Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[Na].O[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=[S:15]>C1C=CC=CC=1.CN(C=O)C.CN(C1C=CN=CC=1)C>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][C:2]1[CH:1]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: On1ccccc1=S
Agent: CN(C)c1ccncc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: c1ccc(Sc2ccccn2)nc1
Yield: 72 %

Procedure:
360 mg (1 mmol) of peracetoquinic acid (32) are taken into solution with stirring in 5 ml of benzene with the addition of 1 ml of oxalyl chloride and 1 drop of DMF for 3 hours. After evaporation to dryness, the residue is taken up in 5 ml of benzene and added with stirring to a suspension of 180 mg (1.1 mmol) of the sodium salt of N-hydroxypyridine-2-thione and 12 mg (0.1 mmol) of DMAP. The reaction mixture is kept refluxing in 10 ml of toluuene under an atmosphere of nitrogen. After 2 hours of heating under reflux, the cooled reaction mixture is filtered on Celite and evaporated to dryness. By flash chromatography on silica (90% of CH2Cl2 ; 10% EtOAc), 306 mg of pyridyl sulfide of formula (34) are obtained in the form of a yellowish oil. Yield 72%.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:7]([NH:6][C:4]([C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccccc1C(=O)NCc1ccccc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 24.8 %

Procedure:
A mixture of 2-amino-N-benzylbenzamide (400 mg), ethyl bromoacetate (295 mg) and potassium carbonate (244 mg) in N,N-dimethylformamide (10 ml) was stirred at 100° C. for 17 hours. After cooling, the reaction mixture was poured into ice-cold water and extracted with diethyl ether. The extract was washed with water and dried. Removal of the solvent gave a residue, which was chromatographed on silica gel. Elution with chloroform gave ethyl 2-[2-(N-benzylcarbamoyl)anilino]acetate (137 mg).
Reaction SMILES: C([N:4]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=2)[C:11]2[C:6](=[C:7]([OH:23])[C:8]([OH:22])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])C.[ClH:24]>C(O)C>[OH2:3].[ClH:24].[OH:22][C:8]1[C:7]([OH:23])=[C:6]2[C:11]([C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=3)[CH2:13][NH:4][CH2:5]2)=[CH:10][CH:9]=1
Reactant: CC(=O)N1Cc2c(ccc(O)c2O)[C@@H](c2ccc(O)c(O)c2)C1
Agent: Cl
Solvent: CCO
Product: O
Product: Oc1ccc([C@H]2CNCc3c2ccc(O)c3O)cc1O

Procedure:
(i) To 1.15 g of (R)-(-)-N-acetyl-7,8-dihydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline 1/4hydrate were added 9 ml of 3N hydrochloric acid and 9 ml of ethanol, and the mixture was heated under an argon gas stream for 24 hours. After the reaction solution was cooled, the crystals which separated out were collected by filtration, affording 1.09 g (R)-(+)-7,8-dihydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride monohydrate. [α]D20 =+15° (C=1, CH3OH)
Reaction SMILES: N1C=CC=CC=1.[C:7]([NH2:16])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=O)=[CH:21][CH:20]=1.C(O)(C)C>C1(C)C(C)=CC=CC=1>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]2[O:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:7](=[O:15])[N:16]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NC(=O)c1ccccc1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Solvent: CC(C)O
Product: COc1ccc(-c2nc(=O)c3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.5 ml pyridine is added to a suspension of 0.25 mol salicylamide in 50 ml xylene. While boiling under reflux (water separator) 0.26 mol 4-methoxybenzoyl chloride is added within 3 hours and it is heated to boiling for a further 3 hours under reflux. A further 2.5 ml pyridine is added and it is heated for a further 8 hours. After cooling to room temperature it is poured onto 400 ml isopropanol and suction filtered. The residue is recrystallized from ethylene glycol monomethyl ether.
Reaction SMILES: [CH2:1]([N:3]([CH2:62][CH3:63])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:61])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][C:53](=[O:60])[N:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].[CH3:64][CH:65]([S:67](Cl)(=[O:69])=[O:68])[CH3:66].S(Cl)(Cl)(=O)=O>>[CH2:62]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:61])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][C:53]([N:54]3[CH2:59][CH2:58][N:57]([S:67]([CH:65]([CH3:66])[CH3:64])(=[O:69])=[O:68])[CH2:56][CH2:55]3)=[O:60])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:63]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCNCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=S(=O)(Cl)Cl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCN(S(=O)(=O)C(C)C)CC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 262b according to the procedure described in Example 290 using propane-2-sulfonyl chloride as the sulfonyl chloride. MS (ES, m/z) 983.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CCN(C(C)C)C(C)C.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26][Br:27].[CH3:28][CH2:29][O:30][C:31]([CH3:33])=O>CN(C=O)C>[F:11][C:3]1[C:2]([N:1]2[CH2:33][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:22][CH2:23][O:24][CH2:25][CH2:26][Br:27])=[O:6]
Reactant: BrCCOCCBr
Reactant: CCOC(C)=O
Reactant: Nc1cccc(C(=O)O)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCCOCCBr)c1cccc(N2CCOCC2)c1F
Temperature: 80 °C
Yield: 38 %

