Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:28][S@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([F:16])([F:15])[F:14])[CH:7]=1.CO.[NH3:38]>C(O)CO.CCOC(C)=O>[CH3:32][C:31]([S:29]([NH:28][C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([F:16])([F:15])[F:14])[CH:7]=1)[CH2:4][C:3]([NH2:38])=[O:2])=[O:30])([CH3:34])[CH3:33]
Reactant: COC(=O)CC(N[S@](=O)C(C)(C)C)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: OCCO
Product: CC(C)(C)S(=O)NC(CC(N)=O)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 120 °C
Yield: 76 %

Procedure:
(R)-methyl-3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)propanoate (prepared as described for Procedure 11, 0.70 g, 1.33 mmol) was dissolved in 8N NH3 in ethylene glycol (6 mL) at room temperature in a microwave vial. The reaction mixture was heated at 120° C. for 1200 sec, and then at 130° C. for 1200 sec under microwave irradiation. After cooling, the cap was removed, and H2O was added. The mixture was extracted with EtOAc (3×), washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, then 10% MeOH in EtOAc) to give 3-(2-methylpropan-2-ylsulfinamido)-3,3-bis(3-(trifluoromethoxy)phenyl)-propanamide as white solid (0.52 g, yield: 76%) LCMS: 3.88 min [M+1] 513.28 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.29 (m, 3H), 7.22-7.12 (m, 3H), 7.11-7.02 (m, 2H), 6.29 (m, 2H), 5.40 (s, br, 1H), 3.78 (d, J=14.50 Hz, 1H), 3.71 (s, 2H), 3.35 (d, J=14.50 Hz, 1H), 1.21-1.28 (m, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13].[K+].[Br-]>>[CH3:9][C:10]1[CH:11]=[C:12]([NH:13][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:2])[CH:14]=[CH:15][C:16]=1[CH3:17]
Reactant: Cc1ccc(N)cc1C
Reactant: N#Cc1ccccn1
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(NC(=N)c2ccccn2)cc1C
Yield: 71.2 %

Procedure:
The title compound was prepared from 2-cyanopyridine (8.6 g, 83 mmol) and 3,4-dimethylaniline (10 g, 83 mmol) by following the procedure described in preparation 10 (13.2 g, yield 71.2%, mp 105-107° C., purity 99.9% by HPLC). 1H-NMR (CDCl3): δ 2.24-2.25 (d, 6H), 5.75-6 (bs, 2H, D2O exchangeable), 6.75-6.81 (m, 2H), 7.11-7.13 (d, 1H), 7.36-7.39 (m, 1H), 7.78-7.82 (m, 1H) 8.39-8.41 (d, 1H), 8.55-8.57 (m, 1H). IR (KBr) cm−1: 3445, 3303, 1645, 1625. MS m/z:227 (M+).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=[O:13])/[CH:10]=[CH:11]/[CH3:12].[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:1]1([CH:9]([OH:13])[CH:10]=[CH:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C/C=C/C=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC=CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
To a cooled (0-55° C.) 927 mL of 1 M solution of phenyl magnesium bromide in tetrahydrofuran was added dropwise a solution of crotonaldehyde (65.0 g) in 130 μL of anhydrous ether over a period of 2 hours and 45 minutes. The reaction was stirred for an additional 45 minutes and then warmed to room temperature. After four more hours of stirring, saturated ammonium chloride aqueous solution (750 mL) was added to the reaction. The mixture was extracted with 750 mL of ether twice. The combined extract was dried over anhydrous potassium carbonate and filtered. The solvent was evaporated to give 135.88 g (99.9%) of the desired 1-phenyl-2-buten-1-ol as an oil which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[NH:7][CH2:8][CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:27][N:28]([CH3:32])[C:29]([Cl:31])=[O:30].O>O1CCCC1>[ClH:31].[CH2:1]([C:3]1[S:19][C:6]2[N:7]([C:29](=[O:30])[N:28]([CH3:32])[CH3:27])[CH2:8][CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(s1)NCCN=C2c1ccc(F)cc1
Reactant: CN(C)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1cc2c(s1)N(C(=O)N(C)C)CCN=C2c1ccc(F)cc1
Product: Cl

