Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13](=[O:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[CH2:18][CH2:19][CH:14]([C:13]([O:12][CH3:11])=[O:20])[CH2:15][CH2:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ccc(OC)cc2)CC1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
4-Methoxybenzyl chloride (1.10 g, 6.98 mmol) was added dropwise to a solution of isonipecotic acid methyl ester (1.00 g, 6.98 mmol) and triethylamine (1.40 g, 14 mmol) in THF (30 ml) and the mixture was stirred at 60° C. for 72 h. 5% strength sodium bicarbonate solution (50 ml) was then added to the reaction mixture and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (2:1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12]C)[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1C(O)=O.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[Cl:11])[C:5]([OH:7])=[O:6]
Reactant: COc1cc(C(=O)O)c(C(=O)O)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1cc(O)c(Cl)c(Cl)c1
Temperature: 180 °C

Procedure:
3,4-Dichloro-5-methoxyphthalic acid (17.5 g., 0.066 mole) is mixed with pyridine hydrochloride (120 g.). The mixture is heated at 180° C. for one hour and then poured into water (1 l.). The solid that separates melts at 211°-212..5° C. and is used without purification in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[CH:24]=2)[NH:28][C:27]1=[O:32])([OH:16])=[O:15]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Temperature: 90 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (562 mg), 5-methoxy-2-oxindole (326 mg), and piperidine (2 drops) in ethanol (2 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added, the temperature was increased to 95° C. and held there for 1 hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 240 mg (65%) of 4-(2-carboxy-ethyl)-3-methyl-5-(5-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15]O)[C:7]=2[CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].S(C1C=CC([N+]([O-])=O)=CC=1)(OC[C@H:29]1[O:31][CH2:30]1)(=O)=O>CN(C=O)C>[CH2:15]([O:14][C:13]1[C:7]2[CH:6]=[C:5]([C:3]([N:2]([CH3:17])[CH3:1])=[O:4])[S:9][C:8]=2[CH:10]=[CH:11][CH:12]=1)[C@H:30]1[O:31][CH2:29]1
Reactant: CN(C)C(=O)c1cc2c(OCO)cccc2s1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2c(OC[C@@H]3CO3)cccc2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of N,N-dimethyl-4-(hydroxymethyloxy)benzo(b)thiophene-2-carboxamide (9.0 g) in DMF (100 ml) was added potassium carbonate (8.0 g), and (S)-glycidyl nosylate (8.0 g) was further added. The mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and water was added. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate to give the title compound (7.5 g).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:38][OH:39])[CH2:29][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[C:35]([Cl:37])[CH:36]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:38]([OH:39])[CH:1]=[O:3])[CH2:29][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[C:35]([Cl:37])[CH:36]=3)(=[O:25])=[O:26])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: O=S(=O)(CC(CCc1cncc(Cl)c1)NO)N1CCN(c2ccc(Cl)cc2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CN(O)C(CCc1cncc(Cl)c1)CS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To formic acid (400 μl, 10.8 mmol) at 0° C. was added acetic anhydride (102 μl, 1.1 mmol) and the mixture was then stirred at RT for 15 minutes. The mixture was then re-cooled to 0° C., and a solution of 1-(4-chlorophenyl)-4-{[4-(5-chloropyridin-3-yl)-2-(hydroxyamino)butyl]sulfonyl}piperazine (100 mg, 0.22 mmol) in THF was added dropwise via syringe. After stirring at RT for 1.5 hours, volatiles were removed in vacuo, and the residue was azeotroped with toluene (2 mL). The residue was then dissolved in methanol (5 mL) and stirred at 40° C. for 1 hour. After cooling to RT, the solvent was evaporated, and the residue dissolved in methanol (0.5 mL). Diethyl ether (5 mL) was then added and the cloudy suspension stirred at RT for 1 hour. The solid that precipitated was filtered, washed with diethyl ether and dried in vacuo, to give the title compound as an off-white solid (48 mg, 0.099 mmol).
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16](Cl)[N:15]=1.C(N(CC)CC)C>C(#N)C>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:15]=1
Reactant: NCc1cccc2ccccc12
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2cccc3ccccc23)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 97.4 %

