Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].[NH:16]1[CH2:25][CH2:24][CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][N:5]1[CH2:4][C:3]2[C:7](=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[N:16]2[CH2:25][CH2:24][CH:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17]2)[C:6]1=[O:14]
Reactant: COC(=O)C1CCNCC1
Reactant: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 90 °C
Yield: 8.4 %

Procedure:
4-Bromo-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (320.0 mg, 1.180 mmol), methyl isonipecotate (1.595 mL, 11.80 mmol), DIPEA (2.056 mL, 11.80 mmol) and DMF (5 mL) were mixed and heated in sealed tube at 90° C. for 3 days. The crude mixture was purified by MDP under basic conditions to obtain the title compound (33 mg, 8.4% yield). MS (ES+): m/z 334.16 (100) [MH+]; HPLC: tR=0.80 min (UPLC, Analytical).
Reaction SMILES: [CH2:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([CH2:3][C:4]([N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCCC(=O)Nc1ccccc1
Reactant: Ic1ccccc1
Product: CCCC(=O)N(c1ccccc1)c1ccccc1
Yield: 56 %

Procedure:
Using 2-ethylacetanilide (4.9 g) and iodobenzene (12.4 ml), a reaction as made in the same manner as in 1) of Production Example 2. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:3) produced 2-ethyl-N-phenylacetanilide (4.0 g; yield, 56%) as a brown oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:34]=[CH:33][CH:32]=[CH:31][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:28]=[C:27]([CH3:29])[C:21]([O:22][CH2:23][C:24](O)=[O:25])=[C:20]([CH3:30])[CH:19]=3)[O:15][C:13]=2[N:14]=1>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:34]=[CH:33][CH:32]=[CH:31][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:28]=[C:27]([CH3:29])[C:21]([O:22][CH2:23][C:24]([Cl:3])=[O:25])=[C:20]([CH3:30])[CH:19]=3)[O:15][C:13]=2[N:14]=1
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)Cl

Procedure:
3 ml of thionyl chloride were slowly added to 336 mg of {4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetic acid. The mixture was allowed to react for 2 days. Then toluene was added and the solvents were removed in vacuo. The addition and removal of toluene was repeated to give 350 mg of the title compound as a brown oil.
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[C:6]([NH:15][NH2:16])[N:5]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[N:4]=1)#[N:2].CO[CH:31](OC)[CH2:32][CH:33](OC)OC.Cl>C(O)C>[C:1]([C:3]1[C:7]([S:8]([C:11]([F:12])([F:13])[F:14])(=[O:10])=[O:9])=[C:6]([N:15]2[CH:33]=[CH:32][CH:31]=[N:16]2)[N:5]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:26])([F:25])[F:27])=[CH:19][C:18]=2[Cl:28])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NN)c1S(=O)(=O)C(F)(F)F
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Solvent: CCO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(-n2cccn2)c1S(=O)(=O)C(F)(F)F
Yield: 34.8 %

