colorless solid. MS (ESI): m/z=547.2 [M+H]+.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([OH:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)=[CH:25][CH:24]=2)=[C:17]([CH3:37])[N:16]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:21][C:19]1[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)=[CH:25][CH:24]=2)=[C:17]([CH3:37])[N:16]=[C:15]([NH2:14])[N:20]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(COC2CCCCO2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)Oc2nc(N)nc(C)c2Cc2ccc(COC3CCCCO3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Mesitylenesulfonyl chloride (3.65 g) was added to a stirred mixture of the product from step (ii) (5 g), TEA (4.2 ml) and DMAP (0.2 g) in DCM (100 ml) at rt under nitrogen. The mixture was stirred at rt for 4 h then partitioned between DCM and water. The organics were separated, washed with aq NaHCO3 soln, water, dried and evaporated under reduced pressure to afford the subtitle compound, 6.49 g.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:93][CH2:92][CH2:91][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:90][CH2:89][CH2:88][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:40][C@H:41]([C@H:46]([CH2:48][C:49]([NH:51][C@H:52]([C:56]([NH:58][C@H:59]([C:68]([NH:70][C@H:71]([C:84]([O:86][CH3:87])=[O:85])[CH2:72][CH2:73][CH2:74][CH2:75][NH:76]C(OC(C)(C)C)=O)=[O:69])[CH2:60][C:61]1[CH:66]=[CH:65][C:64]([OH:67])=[CH:63][CH:62]=1)=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[OH:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4]>C(O)(C(F)(F)F)=O>[NH:1]1[CH2:93][CH2:92][CH2:91][C@H:2]1[C:3]([NH:5][C@H:6]([C:13]([N:15]1[CH2:90][CH2:89][CH2:88][C@H:16]1[C:17]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:38]([NH:40][C@H:41]([C@H:46]([CH2:48][C:49]([NH:51][C@H:52]([C:56]([NH:58][C@H:59]([C:68]([NH:70][C@H:71]([C:84]([O:86][CH3:87])=[O:85])[CH2:72][CH2:73][CH2:74][CH2:75][NH2:76])=[O:69])[CH2:60][C:61]1[CH:62]=[CH:63][C:64]([OH:67])=[CH:65][CH:66]=1)=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[OH:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:39])[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCCN1)C(C)C
Reaction time: 0.5 h

Procedure:
470 mg of Boc-Pro-His-Pro-Phe-His-Sta-Val-Tyr-Lys(Boc)-OMe are dissolved at 25° in 2.3 ml of 95% strength TFA and the whole is left to stand for 30 minutes. The H-Pro-His-Pro-Phe-His-Sta-Val-Tyr-Lys-OMe formed is precipitated at 0° in pulverulent form as the trifluoroacetate by the addition of 20 ml of diisopropyl ether, is filtered off and dried; Rf (C)=0.36; Rf (D)=0.24.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22](=O)[CH3:23])=[C:6]([CH3:21])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[C:12]([CH3:19])[C:11]=2[CH3:20])[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:25][NH2:26]>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:22]([CH3:23])=[N:25][N:26]=[C:1]3[CH3:2])=[C:6]2[CH3:21])=[C:11]([CH3:20])[C:12]=1[CH3:19])[CH3:18]
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(C)c1C
Reactant: NN
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(C)c1C

Procedure:
Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (100 mg, 0.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K2CO3 (50 mg), to afford 1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 328 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (108 mg, 0.3) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as off-white solid: 1H NMR (CDCl3, 500 MHz) δ 6.92 (d, 1H), 6.86 (d, 1H), 4.14 (q, 2H), 2.83 (s, 6H), 2.36 (s, 6H), 2.28 (s, 3H), 1.72 (s, 3H), 1.52 (t, 3H); MS (ESI) 324 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([CH3:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:9]([O:11]CC)=[O:10].Cl>O.O1CCCC1>[CH3:7][C:8]([CH3:23])([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(C)(C)C(=O)O)cc1
Reaction time: 16 h
Yield: 96 %

