Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1nc2ccc(OC(=O)c3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (7.0 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (200 mg., catalyst) in dimethylformamide (25 ml.) is added benzoyl chloride (1.4 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 11/2 hours and then poured into ice water (150 ml.) containing excess hydrochloric acid to give 3.3 g. of 2-sulfamoyl-6-benzothiazolyl benzoate which melts at 208°-210° C. after recrystallization from toluene.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.[C:26](Cl)(Cl)=[O:27].[CH3:30][N:31](C)C1C=CC=CC=1.ClC([O-])=O.CN>>[CH3:25][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:26](=[O:27])[NH:31][CH3:30])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: O=C(Cl)Cl
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Reactant: CN(C)c1ccccc1
Agent: CN
Agent: O=C([O-])Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)NC)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
By reacting 1,2-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran with an equimolar amount of phosgene in the presence of dimethylaniline in a procedure similar to that described in Example 20 and reacting the resulting chloroformate with methylamine, there is obtained 1,2-dihydro-4,4-dimethyl-9-(N-methylcarbamyloxy)-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)[CH:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26]>>[ClH:1].[CH:13]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=[CH:21][C:12]=1[C:4]1[CH:3]=[C:2]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1cc(-c2ccc3c(c2)CCCC3)nc2ccccc12
Reactant: NCC(O)CO
Product: Cl
Product: OCC(O)CNc1cc(-c2ccc3c(c2)CCCC3)nc2ccccc12

Procedure:
The title compound, m.p. 210-230° C. and MS: m/e=348 (M+), was prepared from 4-chloro-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([O:20]C)=[O:19])=[C:8]2[N:3]1[CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][S:22][C:7]=12.[OH-].[K+].Cl>O.CO>[O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([OH:20])=[O:19])=[C:8]2[N:3]1[CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][S:22][C:7]=12
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12

Procedure:
aa) 1.34 g of methyl 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate were heated under reflux and under argon with 0.45 g of potassium hydroxide in 25 ml of water/methanol. After the reaction was completed, the mixture was acidified with 2N hydrochloric acid and the yellow crystals were removed by filtration. After washing with water, the acid was dried in vacuo for several hours. There was obtained 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylic acid of m.p 185°-186° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(NC(=O)C(C)(C)C)cn3)cc2)CC1
Reaction time: 15 h

Procedure:
To a mixture of {4-[4-(5-amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (100 mg, 0.3 mmol) in methylene chloride (10 ml) was added triethylamine (43 ul, 0.3 mmol) and trimethylacetyl chloride (40 ul, 0.3 mmol). After 15 hours at room temperature, the reaction was diluted with hexanes to afford a precipitate which was collected by filtration: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (dd, J=12.69, 1.71 Hz, 2H) 1.26 (s, 10H) 1.42-1.56 (m, 1H) 1.50 (d, J=9.85 Hz, 1H) 1.82 (d, J=11.37 Hz, 5H) 2.26 (d, J=6.69 Hz, 2H) 3.61 (s, 3H) 7.32 (d, J=8.34 Hz, 2H) 7.87 (d, J=8.72 Hz, 1H) 7.95 (d, J=8.34 Hz, 2H) 8.15 (dd, J=8.72, 2.53 Hz, 1H) 8.88 (d, J=2.53 Hz, 1H) 9.53 (s, 1H); (M+H)+409.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:10]([OH:12])=O.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:35])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1>ClCCl.CO>[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:10](=[O:12])[C:9]#[C:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][C:2]=2[Br:1])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH2:33]1
Reactant: CC1CCN(CCc2ccc(N)cc2Cl)CC1
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(CCc2ccc(NC(=O)C#Cc3ccc(-c4ccccc4)cc3Br)cc2Cl)CC1

