Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10]C(C)C(Br)=O>CCOCC>[BrH:10].[CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(Br)C(=O)Br
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Product: Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3,4-dichlorobenzylchloride (49.2 g, 0.254 mole) in dry ether (125 ml) was added dropwise during one hour to magnesium (6.08 g, 0.250 mole) in a three-necked flask equipped with stirrer and reflux condenser. Refluxing was continued until all the magnesium was dissolved and the solution was then cooled. Acetone (15.0 g, 0.258 mole) was added dropwise and the solution heated to reflux for three hours. After cooling the reaction mixture was poured out on ice (125 ml) and concentrated hydrochloric acid (23 ml). The phases were separated and the organic layer was washed with water, dried (Na2SO4) and evaporated in vacuum. The residual oil was distilled affording 1-(3,4-dichlorophenyl)-2-methyl-2-propanol (bp. 81°-83° C./0.2 mm Hg; 31.3 g, 57% yield). After several recrystallizations from petroleum ether the compound melted at 40°-41° C. The substituted propanol above (21.9 g, 0.100 mole) was mixed with dimethylaniline (12.4 g, 0.102 mole) and ether (50 ml). The solution was cooled and α-bromopropionyl bromide (21.4 g, 0.099 mole) was added dropwise during 40 minutes. Stirring at room temperature for 48 hours gave a crystalline precipitate of dimethylaniline hydrobromide, which was filtered off and washed with ether. The etheral solutions were combined and evaporated in vacuo. The residual oil was distilled affording 2-bromopropanoic acid 1-(3,4-dichlorophenyl)-2-methyl-2-propylester (bp. 135°-143° C./0.2 mm Hg; 19.2 g, 55% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N+:6]([O-:20])[C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCCc1cc(Cl)nnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCc1cc(Cl)n[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-3-methyl-4-propyl-pyridazine (8.03 g, 47.06 mmol) in CH2Cl2 (200 ml) is added mCPBA (11.6 g, 77%, 51.77 mmol). The mixture is stirred at room temperature overnight. Saturated K2CO3 aqueous solution (50 ml) is added and the layers are separated. The organic layer is then washed with brine (100 ml) and dried (Na2SO4) and evaporated, which provides 6-chloro-3-methyl-4-propyl-pyridazine 2-oxide as a light yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:25]=[C:26]5[N:32]=[CH:31][N:30](COCC[Si](C)(C)C)[C:27]5=[N:28][CH:29]=4)[CH:19]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN>CN(C=O)C.O>[N:32]1[C:26]2[C:27](=[N:28][CH:29]=[C:24]([C:20]3[CH:19]=[C:18]([C:16]4[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:6])[CH3:7])[CH:9]=[C:10]5[C:15]=4[N:14]=[CH:13][CH:12]=[CH:11]5)[CH:23]=[CH:22][CH:21]=3)[CH:25]=2)[NH:30][CH:31]=1
Reactant: CC(C)(c1cc(-c2cccc(-c3cnc4c(c3)ncn4COCC[Si](C)(C)C)c2)c2ncccc2c1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Solvent: O
Product: CC(C)(c1cc(-c2cccc(-c3cnc4[nH]cnc4c3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(1-methanesulfonyl-1-methyl-ethyl)-8-{3-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-phenyl}-quinoline from Step 2 (1.0 eq.), TBAF (2.0 eq.) and ethylene diamine (1.5 eq.) in DMF (0.2M) was stirred at 80° C. for 3 h. The mixture was cooled, diluted with water, filtered. The resulting solid was stirred in acetone to afford the title compound after filtration. 1H NMR (500 MHz, DMSO-d6): δ 8.94 (dd, 1H), 8.72 (s, 1H), 8.52 (dd, 1H), 8.47 (s, 1H), 8.30–8.25 (m, 2H), 8.08 (d, 1H), 7.98 (s, 1H), 7.79 (d, 1H), 7.68 (d, 1H), 7.63–7.60 (m, 2H), 2.81 (s, 3H), 1.93 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][NH2:18]>CN(C)C=O>[CH3:16][O:15][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[NH:18][CH3:17])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(OC)c(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1c(OC)cc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 100 %