Procedure:
Potassium tert-butoxide (38.0 g, 0.34 mol) was added to a solution of ethyl 2,2-dimethyl-3-(4-methoxyphenyl)propanoate (40.0 g, 0.17 mol) in a mixture of water (4 mL) and tetrahydrofuran (800 mL) at room temperature and stirred for 16 h. The pH of the reaction mixture was adjusted to ˜2 with 2 N HCl (250 mL) and extracted with EtOAc (800 mL). Aqueous layer was saturated with NaCl and extracted again with EtOAc (800 mL). The combined organic layers were washed with brine (350 mL), dried over Na2SO4, and concentrated to afford 34.0 g (96%) of 2,2-dimethyl-3-(4-methoxyphenyl)propanoic acid as a gummy oil; 1H NMR (200 MHz, CDCl3) δ 7.08 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 3.78 (s, 3H), 2.83 (s, 2H), 1.19 (s, 6H).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14]Br>CS(C)=O>[C:1]1([C:7]2([C:8]#[N:9])[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2)CC1
Yield: 91.9 %

Procedure:
Phenylacetonitrile (5.85 g, 50 mmol) in DMSO (dimethylsulfoxide) (20 mL) is added dropwise over 45 min to a slurry of oil-free NaH (3.0 g, 125 mmol) in stirred DMSO (100 mL) at 25° under N2. Vigorous gas evolution occurs. After a further 30 min 1,2-dibromoethane (14.1 g, 75 mmol) in DMSO (20 mL) is added dropwise over 1 h. The reaction mixture turns purple, heats up to about 50°, and further gas evolution occurs. After a further 1 h the reaction mixture is poured slowly onto ice water (250 mL, gas evolution), and is extracted with ether (3×50 mL). The combined extracts are washed with water (2×100 mL) and saturated brine (100 mL) and dried (MgSO4). The solvent is removed under reduced pressure to give 1-phenylcyclopropane carbonitrile (6.58 g, 92%) as a mobile brown oil. Nmr δ (CDCl3) 7.25-7.40 (5H, m), 1.6-1.8, 1.2-1.45 (2H and 2H, AA'BB').
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:22]3[CH:27]=[C:26]([CH:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:29])[CH:25]=[CH:24][C:23]=3[O:35][CH3:36])[CH:15]=[CH:16][C:17]=2[F:21])[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[F:21][C:17]1[CH:16]=[CH:15][C:14]([C:22]2[CH:27]=[C:26]([CH:28]([CH3:29])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:25]=[CH:24][C:23]=2[O:35][CH3:36])=[C:13]2[C:18]=1[CH2:19][CH2:20][NH:11][CH2:12]2
Reactant: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(F)c3c2CNCC3)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of (±)-8-[5-(1-ethoxycarbonyl-ethyl)-2-methoxy-phenyl]-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (57 mg, 0.12 mmol, 1 eq.) in EtOH (40 mL), palladium on activated carbon (10 wt. %, 3.2 mg) was added. The flask was evacuated and backfilled with H2 (3×). The black suspension was stirred at 50° C. under an H2-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH. The filtrate was concentrated in vacuo to afford the title product as a yellow oil. The product was used without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11]>O=[Pt]=O.C(O)(=O)C>[CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C1Cc2ccccc2C1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)C1CC2CCCCC2C1
Yield: 97.1 %

Procedure:
An acetic acid solution of indan-2-carboxylic acid (500 mg, 3.0 mmol) was stirred under hydrogen pressure (40 psi) in the presence of a small amount of PtO2 in a sealed glass pressure vessel equipped with a manometer and pressure valve following a method analogous to General Procedure M to produce octahydro-indene-2-carboxylic acid (490 mg, 95% yield) as a mixture of isomers.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:24][C:25]([OH:27])=[O:26].[OH-].[K+].[I-].[K+].Cl.[Cl-].[Na+]>C(O)(C)(C)C.O>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][C@H:11]1[CH2:21][O:22][CH2:24][C:25]([OH:27])=[O:26])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: O=C(O)CBr
Agent: Cl
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COCC(=O)O
Temperature: 50 °C
Yield: 78.2 %

Procedure:
A mixture of (2S,4R)-4-t-butyldimethylsilyloxy-1-t-butoxycarbonyl-2-(hydroxymethyl)pyrrolidine (0.62 g), 2-bromoacetic acid (0.26 g), 85% potassium hydroxide (0.37 g), and potassium iodide (0.93 g) in t-butyl alcohol (12 ml) was heated at 50° C. for 3 hours. The mixture was poured into water (100 ml), adjusted to pH 4 with 1N hydrochloric acid and saturated with sodium chloride. The aqueous mixture was extracted with three 50 ml portions of ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (30 g ) eluting with a mixture of methanol and dichloromethane (1:9 V/V) to give (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-(carboxymethyloxymethyl)pyrrolidine (0.57 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O.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>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[CH:3][CH:4]=3)[C:12]([CH3:13])=[CH:11][CH:10]=2)[CH:19]=[CH:18][C:17]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: OB(O)c1ccco1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(-c2ccco2)cc1
Yield: 60.7 %

