Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:16]([S:18](Cl)(=[O:20])=[O:19])=[CH2:17]>O.C(#N)C>[CH:16]([S:18](=[O:20])(=[O:19])[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])=[CH2:17]
Reactant: C=CS(=O)(=O)Cl
Reactant: O=S(O)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: C=CS(=O)(=O)S(=O)(=O)c1cccc2ccccc12
Yield: 24.9 %

Procedure:
15 ml of water was added to 9.6 g of 1-naphthalene sulfinic acid and a solution of 2 g of sodium hydroxide in 5 ml of water was added to the mixture. To the solution there was added a solution of 6.3 g of vinylsulfonyl chloride in 20 ml of acetonitrile at room temperature with stirring and the mixture was stirred at room temperature for additional 24 hours. The reaction solution was poured into 300 ml of water, the resulting precipitates were recovered through filtration and recrystallized from a mixed solvent of benzene and ethanol to give 3.5 g of vinyl-1-naphthyldisulfone.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:18]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCON=C(C(C)=O)C(=O)OCC
Yield: 99.5 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 40 g.), N,N-dimethylformaide (200 ml.), potassium carbonate (52 g.) and n-hexyl bromide (41.4 g.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer, 60.7 g.), oil.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.[CH2:19]([N:21](CC)CC)[CH3:20].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:21][CH2:19][CH3:20])=[O:4]
Reactant: CCN(CC)CC
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: CCN
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
First, 320 g (1.983 mol) of L-glutamic acid-γ-methyl ester was suspended in 500 g of methanol. To this, 219 g (2.186 mol, 1.1 eq.) of acetylacetone and 200 g (1.983 mol, 1 eq.) of triethylamine were added. The mixture was stirred at 60° C. for one hour. Subsequently, 1,277 g (19.8 mol) of 70% ethylamine was added to the mixture. After the mixture was allowed to react for 6 hours, the reaction solution was heated under normal pressure. In this manner, 667 g of excessive ethylamine was recovered and deprotection was performed at the same time. To the slurry of the theanine precipitated, 1 L of 2-propanol was added. The crystal was filtrated by suction and washed with 200 mL of 99.5% ethanol to obtain theanine (314.3 g) as a white crystal substance (yield: 91%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C1(C(O)CC(O)C)C=CC=CC=1.[CH2:24]([N:26](CC)CC)[CH3:25].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:26][CH2:24][CH3:25])=[O:4]
Reactant: CCN(CC)CC
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: CC(O)CC(O)c1ccccc1
Agent: CCN
Solvent: CO
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 87 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 5.6 g (34 mmol) of 1-phenyl-1,3-butanediol and 3.1 g (31 mmol) of triethylamine were added. The mixture was heated at 60° C. for 2 hours. Subsequently, 20 g (310 mmol) of 70% ethylamine was added to the mixture and the same procedure as in Example 1 was performed to obtain 4.7 g of theanine (yield: 87%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1.C(Cl)Cl>[S:33]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
In a mixed solvent of 15 ml pyridine and 120 ml of methylene chloride was dissolved methyl 22-hydroxydocosanoate (1.70 g, 4.59 mmoles). p-toluenesulfonyl chloride (1.75 g, 9.18 mmoles) was gradually added to the obtained solution under ice-cooled condition, over a period of 1 hour, and the mixture was stirred for 14 hours in a refrigerator. Then, p-toluenesulfonyl chloride (1.75 g, 9.18 mmoles) was added to the reaction mixture, and reaction was effected for 24 hours. After the completion of reaction, the reaction mixture was treated in the same manner as in Reference Example 1, to give methyl 22-tosyloxydocosanoate (2.28 g, 75%) having the following properties.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[NH2:11][C:12](N)=[O:13]>>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:11][C:12]1=[O:13]
Reactant: NC(N)=O
Reactant: COC(=O)c1sccc1N
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 190 °C

Procedure:
A mixture of methyl 3-amino-2-thiophenecarboxylate (13.48 g, 85.85 mmol) and urea (29.75 g, 5 equivalents) was heated at 190° C. for 2 hours. The hot reaction mixture was then poured onto sodium hydroxide solution (2N, 300 mL) and any insoluble material removed by filtration. The mixture was then acidified to pH 6 by the addition concentrated HCl with cooling. The resultant white precipitate was collected by filtration and air dried (9.49 g, 66%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 72 h