Procedure:
Methyl 4-chloro-3-methoxy-5-nitrobenzoate (available from, for example, Apollo Scientific Ltd) (14 g, 57.0 mmol) was dissolved in N,N-dimethylformamide (DMF) (140 mL) and cooled to ˜0° C. in an ice/water bath. Methanamine (2M in THF) (114 mL, 228 mmol) was added dropwise with vigorous stirring using a dropping funnel and the mixture was flushed with nitrogen and heated at 80° C. for 3 hr. The mixture was allowed to cool to room temperature over the weekend. The reaction mixture was diluted with water (500 mL), and filtered under vacuum to give the title compound as an orange solid (13.69 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: CCNC(=O)Nc1nc2ccc(Cl)cc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCNC(=O)Nc1nc2cc([N+](=O)[O-])c(Cl)cc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Three grams of N-(6-chloro-1,3-benzothiazol-2-yl)-N′-ethylurea was dissolved in about 15 mL of concentrated sulfuric acid (about 92–94%). The solution was cooled to about 0–5° C. About 1.5 g of ice cooled nitric acid (70% concentration was used, though this is not necessary) was added dropwise. The reaction was held at 0–5° C. for about one hour then poured into water. The pH was then adjusted to about 7–8 with ammonia and the solids were isolated by filtration. The solids were washed with water then dried in vacuo. The product was further purified by chromatography then dried in vacuo. 1H NMR 1.08 (t, 3H, J=7.2 Hz), 3.19 (m, 2H), 6.92 (br s, 1H), 8.26 (s, 1H), 8.31 (s, 1H), LC/MS 3.72 min, 302 (M+1)
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]=[C:3]([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:2]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:28]([C:25]4[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=4)[CH:29]=3)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[CH:2]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2cccc(-c3ccccc3)c2)CCOCC1
Product: O=C(NCC1(c2cccc(-c3ccccc3)c2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 56 %

Procedure:
This compound was synthesized from (4-([1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (110 mg, yield 56%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.23-8.21 (d, J=7.7 Hz, 1H), 7.86-7.84 (d, J=8.0 Hz, 1H), 7.58-7.55 (m, 6H), 7.45-7.37 (m, 4H), 5.85-5.82 (t, J=6.1 Hz, 1H), 3.96-3.91 (m, 2H), 3.79-3.78 (d, J=6.4 Hz, 2H), 3.74-3.69 (m, 2H), 2.27-2.22 (m, 2H), 2.10-2.04 (m, 2H). MS (ESI) m/z: Calculated for C28H24F3N3O3: 507.18. found: 508.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2].[C:30](O)(=[O:33])[CH2:31][OH:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(Cl)CCl>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:31](=[O:32])[CH2:30][OH:33])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(O)CO
Reactant: CCOC(=O)CCc1ccc(-c2ccc(N)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CCc1ccc(-c2ccc(NC(=O)CO)cc2)n1-c1ccc(C(N)=O)cc1C
Reaction time: 24 h
Yield: 56.5 %

