Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:24]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:17](=[O:25])[NH:16][C:15]=3[O:14][N:13]=2)[CH2:8][CH2:7]1)=O)C.COC(N1CCC(C2C3C4C=CC=CC=4C(=O)NC=3ON=2)CC1)=O.[ClH:50]>C(O)(=O)C>[ClH:50].[NH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:24]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:17](=[O:25])[NH:16][C:15]=3[O:14][N:13]=2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCC(c2noc3[nH]c(=O)c4ccccc4c23)CC1
Agent: COC(=O)N1CCC(c2noc3[nH]c(=O)c4ccccc4c23)CC1
Agent: Cl
Solvent: CC(=O)O
Product: O=c1[nH]c2onc(C3CCNCC3)c2c2ccccc12

Procedure:
A mixture (1:1, 2.74 g) of 1-(1-ethoxycarbonylpiperidin-4-yl)-isoxazolo[5,4-c]isoquinolin-5(4H)-one and 1-(1-methoxycarbonylpiperidin-4-yl)-isoxazolo[5,4-c]isoquinolin-5(4H)-one was suspended in acetic acid (15 mL) and concentrated hydrochloric acid (15 mL), and the suspension was heated under reflux for 18 hrs. After the completion of the reaction, the solvent was evaporated. Water and a small amount of methanol were added to the precipitated crystals, and the obtained solution was washed with ethyl acetate, and the aqueous phase was concentrated under reduced pressure. The precipitated crystals were washed with isopropyl alcohol and collected by filtration to give 1-(piperidin-4-yl)-isoxazolo[5,4-c]isoquinolin-5(4H)-one hydrochloride (2.39 g).
Reaction SMILES: BrC1C=CC(O)=C(C=1)C(C1C=CC(C)=CC=1)=O.[Br:18][C:19]1[C:20]([CH3:36])=[CH:21][C:22]([O:34]C)=[C:23]([CH:33]=1)[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)=[O:25]>>[Br:18][C:19]1[C:20]([CH3:36])=[CH:21][C:22]([OH:34])=[C:23]([CH:33]=1)[C:24]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)=[O:25]
Reactant: COc1cc(C)c(Br)cc1C(=O)c1ccc(C)cc1
Agent: Cc1ccc(C(=O)c2cc(Br)ccc2O)cc1
Product: Cc1ccc(C(=O)c2cc(Br)c(C)cc2O)cc1

Procedure:
Employing the same general procedure as for the 5-bromo-2-hydroxy-4′-methylbenzophenone (Compound K), 319 mg (1.0 mmol) of 5-bromo-2-methoxy-4-methyl-4′-methylbenzophenone (Compound I) was converted into the title compound using 2.4 mL (2.4 mmol) of boron tribromide (1M in dichloromethane) and 10 mL of dichloromethane. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][CH:2]([CH:5]=O)[CH:3]=O.[NH2:7][C:8]1[CH:12]=[CH:11][NH:10][N:9]=1>C(O)(=O)C>[Br:1][C:2]1[CH:5]=[C:12]2[CH:11]=[N:10][NH:9][C:8]2=[N:7][CH:3]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: Brc1cnc2[nH]ncc2c1
Yield: 11.2 %

