Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[NH2:36][CH:37]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=1)[C:38]([N:40]([CH2:44][CH:45]([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])[CH:41]([CH3:43])[CH3:42])=[O:39]>CN(C=O)C.C(Cl)CCl>[Cl:59][C:56]1[CH:55]=[CH:54][C:53]([CH2:52][CH:37]([NH:36][C:33](=[O:35])[CH2:32][CH2:31][NH:30][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)(=[O:28])=[O:29])[C:38]([N:40]([CH2:44][CH:45]([O:46][CH2:47][CH3:48])[O:49][CH2:50][CH3:51])[CH:41]([CH3:42])[CH3:43])=[O:39])=[CH:58][CH:57]=1
Reactant: COc1ccc(S(=O)(=O)NCCC(=O)O)cc1
Reactant: CCOC(CN(C(=O)C(N)Cc1ccc(Cl)cc1)C(C)C)OCC
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)CCNS(=O)(=O)c1ccc(OC)cc1)C(C)C)OCC
Reaction time: 12 h

Procedure:
52 mg of EDC, 45 mg of HOBt and 100 μl of N-ethylmorpholine are added to a solution of 124 mg of 3-(4-methoxybenzenesulfonylamino)propionic acid in 1 ml of DMF. A solution of 100 mg of 2-amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide in 1 ml of DMF is added dropwise thereto, and the mixture is left to stir for 12 h. The reaction solution is filtered, mixed with ethyl acetate and then extracted with 5% aqueous sodium bicarbonate solution and aqueous sodium chloride solution. Drying of the organic phase with Chromabond XTR is followed by concentration under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The desired product is obtained with MW=598.16 (calculated); measured value (M−C2H6O+H)+: 552.1
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12](=[O:20])[O:13][C:14]2=O.C[Si](N[Si](C)(C)C)(C)C.Cl>C1C=CC=CC=1.[I-].[Zn+2].[I-]>[CH2:1]([N:8]1[C:12](=[O:20])[C:11]2[C:15](=[CH:16][CH:17]=[CH:18][C:10]=2[CH3:9])[C:14]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1cccc2c1C(=O)OC2=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [I-]
Solvent: c1ccccc1
Product: Cc1cccc2c1C(=O)N(Cc1ccccc1)C2=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A solution of benzylamine (0.655 mL, 6 mmol) in benzene (5 mL) was added to a stirred solution of 4-methyl-isobenzofuran-1,3-dione (0.81 g, 5 mmol) in dry benzene (20 mL). An exothermic reaction was observed during this addition. The resulting solution was stirred for an additional 1 h. After this time, zinc iodide (1.92 g, 6 mmol) was added in one portion and the resulting mixture heated to 80° C. To this suspension HMDS (1.48 mL, 7 mmol) in benzene (10 mL) was added slowly and stirred at 80° C. for 1 h. The reaction mixture was cooled to room temperature and treated with 0.5 N HCl (15 mL). The organic phase was separated and the aqueous was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with aqueous NaHCO3 (10 mL), dried over MgSO4, filtered and concentrated to afford 2-benzyl-4-methyl-isoindole-1,3-dione (1 g, 80%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.69 (s, 3H), 4.83 (s, 2H), 7.26-7.59 (m, 7H), 7.67 (d, 1H).