Procedure:
To a solution of 5.5 g of 7-ethyl-5-p-fluorophenyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine in 50 ml of tetrahydrofuran is added 2.2 g of triethylamine, and then to this solution is added dropwise a solution of 2.4 g of dimethylcarbamoyl chloride in 10 ml of tetrahydrofuran with stirring. The whole mixture is stirred under reflux for 6 hours. After cooling, the reaction solution is transferred to water, and extracted with ethyl acetate. After the organic layer is washed with water and dried over anhydrous magnesium sulfate, the solvent is evaporated under reduced pressure. The residue is treated with ethanolic hydrogen chloride to give 7-ethyl-5-p-fluorophenyl-1-dimethylcarbamoyl-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepine hydrochloride as pale yellow crystals. This product, when recrystallized from ethanol, melts at 216°-218° C with decomposition.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH:27]([Cl:30])([Cl:29])[Cl:28]>>[Cl:28][C:27]([Cl:30])([Cl:29])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: ClC(Cl)Cl
Reactant: C=CCCCCCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCCCCCCCC(Cl)(Cl)Cl

Procedure:
It has been disclosed that, when chloroform is reacted with oct-1-ene in the presence of benzoyl peroxide, 1,1,1-trichlorononane is formed in a yield of from 22 to 40%, based on the olefin, and with a selectivity of from 41 to 48%, conversion of the olefin being incomplete (J. Amer. Chem. Soc. 69 (1947), 1100-1104, in particular page 1104; and J. Chem. Soc. 1963, 3921-3927, in particular page 3927). The free-radical addition reactions of chloroform with other olefins also in general give only moderate yields (C. Walling and E. S. Hugser, Org. Reactions 13 (1963), 129).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(N(CC)CC)C.[C:23]1([N:29]2[C:33](=[O:34])[CH2:32][C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:30]2)C=CC=CC=1>C(O)C>[NH2:14][C:13]1[O:34][C:33]2[N:29]([CH3:23])[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:32]=2[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:12]=1[C:11]#[N:15]
Reactant: N#CCC#N
Reactant: O=C1CC(c2ccccc2)=NN1c1ccccc1
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C2C(C#N)=C(N)Oc3c2c(-c2ccccc2)nn3C)cc1
Reaction time: 0.02 h
Yield: 87.1 %

Procedure:
A mixture of anisaldehyde (350 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) is stirred for 1 min, followed by the addition of 1,3-diphenyl-1H-pyrazol-5(4H)-one (678 mg, 2.87 mmol, 1 equ.). The reaction mixture was concentrated after 24 h and the precipitate was washed with ethanol and hexanes. The product was re-crystallized from ethanol to afford 6-amino-4-(4-methoxyphenyl)-1-methyl-3-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1.05 g, 87%, 2.50 mmol) as a white solid. 1H-NMR (400 MHz) DMSO: 7.94-7.92 (d, 2H), 7.63-7.61 (d, 2H), 7.57-7.53 (t, 2H), 7.40-7.36 (t, 1H), 7.29-7.23 (m, 3H) 7.15 (s, 2H), 7.13-7.11 (d, 2H), 6.78-6.76 (d, 2H), 5.02 (s, 1H), 3.65 (s, 3H), 13C-NMR (100 MHz) DMSO: 158.9, 158.4, 146.7, 145.6, 137.9, 136.5, 132.6, 129.8, 129.0, 128.7, 128.5, 127.2, 127.0, 121.2, 120.3, 114.2, 98.3, 60.2, 55.3, 37.1; LC/MS-MS: 421.2→355.0 m/z; GS1 and GS2 at 30, DP=81, CE=35, CXP=24, tR=4.32 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH2:17]O)[CH:10]=[N:9]1)([CH3:7])[CH3:6]>C(Cl)Cl>[Cl:3][CH2:17][C:11]1[CH:10]=[N:9][N:8]([CH:5]([CH3:7])[CH3:6])[C:12]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CC(C)n1ncc(CO)c1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)n1ncc(CCl)c1C(F)(F)F
Reaction time: 2 h
Yield: 86 %