Procedure:
Under a nitrogen atmosphere, 3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (11A, see scheme 11) (102 mg, 0.26 mmol), glycolic acid (40 mg, 0.52 mmol), TBTU (167 mg, 0.52 mmol), and EDC (101 mg, 0.65 mmol) were dissolved in 1 mL N, N-dimethylformamide. After 24 hrs, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC plate (1500 microns, 10% IPA/CH2Cl2). The desired band (rf=0.25) was isolated and dried under high vacuum to yield 3-{1-(4-carbamoyl-2-methylphenyl)-5-[4-(2-hydroxyacetylamino)-phenyl]-1H-pyrrol-2-yl]-propionic acid ethyl ester (18B) (66 mg, 60%, yellow powder).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol) in dichloromethane (5.5 mL) was added trifluoroacetic acid (800 mg, 541 μL, 7.02 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (5 mL), methanol (2.5 mL) and ammonium hydroxide (0.7 mL) and stirred at room temperature for 1 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give 2-bromo-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 269 μmol, 77%) as an off white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH3:27].C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[CH3:27])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC1CCCN1CCCCl
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC1CCCN1CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 15.6 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-2-methyl-pyrrolidine (344 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM, MeOH, NH3) to give the title compound as a yellow oil (120 mg, 16%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.87 (d, 2H), 4.08-3.96 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.18 (td, 1H), 2.98 (m, 1H), 2.40 (s, 2H), 2.29 (m, 1H), 2.20 (m, 1H), 2.16-1.62 (m, 10H), 1.96 (s, 6H), 1.42 (m, 1H), 1.09 (d, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[CH:22]1([NH:28][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NC1CCCCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a solution of 5.0 g (22 mmol) 4-chloro-3-nitrobenzotrifluoride in 100 ml dimethylformamide was added 3.4 ml (24 mmol) triethylamine and 2.8 ml (23 mmol) cyclohexylamine. The reaction mixture was stirred at 80° C. for 2 h. After cooling to 25° C. the reaction mixture was evaporated in vacuo. The residue was stirred with 100 ml water and the precipitate was filtered off. Recrystallization (methanol) gave 3.9 g (61%) N-cyclohexyl-2-nitro-4-trifluoromethylaniline. M.p. 80.1° C., 1H-NMR (CDCl3): 8.4 (1H, s), 8.3 (1H, m), 7.5 (1H, dd), 6.9 (1H, d), 3.5 (1H, broad s).
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.[CH3:14][NH:15][CH3:16]>ClCCl>[CH3:14][N:15]([CH3:16])[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1
Reactant: Brc1nsc2nc3ccccc3n12
Reactant: CNC
Solvent: ClCCl
Product: CN(C)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a cooled mixture of 3-bromo-1,2,4-thiadiazolo [4,5-a]benzimidazole (15.44 g, 0.0603 mole) in 100 mL dichloromethane, dimethylamine (40% solution in water) (5.44 g, 0.121 mole) was added dropwise. The reaction mixture was allowed to stir for 16 h at room temperature. It was then diluted with dichloromethane, washed with water, dried with sodium sulfate and evaporated under vacuum to give 10.47 g (80%) of 3-(dimethylamino)-1,2,4-thiadiazolo[4,5-a]benzimidazole as colourless crystals: mp 102-104° C.; 1H NMR (CDCl3)δ 7.74 (t, 2H), 7.41 (t, 1H), 7.27 (t, 1H), 3.06 (s, 6H) ppm. Anal. Calcd for C10H10N4S: C, 55.03;H, 4.62; N, 25.69. Found: C, 54.53;H, 4.90; N, 25.50.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][N:33]([CH2:2][C:3]([N:5]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[O:9][CH2:8][CH2:7][CH2:6]4)=[O:4])[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)=[CH:21][CH:22]=1
Reactant: O=C(CBr)N1CCCOc2ccccc21
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: O=C(CN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (15) synthesized in Reference Example and the compound (5) synthesized in Reference Example were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C([O:13][CH2:14][CH2:15][N:16]1[C:28]2[CH2:27][CH2:26][CH2:25][CH:24]([C:29]([OH:31])=[O:30])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][C:21]=2[O:32][CH3:33])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[OH:13][CH2:14][CH2:15][N:16]1[C:28]2[CH2:27][CH2:26][CH2:25][CH:24]([C:29]([OH:31])=[O:30])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][C:21]=2[O:32][CH3:33]
Reactant: COc1cccc2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCNCC
Solvent: CO
Product: COc1cccc2c1c1c(n2CCO)CCCC1C(=O)O
Yield: 75.9 %