Reaction SMILES: C[O:2]/[CH:3]=[CH:4]/[C:5]([CH3:14])([CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].C(O)=O.OC1C2NC(=O)SC=2C([C@@H](O)CNCCC(C)(C)CCCCCCN2CCC3(OCCN(C(C4N=C(C(C)C)SC=4)=O)C3)CC2)=CC=1.C(N(CC)CC)C.[CH3:72][S:73](Cl)(=[O:75])=[O:74]>ClCCl>[CH3:72][S:73]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:14])([CH3:13])[CH2:4][CH:3]=[O:2])(=[O:75])=[O:74]
Reactant: CS(=O)(=O)Cl
Reactant: CO/C=C/C(C)(C)CCCCCCO
Agent: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCC(C)(C)CCNC[C@H](O)c4ccc(O)c5[nH]c(=O)sc45)CC3)C2)cs1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CC=O)CCCCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of (E)-9-methoxy-7,7-dimethylnon-8-en-1-ol and (Z)-9-methoxy-7,7-dimethylnon-8-en-1-ol (example 279, step d) (1.6 g) was dissolved in dichloromethane (15 mL) and triethylamine (1.33 mL) was added then the mixture was cooled to 0° C. in an ice bath under argon. Methanesulfonyl chloride (0.68 mL) was added dropwise over 5 minutes and the reaction mixture was stirred at 0° C. for 15 minutes and then at room temperature for 1 hour. The reaction mixture was washed with brine (2×30 mL), dried over magnesium sulfate, filtered and evaporated under vacuum to give the crude product. Purification was by silica gel chromatography, eluting with 0-100% ethyl acetate in cyclohexane to afford the subtitled compound as a colourless oil. Yield 1.2 g.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10](Cl)=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:13]([OH:16])[C:14]#[CH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:7]([O:6][P:4]([CH2:9][C:10]([O:16][CH2:13][C:14]#[CH:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Reactant: C#CCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#CCOC(=O)CP(=O)(OCC)OCC
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
The above 2-(diethoxyphosphoryl)acetic acid chloride and 31.4 g (0.56 mol) of propargyl alcohol were dissolved in 100 mL of toluene and cooled to 5° C. 67.1 g (0.66 mol) of triethylamine was dropwise added to the solution at 15° C. or lower, then stirred at room temperature for 90 minutes, and disappearance of the starting materials was confirmed through gas chromatography. The formed salt was filtered and washed with 30 ml of a saturated saline solution. The organic layer was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/1 for elution) to give 111.9 g (yield 93%) of the intended 2-propynyl 2-(diethoxyphosphoryl)acetate. The obtained 2-propynyl 2-(diethoxyphosphoryl)acetate was analyzed through 1H-NMR to confirm the structure thereof. The results are shown below.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([F:21])[F:20])=[CH:15][CH:16]=2)[C:11](I)=[N:10]1.C([Mg]Cl)(C)C.[CH2:28]([Sn:32]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])Cl)[CH2:29][CH2:30][CH3:31]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([F:21])[F:20])=[CH:15][CH:16]=2)[C:11]([Sn:32]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][CH2:29][CH2:30][CH3:31])=[N:10]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: FC(F)Oc1ccc2c(c1)c(I)nn2CCC1OCCCO1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(CCC2OCCCO2)c2ccc(OC(F)F)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
1-(2-(1,3-dioxan-2-yl)ethyl)-5-(difluoromethoxy)-3-iodo-1H-indazole (242 mg, 571 mmol) was dissolved in THF (3.00 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath), isopropylmagnesium chloride 2M in THF (319 μL, 639 μmol) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min. Then, tributylchlorostannane (214 mg, 178 μL, 656 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum and taken into next step without further purification yielding 1-(2-(1,3-dioxan-2-yl)ethyl)-5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole, assumed quantitative and used into the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:4][CH:3]=1.O=S(Cl)Cl.[NH2:23][C:24]1[C:25]([F:32])=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=1[F:30].C([O-])(O)=O.[Na+]>C1COCC1.O>[F:32][C:25]1[C:26]([OH:31])=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[NH:23][C:8](=[O:10])[C:7]1[C:2]([F:1])=[CH:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:6]=1[CH3:11]