Procedure:
Thionyl chloride (5.26 mL, 72 mmol) was added to [1-isopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanol (Preparation 183, 7.5 g, 36 mmol) in DCM (75 mL) at 0° C. and the mixture was stirred for 2 hours. The mixture was diluted with DCM (30 mL) and the organic phase was washed with water (75 mL), brine (75 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo to afford 4-(chloromethyl)-1-isopropyl-5-(trifluoromethyl)-1H-pyrazole in 86% yield, 7 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>S(=O)(=O)(O)O>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC2CCCCO2)cc1

Procedure:
To a solution of 0.64 mL (2 mmol) of 1-(2-trimethylsiloxyethoxy)-1-trimethylsiloxy-2-methyl-lpropene, 0.55 mL of tetrabutylammonium biacetate (0.04 M in THF), and 0.06 mL of bis(dimethylamino)methylsilane in 40 mL of THF was added dropwise a solution of 20 g (72.5 mmol) of 4-tetrahydropyranyloxybenzyl methacrylate (purified by passing over a column of basic alumina in hexane solution, followed by evaporation of the hexane under reduced pressure) in 30 mL of THF. When the exothermic polymerization was finished, and the temperature had returned to room temperature, the reaction mixture was poured into methanol. Filtration gave 19 g of poly(4-tetrahydropyranyloxybenzyl methacrylate). GPD: Mn =9390, Mw =11,500, MwMn =1.23. DSC: Tg =62.3° C., with a decomposition endotherm at 250.5° C. TGA: rapid loss of 24.74% of weight at 248.1° C. The monomer was prepared from methyl 4-hydroxybenzoate by reaction with an excess of 3,4-dihydro-2H-pyran in the presence of sulfuric acid catalyst to give methyl 4-(2-tetrahydropyranyloxy)benzoate, which was then reduced with lithium aluminum hydride in THF solution to give 4-(2-tetrahydropyranyloxy)benzyl alcohol. Esterification with methacrylyl chloride and triethylamine in dichloromethane solution gave 4-tetrahydropyranyloxybenzyl methacrylate, m.p. 36° C.
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([OH:22])=O.[Cl:23][C:24]1[CH:33]=[CH:32][C:27](C(OC)=O)=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([C:20](=[O:22])[CH2:19][C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
411 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −60° C., under a nitrogen atmosphere, 350 ml of THF are added, followed dropwise by a solution of 67.7 g of 2,4-dichlorophenylacetic acid in 70 ml of THF and the mixture is kept stirred for 2 hours while the temperature is maintained below −40° C. 53.5 g of methyl 4-chlorobenzoate are then added dropwise and at −60° C. and the mixture is kept stirred while the temperature is allowed to rise to 10° C. The reaction mixture is poured over an ice/1 liter 2N HCl mixture, the organic phase is washed with a saturated NaHCO3 solution, with water, extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is taken up in pentane and the crystallized product formed is drained. 70 g of the expected compound are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH:20]([CH:26]([CH3:31])[C:27](=O)[CH2:28][CH3:29])[C:21]([O:23]CC)=[O:22]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:28]([CH3:29])=[C:27]2[CH:26]([CH3:31])[CH:20]([CH3:19])[C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)C(C)C(=O)CC
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Product: Cc1c(C(C)C(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[4-chlorobenzyl]-1-(4-fluorophenyl) hydrazine hydrochloride and ethyl 2,3-dimethyl-4-oxohexanoate as starting materials, the title compound was prepared.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([NH:41][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:31]1[CH:30]=[CH:29][C:28]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:7])=[O:18])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCc1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCc2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]4-carbonyl chloride, and benzylamine the title compound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=428.2.
Reaction SMILES: C(C1C2C(=NC=CC=2C2C=NC3C(C=2)=CC=CC=3)N(C2C(NCCN3CC[O:37]CC3)=C(C=CC=2)C#N)N=1)(C)C.O1CCN(CCN)CC1.[CH:49]([C:52]1[C:60]2[C:55](=[N:56][CH:57]=[CH:58][C:59]=2[C:61]2[CH:62]=[N:63][C:64]3[C:69]([CH:70]=2)=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]([C:71]2[CH:78]=[CH:77][C:74]([C:75]#[N:76])=[C:73]([NH:79][CH2:80][CH2:81][N:82]3[CH2:87][CH2:86][O:85][CH2:84][CH2:83]3)[CH:72]=2)[N:53]=1)([CH3:51])[CH3:50]>>[CH:49]([C:52]1[C:60]2[C:55](=[N:56][CH:57]=[CH:58][C:59]=2[C:61]2[CH:62]=[N:63][C:64]3[C:69]([CH:70]=2)=[CH:68][CH:67]=[CH:66][CH:65]=3)[N:54]([C:71]2[CH:78]=[CH:77][C:74]([C:75]([NH2:76])=[O:37])=[C:73]([NH:79][CH2:80][CH2:81][N:82]3[CH2:83][CH2:84][O:85][CH2:86][CH2:87]3)[CH:72]=2)[N:53]=1)([CH3:51])[CH3:50]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NCCN3CCOCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: CC(C)c1nn(-c2cccc(C#N)c2NCCN2CCOCC2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: NCCN1CCOCC1
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NCCN3CCOCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 43 %