Procedure:
9-(2-Benzyloxy-ethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamine (10) (1.0 g, 2.1 mmol) in methanol (50 ml) was shaken with 10% palladium on charcoal (300 mg), and hydrogen gas excess for 18 h at 55° C. The reaction was then filtered through a pad of celite and the filtrate concentrated in vacuo to give 578 mg (100%) 9-(2-hydroxyethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamine (11) as a foam. The structure was confirmed by 13C NMR (75 MHz; CDCl3) δC 13.0, 14.4, 20.0, 22.0, 28.0, 36.4, 40.6, 42.0, 54.7, 60.6, 99.2, 102.6, 107.0, 116.7, 121.1, 136.1, 137.5, 138.0 153.5, and 175.7.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=1.CNN(NC)C(Cl)=[S:23].[C:27](=[O:30])([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:11][N:12]([CH3:13])[C:27](=[S:23])[OH:30].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=1
Reactant: CNN(NC)C(=S)Cl
Reactant: O=C([O-])[O-]
Agent: COc1ccnc(-c2cc([N+](=O)[O-])ccc2O)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(O)=S

Procedure:
The compound from step (a) above (24.2 mmol), N,N-dimethylaminothiocarbamoyl chloride (37 mmol) in dimethyl formamide (250 ml) were stirred rapidly in the presence of potassium carbonate (60 mmol) for 24 hours, adding more potassium carbonate (1 g) after 18 hours. The mixture was acidified (to pH4) with dilute hydrochloric acid and extracted with ethyl acetate (3 times). The combined extracts were washed with water (4 times), dried (anhydrous sodium sulphate) and evaporated to yield a brown solid, which was triturated with ether, and filtered to give the sub-title compound.
Reaction SMILES: C(O)C.[H][H].[CH3:6][C:7]1[C:15]2[C:10](=[C:11]([CH2:19][CH3:20])[C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[NH:9][CH:8]=1>[Fe].C(O)(=O)C>[CH3:6][C:7]1[C:15]2[C:10](=[C:11]([CH2:19][CH3:20])[C:12]([NH2:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: CCc1c([N+](=O)[O-])ccc2c(C)c[nH]c12
Reactant: [H][H]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(N)ccc2c(C)c[nH]c12
Temperature: 90 °C

Procedure:
A mixture of 0.5 1 of 96° ethanol, 0.5 l of glacial acetic acid and 100 g of hydrogen-reduced pure iron is heated to 90° C. 51 g of 3-methyl-6-nitro-7-ethylindole are added in portions over 15 minutes.
Reaction SMILES: C(C[CH:5]1[C:9]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6]1)(O)=O.C(N(CC)CC)C.ClC([O:26][CH:27](C)[CH3:28])=O.Cl.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1>C(Cl)Cl>[C:36]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:37]=[CH:38][C:33]([CH2:32][NH:31][C:27](=[O:26])[CH2:28][CH:6]2[CH2:5][C:9]3[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:8]=3[O:7]2)=[CH:34][CH:35]=1
Reactant: CC(C)OC(=O)Cl
Reactant: N#Cc1ccc2c(c1)C(CC(=O)O)CO2
Reactant: NCc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CC(CC(=O)NCc1ccc(-c3ccccc3)cc1)O2
Reaction time: 0.33 h

Procedure:
To a cooled (0° C.) suspension of 3-(carboxy-methyl)-5-cyano-2,3-dihydrobenzofuran (300 mg, 1.5 mmol, reference example 9) in CH2Cl2 (4 mL) is added triethylamine (210 mL, 1.5 mmol) followed by isopropyl chloroformate (1.65 mL, 1 M in CH2Cl2). The resulting solution is stirred for 20 min then a further portion of triethylamine is added (455 mL, 3.3 mmol) followed by 4-aminomethyl biphenyl hydrochloride (330 mg, 1.5 mmol). The cold bath is removed and stirring continued for 5 h. The reaction mixture is then diluted with CH2Cl2, washed with water and brine, dried over MgSO4 and concentrated. The residue was triturated with ether and the solid filtered to give 400 mg of the title compound. 1H NMR (CDCl3) δ2.55 (dd, J=16, 8 Hz, 1H), 2.65 (dd, J=16, 6 Hz, 1H), 4.06 (m, 1H), 4.42 (dd, J=8, 7 Hz, 1H), 4.49 (dd, J=15, 6 Hz, 1H), 4.55 (dd, J=15, 6 Hz, 1H), 4.88 (t, J=8 Hz, 1H), 6.83 (m, 1H), 7.38 (m, 3H), 7.37 (m, 1H), 7.45 (m, 4H), 7.61 (m, 4H). MS (EI) m/z 368 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([O:9][CH2:10][CH3:11])=[CH:4][N:3]=1.[CH:12]1([CH:17]([OH:20])[CH:18]=[CH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])(=O)C.[Na+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:19][CH2:18][C:17]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:20])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][N:3]=1
Reactant: C=CC(O)C1CCCC1
Reactant: CCOc1cnc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOc1cnc(Cl)cc1CCC(=O)C1CCCC1
Temperature: 90 °C
Yield: 80.4 %