Procedure:
1-Naphthylmethanamine (5.4 g, 19.7 mmol) was added to a stirred solution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.5 g, 22.3 mmol) (Preparation 19) and triethylamine (4 g, 39.6 mmol) in acetonitrile (150 ml) at room temperature. The reaction mixture was stirred at room temperature for 64 hours. The solvent was removed under reduced pressure, ethyl acetate (100 ml) was added and then the solvent was removed under reduced pressure again. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (1:1 by volume) increasing in polarity to neat ethyl acetate. The solvent was removed under reduced pressure to give the title compound (7.56 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromoindole (1.00 g, 5.10 mmol) in DMF (50 mL) at ambient temperature was added sodium hydride (220 mg of a 60% dispersion in mineral oil, 5.50 mmol). The reaction mixture was stirred for 5 min, then benzenesulfonyl chloride (901 mg, 5.10 mmol) was added and stirring was continued for 15 min. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with CHCl3 (2×75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10, to give the title compound. MS: 7/Z=336 (M+1).
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH2:27]([O:29][C:30]([CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:31])[CH3:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:27]([O:29][C:30](=[O:31])[CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH2:35][CH2:34]1)[CH3:28]
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: CCOC(=O)CN1CCNCC1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN1CCN(C(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (376 mg, 1.96 mmol) and Et3N (275 μL, 1.96 mmol) in anhydrous DCM (2.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (346 mg, 1.44 mmol) and DMAP (17 mg, 0.14 mmol) and stir the resulting solution for 15 min. Add 1-(Ethoxycarbonylmethyl)piperazine (63) (224 mg, 1.30 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with water, separate layers and extract aqu. layer with EtOAc (3 times). Filtrate the combined organic layer through a short pad of silica gel and remove solvent. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/MeOH 9+1) to obtain {4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acid ethyl ester (66) (426 mg, 83%) as a colorless oil. 1H NMR (400 MHz, CDCl3): 1.26 (t, 3H, J=7.1 Hz); 2.45-2.70 (br.m, 6H); 2.89 (t, 2 H, J=7.7 Hz); 3.26 (br.s, 2H); 3.43-3.56 (br.m, 2H); 3.61-3.76 (br.m, 2H); 3.80 (s, 3H); 3.83 (s, 6H); 4.18 (q, 2H, J=7.1 Hz); 6.41 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CCOC(C)=O>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][N:11]([C:14](=[O:16])[CH3:15])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCOc2ccc([N+](=O)[O-])cc21
Reaction time: 15 h

Procedure:
A solution of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.7 g, 3.89 mmol) in acetic anhydride (1.9 mL) and EtOAc (7 mL) was heater under reflux with stirring. After 15 h, the mixture was concentrated under reduced pressure to give 1-(6-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone as a yellow solid, which was carried on crude without purification: Mass Spectrum (ESI) m/e=223.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][C:12](=[CH2:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].S(=O)(=O)(O)O>ClCCl>[C:18]([O:14][C:13](=[O:15])[C:12]([CH2:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[CH2:16])([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C(C)C
Reactant: C=C(CC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C=C(CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
To a stirred solution of 2-(benzyloxycarbonylmethyl)propenoic acid (25.0 g, 114.0 mmole) in dichloromethane (200 ml) at -78° C. was added condensed isobutylene (50 ml) and concentrated sulphuric acid (1 ml). The mixture was allowed to warm to room temperature and kept for 72 hours. After this time the solution was washed with 10% sodium carbonate solution (3×200 ml), dried over magnesium sulphate and evaporated to give the required ester as a pale yellow oil (28.4 g, 90%). Found: C,69.60; H,7.35. C16H20O4 requires: C,69.55; H,7.30%.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O>[CH3:34][O:33][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH3:7])=[C:9]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:32]
Reactant: COC(=O)CCCCCCCBr
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(-c2cccnc2)c(C)c2ccccc21
Temperature: 25 °C

