Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH:24]=O.N1CCCCC1>C(O)C>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH:24]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=2)[NH:10][C:9]1=[O:14]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A mixture of 5-aminosulfonyl-2-oxindole (106 mg), indole-2-carbaldehyde (87 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (4 mg) in ethanol (2 mL) was held in a sealed tube at 90° C. for 3 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 140 mg (83% yield) of 3-(1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]1[O:26][C:13]1([CH3:14])[CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C=CC=CCC(C)CCC=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C=CC=CCC(C)CCC1OC1(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.4 g of 7,11-dimethyl-2,4,10-dodecatrienoic acid methyl ester is dissolved in 30 ml of methylene chloride and mixed portionwise at 0°C., with stirring, with 2.4 g of m-chloroperbenzoic acid (ca 80% by wt.). Subsequently the mixture is stirred for a further 1.5 hours at 0°C. The mixture is poured on to ice, treated with 1-N sodium hydroxide, and extracted with diethyl ether. The ethereal phase is washed to neutrality, dried and evaporated. The product is chromatographed on a 50-fold amount of Kieselgel, using hexane/20% by volume ethyl acetate as the eluant. There is obtained 10,11-epoxy-7,11-dimethyl-2,4-dodecadienoic acid methyl ester, as a colorless oil; boiling point ca. 62°C/0.05 mmHg (bulb tube); nD25 = 1.4958.
Reaction SMILES: [CH3:1][O:2][P:3]([CH:5]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH3:6])[OH:4].C[O-].[Na+].[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>CO.Cl>[CH3:1][O:2][P:3]([CH:5]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH3:6])([CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])=[O:4]
Reactant: C=CC(=O)OC
Reactant: COP(O)C(C)NC(=O)OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCP(=O)(OC)C(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
To a stirred solution of 0.36 gm (0.0014 mol) of 1-benzyloxycarbonylaminoethylphosphonous acid methyl ester in 3 ml of methanol at 0° C. was added a solution of sodium methoxide in methanol (0.77 ml of a 2N solution) dropwise over 10 minutes whereupon was then added methyl acrylate 0.126 ml (0.0014 mol). The reaction mixture was stirred 30 minutes at 0° C. and 4 hours at room temperature whereupon it was diluted with 1N HCl. The mixture was extracted twice with ethyl acetate. The organic fractions were dried over sodium sulfate, filtered through magnesium sulfate and evaporated in vacuo. The product mixture was purified by chromatography (silica, 9:1, ethyl-acetate acetonitrile) to give 0.34 gm of methyl-1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-1-ethyl]-phosphinate.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([F:26])[CH:25]=1)[CH:21]=O>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:15][C:14]([C:3]2[N:4]3[C:5]([S:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=43)=[N:1][CH:2]=2)=[O:16])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Solvent: C1CCOC1
Product: O=C(C=Cc1cc(F)cc(F)c1)c1cnc2sc3c(n12)CCCCC3

Procedure:
1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-ethanone (Formula N-4, 1.8 g in THF (50 mL) was condensed with 3,5-difluorobenzaldehyde according to non-critical variations in PREPARATION 15 to yield pure 3-(3,5-Difluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula N-5, X=3,5-difluoro), 0.51 g, m.p. 207-209°.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[CH:14][CH:13]=3)[N:10]=[C:9]([C:30]([F:33])([F:32])[F:31])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[C:1]1([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:43][S:40]([C:37]4[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=4)(=[O:42])=[O:41])=[O:22])=[CH:16][CH:17]=3)[N:10]=[C:9]([C:30]([F:31])([F:32])[F:33])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccncc1
Reactant: O=C(NCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1)Oc1ccccc1
Product: O=C(NCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1)NS(=O)(=O)c1ccncc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 4 of Example 78) and pyridine-4-sulfonamide: 1H-NMR (CDCl3) δ 8.79-8.73 (2H, m), 7.64-7.62 (2H, m), 7.31-7.07 (9H, m), 6.76 (1H, s), 6.24 (1H, br.s), 3.46-3.37 (2H, m), 2.81-2.72 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](N2C3C(=CC=CC=3)C=C2)=[CH:33][CH:32]=1>>[CH3:27][CH:26]([CH3:28])[C:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:6]3[C:5]4[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=4)[N:8]([C:34]4[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=4)[CH:7]=3)[CH2:13][CH2:14]2)[CH:19]=1)=[O:29]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]c4cc(Cl)ccc34)CC2)c1
Reactant: Cc1ccc(-n2ccc3ccccc32)cc1
Product: Cc1ccc(-n2cc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c3ccccc32)cc1
Yield: 78 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[(6-chloro-1H-indol-3-yl)methyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 1-(4-methylphenyl)-1H-indole (0.207 g, 1.00 mmol) provided 2-methyl-N-[3-(1-{[1-(4-methylphenyl)-1H-indol-3-yl]methyl}-4-piperidinyl)phenyl]propanamide (0.441 g, 78%). 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.73 (d, 1H, J=7.2 Hz), 7.58–7.51 (m, 2H), 7.43–7.36 (m, 3H), 7.35–7.29 (m, 3H), 7.26–7.15 (m, 3H), 6.89 (d, 1H, J=7.7 Hz), 4.07 (s, 2H), 3.36 (d, 2H, J=11.6 Hz), 2.59–2.39 (m, 6H), 2.55 (sept, 1H, J=6.7 Hz), 2.10–1.98 (m, 2H), 1.83 (d, 2H, J=12.9 Hz), 1.23 (d, 6H, J=6.9 Hz); ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([O-:33])=[O:32]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:40]([C:37]1[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:39][CH:38]=1)(=[O:41])=[O:42]
Reactant: N#Cc1cc(Br)c2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)c2ccn(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)c2c1
Temperature: 25 °C

