Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:15]([CH2:16][CH2:17]Cl)=[C:14](Cl)[N:13]2[N:20]=[CH:21][CH:22]=[C:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH2:27])([CH2:25][CH3:26])[CH3:24].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[C:15]2[CH2:16][CH2:17][N:27]([CH:23]([CH2:25][CH3:26])[CH3:24])[C:14]=2[N:13]2[N:20]=[CH:21][CH:22]=[C:12]2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)N
Reactant: ClCCc1c(COCc2ccccc2)nc2ccnn2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C)N1CCc2c(COCc3ccccc3)nc3ccnn3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
In 5.0 ml of dimethylformamide were dissolved 0.44 g of 5-(benzyloxymethyl)-7-chloro-6-(2-chloroethyl)pyrazolo-[1,5-a]pyrimidine. To the solution, were added 0.15 g of sec-butylamine and 0.26 ml of triethylamine. The mixture was stirred for 1 hour at room temperature and then for 3 hours in an oil bath heated to 100-110° C. Additional 0.06 g of sec-butylamine were added, and the resultant mixture was stirred for 6.3 hours at the same temperature. After the solvent was distilled off under reduced pressure, and 1N hydrochloric acid was added to the resudue, the mixture was extracted with chloroform. After the chloroform layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resultant crude product was subjected to column chromatography on silica gel (elution solvent: hexane:ethyl acetate=3:1) to obtain 0.33 g (yield: 75.0%) of the intended product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[C:18]([F:19])=[CH:17][C:16]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][C:14]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][CH3:30])=[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=12)[CH3:2].C(O)(=O)C.Cl>O>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[C:18]([F:19])=[CH:17][C:16]([CH2:20][C:21]([OH:23])=[O:22])=[CH:15][C:14]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][CH3:30])=[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1cc(F)c(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1c(F)cc(CC(=O)O)cc1F)C2
Temperature: 100 °C
Yield: 41.7 %

Procedure:
To ethyl {4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3,5-difluorophenyl}acetate (0.045 g, 0.096 mml) was added acetic acid (3 ml) and 2N hydrochloric acid (3 ml). This was heated to 100° C. for 1 hour. Heating was stopped and the reaction was cooled to room temperature, water added and the resulting yellow solid collected by filtration and dried in the vac oven. This was purified by MDAP (Shallow gradient). The clean fraction was evaporated down to give the title compound as a clear glass (0.018 g, 0.04 mmol) LC/MS: Rt=3.16, [MH]+ 442.
Reaction SMILES: I[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].CCN(CC)CC.C[Si]([C:25]#[C:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.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>[NH2:29][C:28]1[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=1[C:26]#[C:25][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C[Si](C)(C)C#Cc1ccccc1N
Reactant: COc1cc(OC)c(C=O)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Reaction time: 4 h
Yield: 75.5 %

Procedure:
Ex-35C: To a solution of 5-iodo-2,4-dimethoxybenzaldehyde (Ex-35B, 11.7 g, 40 mmol) in 250 ml of THF, PdCl2(PPh3)2 (0.56 g, 0.8 mmol), CuI (0.3 g, 1.6 mmol), Et3N (6.06 g, 60 mmol), and 2-[(trimethylsilyl)ethynyl]aniline (7.92 g, 42 mmol) were added. The mixture was stirred to a homogeneous solution, and then TBAF (10.4 g, 40 mmol) was added. The reaction mixture was aged at room temperature for 4 h and then filtered. The filtrate was concentrated to about 50 ml, and the precipitate was filtered to give first portion of 5-(2-aminophenylethynyl)-2,4-dimethoxybenzaldehyde (8.5 g), as light yellow crystals. The filtrate was concentrated, and the residue was recrystallized from EtOAc/hexanes to give 1.85 g of additional product (total 10.35 g, 92%), mp 180–181° C. 1H-NMR (300 MHz, CDCl3) δ 10.30 (s, 1H), 7.99 (s, 1H), 7.36 (d, J=8 Hz, 1H), 7.11–7.17 (m, 1H), 6.69–6.75 (m, 2H), 6.46 (s, 1H), 4.41 (brs, 2H), 4.02 (s, 3H), 4.00 (s, 3H). HRMS Calcd. for C17H15NO3: 281.1052 (M+); Found: 281.1056. Anal. Calcd. for C17H15NO3: C, 72.58; H, 5.37; N, 4.98; Found: C, 72.74; H, 5.38; N, 4.93.
Reaction SMILES: CC1C2C=CC(OC3C=CC([N+]([O-])=O)=CN=3)=CC=2OC1.[CH3:21][CH:22]1[C:26]2[CH:27]=[CH:28][C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][CH:33]=3)=[CH:30][C:25]=2[O:24][CH2:23]1>>[CH3:21][CH:22]1[C:26]2[CH:27]=[CH:28][C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: CC1COc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Agent: CC1COc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc21
Product: CC1COc2cc(Oc3ccc(N)cc3)ccc21
Yield: 98 %