Procedure:
To a stirred suspension of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole (0.41 g, 1 mmol), 2-furanboronic acid (0.14 g, 1.26 mmol), NaHCO3 (0.19 g, 2.3 mmol) in DME-water (6 mL-2 mL) was added dichlorobis(triphenylphosphine)palladium (80 mg, 0.115 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 6 hours. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to give the title compound (0.24 g, 61% yield).
Reaction SMILES: [CH2:1]([O:9][CH2:10][C:11](Cl)=[O:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:14][C:15]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C1C=CN=CC=1)C.ClCCl.N1C=CC=CC=1>[C:21]([C:20]1[C:15]([NH:14][C:11](=[O:12])[CH2:10][O:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)#[N:22]
Reactant: O=C(Cl)COCCc1ccccc1
Reactant: N#Cc1cccnc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cccnc1NC(=O)COCCc1ccccc1
Reaction time: 3 h

Procedure:
Phenethyloxy-acetyl chloride (3.79 g, 6.12 mmol) was added to a solution of 2-amino-3-cyanopyridine ([24517-64-4], 662 mg, 5.56 mmol) and DMAP (67 mg, 0.55 mmol) in a mixture of dichloromethane (8 ml) and pyridine (8 ml). After 3 h at r.t., the solvent was evaporated, and N-(3-cyano-pyridin-2-yl)-2-phenethyloxy-acetamide was isolated from the residue by column chromatography (silica gel, heptane, ethyl acetate, methanol). MS: m/e=282.1 [M+H+], 1H NMR (d6-DMSO): 2.91 (t, 2H), 3.77 (t, 2H), 4.18 (s, 2H), 7.17-7.23 (m, 5H), 7.47 (dd, 1H), 8.37 (d, 1H), 8.71 (d, 1H), 10.55 (bs, 1H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH2:7]1.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:26][N:25]=[C:16]([C:13]1[S:12][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([O:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[C:2]([F:23])([F:1])[F:22])[CH2:7]2)=[N:15][CH:14]=1)[NH2:17]
Reactant: NO
Reactant: N#Cc1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Temperature: 80 °C

Procedure:
A mixture of 2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carbonitrile (370 mg, 1.1 mmol), hydroxylamine hydrochloride (303 mg, 4.4 mmol) and sodium carbonate (231 mg, 2.2 mmol) in EtOH—H2O (4:1, 20 mL) was heated at 80° C. for 2 h. Solvent was evaporated in vacuo. The residue was diluted with H2O, extracted three times with EtOAc, dried (Na2SO4) and concentrated. Trituration with hexanes:Et2O (1:1) gave the title compound as white powder. 1H NMR (400 MHz, acetone-d6): δ 8.73 (s, 1 H), 7.66 (m, 2 H), 7.52 (s, 1 H), 7.38 (d, 1 H), 7.16 (t, 1 H), 5.46 (m, 3 H), 3.94-3.88 (m, 1 H), 3.75-3.59 (m, 3 H), 2.56-2.30 (m, 2 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:5]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=2)[CH:5]=1
Reactant: N#Cc1ccc(CCOc2cccc([N+](=O)[O-])c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CCOc2cccc(N)c2)cc1
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Nitro-3-[2-(4-cyanophenyl)ethoxy]benzene (3.0 g; 11.2 mmol; from step (i) above) and NH4Cl (2.9 g; 55 mmol) were dissolved in a mixture of EtOH (40 mL) and H2O (10 mL) and heated to reflux. Iron powder (3.0 g; 55 mmol) was added and heating was continued for 1 hour. The mixture was filtered, concentrated in vacuo and partitioned between water and CH2Cl2. After separation, the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (MgSO4) and the solvent was evaporated. Purification by flash chromatography (SiO2; toluene:EtOAc (9:1)) afforded 2.26 g (85%) of the sub-title compound.