Procedure:
A mixture of 2-chloro-5-ethoxy-4-iodo-pyridine (1.5 g, 5.3 mmol), 1-cyclopentyl-2-propen-1-ol (0.83 g, 6.61 mmol), sodium acetate (0.54 g, 6.6 mmol), palladium (II) acetate (24 mg, 0.11 mmol) in DMAC (10 mL) was heated to 90° C. under N2 for 16 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc in hexanes) gave the desired product (1.2 g, 58%). 1H NMR (300 MHz, CDCl3): δ 1.44 (t, J=7.0 Hz, 3H), 1.55-1.87 (m, 8H), 2.75 (m, 2H), 2.86 (m, 3H), 4.11 (q, J=7.0 Hz, 2H), 7.09 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: Cl[CH:2]([SiH3:4])Cl.[CH:5]([C:22]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:25]=[C:24]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:23]=1[OH:36])([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]=1[OH:21])[CH3:6].C(N(CC)CC)C>>[C:28]([C:26]1[CH:25]=[C:24]([C:32]([CH3:33])([CH3:35])[CH3:34])[C:23]2[O:36][SiH:4]([CH3:2])[O:21][C:8]3[C:9]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:12][C:7]=3[CH:5]([CH3:6])[C:22]=2[CH:27]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: [SiH3]C(Cl)Cl
Reactant: CC(c1cc(C(C)(C)C)cc(C(C)(C)C)c1O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2O[SiH](C)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C

Procedure:
Utilizing the procedure of Example 1, this compound is prepared from 23.0 grams (0.20 mole) dichloromethylsilane, 87.7 grams (0.20 mole) 2,2'-ethylidene-bis(4,6-di-t-butylphenol) and 40.5 grams (0.40 mole) of triethylamine.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:14]O>>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH3:14])=[O:7]
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 11 h
Yield: 85.6 %

Procedure:
(2S)-Tetrahydrofuran-2-carboxylic acid (806.2 g) was dissolved in methanol (1779.6 g), and concentrated sulfuric acid (32 mL) was added dropwise at 22° C.-35° C. The reaction solution was heated to 72° C.-75° C., and stirred for 11 hr. The reaction mixture was cooled to room temperature, and partitioned by adding water (5 L) and dichloromethane (5 L). The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by distillation to give methyl (2S)-tetrahydrofuran-2-carboxylate (773.2 g) as a colorless oil. THF (7.4 L) was cooled in an ice-salt-acetone bath, and lithium aluminum hydride (151.0 g) was added by portions. Thereto was added dropwise a solution of methyl (2S)-tetrahydrofuran-2-carboxylate (773.0 g) obtained earlier in THF at an inside temperature of 0° C.-10° C., and the mixture was stirred at an inside temperature of 3° C.-5° C. for 2 hr. Water (150 mL) was added dropwise to the reaction mixture at an inside temperature of 2° C.-4° C., and the reaction was quenched by dropwise addition of 15% aqueous sodium hydroxide solution (150 mL) and water (450 mL), maintained at the same temperature. The insoluble material was filtered off, and washed with THF (2 L), and the filtrate was concentrated under reduced pressure. Thereto were added dichloromethane (3 L) and saturated brine (1.5 L). The organic layer was separated and the aqueous layer was extracted 3 times with dichloromethane. The organic layers were combined, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (567.3 g, yield 90%) as a colorless oil.