Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH2:25]/[CH:26]=[CH:27]/[C:28](Cl)=[O:29])[CH3:24]>CN1C(=O)CCC1>[CH3:22][N:23]([CH3:24])[CH2:25]/[CH:26]=[CH:27]/[C:28]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:12]=[CH:11][N:10]=2)[N:7]=1)=[O:29]
Reactant: CN(C)C/C=C/C(=O)Cl
Reactant: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Solvent: CN1CCCC1=O
Product: CN(C)C/C=C/C(=O)Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of acetonitrile (20 mL) and DMF (0.05 mL) under N2 was added N,N-dimethylamino crotonic acid hydrochloride (0.47 g, 2.8 mmol). After 10 min this solution was cooled to 0-5° C. Oxalyl chloride (0.44 g, 3.5 mmol) was added and the reaction mixture was maintained at 0-5° C. for 30 min. It was allowed to warm to rt and stirring was continued for 2 h. It was then heated to 40° C. for 5 min and again brought to rt and stirred for 10 min to get a light greenish colored solution of dimethylaminocrotonyl chloride that was used as such for next step. To a stirred solution of N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (0.2 g, 0.7 mmol) in NMP (10 mL) was added dropwise under N2 atmosphere at 0° C. the solution of dimethylaminocrotonyl chloride. The reaction mixture was maintained at this temperature for 30 min and was warmed to rt and stirred for 2 h. The mixture was quenched with sodium bicarbonate solution (1 mL) and was extracted with EtOAc (2×35 mL). The combined ethyl acetate extract was washed with water (20 mL) and brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, product was eluted at 4-6% methanol in chloroform) to give (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) as a yellowish solid. 1H NMR (DMSO-d6) δ ppm: 2.24 (s, 6H), 3.13 (d, J=5.76 Hz, 2H), 6.56 (d, J=15.52 Hz, 1H), 6.80 (d, J=15.36 Hz, 1H), 6.95 (t, J=7.36 Hz, 1H), 7.11 (t, J=1.16 Hz, 1H), 7.29 (t, J=7.56 Hz, 2H), 7.58 (s, 1H), 7.65-7.7 (m, 4H), 8.31 (d, J=2.44 Hz, 1H), 9.23 (s, 1H), 9.68 (s, 1H), 10.16 (s, 1H); LCMS: m/e 390.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C(O)C>CCCCCC>[CH2:23]([O:22][C:20]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:21])[CH3:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)cc1F
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)OCC
Yield: 79.4 %

Procedure:
Into an appropriate reactor fitted with warming, cooling and stirring means, were poured 152.5 ml (1.5 mol) of 2,4-difluoroaniline and 425 ml (2.1 mol) of diethyl ethoxymethylenemalonate. The mixture was warmed at 90° to 100° C. for about three hours with evacuation of ethanol appearing in the condensation. This lead to a solid product which was treated with hexane, washed, crystallized from hexane and dried to give 356.5 g (yield 76.5%) of 1-(2,2-diethoxycarbonyl-vinylamino)-2,4-difluoro-benzene. Elemental analysis of the product showed a good correspondence with the formula C14H15NO4F2. 350 g (1.17 mol) of this product were poured into a reactor with 1 liter of diphenyloxide. The mixture was refluxed at 265°-270° C. for 11/2 hours with a subsequent evacuation of the ethanol produced during the cyclisation. After cooling to ambient temperature, there was obtained a residue which was treated with benzene and then with hexane, dried and recrystallized from methanol. This gave 239 g (yiel 80.7%) of 1,4-dihydro-3-ethoxycarbonyl-6,8-difluoro-4-oxo-quinoline, elemental analysis of which showed a good correspondence with the formula C12H9NO3F2.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH2:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][N:5]=1.CC(C)=O>O>[O:6]1[C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:8][C:4]([CH:3]=[O:2])=[N:5]1
Reactant: COC(OC)C1=NOC2(CCCCC2)C1
Solvent: CC(C)=O
Solvent: O
Product: O=CC1=NOC2(CCCCC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