Procedure:
Benzyl bromide (13.1 ml) was added to a stirred mixture of 2-bromo-4-chlorophenol (20.7 g) and potassium carbonate (27.6 g) in DMF (200 ml). After 72 h, the mixture was partitioned between diethylether and water, the organic layer washed with water, dried and the solvent evaporated under reduced pressure. The residue was purified by chromatography (silica, EtOAc/isohexane as eluent). to give the sub-title compound (18.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl.CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 118.7 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (2.0 g, 7.1 mmol) and 4-piperidin-4-yl-morpholine (1.4 g, 8 5 mmol) in DCE (40 mL) was stirred at room temperature for 1.5 hour then triacetoxyborohydride (2.2 g, 10.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (70 g). The cartridge was washed with MeOH/DCM (1/1: v/v) and the desired product was eluted with (2M NH3 in MeOH)/DCM (1/1: v/v). The solvents were removed and the residue was triturated in hot IMS, filtered and dried at 60° C. for 1 hour under vacuum to give 2-Chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as a white solid (2.6 g, 84%). LCMS (Method C): RT 0.34 min and 1.67 min; [M+H]+ 438
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.CCO.[NH3:20]>C1COCC1>[NH2:20][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:9][N+:10]([O-:12])=[O:11]
Reactant: N
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 48.8 %

Procedure:
To 2.59 g (0.01 mole) of 1-(4-chlorobenzyl)amino-1-methylthio-2-nitroethylene were added 45 ml of EtOH, 10 ml of THF and 1.02 g of 25% aqueous ammonia and the mixture was stirred at an external temperature of 60° C. for 5.5 hours. During this period, 1.02 g each of 25% aqueous ammonia was added after 1, 2 and 3 hours of reaction. The reaction mixture was ice-cooled and stirred, whereupon crystals separated out. The crystals were collected by filtration, washed with EtOH and ether in that order, and dried. The procedure gave 1.11 g of the title compound as white crystals.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>[OH-].[Na+].CC(C)=O>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=C(C)C(=O)N1CCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11° C. during the addition of the methacryloyl chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 g (68%) of the desired compound as colorless crystals: mp 102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm−1; [α]D26+80.8° (c=1, MeOH); Anal. Calcd. for C9H13NO3: C, 59.00; H, 7.15; N, 7.65.
Reaction SMILES: [C:1]([CH:4]1[C:13]2([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[O:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=O)(=O)[CH3:2].[NH2:27][N:28](C)[C:29](=O)OC(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.NN(C)C(=O)OCCCC.[ClH:59]>C(O)C>[ClH:59].[ClH:59].[CH3:29][N:28]1[C:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][C:13]3([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:4]=2[C:1]([CH3:2])=[N:27]1
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CC(=O)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: CCCCOC(=O)N(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nn(C)c2c1C1(CCNCC1)Oc1ccccc1-2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 3-acetyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (250 mg, 0.70 mmol), tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) and p-toluene sulfonic acid monohydrate (27 mg, 0.14 mmol) in ethanol (8 mL) was heated at 80° C. overnight. Additional tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) was added and the mixture was heated at 80° C. for 6.5 h, then another portion of ten-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) was added and the mixture was heated at 80° C. for 2 h. HCl (0.87 mL of 4.0 M in dioxane, 3.5 mmol) was added and the mixture was stirred at 80° C. for 1 h. After cooling, the precipitate was collected via filtration and washed with cold EtOH to provide 1,3-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride (295 mg, >100%, may contain some methyl hydrazine HCl salt) as a solid. ESI-MS m/z calc. 269.2. found 270.5 (M+1)+; Retention time: 1.11 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.71 (dd, J=7.8, 1.3 Hz, 1H), 7.33-7.27 (m, 1H), 7.17-7.14 (m, 1H), 7.11-7.05 (m, 1H), 4.02 (s, 3H), 3.28-3.15 (m, 4H), 2.40-2.30 (m, 2H), 2.23 (s, 3H), 2.07-1.97 (m 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1>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.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C#CCNC
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargyl amine (48.4 mg, 0.7 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and Cul (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [F:1][CH:2]([C:21]1[O:22]CC(C)(C)N=1)[CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(Cl)(Cl)Cl.[OH2:32]>Cl>[F:1][CH:2]([CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:21]([OH:22])=[O:32]
Reactant: O
Reactant: CCCCCC=CCCCCC#CCC#CCCC(F)C1=NC(C)(C)CO1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCC/C=C\CCCCC#CCC#CCCC(F)C(=O)O
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
A suspension of 2-(1-fluorononadec-13-en-4,7-diynyl)-4,5-dihydro-4,4-dimethyloxazole (86 mg) in 3 ml of 3 N HCl was refluxed with stirring under argon for 15 min. It was cooled to about 23° C., diluted with 3 ml of water, and extracted three times with ether. The ether extracts were combined, washed with brine, and dried over MgSO4. Concentration of ether at 35° C./35 mmHg gave the crude acid which was purified by flash chromatography on silica gel (8 g, 230-400 mesh). Elution with HOAc-CH3OH--CHCl3 under nitrogen afforded 49 mg (66% yield by weight) of (Z)-2-fluoro-14-eicosene-5,8-diynoic acid as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.N#N.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.O1CCCC1.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.[Cu]I>[C:11]1([C:17]#[C:18][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 99.2 %