Reactant: Cc1c(-c2cccc(F)c2)ccc(F)c1C(=O)O
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2cccc(F)c2)ccc(F)c1C(=O)Nc1c(F)ccc(O)c1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
To 6-fluoro-3-(3-fluorophenyl)-2-methyl-benzoic acid (3 g, 12.0 mmol, 1 eq) was added SOCl2 (60 mL) and the reaction heated at 80° C. overnight. The resulting mixture was concentrated in vacuo and the residue that remained dissolved in THF (20 mL) and added dropwise to a mixture of 3-amino-2,4-difluoro-phenol (1.93 g, 13.2 mmol, 1.1 eq) and NaHCO3 (2.32 g, 36.2 mmol, 3 eq) in THF (5 mL). After the addition, the reaction mixture was stirred at room temperature for 30 min. Water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo to give the title compound (500 mg, 11%) which was used without further purification.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[CH3:40][N:41]1[CH:45]=[C:44](B(O)O)[C:43]([CH3:49])=[N:42]1>>[NH2:32][C:4]1[S:3][C:2]([C:44]2[C:43]([CH3:49])=[N:42][N:41]([CH3:40])[CH:45]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cc1nn(C)cc1B(O)O
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cc1nn(C)cc1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@@H](F)CO2)c(N)s1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (1,3-dimethyl-1H-pyrazol-4-yl)boronic acid gave 254. 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.25 (s, 2H), 5.00-4.73 (m, 2H), 4.16-3.89 (m, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.22 (dd, J=25.0, 9.5 Hz, 1H), 2.56 (s, 3H), 2.10-2.01 (m, 1H), 1.90-1.71 (m, 3H), 1.66-1.58 (m, 1H). LCMS (ES+) m/z 449 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[CH2:23](Br)[CH:24]=[CH2:25]>[OH-].[Na+]>[CH2:25]([S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)[CH:24]=[CH2:23]
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Product: C=CCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1

Procedure:
0.5 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 2.6 ml of 2 N sodium hydroxide solution while stirring. 0.367 g of allyl bromide is added, the mixture is stirred at room temperature for 10 minutes, extracted by shaking twice with 10 ml of toluene each time, the combined aqueous phases are washed twice with 5 ml of 2 N sodium hydroxide solution each time, dried over magnesium sulphate, concentrated by evaporation under reduced pressure and crystallised from hexane. 2-Allylthio-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 57°-58° is obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([F:10])([F:9])[F:8])=[N:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[S:6][C:5]([C:7]([F:10])([F:9])[F:8])=[N:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(C(F)(F)F)s1
Solvent: c1ccccc1
Product: FC(F)(F)c1ncc(CBr)s1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
5-Methyl-2-trifluoromethylthiazole (2.26 g, 13.5 mmol), N-bromosuccinimide (2.64 g, 14.6 mmol), and 50 mL of benzene were placed in a jacketed flask and the resulting mixture was stirred and irradiated with a 250 Watt sun lamp placed 10 cm from the flask. The temperature rose from 25° to 40° C. After 3 hr an additional 0.26 g (1.5 mmol) of N-bromosuccinimide was added and the reaction continued another 30 min. Analysis of an aliquot by gas-liquid chromatography indicated that the mixture contained about 7 percent starting material, 73 percent title compound, and 17 percent dibrominated material. The mixture was extracted with 50 mL of 2 percent aqueous sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a yellow oil. This was purified by medium pressure liquid chromatography to obtain 1.86 g (56 percent of theory) of 5-bromomethyl-2-trifluoromethylthiazole as a pale yellow oil which was 97 percent pure by gas liquid chromatography. The proton NMR spectrum had absorptions at δ4.69 (s, 2H) and 7.87 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH3:15])[CH2:22][CH2:21]1
Reactant: OCCN1CCNCC1
Reactant: CC(Cl)c1ccc(-c2ccc(F)cc2)cc1