Procedure:
A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydrazino-4-trifluoromethylsulphonylpyrazole (1.6 g), 1,1,3,3-tetramethoxypropane (0.58 g), ethanol (10 ml) and concentrated hydrochloric acid (1 ml) was heated under reflux for 4 hours. After evaporation in vacuo the residue was dissolved in dichloromethane (200 ml) and washed in turn with sodium bicarbonate solution (2×50 ml) and with water (50 ml). Filtration (phase separating paper), followed by evaporation gave a red solid, which was purified by chromatography on silica, eluting with dichloromethane/hexane (1:1). The product was recrystallised from toluene giving 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-pyrazol-1-yl-4-trifluoromethylsulphonylpyrazole (0.6 g) as a white solid, m.p. 191°-193° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH2:12]([NH:15][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:13][CH3:14]
Reactant: CCCN
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: CCCNC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-dioxaspiro[4.5]decan-8-one (2 g, 12.8 mmol), and propylamine (1.05 mL, 12.8 mmol), and sodium triacetoxyborohydride (8 g, 38 mmol) were taken in acetonitrile and stirred for 18 h at room temperature. The mixture concentrated under vacuum and the residue basified with NaHCO3, saturated with solid NaCl and extracted with EtOAc/iPrOH (4:1) four times. Organic layer separated, dried over Na2SO4 and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([C:6](SC)=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[N:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH2:21][NH:22][CH:23]2[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[N:10]2[C:5]([C:6]([N:22]([CH:23]3[CH2:25][CH2:24]3)[CH2:21][C:20]3[CH:26]=[CH:27][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[N:4][CH:3]=1
Reactant: CSc1nc(SC)c2ncc(Br)n2n1
Reactant: COc1ccc(CNC2CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nc(SC)nn3c(Br)cnc23)C2CC2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a 25 mL flask was added a mixture of 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (2.0 g, 6.87 mmol), N-(4-methoxybenzyl)cyclopropanamine (1.34 g, 7.56 mmol) in anhydrous THF (20 mL). The reaction solution was cooled to −78° C. and treated dropwise with 1.0 M lithium bis(trimethylsilyl)amide in THF solution (20.61 mL, 20.61 mmol, 3 eq, 1M solution in THF). The reaction was stirred at −78° C. for 1 hour, then allowed to come to room temperature and stirred for 3 hours The reaction was quenched with saturated ammonium chloride. The product was extracted with ethyl acetate, the organic layer was dried with sodium sulfate and concentrated in vacuo. The crude product mixture was purified via ISCO (0-100% of ethyl acetate/heptane in 10 minutes, 24 g silica column) to give the pure product 7-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-2-(methylthio)imidazo[2,1-f][1,2,4]triazin-4-amine (2.1 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.[C:11]([C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)#[C:12][CH3:13]>C(NCC)C.[Cu](I)I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:17]2[CH:18]=[CH:19][C:14]([C:11]#[C:12][CH3:13])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: CC#Cc1ccc(I)cc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC#Cc1ccc(C#Cc2ccc(OC)cc2)cc1

Procedure:
4-Methoxyphenyl acetylene (2.65 g, 0.02 mol) and 4-(1-propynyl)iodobenzene (5.0 g, 0.02 mol) were dissolved in diethylamine (20 ml), and then added copper iodide (0.06 g) and dichlorobistriphenylphosphinepalladium dichloride (0.21 g) were added. The resulting mixture was subjected to reaction and purification operations in the same manners as in Example 1, to obtain the objective 4-methoxy-4'-(1-propynyl)tolan (No. 297) (1.35 g).
Reaction SMILES: C(O[C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)C1C=CC=CC=1.[O-]CC.[Na+].[CH3:27][C:28]([CH3:32])=[CH:29]C=O.C(O)(=O)C>C(O)C.[Pd]>[C:18]([C:12]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:28]([CH3:32])([CH3:29])[CH2:27][CH2:9][NH:11]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)=CC=O
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: [Pd]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)NCCC1(C)C
Reaction time: 24 h
Yield: 37 %

Procedure:
Diethyl benzyloxycarbonylaminomalonate (3.09 g, 10 mM) was dissolved in dry ethanol (15 ml) and added to a solution of sodium ethoxide (from 100 mg sodium) in ethanol (3 ml). 3-Methylbut-2-enal (840 mg, 10 mM) in ethanol (6 ml) was added and the solution stirred at 25° for 24 hrs. Acetic acid (0.28 ml) was then added and the solution hydrogenated for 24 hrs using palladium on carbon (10% 500 mg) as catalyst. The solution was filtered, evaporated and the residue chromatographed on silica column using ether/petroleum ether (40°-60°) (1 : 1) as eluant to give 2,2-dicarboethoxy-3,3-dimethylpyrrolidine (0.9 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[NH4+].[H][H]>[Pd].C(O)C>[C:5]1([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: CCOC(=O)NNc1ccc(-c2ccc(Br)cc2)nn1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)NNc1ccc(-c2ccccc2)nn1