Procedure:
The procedure of Example 1 was repeated except that the 2-(3-methyl-2,3-dihydro-6-benzofuryloxy)-5-nitropyridine was replaced by 4-(3-methyl-2,3-dihydro-6-benzofuryloxy)nitrobenzene. The reaction mixture was worked up in the same manner as in Example 1, obtaining the end product in the form of brown liquid (yield 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.N1C=CN=C1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of 4-(5-bromo-2-chloro-benzyl)-phenol (9.01 g, 30.28 mmol) dissolved in N,N-dimethylformamide (100 mL) and cooled to 0 degrees Celsius (ice bath) was added imidazole (4.53 g, 66.6 mmol) and 4-dimethylaminopyridine (370 mg, 3.03 mmol). tert-butylchlorodimethylsilane (6.85 g, 45.4 mmol) was added and the ice bath was removed. The reaction mixture was allowed to stir at room temperature overnight (˜16 hours), water (400 mL) was added and the resulting mixture was extracted with ethyl acetate (200 mL). The aqueous layer was extracted two additional times with ethyl acetate (200 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (120 g silica gel column) and eluting with a gradient of 0 to 50% ethyl acetate in heptane. 12.4 g (99% yield) of product obtained as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 0.18 (s, 6 H), 0.97 (s, 9 H), 3.96 (s, 2 H), 6.77 (d, J=8.4 Hz, 2 H), 7.01 (d, J=8.4 Hz, 2 H), 7.17-7.30 (m, 3 H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>C(O)C>[N:16]1[CH:17]=[CH:18][C:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[NH:4][CH2:5][CH2:6]3)=[CH:14][CH:15]=1
Reactant: CC(=O)N1CCc2cc(-c3ccncc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cc(-c2ccc3c(c2)CCN3)ccn1
Yield: 40.8 %

Procedure:
To a suspension of 1-acetyl-5-(4-pyridinyl)indoline (715 mg) in ethanol (20 mL) was added 1N sodium hydroxide aqueous solution (1.8 mL) and the mixture was refluxed for 16 hours. The mixture was extracted with ethyl acetate and the separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give 5-(4-pyridinyl)indoline (240 mg) as an yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([O:30][C:31](=[O:44])[C:32]#[C:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:44])[CH:32]=[C:33]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][CH2:16][CH2:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])[CH3:8])[N:10]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1)[C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:29]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(CCOc2ccc3[nH]ccc3c2)n1
Reactant: CCOC(=O)C#Cc1cnc2ccccc2c1
Product: CCOC(=O)C=C(c1cnc2ccccc2c1)n1ccc2cc(OCCc3cccc(N(C)C(=O)OC(C)(C)C)n3)ccc21
Yield: 48 %