Procedure:
1-Bromo-4-iodobenzene (20.0 g, 70.7 mmol), bis(triphenylphospine)palladium(II) dichloride (PdCl2(PPh3)2) (250 mg), and CuI (68 mg) were suspended in 50 mL triethylamine (NEt3) and 100 mL tetrahydrofuran (THF). The suspension was treated with 3 cycles of evacuation and refilling with N2. Phenylacetylene (7.21 g, 7.75 mL, 1.0 eq) was added in 0.5 mL portions every 5 minutes to the stirred suspension. The solution was then stirred at room temperature for 22 hours. The solvents were then evaporated. Methylene chloride (100 mL) and 1 M HCl (aqueous) (50 mL) were added, the organic layer was retained, and then was washed again with 1 M HCl (aqueous) (50 mL) and 2×50 mL water, dried (MgSO4), filtered, and the solvent evaporated in vacuum to give 18 g of the title compound as a yellow solid, which was used without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 66.9 %

Procedure:
A mixture of 5-fluoro-2-nitroanisole (3.00 g, 17.5 mmol), tert-butyl piperazine-1-carboxylate (4.57 g, 24.5 mmol) and potassium carbonate (3.63 g, 26.3 mmol), in dimethyl sulfoxide (20 mL) was heated at 90° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled and diluted with water (100 mL). The resulting precipitate was filtered and dried to give a bright yellow solid. The solid was suspended in a 5:1 solution of petroleum ether/diethyl ether (50 mL), sonicated for 2 minutes, filtered and dried to give the title compound (I1) (3.95 g, 66%) as a bright yellow solid; 1H NMR (300 MHz, d6-DMSO) δ 1.42 (s, 9H), 3.46 (brs, 8H), 3.90 (s, 3H), 6.52 (s, 1H), 6.57 (d, 1H, J=9.5 Hz) and 7.89 (d, 1H, J=9.3 Hz). LCMS Method B: rt 7.45 min; m/z 338.2 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].[C:12]([O:20][CH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C>[C:12]([O:20][CH:21]1[CH2:22][C:23]2[C:8]3[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=3)[NH:10][C:24]=2[CH2:25][CH2:26]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC(OC(=O)c2ccccc2)CC1
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(OC(=O)c1ccccc1)CC3
Yield: 47.9 %

Procedure:
4-Cyanophenyl hydrazine hydrochloride (20.2 g) and 4-benzoyloxycyclohexanone (25.9 g) were dissolved in glacial acetic acid (400 ml) and the mixture was heated under reflux for 1.5 hr. After allowing to cool, the mixture was filtered, and the filtrate was evaporated to dryness, and neutralized with aqueous sodium bicarbonate solution to give a solid precipitate, which was purified by chromatography (SiO2 ; hexane/ethyl acetate) to give 3-benzoyloxy-6-cyano-1,2,3,4-tetrahydrocarbazole (18 g). This product (11.6 g) was suspended in ethanol (230 ml) and treated with 2.5% aqueous potassium hydroxide solution (120 ml), and heated under reflux for 1 hr. The cooled mixture was neutralized with glacial acetic acid and evaporated to a solid residue, which was washed with water, and dried to give 3-hydroxy-6-cyano-1,2,3,4-tetrahydrocarbazole (6.6 g).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])(=O)C.Cl.[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[S:8]([CH2:7][CH2:6][CH2:5][OH:4])(=[O:10])=[O:9]
Reactant: CC(=O)OCCCS(=O)(=O)Cl
Reactant: CNC
Agent: Cl
Product: CN(C)S(=O)(=O)CCCO

Procedure:
Using 3-acetoxypropane-1-sulfonyl chloride and dimethylamine hydrochloride, the same reaction as in Reference Example 44 and 46 was conducted to produce the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Br:16])[CH:9]=2)=[O:5])[CH3:2].[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:23]1[CH2:24][CH2:25][N:20]([CH:17]([CH3:19])[CH3:18])[CH2:21][CH2:22]1)=[C:10]([Br:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc2cc(O)c(Br)cc2[nH]1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2[nH]1
Temperature: 0 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
To a suspension of 5.7 g (20.0 mmol) 6-bromo-5-hydroxy-1H-indole-2-carboxylic acid ethyl ester in 120 mL tetrahydrofuran, 3.44 g (24.0 mmol) isopropyl-piperidin-4-ol and 6.30 g (24.0 mmol) triphenylphosphine were added. The suspension was cooled to 0° C. and 5.53 g (24.0 mmol) di-tert-butyl azodicarboxylate was added. The ice bath was removed and the reaction mixture was stirred for 18 h at room temperature. The volatile components were removed and the residue was chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to afford 6.2 g (76%) of the compound as a light-yellow foam.
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[N:15]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Temperature: 25 °C
Yield: 73.1 %

Procedure:
Dowtherm A (Fluka, 500 mL) was brought to boiling (250° C.) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distill over. The resulting solution was cooled to RT and diluted with hexanes (750 mL). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72 g, 73%).