Solvent: O
Product: CC(c1ccc(-c2ccc(F)cc2)cc1)N1CCN(CCO)CC1

Procedure:
With stirring, heat (on a steam bath) a mixture of 13g of 4'-fluoro-4-(1-chloroethyl)[1,1']biphenyl and 20g of 1-(2-hydroxyethyl piperazine for twenty hours. Treat the reaction mixture with 200 ml of water, filter and wash the solid with water to yield 1-(2-hydroxyethyl)-4-[1-(4'-fluoro[1,1']biphenyl-4-yl)ethyl]piperazine: m.p. 120°-123°. Recrystallize the product from acetonitrile, m.p. of 122°-123°.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[O:6]1C[CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[Na+]>O>[CH2:1]([O:6][CH2:7][CH:8]1[O:9][CH2:10]1)[CH:3]1[O:5][CH2:4]1
Reactant: ClCC1CO1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C(OCC1CO1)C1CO1

Procedure:
Glycidyl ether of novolak type substituted phenolic resin was produced from the novolak type phenolic resin synthesized in Example 1, using a 1-liter flask equipped with a thermometer, dropping funnel, stirrer, and separating tube with cooler. In the flask were placed 1.0 mol (as phenolic hydroxyl group) of novolak type phenolic resin, 7.0 mols of epichlorohydrin, and 0.4 times (by weight) as much dioxane as epichlorohydrin. Then, 48% NaOH (1.0 mol as NaOH) was added dropwise over 4 hours. During this time, epichlorohydrin, dioxane, and water were azeotropically boiled at 58° to 60° C. under reduced pressure (150 mmHg) and cooled in the separating tube, whereby the organic layer containing major amounts of epichlorohydrin and dioxane were returned to the reaction system whereas the water layer was discharged from the reaction system. After the reaction was completed, epichlorohydrin and dioxane were distilled away, and the reaction product was dissolved in methyl isobutyl ketone. Then the salt formed as a by-product was filtered out, and then methyl isobutyl ketone was distilled away. Thus, there was obtained a glycidyl ether of the novolak type substituted phenolic resin. This product was found to contain 0.029% (290 ppm) of hydrolyzable chlorine and to have an epoxy equivalent of 203, a softening point of 62° C., and a density of 1.19 g/cm3.
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>N1C=CC=CC=1>[C:28]([C:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:36](=[O:35])[CH2:37][OH:38])[N:31]=3)[CH:9]=2)[CH:12]=1)=[O:30])([CH3:27])[CH3:26])#[N:29]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)nn4c3)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)CO)nn4c3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (219 mg, 0.531 mmol) in pyridine (10 mL) was added 2-chloro-2-oxoethyl acetate (171 μL, 1.59 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 mL). Potassium carbonate (147 mg, 1.06 mmol) was added thereto, and the mixture was stirred at room temperature for 19 hr. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL, 2×10 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→90/10), and fractions containing the desired product were concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue. The obtained precipitate was collected by filtration, and dried to give the title compound (140 mg, 56%) as a pale-yellow powder.
Reaction SMILES: [Li+].[OH-].C([O:6][CH:7]([C:20]1[C:24]([OH:26])([CH3:25])[O:23][C:22](=[O:27])[CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)C.C(O)(=O)C>C1COCC1>[OH:6][CH:7]([C:20]1[C:24]([OH:26])([CH3:25])[O:23][C:22](=[O:27])[CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCC(OC(C)=O)C1=CC(=O)OC1(C)O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)C1=CC(=O)OC1(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiOH (0.5M, 22.6 mL, 11.32 mmol) was added to a solution of 4-(1-acetoxytridecyl)-5-hydroxy-5-methyl-2-furanone (1.00 g, 2.83 mmol) in THF (15 mL). After stirring for 3 hours at room temperature the reaction was quenched with glacial acetic acid (680 mg, 11.3 mmol) and extracted with ethylacetate. The combined organic fractions were washed with a saturated solution of aqueous sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 40% ethyl acetate/hexane to give the title alcohol.