Procedure:
Prepared analogously to Example 2.3.f. from (3-bromobiphenyl-4-yl)propynoic acid and 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethyl]phenylamine. Yield: 0.24 g (50% of theory); C29H28BrClN2O (M=535.90); calc.: molecular ion peak (M+H)+: 535/37/39; found: molecular ion peak (M+H)+: 535/37/39; Rf value: 0.48 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C@@H:11]([CH3:16])[CH2:10]2)[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>CS(C)=O>[CH3:16][C@@H:11]1[N:12]([CH3:15])[CH2:13][CH2:14][N:9]([C:6]2[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=2)[CH2:10]1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(NN)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
To 4-chloro-6-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (0.254 g, 0.98 mmol) in DMSO (3 mL) was added hydrazine monohydrate (2 mL). The reaction was stirred at room temperature for 3 days. The volatiles were removed in vacuo, and the residue was purified by RP-HPLC to provide 4-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine as a yellow solid (0.161 g, 64%). LCMS: (M+H)+=255.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cl
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.4 %

Procedure:
In dichloromethane (50 ml) was dissolved t-butyl 4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-1-piperidinecarboxylate (1.56 g, 3.21 mmol). Under ice cooling, trifluoroacetic acid (5.0 ml) was added dropwise to the resulting solution. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. Dichloromethane (10 ml) and a 1N ethanol solution (10 ml) of hydrochloric acid were added, followed by concentration under reduced pressure to give a white solid. The resulting solid was washed with diethyl ether, whereby the title compound (1.36 g, 3.12 mmol, 97%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[N:7][CH:8]=1.P(Cl)(Cl)([Cl:22])=O>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:8]1[N:7]=[N:6][C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Oc2cc(C(F)(F)F)nn2C)nnc1Cl
Yield: 64 %

Procedure:
5-Methoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine, 1-oxide (Compound No. 55, 1.0 g, 0.00344 mole) and phosphorus oxychloride (0.6 g, 0.00391 mole) were refluxed under N2 in carbon tetrachloride (40 mL) for 18 hours. The mixture was then partitioned between water and ethyl acetate. The aqueous layer was extracted again with ethyl acetate and the combined organic layers were washed with saturated sodium bicarbonate, brine, filtered through silica gel with ethyl acetate and evaporated in vacuo. The crude solid was recrystallized from ethyl acetate/cyclohexane to give 3-chloro-4-methoxy-6-[[1-methyl-3-(trifluoromethyl)- 1H-pyrazol-5-yl]oxy]pyridazine (0.681 g, 64% yield) as an off-white solid.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>CC(O)C.O>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([OH:30])[CH2:31][N:7]2[CH2:8][CH:1]3[CH2:9][CH:5]([CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]3)[CH2:6]2)=[CH:23][CH:22]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: CC(C)(C)c1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C(C)(C)C)cc3)C2)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 6.7 %

Procedure:
A mixture of tert-butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (2.2 g; 9.70 mmol; see Example F above) and 4-tert-butyl-1-(2-oxiranylmethoxy)benzene (2.0 g; 9.70 mmol; from step (a) above) in 2-propanol (10 mL) and water (1 mL) was stirred at 60° C. for 18 h. The reaction mixture was concentrated to give an oil which was dissolved in hexanes and allowed to stand until solids formed. The solids were collected and dried to give the desired product (0.28 g; 7%) as a white solid.
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[C:8]([NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:12])=[O:9].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.N>C(O)(=O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[C:8]([NH:10][C:11](=[O:12])[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:1][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][CH:24]=2)[CH2:16][CH2:15]1)=[O:9]
Reactant: C=O
Reactant: COc1cccc(C(=O)NC(=O)NC2CCNCC2)c1
Reactant: c1ccc2[nH]ccc2c1
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C(=O)NC(=O)NC2CCN(Cc3c[nH]c4ccccc34)CC2)c1
Reaction time: 5 h