Procedure:
According to Example 1(6), 4-{(3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(2-morpholinoethylamino)benzonitrile was prepared using compound (6d) instead of compound (1e) and using 2-morpholinoethylamine instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (31) (the second stage yield: 43%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(2-morpholinoethylamino)benzonitrile instead of compound (1f).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH2:14][CH2:13][C@@H:12]3[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])O1.[OH-:28].[Na+].OO>O1CCCC1>[OH:28][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C@@H:12]2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCOc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of tert-butyl (4S)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-4-ylcarbamate (1.09 g, 2.90 mmol) in tetrahydrofuran (10 mL) was added sodium hydroxide (6 mL, 1 N, 6 mmol) followed by hydrogen peroxide (10 mL, 30%). The reaction mixture was stirred at room temperature for 2 h and then quenched with sodium hydrogen sulfite (5 g in 10 mL of water). The mixture was adjusted to pH 4 with 2 N sodium hydroxide and then extracted with ethyl acetate (3×50 mL). The combined extracts were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Flash chromatography (silica gel, 10–25% ethyl acetate/hexanes) provided (650 mg, 85%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 6.75 (d, J=2.7 Hz, 1H), 6.72–6.63 (m, 1H), 5.03 (d, J=7.5 Hz, 1H), 4.77–4.75 (m, 1H), 4.16–4.08 (m, 2H), 2.30 (s, 1H), 2.16–2.13 (m, 1H), 2.05–1.99 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][NH:5][CH2:6][C:7]#[C:8][C:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[S:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[CH:10]=1>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[CH:10]=[C:9]([C:8]#[C:7][CH2:6][N:5]([CH3:4])[CH2:2][CH2:1][OH:3])[C:15]=2[CH:16]=1
Reactant: C1CO1
Reactant: CNCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Solvent: CCO
Product: CN(CC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21)CCO

Procedure:
A solution of 2 ml. of ethylene oxide in 10 ml. of ethanol is treated with a solution of 0.6 g. of N-methyl-3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynylamine in 5 ml. of ethanol and stirred at room temperature for about 4 hours. The solvent is evaporated and the residue partitioned between water and ether. The ethereal phase is washed with a dilute aqueous ammonia solution, dried over sodium sulfate and evaporated, whereby there is obtained 2-{[3-(8-chloro-dibenzo[b,f]thiepin-10yl)-2-propynyl]-methylamino}-ethanol which melts at 86-88° C. after recrystallization from ether/n-pentane.
Reaction SMILES: O=[C:2]([CH2:7][CH2:8][C:9]([O-:11])=[O:10])[C:3]([O:5][CH3:6])=[O:4].S(Cl)([Cl:14])=O>ClCCl.CN(C)C=O>[Cl:14][C:2]1([C:3]([O:5][CH3:6])=[O:4])[CH2:7][CH2:8][C:9](=[O:10])[O:11]1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(=O)CCC(=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1(Cl)CCC(=O)O1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In 10 ml of dichloromethane was dissolved 1.0 g of Compound (10). To the solution were added 911 μl of thionyl chloride and one drop of N,N-dimethylformamide. The mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated. The concentrate was subjected to a flash chromatography using silica gel, followed by elution with hexane-ethyl acetate (1:2) to give 985 mg of the subject Compound (13).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: O=C(O)Cc1ccccc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1I
Yield: 95 %