Procedure:
Dimethylformamide (1640 ml) was charged into a 20 gallon glass kettle along with 430 g of potassium t-butoxide. This solution was stirred under nitrogen and cooled to -8°. A solution of 682 g of 3-methyl-2-(3-pyridyl)indole in 3280 ml of dimethylformamide was added over 0.75 hour while the temperature is maintained below 0°. After 2 hours of stirring of -10°, 1640 ml of a solution of 780 g of methyl 8-bromooctanoate in dimethylformamide was added over 1 hour. Reaction temperature was maintained below 0°. After 2 hours stirring, the reaction mixture was allowed to warm to room temperature overnight. The rust-colored mixture was then cooled to about 5° and treated with 19.7 L of ice water. The temperature rose to 25°. After 0.5 hour stirring, the mixture was extracted with 2×8 L of ether. The extracts were dried (MgSO4) and concentrated in vacuo to give the methyl ester of 1-(7-methoxycarbonylheptyl)-3-methyl-2-(3-pyridyl)indole as an oil. 1293 g of this oil was treated with 6.53 L of IN NaOH and warmed over steam to 90° for 2.5 hours. After cooling to room temperature, the solution was washed with 3×3 L of ether. The aqueous layer was cooled to 10° and acidified to pH 3.5 with 3.4 L of 2N HCl. The heavy suspension which resulted was extracted with 4×4 L of methylene chloride. The combined extracts were washed once with 4 L of water and dried (MgSO4). After filtration and evaporation of solvent in vacuo at 60°, ether (1.5 L) trituration of the residue and drying gave 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)indole, m.p. 113°-115°. Recrystallization from ethanol raised melting point to 114°-116°.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32].Br[C:40]1[CH:41]=[C:42]([CH2:61][CH2:62][C:63]([O:65][CH3:66])=[O:64])[C:43]2[CH2:44][CH2:45][CH:46]([NH:50][S:51]([C:54]3[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=3)(=[O:53])=[O:52])[CH2:47][C:48]=2[CH:49]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:60][C:57]1[CH:56]=[CH:55][C:54]([S:51]([NH:50][CH:46]2[CH2:47][C:48]3[C:49]([CH:32]=[CH:31][C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:40][CH:41]=[C:42]([CH2:61][CH2:62][C:63]([O:65][CH3:66])=[O:64])[C:43]=3[CH2:44][CH2:45]2)(=[O:53])=[O:52])=[CH:59][CH:58]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)CCc1cc(Br)cc2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C=CC(=O)OC(C)(C)C)c2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1.25 g (4 mmol) of tri-o-tolylphosphine, 8.5 ml of triethylamine, 230 mg (1 mmol) of palladium acetate and 9 ml of tert-butyl acrylate are added to a solution of 10 g (20.5 nmol) of methyl 3-(3-bromo-6-{[(4-chlorophenyl)sulphonyl]amino}-5,6,7,8-tetrahydro-1-naphthyl)propanoate, described in Application EP 864 561, in 250 ml of DMF. The reaction mixture is stirred at 110° C. for 8 hours. The solvent is then evaporated off, and purification by chromatography on silica gel, using as eluant a cyclohexane/ethyl acetate mixture (80/20), yields the expected product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH:7]=[O:15])[CH:17]=[CH2:16]
Reactant: O=Cc1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccccc1C=O
Yield: 91.1 %

Procedure:
Potassium carbonate (24.0 g, 173.9 mmol), was added to an ethanolic solution containing salicylaldehyde (19.0 g, 155.7 mmol), and allyl bromide (22.0 g, 181.8 mmol). The resulting suspension was heated to reflux overnight. The precipitated inorganic salt was filtered off. The filtrate was evaporated under reduced pressure to give the desired product, 2-allyloxy-benzaldehyde 23.0 g, yield 91%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:19](=[O:21])[CH3:20]>C1COCC1>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:19](=[O:21])[CH3:20])[CH:10]=2)[CH:6]=[N:7]1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cn[nH]c2c1
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a solution of 6-bromo-1H-indazole (5.0 g, 25.4 mmol) in 40 mL THF was added dropwise n-BuLi (2.5M, 30 mL, 76.2 mmol) at −65° C., and the mixture was stirred for 2 h. Then, N-methoxy-N-methylacetamide (2.9 g, 27.9 mmol) was added. The reaction mixture was stirred for another 2 h at −65° C., then quenched with 40 mL H2O. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with 100 mL brine, dried, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EA=40/1) to give the title compound 24-a (370 mg, 9%) as a yellow solid. [M+H] Calc'd for C9H8N2O, 161. Found, 161.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCBr
Reactant: COC(=O)C=Cc1ccc(O)cc1
Product: CCCCOc1ccc(C=CC(=O)OC)cc1