Procedure:
Dissolve 2-bromomalonaldehyde (Aldrich; 2.5 g, 16.5 mmol) and 3-aminopyrazole (Aldrich; 1.38 g, 16.5 mmol) in glacial acetic acid (25 mL) and reflux under nitrogen for 2 h. Concentrate under reduced pressure and dissolve the residue in absolute methanol (150 mL), vacuum filter through a pad of diatomaceous earth and concentrate under reduced pressure. Purify via chromatography (silica gel, hexane to 50% ethyl acetate/50% hexane) to obtain 365 mg (11%) of the title compound as a light yellow solid. TOF MS ES+ exact mass calculated for C6H5N3Br (p+H): m/z=197.9667, Found: 197.9674.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:32]C)[N:6]2[CH2:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][P:22](=[O:29])([O:26]CC)[O:23]CC)=[CH:19][CH:18]=1.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:32])[N:6]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][P:22](=[O:23])([OH:29])[OH:26])=[CH:30][CH:31]=1
Reactant: CCOP(=O)(Cc1ccc(Cn2c(OC)nc3c(N)nc(OCCOC)nc32)cc1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COCCOc1nc(N)c2[nH]c(=O)n(Cc3ccc(CP(=O)(O)O)cc3)c2n1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To a solution of diethyl 4-((6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzylphosphonate (1 equiv.) in CH2Cl2 (0.10 M) at 0° C. was slowly added trimethylsilyl bromide (10 equiv.). After 1 h the ice-bath was removed and the reaction mixture was allowed to stir at 22° C. for 2 h. At this point the volatiles were removed in vacuo and the resulting residue was purified by Reverse Phase-HPLC using a 20-90% 0.5 mM NH4OAc (in MeCN) to 10 mM NH4OAc (in water) gradient to deliver the title compound (29%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N(CC)CC)C.[NH:32]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[NH2:33]>C(Cl)Cl>[CH2:37]([O:36][C:34]([NH:32][NH:33][C:14]([C@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1C(=O)O
Reactant: NNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1C(=O)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A solution of (R)-1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid (1.146 g, 5.00 mmol) in dehydrated methylene chloride (25 mL) was cooled to 0° C. under an argon atmosphere and gradually added dropwise isobutyl chloroformate (0.682 g) so that the temperature does not exceed 0° C. Then, triethylamine (0.505 g) was gradually added so that the temperature does not exceed 0° C., followed by stirring 30 minutes, thereby a mixed acid anhydride was prepared in the reaction system. To this reaction mixture was gradually added benzyl hydrazinecarboxylate (0.830 g), after the addition, followed by raising the temperature to room temperature and stirring for 1 hour. This reaction mixture was washed with 0.5M hydrochloric acid and saturated brine, the organic layer was dried over magnesium sulfate and then distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=30/1) to afford 1.53 g of the title compound (yield 80.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[C:11]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc(Br)cc(-c2nc3ccccc3n2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 g (75.8 mmol) of 3,5-dibromobenzaldehyde and 16.8 g (90.9 mmol) of N-phenyl-o-phenylenediamine were dissolved in 150 mL of acetic acid. The solution was agitated at room temperature for 30 minutes. Next, 37 g (83.4 mmol) of lead (IV) acetate was added thereto. The resulting product was agitated at 50° C. for 1 hour. Then, water was poured into the acquired reactant. The resulting product was treated with ethyl acetate to perform extraction and the solvent was removed under reduced pressure. The extract was separated through a column and dried, gaining 9.5 g (Y=29%) of a yellow solid.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:30][CH2:31][CH2:32][CH2:33][S:34](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:36])=[O:35]>>[C:26]([O:25][C:23]([NH:22][CH:19]([CH2:20][NH:21][S:34]([CH2:33][CH2:32][CH2:31][Cl:30])(=[O:36])=[O:35])[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)OC(C)(C)C

Procedure:
3-Hexadecylthio-2-tert-butoxycarbonylaminopropylamine IVe4 is allowed to react and worked up by the same procedure as described in (4). m.p. 100.5°-101.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][NH:6][C:7]1([CH3:17])[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]([CH3:16])([CH3:15])[CH2:8]1)#N.[ClH:18]>C(O)C.[Pd]>[ClH:18].[CH3:17][C:7]1([N:6]2[CH2:5][CH2:4][CH2:3][CH2:1]2)[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]([CH3:16])([CH3:15])[CH2:8]1
Reactant: CC1(C)CC(C)(C)CC(C)(NCCCC#N)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1(C)CC(C)(C)CC(C)(N2CCCC2)C1
Yield: 49 %