3-Dimethoxymethyl-1-oxa-2-aza-spiro[4.5]dec-2-ene (1.06 g, 4.97 mmol, as prepared in the previous step) was placed in a 50 mL round-bottom flask equipped with a stir bar. Acetone (20 mL), water (0.3 mL), and Amberlyst-15 resin (200 mg) were added. The mixture was stirred at rt for 24 h. The solids were removed by filtration and rinsed with acetone (20 mL), and the solvent was removed under reduced pressure. The residue was purified by column chromatography using a 40-g SiO2 pre-packed column eluting with EtOAc/heptane, 0:1 to 3:2, v/v over 30 min, yielding 451 mg (54%) of the desired compound. 1H-NMR (400 MHz, CDCl3) δ: 9.90 (s, 1H), 2.81 (s, 2H), 1.72-1.87 (m, 4H), 1.58-1.69 (m, 2H), 1.40-1.53 (m, 4H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Cl:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[C:20](Cl)(=[O:22])[CH3:21].CN(C=O)C.CC(C)([O-])C.[K+]>O>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:20](=[O:22])[CH3:21])[C:10]3[C:15]([S:16][C:17]=2[C:18]=1[Cl:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.1 g of 3-acetoxy-4-chloro-10H-phenothiazine (see Example 4) was added acetyl chloride (7 ml), DMF (5 ml) and potassium tert-butoxide (0.42 g). The reaction mixture was stirred at ambient temperature for 1 hour and then, poured in water. The resulting precipitate was filtered and purified by chromatography on silica gel to give (1.08 g) 3-acetoxy-10-acetyl-4-chloro-10H-phenothiazine (m.p. 155° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[NH:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(O[CH2:32][CH3:33])(=O)C>CCC(C)=O>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:11][CH2:12][N:13]3[CH2:33][CH2:32][CH2:15][CH2:14]3)[CH:18]=2)[NH:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1[nH]c2ccc(OCCN3CCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 26.8 %

Procedure:
5-Hydroxy-2-methyl-1H-indole-3-carboxylic acid benzyl ester (5.0 g, 17.8 mmol), K2CO3 (6.14 g, 44.4 mmol), KI (0.029 g, 1.78 mmol) and N(chloroethyl)cyclopentyl hydrochloride (3.02 g, 17.8 mmol) were mixed together in MEK (100 mL) and refluxed at 80° C. for 72 hours. The reaction was then permitted to cool and diluted with ethyl acetate. Then solution was washed with deionized water and brine, dried on Na2SO4, filtered and concentrated under reduced pressure. The resulting crude mixture was then chromatographed (10% MeOH/CH2Cl2) to give 1.20 g (26.8%) of the desired ester as a white solid, mp 110-116° C. 1HNMR (400 MHz, DMSO): δ 1.64 (b,4H), 2.45 (b, 4H), 2.59 (s, 3H, ArCH3), 4.00 (m, 2H), 5.27 (s, 2H), 6.70 (dd, J=8.54 Hz, J=2.44 Hz, 1H), 7.15 (d, J=8.79 Hz, 1H), 7.28-7.47 (m, 5H), 11.71 (s, NH); MS(APCI+) m/z 379.1(MH+). Anal. Calcd for C23H26N2O3.0.42H2O: C, 71.56;H, 7.01; N, 7.26. Found: C, 71.36: H, 6.93: N, 7.04; IR(KBr): 3371, 2909, 1665, 1481, 1448, 1178, 1087 cm−1.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH2:12]O)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[I:39]I.Cl>ClCCl>[I:39][CH2:12][CH2:11][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(CCO)CCc1ccccc1
Reactant: II
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(CCI)CCc1ccccc1
Yield: 210.7 %

Procedure:
5 g (28 mmol) Phenoxanol (3-Methyl-5-phenyl-pentan-1-ol) is dissolved in 200 ml dichloromethane under nitrogen and stirring. Triphenylphosphine (8.8 g, 34 mmol) and 4.2 g (53 mmol) pyridine are added at 25° C. After cooling to 0° C. iodine (8.5 g, 34 mmol) is added. After 2 h stirring at 0° C. the reaction mixture is poured on ice-cooled 1 N HCl and extracted with dichloromethane. The combined organic phases are washed with 10% Na2S2O3, sat. NaHCO3 and sat. NaCl. Drying over MgSO4 and evaporation gives 17 g of a residue which is triturated with hexane and filtered over a 5 cm Silicagel pad. The filtrate is evaporated under reduced pressure and dried under high vacuum giving 7.1 g of 7c as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[C:24]([O:28][C:29](ON=C(C1C=CC=CC=1)C#N)=[O:30])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1>[CH3:1][N:2]([CH2:3][CH:4]1[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1)[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CNCC1CCSc2c1[nH]c1ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CC1CCSc2c1[nH]c1ccccc21)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A