Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[O:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C=O)ccc23)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 10 ml round-bottomed flask is charged with 54 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde, prepared in step 5 of example 2, in 5 ml of DCM. After cooling to 0° C. using an ice bath, 0.3 ml of TFA is added and the mixture is stirred at RT for 16 h. It is concentrated under RP and the solid obtained is taken up in 5 ml of saturated aqueous NaHCO3 solution. It is extracted with AcOEt, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of DCM/AcOEt (50/50 by vol.). This gives 9 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde (yellow solid). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (m, 2 H) 2.11 (m, 2 H) 2.88 (s, 3 H) 2.90 (m, 2 H) 3.57 (m, 2 H) 3.81 (m, 1 H) 6.16 (broad m, 1 H) 7.36 (t, J=7.8 Hz, 2 H) 7.71 (m, 1 H) 8.23 (broad s, 1 H) 8.34 (broad d, J=8.5 Hz, 1 H) 8.57 (d, J=8.2 Hz, 1 H) 10.10 (s, 1 H) 13.02 (broad s, 1 H). LC-MS-DAD-ELSD: 486 (+)=(M+H)(+).
Reaction SMILES: [N+]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+].Cl>C(O)C.O>[C:11]1([OH:14])[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.9 %

Procedure:
To a slurry of 2.88 g (15 mmol) of 7-nitro-1-tetralone in 60 mL absolute ethanol was added 0.58 g (15 mmol) of sodium borohydride. The reaction mixture was then stirred at room temperature for 2 hours. The resulting mixture was then rotaevaporated to dryness and the residue obtained was suspended in 100 mL of water. 3 N hydrochloric acid was added dropwise until the reaction mixture had pH 7. The suspension obtained was then extracted with five 50 mL portions of ethyl ether and the combined ether layer was washed once with 100 mL water. The ether layer was dried over anhydrous sodium sulfate, filtered and rotaevaporated to give an off-white residue which was recrystallized from a 1:1 mixture of absolute ethanol and water to yield 2.68 g (92%) of the napthalenol; mp 112-113° C.; IR (KBr): 3300; 1H NMR: δ1.73-2.26 (4H, m), 2.29 (1H, s), 2.78-2.91 (2H, m), 4.83(1H, m), 7.24 (1H, d, J=8.1), 8.00-8.04 (1H, dd, J=8.1, 2.4), 8.35(1H, d, J=2.4),; 13C NMR: δ19.2, 29.9, 32.5, 68.3, 122.7, 124.1, 130.3, 140.9, 145.4.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[O-:31][CH2:32][CH3:33].[Na+]>C(O)C.CS(C)=O>[CH2:32]([O:31][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH3:33]
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1

Procedure:
3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (60 mg, 0.129 mmol) was reacted with sodium ethoxide (0.5 M in ethanol, 0.5 mL, 0.25 mmol) in a mixture of ethanol (5 ml) and DMSO (0.2 mL) at reflux for 16 h to form the desired product which was purified by reverse phase HPLC eluting with 10% B to 70% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (10 mg, 17%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3c2C1
Yield: 7.9 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 16.9 mg (0.101 mMol) 4-nitrobenzoic acid, 1.2 mg (8%) of the title compound were recovered as a dark brown solid.