Procedure:
The title compound was synthesized from {6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acid tert-butyl ester and quinolin-3-yl-propynoic acid ethyl ester, using the procedure described in Example 16, step (d1), in 48% yield, as an E/Z isomeric mixture. H1 NMR (Cl3CD), δ: 8.91 (d, 0.3H, J=2.1 Hz), 8.88 (d, 0.3H, J=2.3 Hz), 8.17 (d, 0.7H, J=8.8 Hz), 8.14–8.11 (m, 1H), 7.97 (d, 0.3H, J=2.0 Hz), 7.82–7.74 (m, 2H), 7.60 (m, 1H), 7.53 (m, 1H), 7.49 (m, 1H), 7.17 (m, 1H), 7.11 (m, 1H), 6.92–6.97 (m, 2H), 6.78 (dd, 0.7H, J=2.5, 9.0 Hz), 6.70 (dd, 0.3H, J=2.5, 9.0 Hz), 6.64 (d, 0.3H, J=3.2 Hz), 6.55 (d, 0.7H, J=3.5 Hz), 6.39 (s, 0.3H), 6.32 (s, 0.7H), 4.39 (m, 2H), 4.10 (q, 1.4H, J=7.2 Hz), 4.04 (q, 0.6H, J=7.2 Hz), 1.39 (s, 0.9H), 1.38 (s, 2.1H), 3.21 (m, 2H), 1.51 (s, 9H), 1.14 (t, 2.1H, J=7.2 Hz), 1.05 (t, 0.9H, J=7.2 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:13]=[C:12]([NH:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].[C:21](C1NC=CN=1)(C1NC=CN=1)=[S:22]>C(Cl)Cl>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:13]=[C:12]([NH:14][CH3:15])[CH:11]=[CH:10][C:9]=1[N:16]=[C:21]=[S:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNc1ccc(N)c(Oc2ccccc2C(C)(C)C)n1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CNc1ccc(N=C=S)c(Oc2ccccc2C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 136d (16.28 mg, 0.0600 mmol) in anhydrous DCM (1.0 mL) was added dropwise to a cold solution of thiocarbonyl diimidazole (21.39 mg, 0.1200 mmol) in anhydrous DCM (0.50 mL). The reaction was stirred at 0° C. for 1 h and then warmed to rt with stirring for 2 h. The mixture was concentrated down and the residue was flushed through a plug of silica gel with 10% EtOAc in hexanes. Concentration of the eluent afforded 136e.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]1[C:8](=[O:9])[CH:7]=[CH:6][CH2:5]1.[C:10](=[O:20])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:11].O.O.O.O.O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Bi+3].O>ClCCl>[CH2:3]([CH:4]1[C:8](=[O:9])[CH2:7][CH:6]([NH:11][C:10](=[O:20])[O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:5]1)[CH:2]=[CH2:1]
Reactant: NC(=O)OCc1ccccc1
Reactant: C=CCC1CC=CC1=O
Agent: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: O
Solvent: ClCCl
Product: C=CCC1CC(NC(=O)OCc2ccccc2)CC1=O
Reaction time: 18 h

Procedure:
A solution of 5-(propene-3-yl)cyclopent-2-enone (4.28 g, 35 mmol) in dichloromethane (15 mL) was treated with benzyl carbamate (10.6 g, 70 mmol) and bismuth trinitrate pentahydrate (2.2 g, 4.5 mmol), stirred rapidly for 18 h, then diluted with dichloromethane (50 mL). The mixture was filtered through Celite® (rinse with dichloromethane) and the filtrate added directly to a silica gel column (˜550 cc). Elution first with 3:2 petroleum ether/dichloromethane afforded recovered starting material (1.01 g), then 4:1 heptane/ethyl acetate gave the subject compound (4.54 g, 47.5% uncorrected yield) as a pale yellow oil. NMR (CDCl3): δ 7.28 (br s, 5 H), 5.55-5.70 (m, 1 H), 5.03 (br s, 2 H), 4.90-5.10 (m, 2 H), 4.75-4.90 (m, 1 H), 4.10-4.30 (m, 1 H), 2.40-2.80 (m, 2 H), 2.15-2.40 (m, 2 H), 1.85-2.15 (m, 3 H). MS (M+Na): 296.0; MS (M−H2O+1): 256.0 (no M+1 visible).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[Cl:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1.CN1CCCC1=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[O:20][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:21]=2)=[CH:22][CH:23]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: NC(=O)COc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2coc(COc3ccc(Cl)cc3)n2)cc1
Temperature: 100 °C
Yield: 40.1 %