solution of 4-methylaminomethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (5.47 g) in dry tetrahydrofuran (50 ml) is mixed with triethylamine (3.58 g) and 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (5.93 g), allowed to stand at room temperature for 4 hours and evaporated to dryness. The residue is dissolved in methylene chloride and washed with a dilute sodium hydroxide solution. The solution is washed with water, dried and evaporated to dryness. The residue is applied to column chromatography on silica gel eluted with benzene/ether (20:1) to give 4-(N-methyl-N-t-butoxycarbonylaminomethyl)-2,3,4,5-tetrahydrothiopyrano[ 3,2-b]indole (5.33 g): Yield 68.2%. Recrystallization from benzene/petroleum benzine gives crystals melting at 151°-153° C. (decomp.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](C2C=C(Cl)C=CC=2Cl)[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(S(N)(=O)=O)C=CC=CC=1.Cl[C:40](OC)=[O:41]>>[CH3:40][O:41][C:17]([NH:16][CH2:15][CH2:14][CH2:13][C@H:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH3:20])=[O:19]
Reactant: COC(=O)Cl
Reactant: CC(=O)NCCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: NS(=O)(=O)c1ccccc1
Product: COC(=O)NCCC[C@@H](C)NS(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
4-chloro-N-2,5-dichlorophenyl)-N-[4-[[(methoxy)carbonyl]amino]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-4-(acetylamino)butyl]benzenesulfonamide by reacting 4-chloro-N-[2,5-dichlorophenyl]-N-[R]-1-methyl-4-aminobutyl]benzenesulfonamide with methyl chloroformate. Yield=96%; MS (ESI+), 479 (M+H)+.
Reaction SMILES: [NH:1]([CH:8]1[CH2:12][CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C.[C].[Pd]>[NH:1]([CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC(Nc3ccccc3)C2)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: c1ccc(NC2CCNC2)cc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
3-Anilino-1-benzylpyrrolidine (1.2 g) was dissolved in ethanol (20 ml), 10% palladium-carbon (0.5 g) was added thereto. The mixture was stirred at room temperature, and hydrazine monohydrate (0.24 g) was added. The mixture was stirred under heating for 2 hours and cooled to room temperature. 10% Palladium-carbon was filtered off with celite, and the filtrate was concentrated to give 3-anilinopyrrolidine (0.67 g).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:11]=1[NH2:12].[CH:18]1([N:21]2[C:30]3[C:25](=[C:26](F)[C:27]([F:32])=[CH:28][C:29]=3[F:31])[C:24](=[O:34])[C:23]([C:35]([OH:37])=[O:36])=[CH:22]2)[CH2:20][CH2:19]1>C1COCC1.CN1C(=O)CCC1>[CH:18]1([N:21]2[C:30]3[C:25](=[C:26]([NH:12][C:11]4[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:10]=4[F:9])[C:27]([F:32])=[CH:28][C:29]=3[F:31])[C:24](=[O:34])[C:23]([C:35]([OH:37])=[O:36])=[CH:22]2)[CH2:19][CH2:20]1
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1cn(C2CC2)c2c(F)cc(F)c(F)c2c1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C(O)c1cn(C2CC2)c2c(F)cc(F)c(Nc3ccc(I)cc3F)c2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 4.3 %

Procedure:
LDA (2N solution in heptane/tetrahydrofuran/ethylbenzene, 0.39 mL, 0.77 mmol) was added dropwise to a stirred solution of 2-fluoro-4-iodoaniline (165 mg, 0.70 mmol) in THF (1.2 mL) at −78° C. After 15 minutes, a solution of example 1d (100 mg, 0.35 mmol) in NMP (1.8 mL) was then added at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 25 h. Purification by preparative HPLC mass triggered gave 7.6 mg (5%) of the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.92 (s, 1H), 10.39 (s, 1H), 8.71 (s, 1H), 8.11 (t, 1H, J=11.2 Hz), 7.65 (d, 1H, J=10.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 6.74-6.79 (m, 1H), 4.12-4.19 (m, 1H), 1.15-1.22 (m, 4H). MS (ES) [m+H] calc'd for C19H12F3IN2O3, 501; found 501.