Procedure:
N-(3-Cyanopropyl)-1,3,3,5,5-pentamethylcyclohexylamine (2) (1.2 g, 5.1 mmol) in ethanol (120 ml) and conc. HCl (4 ml) was hydrogenated over 10% Pd/C (250 mg) at 7 bar for 40 h (after 24 h additional portion of catalyst (260 mg) was added). The catalyst was removed by filtration through celite pad and solvent evaporated. The residue was treated with acltornitrile, the solids filtered off and the filtrate evaporated. The crude product was crystallized from ether to give N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine hydrochloride (3) (0.67 g, 49%) with m.p. 156-158° C.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[C:34]1[N:38]([CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[N:37]=[CH:36][C:35]=1[C:45]([O:47][CH2:48][CH3:49])=[O:46].BrC1C(C)=CC(C#N)=NC=1C>O1CCOCC1.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.O>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]([O:10][CH3:11])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=2[CH3:8])[CH:22]=[CH:21][C:20]=1[C:34]1[N:38]([CH:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[N:37]=[CH:36][C:35]=1[C:45]([O:47][CH2:48][CH3:49])=[O:46]
Reactant: COc1nc(C)cc(C)c1Br
Reactant: CCOC(=O)c1cnn(C2CCOCC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C#N)nc(C)c1Br
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(C2CCOCC2)c1-c1ccc(-c2c(C)cc(C)nc2OC)cc1F

Procedure:
Water (5 mL), 3-bromo-2-methoxy-4,6-dimethylpyridine obtained in Preparation Example 26 (784 mg), Pd(PPh3)4 (380 mg) and cesium carbonate (2.36 g) were added to a solution of ethyl 5-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate obtained in Preparation Example 3 (2.04 g) in 1,4-dioxane (20 mL), and the reaction mixture was reacted at 110° C. for two hours in a nitrogen atmosphere. The reaction mixture was returned to room temperature and then filtered through Celite™. The filtrate was concentrated under reduced pressure. Ethyl acetate (100 mL) and water (100 mL) were added to the residue. The aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 10% to 23%). The title compound obtained by the same method (578 mg) was combined, and the combined product was purified again by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 70%) to give the title compound (2.07 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].[Cl:15][C:16]1[CH:17]=[C:18]([N:23]=[C:24]=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>CC(C)=O>[F:10][C:7]([F:8])([F:9])[C:6]([NH:5][C:4]1[CH:3]=[C:2]([NH:1][C:24]([NH:23][C:18]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=2)=[O:25])[CH:14]=[CH:13][CH:12]=1)=[O:11]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: Nc1cccc(NC(=O)C(F)(F)F)c1
Solvent: CC(C)=O
Product: O=C(Nc1cccc(NC(=O)C(F)(F)F)c1)Nc1ccc(Cl)c(Cl)c1