Procedure:
A solution of 2-iodophenylacetic acid (5.05 g, 19.3 mmol) and sulfuric acid (0.5 mL) in methanol was heated under reflux for 6 h, then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, organic phase was collected, washed with 1M NaOH, brine, dried (MgSO4), filtered and concentrated to afford pure 318 (5.05 g, 95% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.85 (dd, J=8.0, 1.2 Hz, 1H); 7.34-7.27 (m, 2H); 6.97 (dt, J=7.6, 2.2 Hz, 1H); 3.81 (s, 2H); 3.73 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]([NH:14][C:15]3[CH:16]=[C:17](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[OH-:41].[K+].Cl.[NH2:44]O>O1CCCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[CH:10]=[CH:11]/[C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[C:23]([NH:44][OH:41])=[O:25])[CH:16]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NO
Reactant: [OH-]
Reactant: O=C(O)/C=C/c1cccc(NC(=O)/C=C/c2ccc3c(c2)OCO3)c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(/C=C/c1cccc(NC(=O)/C=C/c2ccc3c(c2)OCO3)c1)NO
Reaction time: 0.25 h

Procedure:
(Method G5) To a solution of 3-[3-[[(E)-3-(1,3-benzodioxol-5-yl)-1-oxo-2-propenyl]amino]phenyl]-(E)-2-propenoic acid (4a) (0.24 g, 0.71 mmol) in tetrahydrofuran (5.0 ml) at 0° C. temperature iso-butylchloroformate (0.1 ml, 0.80 mmol) and triethylamine (0.12 ml, 0.88 mmol) were added, and the mixture was stirred for 15 min. To a solution of KOH (0.084 g, 1.43 mmol) in methanol (0.40 ml) at 0° C. hydroxylamine hydrochloride (0.10 g, 1.43 mmol) in methanol (1.0 ml) was added and the reaction mixture was stirred for 15 min. The precipitated KCl was removed and the filtrate was added to the first solution. The reaction mixture was stirred at room temperature for 1 hour and then the mixture was partitioned between 1N KH2PO4 and ethyl acetate. The organic layer was washed with water, saturated NaCl, and dried (Na2SO4). The solvent was evaporated and the residue was washed with hot ethyl acetate and hot methanol affording pure title compound (0.13 g, 52%). M.p. 128° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.49 (d, 1H, J=16.0 Hz); 6.67 (d, 1H, J=16.0 Hz); 6.87-7.76 (m, 8H); 7.98 (br s, 1H); 9.03 (br s, 1H); 10.18 (br s, 1H); 10.80 (br s, 1H). HPLC analysis on Symmetry C18 column: impurities 3.2% (column size 3.9×150 mm; mobile phase acetonitrile −0.1M phosphate buffer (pH 2.5), 50:50; sample concentration 0.5 mg/ml; flow rate 1.0 ml/min; detector UV 254 nm). Anal. Calcd for C19H16N2O5*H2O, %: C, 61.62; H, 4.90; N, 7.56. Found, %: C, 61.93; H, 5.03; N, 7.24.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[CH2:11]=O>CO>[C:5]1([C@H:2]2[CH2:3][O:4][CH2:11][NH:1]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=O
Reactant: N[C@H](CO)c1ccccc1
Solvent: CO
Product: c1ccc([C@H]2COCN2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a solution of (S)-2-amino-2-phenylethanol (1.5 g, 10.93 mmol) in methanol (36.4 mL) was added formaldehyde (1.065 g, 13.12 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to dryness. The crude material was purified by flash chromatography (0-50% EtOAc/heptanes) to give (S)-4-phenyloxazolidine in 40% yield. LCMS (m/z): 150.1 (MH+), 0.31 min.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)CC)C.[Cl:20][C:21]1[N:26]=[C:25]([N:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]2[CH3:37])[C:24]([CH3:38])=[C:23]([CH3:39])[N:22]=1>CN(C)C=O>[ClH:20].[CH3:38][C:24]1[C:25]([N:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]2[CH3:37])=[N:26][C:21]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)=[N:22][C:23]=1[CH3:39]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NCc2cccc(C(F)(F)F)c2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 78.2 %

Procedure:
After 3-trifluoromethylbenzylamine(0.30 ml, 2.61 mmol) and triethylamine(0.36 ml, 2.59 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.74 mmol) in dimethylformamide, 630 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.