Procedure:
4-Bromo-1H-indole-6-carbonitrile (207 mg), PS-BEMP (900 mg) and 4-nitrobenzenesulfonyl chloride (380 mg) were weighed to a round bottom flask, then N,N-Dimethylformamide (4 ml) was added and the reaction was stirred at RT. The reaction was filtered and washed with DMF. The DMF was evaporated and the residue was dissolved in DCM:methanol and passed through a 5 g SAX cartridge (preconditioned with methanol) washing with DCM:methanol. The residue was evaporated to afford the title compound, 360 mg as a pale orange solid.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:35]=[C:34]([N+:36]([O-])=O)[CH:33]=[CH:32][C:8]=1[O:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:21][CH2:20]2)=[O:18])[CH:11]=1.[H][H]>[C].[Pd].CO>[NH2:36][C:34]1[CH:33]=[CH:32][C:8]([O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:21][CH2:20]3)=[O:18])[CH:11]=2)=[C:7]([F:6])[CH:35]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCN(CCN2CCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCCC4)CC3)ncn2)c(F)c1
Reaction time: 4.5 h
Yield: 81.6 %

Procedure:
After adding tetrahydrofuran (3 ml) and methanol (3 ml) to a crude product of 4-[2-(pyrrolidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (129 mg) under a nitrogen atmosphere, 10% palladium-carbon (60 mg) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 4.5 hours. The atmosphere in the reaction vessel was then replaced with nitrogen, and the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=19:1), and then Fractions containing the target compound were concentrated under reduced pressure to provide a crude product of the title compound (98.4 mg) as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22]1([O:28]C(Cl)=O)C=CC=CC=1.[NH2:32][C:33]1[N:38]=[C:37]([NH:39][C:40]([NH:42][CH3:43])=[O:41])[CH:36]=[C:35]([O:44][CH3:45])[CH:34]=1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9]([NH:12][C:22](=[O:28])[NH:32][C:33]3[CH:34]=[C:35]([O:44][CH3:45])[CH:36]=[C:37]([NH:39][C:40](=[O:41])[NH:42][CH3:43])[N:38]=3)(=[O:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: NS(=O)(=O)c1cc2cc(Cl)ccc2s1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNC(=O)Nc1cc(OC)cc(N)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1cc(OC)cc(NC(=O)NS(=O)(=O)c2cc3cc(Cl)ccc3s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a suspension of 5-chloro-benzo[b]thiophene-2-sulfonic acid amide (cf. Example 1a, 0.08 g, 0.32 mmol) in acetonitrile (3 mL) was added triethyamine (0.11 mL, 0.8 mmol) and, at 0-5° C., phenylchloroformate (0.061 g, 0.40 mmol). The mixture was stirred at rt for 2 h, and 1-(6-amino-4-methoxy-pyridin-2-yl)-3-methyl-urea (cf. Example 1b, 0.095 g, 0.52 mmol) was added. The reaction mixture was stirred at 55-60° C. for 3 h. After cooling to rt the solution was chromatographed directly over silica gel using dichloromethane/methanol as eluent. The compound containing fractions were evaporated. The crude compound was dissolved in a mixture of THF/methanol 1:1 (100 mL) and treated briefly with Amberlite IR-120 (H+). After filtration the filtrate was concentrated to obtain the title compound (0.066 g) as a colorless solid. MS (ISN): m/e 468.3, 470.1 (M−H)+
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].N(CC)(CC)CC.FC(C(O)=O)(F)F.C(O)(C(F)(F)F)=O>C(O)(C)C.CCN(CC)CC>[F:24][C:23]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[NH:14][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1-c1ccncn1
Reactant: Nc1cc(C(=O)O)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(F)c(Nc2ncccc2-c2ccncn2)c1
Reaction time: 0.5 h