Procedure:
A mixture of 15.57 g. of ethyl 3-[6-(p-bromophenyl)-3-pyridazinyl]carbazate, 1.5 g. of 10% palladium on carbon catalyst, 200 ml. of ethanol and 60 ml. of ammonium hydroxide is shaken under 40 lb. of hydrogen pressure for 4 hours with external heating of bottle by means of a heated jacket. The reaction mixture is filtered and the filtrate concentrated to a solid which is washed with water to give 10.1 g. of cream colored crystals. Recrystallization by dissolving in ethanol and diluting with petroleum ether gave white crystals, m.p. 158°-160° C.
Reaction SMILES: [CH:1]([C:4]1[CH:31]=[CH:30][C:7]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([OH:29])=[C:13]3[C:22]=2[C:21](=[O:23])[C:20]2[C:19]([OH:24])=[CH:18][CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[C:15]=2[C:14]3=[O:28])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33].CN(C)C>ClCCl>[CH:1]([C:4]1[CH:31]=[CH:30][C:7]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:29][S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])=[C:13]3[C:22]=2[C:21](=[O:23])[C:20]2[C:19]([O:24][S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:34])=[O:33])=[CH:18][CH:17]=[C:16]([N+:25]([O-:27])=[O:26])[C:15]=2[C:14]3=[O:28])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(Nc2ccc(O)c3c2C(=O)c2c(O)ccc([N+](=O)[O-])c2C3=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Nc3ccc(C(C)C)cc3)c3c2C(=O)c2c([N+](=O)[O-])ccc(OS(=O)(=O)c4ccc(C)cc4)c2C3=O)cc1
Yield: 95.9 %

Procedure:
A 1.2 g of 8-(4′-isopropylanilino)-1,5-dihydroxy-4-nitroanthraquinone and a 1.4 g of tosyl chloride were dissolved in 20 ml of dichloromethane, and a 1.0 ml of trimethylamine was added to the solution and allowed to react for 12 hours at room temperature under stirring. The reaction solution was extracted with adequate amounts of ethyl acetate and 1N-hydrochloric acid to separate into two layers. The extracted organic layer was dried with magnesium sulfate and concentrated. The obtained product was purified by silica gel chromatography to give a 2.0 g of 8-(4′-isopropylanilino)-4-nitro-1,5-bis(p-toluenesulfonyloxy)anthraquinone in a 94% yield.
Reaction SMILES: [C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH2:30])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])(=[O:3])[CH3:2].[H-].[Na+].I[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>CN(C)C=O>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][CH2:6][CH2:7][N:8]([CH3:9])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCN(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CCCN(C)C)C(C)=O)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 64.7 %

Procedure:
1.01 g (2.33 mmol) of the above 2-[4-[N-acetyl-N-(3-dimethylaminopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 20 mL of dimethylformamide under argon atmosphere, 190 mg (4.75 mmol) of sodium hydride (60% oil dispersion) and 0.61 mL (4.7 mmol) of 1-iodopentane were added under ice-cooling and the mixture was stirred at room temperature for 50 minutes. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1-9:1) to give 759 mg of 2-[4-[N-acetyl-N-(3-dimethylaminopropyl)amino]-3-fluorophenyl]-6,8-difluoro-5-pentylamino-4H-1-benzopyran-4-one (yield: 65%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][Sn:5]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9].[CH3:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)[CH3:30].O>C1C=CC=CC=1>[CH3:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:23][CH2:22][CH2:21][CH2:20][Sn:15]([O:14][Sn:5]([CH2:10][CH2:11][CH2:12][CH2:13][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:29]([CH3:30])[CH3:28])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][CH2:3][CH2:2][CH3:1])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:24][CH2:25][CH2:26][CH3:27])[CH3:30]
Reactant: CN(C)Cc1ccccc1O
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCCc1ccccc1CN(C)C)O[Sn](CCCC)(CCCC)CCCCc1ccccc1CN(C)C