Procedure:
A solution of formaldehyde (0.4 cm3, 40% aqueous solution) was added to a stirred solution of 1-(3methoxy benzoyl)-3-(piperid-4-yl)urea (1.39 g, 5 mmol) and indole (0.6 g, 5 mmol) in acetic acid (3 cm3). The solution was allowed to stand for 5 hours then diluted with water (50 cm3), basified by addition of ammonia and the precipitated product collected, washed with water, and dried yielding the title compound as the free base (2.1 g). The base was dissolved in hot ethanol (30 cm3), cooled, and acidified with ethanolic hydrogen chloride to precipitate the hydrochloride (2.3 g, 100%). Recrystallisation from aqueous methanol (60% methanol, 70 cm3) gave 1.8 g (81%) m.p. 234°-5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.CI.[C:11]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH3:11])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ncc(Br)c[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)cnc1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5-bromopyrimidin-2(1H)-one (3 g), methyliodide (1.1 mL) and K2CO3 (2.4 g) in N,N-dimethylformamide (60 mL) is stirred for 5 hours at room temperature. The mixture is filtered and the mother liquor is concentrated. The residue is partitioned between water and dichloromethane. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound. Yield: 385 mg; LC (method 9): tR=0.25 min; Mass spectrum (ESI+): m/z=189 [M+H]+.
Reaction SMILES: ClC(Cl)C.CN([CH:8]=[O:9])C.P(Cl)(Cl)(Cl)=O.[CH:15]1[C:16]([C:24]([O:26][CH3:27])=[O:25])=[CH:17][N:18]2[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]2>C(#N)C>[CH:8]([C:15]1[C:16]([C:24]([O:26][CH3:27])=[O:25])=[CH:17][N:18]2[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:9]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc2n(c1)CCCC2
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1cn2c(c1C=O)CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A 100-mL round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with anhydrous dichloroethane (10 mL) and anhydrous DMF (0.7 mL, 9.0 mmol). The reaction mixture was cooled to 0° C. and phosphorus oxychloride (0.7 mL, 7.3 mmol) was added over a period of 2 min, while maintaining the reaction temperature between 0° C. and 10° C. The cooling bath was removed and the reaction was stirred at room temperature for 1 hour. A solution of methyl 5,6,7,8-tetrahydroindolizine-2-carboxylate 112a (1.0 g, 5.6 mmol) in acetonitrile (10 mL) was added and the mixture was stirred at room temperature for additional 3 hours. After this time, the solvent was concentrated under reduced pressure and the oily residue was taken up with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×70 mL). The combined organic layer was washed with water (20 mL), dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:1 ethyl acetate/petroleum ether to afford 192a as a white solid (406 mg, 33%). MS: (M+H)+ 208.3. 1H NMR (500 MHz, DMSO) δ 10.29 (s, 1H), 7.43 (s, 1H), 3.99 (t, J=6.0 Hz, 2H), 3.76 (s, 3H), 2.95 (t, J=6.5 Hz, 2H), 1.90-1.85 (m, 2H), 1.78-1.74 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.Cl[CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:23]([N:22]([CH2:25][CH3:26])[C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1)[CH3:24]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)C(=O)COc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Yield: 53.7 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (0.905 g, 4.00 mmol) and 2-chloro-N,N-diethylacetamide (0.748 g, 5.00 mmol) in acetone (10 mL) was added potassium carbonate (0.663 g, 4.80 mmol), and the mixture was heated under reflux for 2 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-70% ethyl acetate/hexane) to give the title compound (0.729 g, yield 54%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]([OH:15])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:33][C@H:32]3[N:28]([CH2:29][CH2:30][CH2:31]3)[C:27]([CH3:35])([CH3:34])[CH2:26]2)[C:21]([C:36]#[N:37])=[CH:20][N:19]=1.[C:38]1([S:44]([OH:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CC(O)C>[CH3:34][C:27]1([CH3:35])[CH2:26][C@H:25]([NH:24][C:22]2[C:21]([C:36]#[N:37])=[CH:20][N:19]=[C:18]([NH:1][C:2]3[C:3]([F:16])=[CH:4][C:5]([OH:15])=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[CH:7]=3)[N:23]=2)[CH2:33][C@H:32]2[N:28]1[CH2:29][CH2:30][CH2:31]2.[C:38]1([S:44]([OH:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cn1nnn(-c2cc(N)c(F)cc2O)c1=O
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2C#N)C[C@@H]2CCCN21
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(C#N)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2O)c1=O
Temperature: 80 °C