Procedure:
4-(2-Chloro-pyridin-3-yl)-pyrimidine (240 mg, 1.2 mmol), 3-amino-4-fluorobenzoic acid (217 mg, 1.40 mmol), and 340 mg Et3N-TFA salt were mixed together in a sealed tube under argon. (The liquid Et3N-TFA reagent was generated by adding 2.5 mL TFA dropwise to a 0° C. solution of 3 mL Et3N in isopropanol, then concentrating by rotary evaporator followed by 30 minutes under high vacuum.). The mixture was melted at 95° C., and heating was continued overnight. The residue was triturated with a small amount of methanol and filtered to obtain the title compound as a solid. MS m/z=311 [M+H]+. Calc'd for C16H11FN4O2: 310.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: COc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(CSc1cccc(OC)c1)OCC
Yield: 102.5 %

Procedure:
3-Methoxythiophenol (10.00 g, 71.33 mmol), bromoacetaldehyde diethyl acetal (11.47 mL, 76.24 mmol), potassium carbonate (10.35 g, 74.89 mmol) and acetone (100 mL) were stirred at ambient temperature under nitrogen for 3 h. The white suspension was filtered, washed with acetone (2×25 mL) and the combined filtrate and washings concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with 0.5N NaOH (aq.) (2×15 mL), water 15 mL) and brine (15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo and then further dried at 130° C. under high vacuum to give the title compound (18.74 g, quantitative).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=O)[C:2]1=[O:12].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:15][CH:3]1[NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][C:2]1=[O:12]
Reactant: O=c1[nH]c2ccccc2oc1=O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1Oc2ccccc2NC1Cl
Temperature: 130 °C

Procedure:
A mixture of 25 g of 4H-1,4-benzoxazin-2,3-dione and 14.3 ml of thionylchloride in 500 ml of toluene and 5 ml dimethylformamide was heated at about 130° C. until all solids dissolved (about 2-3 hours). The solution was decanted hot (if the solution was deeply colored, charcoal was added and following stirring, the solution was filtered) and the organic solution was evaporated to dryness to give 29 g of 3-chloro-4H-1,4-benzoxazin-2-one, m.p. 133°-136° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:17][NH2:18])=[CH:11][C:10]=1[C:30]([CH3:33])([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:17][NH:18][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:11][C:10]=1[C:30]([CH3:33])([CH3:32])[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(CC(CN)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(CC(CNS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 3-(4-benzyloxy-3-tert-butylphenyl)-2-benzyloxycarbonylaminopropylamine (1.27 g, 2.84 mmol) in methylene chloride (29 ml), TEA (0.6 ml, 4.26 mmol) and then methanesulfonyl chloride.(0.3 ml, 3.69 mmol) were added slowly under cooling with ice. After stirring for 30 min., the mixture was mixed with water and extracted with chloroform. The organic layer was dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:ethyl acetate:n-hexane=1:1:2), giving the titled compound (1.23 g, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][C:3]=1[C:4]#[N:5].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][C:3]=1[C:4]1[NH:21][N:20]=[N:19][N:5]=1
Reactant: CCCCCCCCCc1ccc(O)c(C#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCc1ccc(O)c(-c2nnn[nH]2)c1
Reaction time: 4 h