Procedure:
2-(Dimethylaminomethyl)phenyltributylstannyl Ether is prepared as follows: 59.6 gm (0.1 mole) bis(tributyltin) oxide and 30.0 gm (0.2 mole) 2-dimethylaminomethyl phenol (as just prepared) are placed in 200 ml benzene. This is slowly heated to reflux in a system equipped with a Dean-Starke tube. After about 30 minutes water began to separate in the Dean-Starke tube. After 72 hours at reflux 1.9 ml of water had separated (theory 1.8 ml). A clear straw colored reaction mixture resulted and benzene is evaporated therefrom on a rotating evaporator to provide 87.7 gm of a yellow liquid. This is fractionated at reduced pressure. The product collected at 165°-168° C. at 0.5 mm is 75.0 gm of a straw colored liquid (Percent yield - 82). Infrared spectral analysis provided bands characteristic of the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH:32]([OH:33])[CH2:34][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:28][CH:27]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(C)(C)c1ccc(OCC2CO2)cc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)c1ccc(OCC(O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 28.4 %

Procedure:
To a mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.15 g, 0.5 mmol) in acetonitrile (3.0 mL) was added 2-[(4-tert-butylphenoxy)methyl]oxirane (0.11 g, 0.55 mmol) followed by lithium perchlorate (0.058 g, 0.55 mmol). The reaction mixture was stirred at 80° C. for 16 hours. The solvent was removed under vacuum. The crude product was purified by flash column chromatography (SiO2, 100% EtOAc to 2% methanol in EtOAc) to give the desired product as a purple solid (0.072 g, 29%). M.p.=137-140° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.35 (d, 2H), 6.9 (d, 2H), 4.15 (m, 1H), 4.0 (d, 2H), 2.95 (m, 3H), 2.8 (m, 2H), 2.65 (m, 2H), 2.55 (t, 2H), 2.15 (d, 2H), 1.9 (m, 2H), 1.3 (s, 9H); LCMS: 508 [M+H].
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOCCN
Reaction time: 24 h
Yield: 84.7 %