Reaction SMILES: [OH-].[Na+].S(S([O-])=O)([O-])=O.[CH:9]1[C:14]([C:15]([C:27](F)(F)F)([C:23](F)(F)F)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[C:11]([OH:31])[CH:10]=1.C(Cl)(Cl)=O.C(C1C=CC(O)=CC=1)(C)(C)C>C(N(CC)CC)C.C(Cl)Cl.O>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:14]2[CH:13]=[CH:12][C:11]([OH:31])=[CH:10][CH:9]=2)([CH3:27])[CH3:23])=[CH:21][CH:20]=1
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: CC(C)(C)c1ccc(O)cc1
Agent: O=C(Cl)Cl
Agent: O=S([O-])S(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 0.83 h

Procedure:
2371 Parts of deionized water, 156 parts of a 48.5% aqueous sodium hydroxide solution, and 0.6 parts of hydrosulfite were placed in the same apparatus as used in Example 1, and after deoxidation was carried out in the same way as in Example 1, 157.6 parts of bisphenol AF of 99.98% purity and 134.6 parts of bisphenol FL of 99.8% purity were dissolved therein, then 2548 parts of methylene chloride was added, and 98.5 parts of phosgene was blown thereinto at 13° to 16° C. over about 50 min with stirring. Then, 53.2 parts of a 48.5% aqueous sodium hydroxide solution and 8.5 parts of p-tert-butylphenol were added and after they were emulsified by stirring, 0.2 parts of triethylamine was added, followed by stirring at 30° C. for about 2 hours, to complete the reaction. Then the reaction mixture was treated in the same way as in Example 1, to obtain a copolymerized polymer. The specific viscosity of this copolymerized polymer was 0.178, the retention of the specific viscosity after the steam treatment was 85% and the glass transition temperature was 215° C., which show high hydrolysis resistance and high heat resistance, the light transmittance was 89%, which is good, the light transmittance after the heat treatment was 89%, showing excellent heat stability; and the oxidation resistance was remarkably excellent in comparison with the polymer obtained from bisphenol A as shown by curve 3 () in FIG. 2.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:21])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4].[CH2:22]([N:24]([CH2:27][CH2:28]Cl)[CH2:25][CH3:26])[CH3:23].Cl.[CH:31]1([NH:37][S:38](=[O:41])(=[O:40])[OH:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(OCC)C.C(O)(C)C.C1(C)C=CC=CC=1.CN(C)C=O>[CH:31]1([NH:37][S:38]([OH:41])(=[O:40])=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1.[CH2:25]([N:24]([CH2:22][CH3:23])[CH2:27][CH2:28][N:2]([CH3:1])[C:3]([C:5]1[N:6]([CH3:21])[C:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4])[CH3:26]
Reactant: CCN(CC)CCCl
Reactant: CNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Agent: Cl
Agent: O=S(=O)(O)NC1CCCCC1
Solvent: CCOCC
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCN(CC)CCN(C)C(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 15.0 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid methylamide in 190 ml. of dimethylformamide is treated under an atmosphere of argon with 8.25 g. of potassium tertiary butylate and the mixture is stirred in an ice-bath for 15 minutes. At 0°-5° C., there is then added a solution of 0.1 mol. of diethylaminoethyl chloride in 150 ml. of toluene (freshly prepared from the corresponding hydrochloride and dried over sodium sulfate), the mixture is stirred first at room temperature for 30 minutes and then at 100° C. for 30 minutes. After cooling, the toluene is removed by distillation under reduced pressure and the residual solution poured on to 600 ml. of ice-water. The separated thick oil is extracted with methylene chloride, and the extract washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. The residue obtained is dissolved in 60 ml. of isopropanol and treated with 9.0 g. of N-cyclohexylsulfamic acid. 200 Ml. of diethyl ether are gradually added and the mixture is left to stand at room temperature for 1 hour. The almost colorless salt which crystallizes out is removed by filtration, washed with a small amount of diethyl ether and dried in a desiccator. Recrystallization from acetone yields 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [2-(diethylamino)ethyl]methylamide cyclohexanesulfamate having a melting point of 166°-168° C. (decomposition).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:19])[CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:20][C:21]1[N:22]=[N:23][C:24]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:6][CH2:7]3)=[O:19])[CH2:18][CH2:17]2)=[CH:25][CH:26]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: O=C(CN1CCNCC1)N1CCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CN1CCN(c2ccc(Cl)nn2)CC1)N1CCN(C2CCC2)CC1

Procedure:
Dissolve 1-cyclobutyl-4-(piperazin-1-ylacetyl)piperazine (2.05 g, 5.46 mmol) and 3,6-dichloropyridazine (810 mg, 5.46 mmol) in dry DMSO (25 mL). Add K2CO3 (3.77 g, 27.3 mmol) and heat the mixture at 120° C. overnight. Cool and partition between CH2Cl2 (100 mL) and 1 N NaOH (150 mL). Extract the aqueous phase with CH2Cl2 (2×100 mL). Combine, dry and evaporate the organic extracts. Triturate the resulting residue with ether and filter off the solid (product). Evaporate the filtrate and chromatograph the resulting residue with EtOAc followed by EtOAc/MeOH (95:5) and EtOAc/MeOH/TEA(95:5:5) to yield additional product. 1H NMR (CDCl3) δ 7.21 (d, 1H), 6.89 (d, 1H), 3.68-3.59 (m, 8H), 3.22 (s, 2H), 2.78-2.62 (m, 5H), 2.38-2.28 (m, 4H), 2.13-2.03 (m, 2H), 1.93-1.8 (m, 2H), 1.73-1.69 (m, 2H); LC-MS (M+1) 378.98.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.[Cl:23][C:24]1[CH:50]=[CH:49][C:27]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[C:30]2[C:38]([N:40]2[CH2:45][CH2:44][CH:43]([C:46]([OH:48])=O)[CH2:42][CH2:41]2)=[O:39])=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C.[N:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[CH2:66][CH2:67][NH2:68]>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:23][C:24]1[CH:50]=[CH:49][C:27]([CH2:28][N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[C:30]2[C:38]([N:40]2[CH2:45][CH2:44][CH:43]([C:46]([NH:68][CH2:67][CH2:66][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][N:60]=3)=[O:48])[CH2:42][CH2:41]2)=[O:39])=[CH:26][CH:25]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: NCCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(NCCc1ccccn1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (235 mg, 1.228 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (166 mg, 1.228 mmol), and 1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (390 mg, 0.982 mmol) were dissolved in 4.0 mL of DCM. The reaction was stirred for ten minutes before adding N-ethyl-N-isopropylpropan-2-amine (0.214 ml, 1.228 mmol) and 2-(pyridin-2-yl)ethanamine (100 mg, 0.819 mmol) as a 1.0 mL DCM solution. The reaction was stirred overnight at room temperature. It was diluted with water and ethyl acetate. The organic phase was washed with water, saturated sodium bicarbonate (twice), and saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude material was triturated with ether and ethyl acetate and filtered to obtain white solid as a product. 1H-NMR (400 MHz, DMSO-d6) 8.46, 7.84, 7.66, 7.60, 7.51, 7.37-7.27, 7.24-7.14, 7.12-7.03, 6.69, 5.46, 4.58-3.75, 3.37, 3.12-2.67, 2.34-2.25, 1.59, 1.33
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([CH3:26])[N:19]=1)=[O:16])(=[O:13])=[O:12].[H][H]>C(OCC)(=O)C.[Pd]>[F:27][C:2]([F:1])([F:28])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([CH3:26])[N:19]=1)=[O:16])(=[O:12])=[O:13]
Reactant: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CC(F)(F)F)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2CCC(F)(F)F)n1

Procedure:
2.9 g of N-[2-(3,3,3-trifluoro-1-propenyl)-phenylsulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea are dissolved in 50 ml of ethyl acetate; there are then added 1.5 g of a 5% palladium/charcoal catalyst, and the mixture is shaken for 16 hours at 20°-25° C. in a hydrogen atmosphere. The catalyst is filtered off, and the residue is completely concentrated by evaporation and subsequently crystallised from an acetone/ether mixture to thus obtain 2.2 g of N-[2-(3,3,3-trifluoropropyl)-phenylsulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea, m.p. 157°-158° C.
Reaction SMILES: [C:1]1([CH:7]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:34]CC3C=CC(OC)=CC=3)([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O>ClCCl.CCOC(C)=O>[C:1]1([CH:7]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:31])([F:32])[F:33])[C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=2)[CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH:14]=[O:15])=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(COC(c2ccc(OC(COc3ccc(C=O)cc3)c3ccccc3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(OCC(Oc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To 44 mg (0.07 mmol) of rac 4-(2-phenyl-2-{4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-benzaldehyde in 2 mL of dichloroethane 33 mg (0.15 mmol) of DDQ and a drop of water were added. The reaction mixture was stirred at 70° C. overnight, cooled to room temperature and was diluted with dichloromethane and EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography on silica gel with EtOAc/n-heptane 1:5 gave 22 mg (62%) of rac 4-{2-phenyl-2-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-benzaldehyde, MS: 483 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:10]2.I[CH2:32][CH3:33].FC1C=C(F)C=CC=1[C@]12CO[C@@H](COC)C[C@H]1[C@@H](C)SC(NC(=O)C1C=CC=CC=1)=N2.CO>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:32][CH3:33])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[N:10]2