Procedure:
To a solution of 3-amino-2-fluorobenzoic acid (500 mg, 3.1 mmol) in DMF (10 mL) was added DIEA (4.5 mL) and 2-bromoethylether (5 eq) and the reaction heated to 80° C. for 18 h. The reaction was allowed to cool to rt, diluted with EtOAc and washed with saturated NH4Cl (aq). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (petroleum ether: EtOAc) to give 2-(2-bromoethoxy)ethyl 2-fluoro-3-morpholinobenzoate (450 mg, 38%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:28]=[C:27]([NH:26][C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=4)[N:29]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccc(Cl)cc1
Product: O=C1Cc2cnc(Nc3ccc(Cl)cc3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(4-chlorophenyl)guanidine were converted to I-11 (23%): HRMS Calcd. for C18H12Cl2N4O: 371.0466, Found 371.0471.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C@:16]12[CH2:33][CH2:32][C@H:31]3[C@@H:21]([CH2:22][CH2:23][C:24]4[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:34])[CH:25]=4)[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[C:35](O)=[O:36].C(N(CC)CC)C.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:35]([C@H:17]2[CH2:18][CH2:19][C@H:20]3[C@H:21]4[C@H:31]([CH2:32][CH2:33][C@:16]23[CH3:15])[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]2)[CH2:23][CH2:22]4)=[O:36])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 74 %

Procedure:
0.108 ml of benzhydrylamine was added to a solution of 100 mg of androsta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of 4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml of methylene chloride. 0.037 ml of methanesulfonyl chloride was divided into three portions and added to this reaction mixture at intervals of 30 minutes at room temperature, whilst stirring. One hour after finishing the addition of methanesulfonyl chloride, the reaction mixture was diluted with methylene chloride, washed with 1N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was crystallized from acetone to give 113.2 mg (yield 74%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[C:10]([F:12])=[CH:11][C:6]=2[N:5]=[C:4]1CC#N)[CH3:2].C([N:25]([CH2:28]C)CC)C.[SH2:30]>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[C:10]([F:12])=[CH:11][C:6]=2[N:5]=[C:4]1[C:28](=[S:30])[NH2:25])[CH3:2]
Reactant: CCN(CC)CC
Reactant: S
Reactant: CCn1c(CC#N)nc2cc(F)c(N3CCN(C)CC3)cc21
Solvent: c1ccncc1
Product: CCn1c(C(N)=S)nc2cc(F)c(N3CCN(C)CC3)cc21
Yield: 80 %

Procedure:
1-Ethyl-5-fluoro-6-(4-methyl-1-piperazinyl)-2-benzimidazoleacetonitrile (834 mg, 2.77 mmol) is dissolved in pyridine (20 ml) and triethylamine (2.8 g, 27.7 mmol). The solution is cooled to 0°. Subsequently, hydrogen sulfide is introduced during 30 minutes. The thus-obtained deep green solution is heated to 45° for 2 hours. The solvent is distilled off and the residue is dried in a high vacuum and then crystallized from acetonitrile. The crystals are filtered off, dissolved in an ethyl acetate/methanol mixture (10 ml, 1:1) and then chromatographed on silica gel (eluent: ethyl acetate/methanol 6:4). The product is recrystallized from ethyl acetate. There are obtained 745 mg (80%) of 1-ethyl-5-fluoro-6-[4-methyl-1-piperazinyl]-2-benzimidazolecarbothioamide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.O>[CH3:24][S:25]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:3]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCN2CC[C@H](O)C2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1