Procedure:
2-Bromo-1-(4-hydroxyphenyl)ethanone (2.90 g) and 2-(4-chlorophenoxy)acetamide (5.0 g) were added to N-methylpyrrolidone (5 ml), and the mixture was stirred at 100° C. under a nitrogen atmosphere. After being cooled to room temperature, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture and separated into layers. The organic layer was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. Sodium acetate (11.1 g) in DMF (20 ml) were added to the residue and then stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and the prepared insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) and recrystallized from hexane-ethyl acetate to afford the title compound as a pale yellow powder (1.63 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[F:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:10][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=2)(=[O:20])=[O:19])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(C)cnc1N
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccc(F)c1

Procedure:
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 3-fluorobenzenesulphonyl chloride.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:17].COC(C)(C)C>C(OCC)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[CH2:12][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(-c2ccccc2)cc1CO
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Cc1ccc(-c2ccccc2)cc1CBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 180.1 %

Procedure:
To a solution of 1.33 g (6.71 mmol) of 5-phenyl-2-methylbenzylalcohol in 30 ml of dry diethyl ether was added dropwise 0.91 g (3.02 mmol) of phosphorous tribromide with ice-cooling. After the mixture was stirred for 3 hours with ice-cooling, to the reaction solution were added ice water and tert-butyl methyl ether with ice-cooling. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium hydrogencarbonate and water, then dried and concentrated to obtain 1.42 g (5.44 mmol) of 5-phenyl-2-methylbenzylbromide as an oil.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14](=O)/[CH:15]=[CH:16]/[C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C>C1COCC1>[C:19]1([C:18]#[C:17]/[CH:16]=[CH:15]/[CH2:14][OH:13])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)/C=C/C#Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OC/C=C/C#Cc1ccccc1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Diisobutylaluminium hydride (1.0 M solution in toluene, 42 mL, 42 mmol) was added, under a nitrogen atmosphere at −70° C., to a stirred solution of (E)-5-phenyl-pent-2-en-4-ynoic acid ethyl ester (1.2 g, 5.99 mmol) in dry THF (105 mL). After stirring for 1.5 h, the reaction mixture was quenched with methanol (5 mL) followed by saturated aqueous Rochelle's salt (90 mL) and 1 N sodium hydroxide (40 mL). The organic phase was separated, and the aqueous phase extracted with ethyl acetate (250 mL, 2×). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give 948 mg (100%) of (E)-5-phenyl-pent-2-en-4-yn-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=1)[N:8]=[C:7]([C:22]1[CH:23]=[N:24][C:25]([NH:28]C(=O)OC(C)(C)C)=[N:26][CH:27]=1)[N:6]=[C:5]2[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=1)[N:8]=[C:7]([C:22]1[CH:23]=[N:24][C:25]([NH2:28])=[N:26][CH:27]=1)[N:6]=[C:5]2[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3cc(F)c(-c4cccc(S(C)(=O)=O)c4)cc3n2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3cc2F)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 20.8 %

Procedure:
To a 25 mL flask, tert-butyl (5-(6-fluoro-7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)carbamate (0.06 g, 0.0001 mol) and 1,4-dioxane (4 mL) were added. The reaction mixture was cooled to 0° C. To the flask, 4 N HCl in 1,4-dioxane (6 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. The volatiles were evaporated under reduced pressure to provide the crude product. The crude product was purified by preparative HPLC (10 mM ammonium acetate in water and acetonitrile) to provide the title compound (0.01 g, 7%). 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 2H), 8.23 (s, 1H), 8.13-8.07 (m, 3H), 8.02 (d, J=11.2 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.42 (br s, 2H), 3.96 (br s, 4H), 3.84 (br s, 4H), 3.43 (s, 3H): LC-MS (ESI): Calculated mass: 480.1; Observed mass [M+H]+: 481.1 (RT=0.30 min).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:31]
Reactant: c1ccc(Nc2ccc3ccccc3n2)nc1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc2ccccc2n1
Reaction time: 0.17 h
Yield: 55 %