Reaction SMILES: [CH3:1][NH2:2].Cl.[OH-].[K+].[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[C:10]([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH:19]=O)[CH:9]=1>CO>[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[C:10]([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19][NH:2][CH3:1])[CH:9]=1
Reactant: CN
Reactant: COc1cc(C(CC=O)c2ccccc2)c2cc[nH]c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CNCCC(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
To a mixture of MeNH2.HCl (0.60 g, 9 mmol) and KOH (0.1 g, 1.8 mmol) in MeOH (5 ml) was added a solution of 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-propionaldeyde CXVIII (0.25 g, 0.89 mmol) in MeOH (6 ml) at RT. The resulting mixture was stirred at room temperature for 5 minutes and NaCNBH4 (21 mg, 0.33 mmol) was added. The reaction mixture was stirred for 45 minutes at room temperature and then quenched with HCl (1M, 50 ml). The resulting mixture was extracted with Et2O (25 ml), and the aqueous layer was basified until pH>12 by addition of a saturated solution of NaOH (50 ml). The aqueous layer was extracted with Et2O (35 ml). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH) to afford [3-(6-Methoxy-1H-indol-4-yl)-3-phenyl-propyl]-methyl-amine compound CXIX (33 mg, 13% yield). MS (M+H)=295.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Solvent: CC#N
Product: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Yield: 87.6 %

Procedure:
A solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (7.8 g, 34 mmol) and piperazine (8.93 g, 103 mmol) in acetonitrile (100 mL) was heated to refluxed for 2 hours. The solvent was removed by evaporation and the residue was dissolved in water (100 mL). The aqueous solution was extracted with dichloromethane (5×100 mL) and the organic extract was dried over anhydrous Na2SO4, filtered through a pad of silica gel and concentrated to give 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (8.2 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.90-7.87, 6.89, 3.78-3.50, 3.12-2.90, 1.77-1.49, 0.83-0.60, 0.51-0.36, 0.15-0.01.
Reaction SMILES: Cl.[F:2][C:3]([F:26])([F:25])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:33][CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:40][CH3:41]>C(Cl)(Cl)Cl>[F:2][C:3]([F:26])([F:25])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH:33][CH2:34][CH:35]4[CH2:39][CH2:38][CH2:37][N:36]4[CH2:40][CH3:41])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCN1CCCC1CN
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNS(=O)(=O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Temperature: 0 °C
Yield: 28.2 %

Procedure:
4-(7-Trifluoromethyl-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (4.3 g, 0.01 mol) was added portionwise to a well stirred mixture of aqueous sodium carbonate (12.3 g in 70 ml of water) and 2-aminomethyl-1-ethylpyrrolidine (1.3 g, 0.01 mol) in chloroform (70 ml) at about 10° C. The ice bath used for cooling was removed and, after 11/2 hours, the mixture was filtered. The solid was washed with water and then air-dried. Recrystallisation from ethanol-water, followed by drying, gave the title compound (1.35 g), melting point 194°-5° C.
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](F)(F)[CH:5]([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].[Si](=O)=[O:17].S(F)(=O)(=O)O>>[F:7][C:6]([F:9])([F:8])[CH:5]([C:10]([F:13])([F:12])[F:11])[C:4]([O:3][CH2:2][Cl:1])=[O:17]
Reactant: FC(F)(F)C(C(F)(F)F)C(F)(F)OCCl
Reactant: O=[Si]=O
Agent: O=S(=O)(O)F
Product: O=C(OCCl)C(C(F)(F)F)C(F)(F)F
Reaction time: 21 h

Procedure:
In a four necked 1 liter flask equipped with a thermometer, a condenser and a stirrer, 1-chloromethoxy-1,1-difluoro-2-trifluoromethyl-3,3,3-trifluoropropane (276.6 g, 1.04 mol), silicon dioxide and fluorosulfuric acid (70.0 g, 0.70 mol) were charged. The reaction was continued at 110° C. for 21 hours. Then, the reaction mixture was distilled to give monochloromethyl 2-trifluoromethyl-3,3,3-trifluoropropanoate (190.3 g).