Procedure:
(S)-3-Hydroxy-1-(4-methoxyphenethyl)pyrrolidine (541 mg, 2.45 mmol) was dissolved in dichloromethane (15 ml). Triethylamine (272 mg, 2.69 mmol) and methanesulfonyl chloride (295 mg, 2.58 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred at 0° C. for 1 hour. The reaction liquid was distributed in dichloromethane and water. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a solvent mixture of dichloromethane and methanol (50:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-(4-methoxyphenethyl)pyrrolidine in the form of a white solid (734 mg, 100%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[NH2:29])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[NH:29][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1
Product: COc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (167 mg, 0.94 mmol) was reacted with the product from Example 50b (245 mg, 0.94 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (325 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.35 (s, 3H) 2.77 (s, 3H) 3.73 (s, 3H) 6.26 (d, J=6.99 Hz, 1H) 6.85 (d, J=8.82 Hz, 2H) 7.11 (d, J=7.72 Hz, 1H) 7.26 (d, J=8.82 Hz, 2H) 7.31 (s, 1H) 7.80 (d, J=8.46 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.82 Hz, 1H) 11.04 (br. s., 1H) 14.32 (br. s., 1H); MS ESI+ m/z 388 (M+H)+.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:51]([O:55][C:56](=[O:63])[C@H:57]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH2:58])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C.C(Cl)CCl>[C:51]([O:55][C:56](=[O:63])[C@@H:57]([NH:58][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:30])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:28])[CH2:59][CH:60]([CH3:61])[CH3:62])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
To a solution of 250 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 4 ml DMF were added 124 mg HOAt, 174 mg EDC, 0.37 ml DIPEA and 136 mg leucine tert-butyl ester hydrochloride. After stirring for 12 h it was concentrated and the residue dissolved in dichloromethane. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:21][C:22]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[S:23])[C@H:14]([CH2:15]O)[CH2:13][C@H:12]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[O:11][CH2:10]1.C(OC[C@@H]1OC[C@]2(C3C=CC(F)=CC=3F)N=C(NC(=O)C3C=CC=CC=3)SC[C@@H]2C1)C1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@@H:12]([C:17]3([CH3:20])[CH2:18][CH2:19]3)[CH2:13][C@H:14]1[CH2:15][S:23][C:22]([NH:24][C:25](=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[N:21]2
Reactant: CC1([C@H]2C[C@@H](CO)[C@](NC(=S)NC(=O)c3ccccc3)(c3ccc(F)cc3F)CO2)CC1
Agent: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Product: CC1([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)CC1

Procedure:
rel-N-{[(3S,4R,6R)-3-(2,4-Difluorophenyl)-4-(hydroxymethyl)-6-(1-methylcyclopropyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C59) was converted to the product using the method described for synthesis of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C8) in Preparation P1. The product was obtained as a white solid. Yield: 1.1 g, 16.8 mmol. LCMS m/z 443 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[OH:15][C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[OH:15][C:16]1[N:20]([CH3:21])[N:19]=[CH:18][C:17]=1[C:12]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)=[O:13]
Reactant: Cc1ccc(C(=O)Cl)c2cccnc12
Reactant: Cn1nccc1O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)c2cnn(C)c2O)c2cccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 0° C., 1.70 g of 8-methylquinoline-5-carbonyl chloride were added to 0.81 g of 5-hydroxy-1-methylpyrazole and 0.92 g of triethylamine in 30 ml of acetonitrile. The reaction mixture was stirred for 3 hours at room temperature and then taken up in ethyl acetate and washed with aqueous sodium carbonate solution, and the organic phase was then dried and concentrated. The residue was treated with 10 ml of dioxane and 1.71 g of dry potassium carbonate and heated under reflux for 14 hours. After cooling, water was added and the aqueous phase was washed with ethyl acetate and acidified with 2N hydrochloric acid. The precipitate was filtered off under suction and the acidified aqueous phase was extracted with ethyl acetate. This organic phase was dried and concentrated. The residue and the precipitate were combined.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH2:30][O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][C:35]2=[O:40])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH2:30][O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][C:35]3=[O:40])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1COCCN1CCOCC1=O
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1COCCN1CCOCC1=O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 4-{2-[(6-chloro-2-methylpyridin-3-yl)methoxy]ethyl}morpholin-3-one (137 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C1O[C:40]2[CH:39]=[CH:38][C:12]([CH2:13][N:14]([C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=4)[CH:26]=3)[CH2:15][CH2:16][CH2:17][N:18]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:11][C:10]=2O1.C1O[C:61]2[CH:60]=CC(CNCCCN3C=CC=CC=C3)=[CH:45][C:44]=2O1>>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[C:12]1([CH2:13][N:14]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=3)[CH:26]=2)[CH2:15][CH2:16][CH2:17][N:18]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=[CH:19]2)[C:11]2[C:10](=[CH:45][CH:44]=[CH:61][CH:60]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: C1=CC=CN(CCCNCc2ccc3c(c2)OCO3)C=C1
Reactant: Fc1cc(F)cc(-c2cc(N(CCCN3C=CC=CC=C3)Cc3ccc4c(c3)OCO4)on2)c1
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(F)cc(-c2cc(N(CCCN3C=CC=CC=C3)Cc3cccc4ccccc34)on2)c1