Procedure:
NaH (35 mg, 0.91 mmol) was added to II (344 mg, 0.91 mmol) in DMF (5 mL) at rt. After 10 min, KI (227 mg, 1.37 mmol) and ethyl 7-bromoheptanoate (0.267 mL, 1.37 mmol) were added. The reaction mixture was stirred at 90° C. for 19 h after which 0.1 M Na2S2O3 (50 mL) and EtOAc (50 mL) were added; the phases were then separated and the aqueous phase extracted with EtOAc (2×25 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with hexane/EtOAc (90:10 to 85:15), to furnish III as a colourless oil (189 mg, 55%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([C@H:19]([N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[CH3:20])[CH2:18][O:17]1.O>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:17])([C@H:19]([N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1)[CH3:20])[CH2:18][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: C[C@@H](n1cccn1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1cccn1)[C@](O)(Cn1ccnc1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
In dimethylformamide (2 ml) was dispersed 60% sodium hydride in oil (52 mg). Imidazole (89 mg) was added to the dispersion under ice-cooling and the mixture was stirred for 15 minutes at room temperature. To the mixture was added a solution of (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-pyrazol-1-yl)ethyl]oxirane (166 mg) in dimethylformamide (1 ml). The mixture was heated for 5 hours at 50° C. and cooled. To the reaction mixture were added cold water (5 ml) and ethyl acetate (30 ml). The separated aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated saline, dried over magnesium sulfate and distilled under reduced pressure. The residue was allowed to stand to crystallize. The obtained crystals were recrystallized from ethyl acetate-hexane to form the title compound (Compound 1, 193 mg) as colorless prisms.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:21]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]2[CH:42]([F:44])[F:43])[CH:22]=1.[Cl-].[Na+].S([O-])(O)(=O)=O.[K+]>CN(C)C(=O)C.O1CCCC1.C(OCC)(=O)C>[F:44][CH:42]([F:43])[C:34]1[N:33]([C:23]2[N:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:26]=[C:21]([NH:17][S:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:13][CH:12]=3)(=[O:15])=[O:16])[CH:22]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=1
Reactant: FC(F)c1nc2ccccc2n1-c1cc(Cl)nc(N2CCOCC2)n1
Reactant: NS(=O)(=O)c1ccc(CN2CCOCC2)cc1
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [H-]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cc(-n2c(C(F)F)nc3ccccc32)nc(N2CCOCC2)n1)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
4-(Morpholin-4-ylmethyl)benzenesulfonamide (35 mg) was dissolved in N,N-dimethylacetamide (1.25 mL), and 60% sodium hydride (4 mg) was added thereto, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 1-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (50 mg), followed by stirring at 120° C. for 1 hour. The mixture was cooled to room temperature, and then a saturated aqueous sodium chloride solution, ethyl acetate, and tetrahydrofuran were added thereto, followed by neutralization with a 10% aqueous potassium hydrogen sulfate solution, and then the organic layer was extracted. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80-0:100 and subsequently chloroform:methanol=100:0-80:20) to obtain N-{6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}-4-(morpholin-4-ylmethyl)benzenesulfonamide (13 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13](C(O)=O)=[O:14].S(Cl)([Cl:20])=O>N1C=CC=CC=1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([Cl:20])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1onc(-c2ccccc2)c1C(=O)C(=O)O
Solvent: c1ccncc1
Product: Cc1onc(-c2ccccc2)c1C(=O)Cl

Procedure:
A mixture of 111.76 g of 5-methyl-3-phenyl-4-isoxazoloyl carboxylic acid, 6 drops of pyridine and 29.5 ml of thionyl chloride is stirred under reflux for 4 hrs. The excess thionyl chloride is evaporated in vacuo. Distillation of the residue yields 113.74 g of yellow liquid.