Procedure:
A mixture of 13.5 parts of 2-hydroxy-5-nonyl benzonitrile, 3.6 parts of sodium azide and 2.95 parts of ammonium chloride, 50 parts of dimethyl formamide and 0.5 parts of water was stirred and boiled for four hours. After cooling the mixture was diluted with water and extracted into chloroform. The chloroform solution was washed with water and with 2 × 200 mls of a 2N solution of sodium hydroxide to extract the product. The aqueous alkaline solution was neutralised with 2N sulphuric acid and re-extracted with chloroform. The extract was washed with water, dried, and evaporated to give 7.1 parts of 5-(2-hydroxy-5-nonylphenyl)tetrazole.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[CH3:11][C:12]1([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:23])([CH3:22])[CH2:14][CH2:13]1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][C:8]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[C:15]([CH3:23])([CH3:22])[CH2:14][CH2:13][C:12]2([CH3:24])[CH3:11])=[O:9]
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)CCCl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
73.5 g (0.55 mole) of anhydrous aluminum chloride were added a little at a time, at 0°-5° C., to a solution of 70 g (0.55 mole) of 3-chloropropionyl chloride in 200 ml of methylene chloride, after which a solution of 94 g (0.5 mole) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 200 ml of methylene chloride was added dropwise at the same temperature. The mixture was stirred overnight at room temperature, poured onto 1 l of ice/water and extracted with 3 times 300 ml of methylene chloride. The combined organic phases were washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated down. 138 g of 6-(3-chloropropionyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene remained as an oil. The structure was determined by H-NMR spectroscopy.
Reaction SMILES: N1C2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[C:13]([O-])([O-])=O.[K+].[K+].CI.C[N:22]([CH:24]=O)[CH3:23]>>[CH3:23][N:22]1[C:24]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CI
Product: COC(=O)c1nn(C)c2ccccc12
Temperature: 50 °C
Yield: 68 %

Procedure:
Indazole-3-carboxylic acid (5.0 g, 30 mmole), K2CO3 (12.4 g, 90 mmole), and MeI (9.3 mL, 150 mmole) were combined in dry DMF (100 mL) and heated to 50° C. After 18 hr the mixture was cooled to RT and concentrated in vacuo. The residue was taken up in EtOAc and filtered, and the filtrate was concentrated under reduced pressure. The residue was flash chromatographed on silica gel (25% EtOAc/hexanes) to give the title compound (3.88 g, 68%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.24 (m, 1H), 7.47 (m, 2H), 7.34 (m, 1H), 4.19 (s, 3H), 4.05 (s, 3H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1.CCOC(C)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:5]([O:4][C:2](=[O:3])[NH:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)c1cc(N)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1cc(NC(=O)OCc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.5 %

Procedure:
Benzyl chloroformate (3 mL, 21.5 mmol) was added to a mixture of 1-(5-amino-2-fluorophenyl)ethanone (3 g, 19.6 mmol) and tetrabutylammonium bromide at room temperature. The reaction was stirred at room temperature for 24 hours, the crude was treated with AcOEt (50 mL) and H2O (50 mL), the organic phase was separated and evaporated in vacuo. The crude was purified by column chromatography (silica gel; MeOH/DCM). The desired fractions were collected and the solvents evaporated in vacuo to afford intermediate A40 as a cream solid (4.7 g, 84%). LCMS: 286 [M−H]−; Rt: 2.81 min (method 3).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][NH2:35])[CH2:28]1)[CH2:24][CH3:25])[CH3:22]>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([NH:35][CH2:34][CH2:33][N:29]3[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][N:23]([CH2:21][CH3:22])[CH2:24][CH3:25])[CH2:28]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CCN(CC)CC1CCCN(CCN)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Solvent: CC#N
Product: CCN(CC)CC1CCCN(CCNC(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)C1
Yield: 73 %

Procedure:
Prepared analogously to Example 46 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 73% of theory. Colourless crystals, m.p. 125° C. (D.) (acetonitrile).
Reaction SMILES: [C:1](=[O:3])=[O:2].[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[CH:5]>>[C:6]1([C:4]#[C:5][C:1]([OH:3])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C=O
Reactant: C#Cc1ccccc1
Product: O=C(O)C#Cc1ccccc1
Yield: 52 %

Procedure:
The longer reaction time for the P1 catalysed reaction may be due to the heterogeneous reaction behavior in this solid catalyst system. A reaction intermediate Poly(NHC—CO2)0.5(NHC—Cu)0.5 was synthesized by reaction of Poly(NHC)0.5(NHC—Cu)0.5 (P1) with CO2. This intermediate was directly used to react with stoichiometric amount 1-ethynylbenzene (1 eq. to NHC—CO2) under standard condition without an additional CO2 source. 52% yield of phenylpropiolic acid was obtained in 24 hours. With these experiment results, it is believe that the unique structure of P1 catalyst is the key to the high activities. The free carbene species in the structure are randomly located around copper center and act as an organo catalyst to activate CO2. This essential step may reduce the activation energy barrier for CO2 insertion.