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][C:6](=[O:18])[C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[N:20]12[CH2:27][CH2:26]N(CC1)CC2>>[CH3:13][CH:12]([C:7]1[CH:6]=[CH:5][CH:4]=[C:26]([CH:9]([CH3:10])[CH3:8])[C:27]=1[NH:20][C:4](=[O:19])[CH2:5][C:6](=[O:18])[C:7]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:17]
Reactant: CCOC(=O)CC(=O)C1(c2ccccc2)CCCC1
Reactant: C1CN2CCN1CC2
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)C1(c2ccccc2)CCCC1

Procedure:
The title compound was prepared from β-oxo-1-phenylcyclopentanepropanoic acid ethyl ester (8.0 g, 0.03 mol), 1,4-diazabicyclo[2.2.2]octane (34.4 g, 0.30 mol) and xylenes (54.8 ML, 15.0 eq) using the procedure described in Example 3, Step B. 1H NMR (ppm, CDCl3): 1.62-1.73 (m, 4H), 1.85-1.90 (m, 2H), 1.93 (s, 3H, CH3), 2.43-2.52 (m, 2H), 7.20-7.36 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([O:12][CH:13]([CH3:26])[CH2:14][CH2:15][C:16]1[CH:21]=[C:20](Cl)[N:19]2[N:23]=[CH:24][CH:25]=[C:18]2[N:17]=1)(=O)C.[H-].[Na+]>CN(C=O)C>[OH:12][CH:13]([CH3:26])[CH2:14][CH2:15][C:16]1[CH:21]=[C:20]([O:1][CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:19]2[N:23]=[CH:24][CH:25]=[C:18]2[N:17]=1
Reactant: CC(=O)OC(C)CCc1cc(Cl)n2nccc2n1
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)CCc1cc(OCc2ccncc2)n2nccc2n1

Procedure:
The procedure of Example 1 was followed except using 340 mg of 4-(hydroxymethyl)pyridine, 280 mg of 5-(3-acetoxybutyl)-7-chloropyrazolo[1,5-a]pyrimidine and 105 mg of 60% sodium hydride and using DMF as a solvent. The title compound was obtained as colorless crystals (50 mg). The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]#[N:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:5]2=[N:6][CH:7]=1.C[O-].[Na+].[Cl-].[NH4+:25].[C:26]([OH:29])(=[O:28])[CH3:27]>CO>[C:26]([OH:29])(=[O:28])[CH3:27].[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[NH:25])[NH2:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:5]2=[N:6][CH:7]=1
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncc(F)cc12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.1 g (41.07 mmol) of 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (Example 27A) were added to 2.22 g (41.07 mmol) of sodium methoxide in methanol (270 ml), and the mixture was stirred at RT for 2 h. 2.64 g (49.29 mmol) of ammonium chloride and acetic acid (9.17 ml) were then added, and the mixture was heated to reflux overnight. It was then concentrated to dryness and the residue was taken up in water (100 ml) and ethyl acetate (100 ml) and adjusted to a pH of 10 using 2N aqueous sodium hydroxide solution. The mixture was stirred vigorously at RT for about 1 h. The resulting suspension was filtered with suction and washed through with ethyl acetate (100 ml), with water (100 ml) and once more with ethyl acetate (100 ml). The residue was dried under high vacuum over phosphorus pentoxide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:15]/[N+:12]([O-:14])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 3-methyl-p-anisaldehyde (23.13 g, 154 mmol) and nitromethane (9.40 g, 154 mmol) in MeOH (260 ml) was cooled in an ice bath and treated dropwise with NaOH (162 ml of 1N solution; 162 mmol). The reaction mixture was stirred at rt for 1 hr. Water (50 ml) was then added and the mixture poured into 1N HCl (300 ml). The precipitate was collected and purified by flash chromatography on silica gel eluting with dichloromethane to provide methyl 2-methyl-4-[(E)-2-nitroethenyl]phenyl ether as a yellow solid (14.61 g; 49% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[S:25].NCCC(O)=O.O>C(O)(=O)C>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:23]2[N:19]([CH3:18])[C:20](=[S:25])[NH:21][C:22]2=[O:24])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CN1CC(=O)NC1=S
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=S)NC(=O)C1=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 5 h