Procedure:
Methyl 4-butoxycinnamate was prepared according to the method of Example 1, part a, except using methyl 4-hydroxycinnamate instead of 4-hydroxyacetophenone and using 1-bromobutane instead of benzylbromide.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1.[C:29](O)(=[O:31])[CH3:30]>>[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1
Reactant: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nc(C)cc4occc34)CC2)CC1

Procedure:
The title compound, white solid (101 mg, 88%), MS (ISP) m/z=385.4 [(M+H)+], mp 207.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate D) (136 mg, 0.3 mmol) and acetic acid.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.C([O:33][C:34](=[O:40])[C:35]([CH3:39])([CH3:38])[CH2:36][NH2:37])(C)(C)C.Cl>CO.O>[C:27]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:37][CH2:36][C:35]([CH3:39])([CH3:38])[C:34]([OH:40])=[O:33])=[O:7])[N:9]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 1-cyano-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg, 0.21 mmol) (prepared according to U.S. Pat. No. 7,928,120) and 3-Amino-2,2-dimethyl-propionic acid tert-butyl ester (71 mg, 0.41 mmol) in MeOH (1.5 mL) was microwaved at 120° C. For 1 h. Reaction mixture was diluted with water (80 mL), acidified by 1 N HCl and then extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Residue was then treated with 3 mL of (½) TFA/CH2Cl2. Resultant mixture was stirred at room temperature for 5 h and concentrated to provide the title compound 90 mg (0.21 mmol) in 100% yield. LC-MS ESI−: 422.07 (M−1)−.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:20][C:21]([N:23]3[C@H:28]([C:29](=[O:40])[NH:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=4[F:39])[CH2:27][C@@H:26]4[C@H:24]3[CH2:25]4)=[O:22])=[CH:13][N:14]2[C:17](=[O:19])[NH2:18])=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:17]([N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([CH2:7][C:6]([OH:41])=[O:5])[CH:16]=2)[C:12]([NH:20][C:21]([N:23]2[C@H:28]([C:29](=[O:40])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=3[F:39])[CH2:27][C@@H:26]3[C@H:24]2[CH2:25]3)=[O:22])=[CH:13]1)(=[O:19])[NH2:18]
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(NC(=O)N3[C@@H]4C[C@@H]4C[C@H]3C(=O)NCc3cccc(Cl)c3F)cn(C(N)=O)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)n1cc(NC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(CC(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
to a solution of (1-carbamoyl-3-{[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carbonyl]-amino}-1H-indol-6-yl)-acetic acid tert-butyl ester Example 127 (30 mg, 0.051 mmol) in CH2Cl2 (0.5 mL) was added TFA (157 μL, 2.05 mmol) and the mixture was stirred at RT for 1 h. Then concentrated and the crude residue was taken up in Et2O and filtered-off to give the desired material. MS (UPLC): 528.2/530.3 [M+H]+, 1055.6/1057.2 [2M+H]+, 483.1/485.1 [M−CONH2]−, 1053.6/1055.6 [2M−H]−; tR (HPLC conditions f): 1.75 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([NH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10].CCN(C(C)C)C(C)C>[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:18][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: Clc1ccc(Cl)nn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(Nc1ccc(Cl)nn1)c1ccccc1
Temperature: 225 °C
Yield: 5.2 %

Procedure:
To a 5 mL microwave reaction vial was added 3,6-dichloropyridazine (544 mg, 3.7 mmol, 1.0 equiv), cumylamine (500 mg, 3.7 mmol, 1.0 equiv), and DIPEA (640 μL, 3.7 mmol, 1.0 equiv). The reaction was heated in a microwave reactor to 225° C. for 15 min and then diluted with brine (20 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20% EtOAc/hexanes) to yield 48 mg (5%) of 6-chloro-N-(2-phenylpropan-2-yl)pyridazin-3-amine as a white solid.