Procedure:
A mixture of 1-(5-amino-4-fluoro-2-hydroxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (210 mg), (7R,8aS)—N-(2-chloro-5-cyanopyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (220 mg), and benzenesulfonic acid (200 mg) in IPA (2 mL) were heated to 80° C. for overnight. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The crude product was absorbed onto silica gel and purified by CombiFlash chromatography (2N NH3 in MeOH/CH2Cl2=0-30%) to give compound 1-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-cyanopyrimidin-2-ylamino)-4-fluoro-2-hydroxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (540 mg with some benzenesulfonic acid).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:13][O:14][NH2:15].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:15][O:14][CH3:13])=[O:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a mixture of 2,5-difluorobenzoyl chloride (1.77 g, 10 mmol) and O-methylhydroxylamine hydrochloride (830 mg, 10 mmol) in methylene chloride (25 mL) at 0° C. was added dropwise triethylamine (2.8 mL, 20 mmol) and the mixture was stirred at room temperature for 8 h. The mixture was then washed with water, brine, dried with MgSO4 and concentrated under reduced pressure. The residue was chromatographed (hexane-EtOAc 2:1) to afford 1.4 g of the title compound. 1H NMR (300 MHz-DMSO-d6) δ 3.70 (s, 3H), 7.42 (m, 3H), 11.64 (s, 1H); MS (DCI/NH3) m/z 188 (M+H)+, 205 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1cc(-c2cccc(Cl)c2)on1
Temperature: 0 °C

Procedure:
In a screw cap vial equipped with stir bar was added 1-[5-(3-chloro-phenyl)-isoxazole-3-yl]-ethanol (10 mg, 0.49 mmol), dichloromethane (3 ml) and triethylamine (0.34 ml, 2.46 mmol). Cooled the mixture down to 0° C. and to it added methane sulfonyl chloride (0.08 ml, 0.98 mmol). Left the reaction mixture stirring at room temperature for 30 min. Reaction was quenched with saturated sodium bicarbonate (aqueous, 40 ml) and extracted with dichloromethane (3×30 ml). Combined organic phase was washed with brine (40 ml), dried (sodium sulfate), filtered and concentrated, in-vacuo to isolate the desired compound as brown oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][O:10][SiH:11]([O:14][CH3:15])[O:12][CH3:13]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][Si:11]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:9])[CH:2]1[O:4][CH2:3]1
Reactant: C=CCOCC1CO1
Reactant: CO[SiH](OC)OC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CO[Si](CCCOCC1CO1)(OC)OC
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 86 %

Procedure:
The apparatus of Example B was charged with 136.8 gm (1.2 mol) of allyl glycidyl ether, 2.6 gm of a carboxylic acid promoter and 0.14 ml of 10% chloroplatinic acid solution. The addition funnel was charged with 122.8 gm (1.0 mol) of trimethoxysilane. The contents of the flask were heated to 90° C. and dropwise addition of trimethoxysilane was begun. The exotherm of the reaction was controlled with an ice bath to maintain the temperature at 90°-95° C. The addition was completed in 25 minutes and temperature was maintained at 90°-95° C. for another hour. Analysis by gas chromatography showed an 86% yield of 3-glycidoxypropyltrimethoxysilane. This example demonstrates a standard preparation of 3-9lycidoxypropyltrimethoxysilane using chloroplatinic acid solution as the catalyst.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OCC1=CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To an ice-cooled solution of 4.13 g (20.7 mmol) 3-hydroxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert-butylester and 244 mg (2 mmol) DMAP in 50 ml pyridine was added 3.06 g (30 mmol) acetic anhydride. The mixture was stirred for 30 min at 0° C., then for additional 60 min at room temperature. The mixture was poured on ice and extracted twice with ether. The combined organic layers were evaporated in vacuo, dissolved in ether, washed with sat. CuSO4, water and brine and dried over MgSO4. Evaporation and bulb-to-bulb distillation gave 4.82 g (97%) 3-acetoxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester as a colorless oil, b.p. 105° C. (0.2 mbar).