Yield: 62.4 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (19.0 g, 81 mmols), 1-methyl-2-thioxo-4imidazolidinone (10.6 g, 81 mmols) and beta-alanine (4.7 g, 53 mmols) in acetic acid (150 ml) is stirred under an inert atmosphere and heated to reflux. After 5 hours the mixture is allowed to cool, and is stirred into water (1.5 L). After an hour the product is filtered off, washed three times with water, and dried. Recrystallization from acetonitrile gave the 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1-methyl-2-thioxo-4-imidazolidinone (17.5 g), mp 242°-244° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N1C=CC=CC=1.[CH3:18][O:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>C(OCC)(=O)C>[CH3:18][O:19][CH2:20][CH2:21][S:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)(=[O:24])=[O:23]
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: COCCS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COCCS(=O)(=O)Nc1ccc2oc(C)nc2c1
Temperature: 0 °C
Yield: 77.6 %

Procedure:
Into a 1.0 L round bottom flask equipped with mechanical stirrer, addition funnel, thermometer and nitrogen inlet tube was placed 100 grams (0.67 Mol) of 5-amino-2-methylbenzoxazole and 350 mL of pyridine. The slurry was stirred in an ice/ethanol bath at 0° C. then 110 grams (0.69 Mol) of Intermediate 1 was added dropwise so as to maintain a reaction temperature below 7° C. The reaction was stirred at 0° C. for two hours then the resulting red colored mixture was poured into 1.0 L of ethyl acetate. The slurry was stirred for 30 minutes then filtered and the collected solids were discarded. The filtrate was extracted with 4×200 mL of 10% hydrochloric acid and the organic phase was collected and dried over magnesium sulfate. The solvents were removed in vacuo to afford 140 grams (0.52 Mol, 76.7% yield) of desired product as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[N:17]1([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[N:18]1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:24]=[CH:23][C:22]([N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[CH:27][CH:26]=1)(=[O:29])=[O:30])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-n2cccn2)cc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-phenyl-methanone and 121 mg of 4-Pyrazol-1-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 6.47 (m, 1H), 7.25 (m, 2H), 7.30-7.35 (m, 3H), 7.41 (m, 1H), 7.49-7.55 (m, 3H), 7.67-7.72 (m, 3H), 7.75-7.78 (m, 2H), 9.62 (s, 1H). MS: m/z 438.9 (M++1).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[O:19][N:18]=[C:17]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[O:19][N:18]=[C:17]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:16]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: ClCc1cc(OCc2ccc3ccccc3n2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1cc(OCc2ccc3ccccc3n2)no1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (298 mg), 2-(5-chloromethyl-3-isoxazolyloxymethyl)quinoline (481 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [1-methyl-3-[3-(2-quinolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetate (676 mg, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[CH2:16]([O:18][SiH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:17]>>[CH3:15][O:14][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Si:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:18][CH2:16][CH3:17]
Reactant: C=CCCCCCCCCC(OC)OC
Reactant: CCO[SiH](OCC)OCC
Product: CCO[Si](CCCCCCCCCCC(OC)OC)(OCC)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
36.39 g of 11,11-dimethoxyundec-1-ene (7) obtained above in the first stage (170 mmol) are dissolved in 31.025 g of 97% triethoxysilane (34.86 ml, 183 mmol, 1.08 eq.). Subsequently, 0.424 g (0.45 mmol, 0.0026 eq.) of Karstedt catalyst is added very slowly. After stirring at ambient temperature for 3 hours, the crude reaction product is purified by distillation to give 41.88 g of a colorless liquid (yield of 65%) melting at a temperature of 115°-120° C. (at a pressure of 10−2 mm of mercury).