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Reactant: CCI
Agent: COC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Solvent: CO
Solvent: ClCCl
Product: CCOC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) was reacted with iodoethane according to the method described for synthesis of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C20) in Example 2. In this case, additional silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) was carried out. The product was obtained as a white solid. Yield: 24.8 mg, 53.8 μmol, 41%. LCMS m/z 461.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.39-7.48 (m, 3H), 7.01-7.11 (m, 2H), 4.14 (br d, J=12 Hz, 1H), 3.89 (d, J=11.9 Hz, 1H), 3.82-3.89 (m, 1H), 3.47-3.61 (m, 4H), 3.19-3.27 (br m, 1H), 2.97-3.04 (m, 1H), 1.74-1.82 (m, 1H), 1.51-1.63 (m, 1H), 1.25 (d, J=6.8 Hz, 3H), 1.17 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Reactant: COc1ccc(CCl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a mixture of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.40 g), 1-(chloromethyl)-4-methoxybenzene (0.21 g) and sodium carbonate (0.28 g) in 1,2-dimethoxyethane (6.00 mL)-water (2.00 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.08 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.30 g).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([C:17](SC)=[S:18])[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2=[O:16])[CH:5]=1.C>C(O)C.C(C(C)=O)C.C(OC(C)C)(C)C>[CH2:1]([NH:3][C:17]([C:10]1([C:6]2[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][S:11]1=[O:16])=[S:18])[CH3:2]
Reactant: CSC(=S)C1(c2cccnc2)CCCCS1=O
Reactant: CCN
Solvent: CCO
Solvent: CC(C)OC(C)C
Solvent: CCC(C)=O
Product: CCNC(=S)C1(c2cccnc2)CCCCS1=O
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
Ethylamine (34 g) is added dropwise, in the course of 5 minutes, to a solution of methyl 2-(pyridin-3-yl)tetrahydrothiopyran-2-carbodithioate 1-oxide (10.7 g) in ethanol (120 cc), kept at between 20° and 25° C. The solution is then stirred for 1 hour 30 minutes at the same temperature and then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The product obtained (12 g) is chromatographed on neutral silica gel (0.040-0.063 mm; 145 g) contained in a column of diameter 4 cm, under a pressure of 40 kPa. The column is eluted with a mixture of ethyl acetate and methanol (90/10 by volume), one 300 cc fraction and thirty-two 120 cc fractions being collected. Fractions 16 to 33 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The product obtained (4 g) is dissolved in a boiling mixture of methyl ethyl ketone (9 cc) and diisopropyl ether (2 cc); after cooling, the solution is kept at a temperature of about 0° C. for 2 hours. The resulting crystals are filtered off, washed with methyl ethyl ketone (3 cc) and with diisopropyl ether (0.5 cc) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The product obtained (2.6 g), to which 1.2 g prepared under the same condtions in an earlier operation have been added, is dissolved in boiling methyl ethyl ketone (25 cc); the solution is treated with decolourising charcoal (0.2 g) and filtered hot and the filtrate is cooled and kept at a temperature of about 0° C. for 1 hour 30 minutes. The resulting crystals are filtered off, washed with methyl ethyl ketone (6 cc) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. This gives the A form of N-ethyl-2-(pyridin-3-yl)tetrahydrothiopyran-2-carbothioamide 1-oxide (3 g) melting initially at about 169° C. and then, after resolidification, at 183° C. [Rf=0.32; chromatography on a thin layer of silica gel; solvent: ethyl acetate/methanol (80/20 by volume)].
Reaction SMILES: C(OC(=O)[N:5]([C:16]1[N:21]=[C:20]([CH3:22])[C:19]([C:23]#[N:24])=[CH:18][N:17]=1)[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)C.[OH-].[Na+]>CO>[CH3:22][C:20]1[C:19]([C:23]#[N:24])=[CH:18][N:17]=[C:16]([NH:5][CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:21]=1
Reactant: CCOC(=O)N(CCCC1CCN(C)CC1)c1ncc(C#N)c(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 ml 3-neck flask, (5-cyano-4-methyl-pyrimidin-2-yl)-[3-(1-methyl-piperidin-4-yl)-propyl]-carbamic acid ethyl ester (1.4 g, 4.05 mmol) was dissolved in MeOH (16.0 g). The resultant solution was cooled to about 0-5° C., and then a sodium hydroxide solution [prepared from NaOH (0.6 g) and water (1.2 g)] was added at about 0-5° C. The resultant mixture was stirred at 0° C., then warmed to ambient temperature over 3 h. The reaction was monitored by HPLC. The resultant mixture was concentrated by rotary evaporation at about 20-25° C. and the resultant solid was slurried in water (20 g), overnight at ambient temperature. The solid was collected by filtration, washed with water (20 g) and dried in a vacuum oven at about 70-80° C. overnight to yield the title compound.