Procedure:
The title compound is prepared using a similar procedure as described for the preparation of 3,4-methylenedioxybenzyl-[3-(3,5-difluorophenyl)-isoxazol-5-yl]-(3-azepin-1-yl-propyl)-amine TFA salt (example 4) while substituting 1-Naphthylmethyl-(3-azepin-1-yl-propyl)-amine for 3,4-methylenedioxybenzyl-(3-azepin-1-yl-propyl)-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8](Cl)(Cl)=[S:9]>C1COCC1>[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[C:8]=[S:9]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccn1
Solvent: C1CCOC1
Product: S=C=Nc1ccccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of 2-aminopyridine (0.94 g, 9.99 mmol, Sigma Aldrich) and TEA (3.06 mL, 21.97 mmol) in THF (40.0 mL) was set stirring at 0° C. under nitrogen. A solution of thiophosgene (0.804 mL, 10.49 mmol, Fluka) in 2 mL THF was added dropwise over 5 minutes, and the reaction was stirred for 3 h at 0° C. Silica was added, and the reaction mixture was adsorbed under reduced pressure. It was purified on 16 g SiO2 (eluent: 0-100% EtOAc/hexanes over 30 min, RediSep Gold). The product fractions containing the product by TLC (50% EtOAc/hexanes) were combined and concentrated under reduced pressure to give 2-isothiocyanatopyridine (852 mg, 63%). m/z (ESI, +ve) 137.0 (M+H)+.
Reaction SMILES: [OH-].[OH:2]CC[N+](CCO)(C)C.[CH3:11][N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15].[CH2:19]1[O:21][CH2:20]1>O>[OH-:2].[OH:15][CH2:14][CH2:13][N+:12]([CH2:19][CH2:20][OH:21])([CH2:16][CH2:17][OH:18])[CH3:11]
Reactant: C1CO1
Reactant: C[N+](C)(CCO)CCO
Reactant: CN(CCO)CCO
Agent: [OH-]
Solvent: O
Product: C[N+](CCO)(CCO)CCO
Reaction time: 96 h

Procedure:
The procedure of Example 1 for the reparation of bis-(2-hydroxyethyl) dimethyl ammonium hydroxide was followed, except that about 357 grams of methyl diethanolamine (MDEA) was used instead of DMEA, 489 grams of de-ionized water, and 115 grams of ethylene oxide were used. The product is a clear and colorless solution. However, after about four days of standing at room temperature, the product darkened somewhat.
Reaction SMILES: C(OC)(=O)C(C)=C.C=CC1C=CC=CC=1.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=[CH2:25])=[CH2:17].C1(S(OCCCCCCCCCCCC)(=O)=O)C=CC=CC=1.[Na]>O>[CH2:24]1[CH:19]2[CH:18]([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16][CH2:17][CH2:25]1
Reactant: C=Cc1ccccc1C=C
Agent: C=C(C)C(=O)OC
Agent: CCCCCCCCCCCCOS(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: C=Cc1ccccc1
Solvent: O
Product: C1CCC2CCCCC2C1
Temperature: 80 °C

Procedure:
To a 50 kgf/cm2 pressure resistant autoclave equipped with a stirrer, methyl methacrylate 200 parts, styrene 150 parts, a cross-linkable monomer constituted by divinyl benzene 5 parts, sodium dodecyl benzenesulfonate 10 parts, ion exchanged water 1200 parts, and a polymerization initiator constituted by azobis butyronitrile 10 parts were charged. The mixture was sufficiently stirred, then was heated to 80° C. to perform the polymerization. Further, after the start of polymerization, when the amount of consumption of the monomer reached 99.8%, the mixture was cooled to stop the polymerization reaction and thereby obtain a latex of the polymer particles D. The obtained latex of the polymer particles D had a solid content concentration of 39%. Note that, polymer particles D are particles which do not have a core-shell structure. Further, the obtained polymer particles D had an average particle size of 190 nm. Next, to the obtained latex of the polymer particles D, decalin: 15,000 parts were added and the particles were sufficiently dispersed. After that, the moisture was removed by drying in vacuo to thereby obtain a decalin dispersion of the polymer particles D. The obtained dispersion had a solid content concentration of 5%.