Procedure:
A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 35.3 g of crude tert-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]S(C)(=O)=O)=[CH:6][C:5]([N:13]=[C:14]2[N:18]3[CH2:19][CH2:20][CH2:21][CH:17]3[CH2:16][S:15]2)=[C:4]([F:22])[CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:13]=[C:14]2[N:18]3[CH2:19][CH2:20][CH2:21][CH:17]3[CH2:16][S:15]2)=[C:4]([F:22])[CH:3]=1
Reactant: CS(=O)(=O)Oc1cc(N=C2SCC3CCCN23)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(N=C2SCC3CCCN23)c(F)cc1Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
22 g 3-(4-Chloro-2-fluoro-5-methylsulphonyloxyphenylimino)-tetrahydro-1H,3H-pyrrolo[1,2-c]thiazole in 400 ml ethanol was treated with 400 ml 2 N caustic soda and stirred at 40° C. for 4 hours. With ice cooling it was then neutralised with 10% hydrochloric acid and extracted with methylene chloride. After drying over magnesium sulphate and concentrating, the residue was recrystallised from isopropanol.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])=[O:3].[H-].[Na+].I[CH3:20]>C1COCC1>[CH3:20][N:5]([CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CI
Reactant: CS(=O)(=O)NC1CCCOc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C1CCCOc2ccccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A solution of 1.1 g (6.2 mmol) of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF was added dropwise to a suspension of 0.23 g (6.2 mmol) of 80 percent sodium hydride in 10 ml of THF. After 2 h at RT, 0.94 g (6.7 mmol) of iodomethane were added and the mixture was stirred overnight at RT. After distilling off the solvent in vacuo, the residue was taken up in EA, and the solution was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated. Subsequent recrystallization of the product from isopropanol yielded 0.5 g of 5-(N-methyl-N-methylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine, m.p. 143-145° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[CH3:39]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([C:28]([OH:30])=[O:29])[CH3:39])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)OCc4ccccc4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(C)C(=O)O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 82, Step 1, using 1-[4′-(4-benzyloxycarbonylmethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and iodomethane.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15]Cl)=[O:12])=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[OH:30][C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1>O1CCOCC1>[Cl:1][C:2]1[C:10]([C:11]2[O:12][CH2:15][C:14]([CH3:18])([CH3:17])[N:13]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[OH:30])=[O:5]
Reactant: CC(C)(CCl)NC(=O)c1c(S(C)(=O)=O)ccc(C(=O)Cl)c1Cl
Reactant: Cn1nccc1O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NC(C)(C)CO3)c2Cl)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
At 15° C., 1.65 g (4.3 mmol) of 2-chloro-3-(1-chloro-2,2-dimethyleth-2-ylaminocarbonyl)-4-methylsulfonylbenzoyl chloride in 25 ml of dioxane and 0.45 g (4.5 mmol) of triethylamine in 10 ml of dioxane were added dropwise to a mixture of 0.42 g (4.3 mmol) of 5-hydroxy-1-methylpyrazole in 10 ml of dioxane. The mixture was stirred at room temperature for 4 hours and then filtered off through silica gel, which was rinsed with dioxane. The combined filtrates were concentrated to 60 ml and admixed with 1.24 g (9 mmol) of finely powdered potassium carbonate. The mixture was heated under reflux for 5 hours and cooled, the solvent was removed under reduced pressure, the residue was taken up in water, insoluble components were filtered off and the solution was acidified using 10% strength hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases were subsequently washed with water, dried and concentrated. 1.2 g (68% of theory) of 4-[2-chloro-3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4-methylsulfonylbenzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:33])[C:19]([CH3:32])([S:21]([CH:24]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH3:25])(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOCC>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:33])[C:19]([CH3:32])([S:21]([CH:24]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH3:25])(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH3:1]
Reactant: CC(C1CCOCC1)S(=O)(=O)C(C)(C)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C1CCOCC1)S(=O)(=O)C(C)(C)C(=O)Nc1cc(C(C)(C)CO)no1
Yield: 76.6 %

Procedure:
A solution of 100 mg (0.24 mmol) of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-[1-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionamide in DCM/ethanol (1/1, 10 mL) is treated with 145 mg (0.48 mmol) of MP-TsOH resin (loading 3.3 mmol/g) at room temperature for 18 h. The resin is removed by filtration and washed with DCM (10 mL) and methanol (10 mL). The combined filtrates are concentrated under reduced pressure and the resulting residue is slurried in heptanes/ethyl acetate (7/3) to yield 74 mg of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-[1-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionamide. Yield 87%; ES-MS: m/z 403 [M+H].
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH2:7]O)[CH2:5][OH:6].[CH3:10][O:11][CH2:12][CH:13]=[O:14].C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH3:10][O:11][CH2:12][CH:13]1[O:6][CH2:5][C:4]([CH2:3][O:2][CH3:1])([CH3:9])[CH2:7][O:14]1
Reactant: COCC(C)(CO)CO
Reactant: COCC=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COCC1OCC(C)(COC)CO1
Yield: 91 %

Procedure:
A mixture of 670 g (5 moles) of 2-methoxymethyl2-methyl-1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxyacetaldehyde and 250 ml of chloroform was heated with 10 g of pyridinium p-toluenesulfonate under a water separator until water no longer separated off. The solution was deionized using a mixed-bed ion exchanger, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 864 g (91% yield) of 2,5-dimethoxymethyl-5-methyl-1,3-dioxane of boiling point 95° C./10 mbar were obtained.