Procedure:
Four and one-tenth grams of m-amino trifluoro acetanilide is dissolved in 100 ml of acetone and 3.8 g. of 3,4-dichlorophenyl isocyanate is added. The mixture is heated to reflux and crystallizes from acetone on cooling. Yield is 6.4 g., m.p. 221°-223° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([CH:15]([O:17][C:18]2[CH:40]=[CH:39][C:21]3[C:22]4[N:26]([CH2:27][CH2:28][O:29][C:20]=3[CH:19]=2)[CH:25]=[C:24]([C:30]2[N:31]([CH:36]([CH3:38])[CH3:37])[N:32]=[C:33]([CH3:35])[N:34]=2)[N:23]=4)[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:14][CH2:13][CH2:12][CH:11]([CH:15]([O:17][C:18]2[CH:40]=[CH:39][C:21]3[C:22]4[N:26]([CH2:27][CH2:28][O:29][C:20]=3[CH:19]=2)[CH:25]=[C:24]([C:30]2[N:31]([CH:36]([CH3:37])[CH3:38])[N:32]=[C:33]([CH3:35])[N:34]=2)[N:23]=4)[CH3:16])[CH2:10][CH2:9]1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCCNCC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 4-{1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}azepane-1-carboxylic acid tertbutyl ester (60 mg, 0.11 mmol) in dioxane (1 mL) was added HCl (2.5M in MeOH, 1 mL) and the reaction mixture was stirred for 1 h at RT. Volatiles were then removed in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording 8-(1-Azepan-4-ylethoxy)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (50 mg, quantitative). LCMS: RT 2.26 min [M+H]+ 451.2
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[S:37][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:40]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:39][CH:40]=1)(=[O:34])=[O:35])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.6) (0.404 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as an off-white solid (0.24 g, 41%). MS (ISN) 585.2 [(M−H)−]; mp 237° C.
Reaction SMILES: [OH-].[K+].S([O-])([O-])(=O)=O.C([N+:12]([CH2:21][CH2:22][CH2:23][CH3:24])(CCCC)CCCC)CCC.C([N+:29](CCCC)(CCCC)CCCC)CCC.O.[ClH:43].[O:44]1CCO[CH2:46][CH2:45]1>C1(C)C=CC=CC=1.CO.C(Cl)(Cl)Cl>[ClH:43].[ClH:43].[O:44]1[CH2:45][CH2:46][CH2:24][CH2:23][CH:22]1[CH2:21][NH:12][NH2:29]
Reactant: C1COCCO1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: NNCC1CCCCO1
Temperature: 50 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of the Compound (Ih) (10 g, 58 mmol), 2-(tetrahydropyranyl)methylbromide (10 mL, 81 mmol), potassium hydroxide (4.89 g, 87 mmol) and tetrabutylammonium sulfate (1.97 g, 5.8 mmol) in toluene (200 mL) was heated under reflux for 9 hours. To the reaction mixture was added water (200 mL), and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give Compound (IIh) (9.30 g). The Compound (IIh) was dissolved in a mixed solvent of methanol (65 mL) and chloroform (30 mL), to the solution was added 4 mol/L HCl/1,4-dioxane (65 mL) at room temperature, and the reaction mixture was stirred at 50° C. for 1 hour. The solvent was evaporated under reduced pressure, to the concentrated residue was added ethyl acetate (100 mL), and the mixture was stirred for 1 hour at room temperature. The resulting precipitate was collected by filtration, washed with ethyl acetate (5 mL) twice, and dried under reduced pressure to give the title Compound (IIIh) (6.79 g, 70%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:9]2[S:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:20]O>>[CH2:13]([C:12]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([O:3][CH3:20])=[O:2])[C:9]=2[S:10][CH:11]=1)[CH3:14]
Reactant: CO
Reactant: CCc1csc2c(C(=O)O)cccc12
Agent: O=S(=O)(O)O
Product: CCc1csc2c(C(=O)OC)cccc12

Procedure:
7-Carboxy-3-ethylbenzo[b]thiophene (3.20 g) and concentrated sulfuric acid were stirred in methanol (100 ml) at 60° C. for 16 hr. The reaction mixture was concentrated and chloroform was added thereto. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. The chloroform was separated, and the residue was dried over magnesium sulfate, and concentrated to give the objective compound (3.04 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:25])[N:17]=[C:16]([S:26][CH3:27])[N:15]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO[CH:32](OC)[N:33]([CH3:35])[CH3:34]>>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18](/[CH:25]=[CH:32]/[N:33]([CH3:35])[CH3:34])[N:17]=[C:16]([S:26][CH3:27])[N:15]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Product: CCOC(=O)c1c(/C=C/N(C)C)nc(SC)nc1Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in Example 1e by starting from ethyl 4-(3,5-bis(trifluoro methyl)phenylamino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (1.52 g, 3.6 mmol) and N,N-dimethylformamide dimethylacetal (743 uL, 5.2 mmol) and continuing until the reaction yielded the crude title compound (E)-ethyl 4-(3,5-bis(trifluoromethyl)phenylamino)-6-(2-(dimethylamino)vinyl)-2-(methyl thio)pyrimidine-5-carboxylate. The resultant compound was used for the next step without further purification.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.CN(C)CCN(C)C.[Cl:22][C:23]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:26]>O1CCCC1.O>[Cl:22][C:23]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)([C:10]1[N:9]([CH2:8][O:7][CH3:6])[CH:13]=[CH:12][N:11]=1)[OH:26]
Reactant: COCn1ccnc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
At -60° C. and under a nitrogen atmosphere, 44 ml. (0.072 mol) of n-butyl lithium (15% solution in n-hexane) was added dropwise under stirring to a solution of 7.8 g (0.07 mol) of 1-(methoxymethyl)imidazole and 8.1 g (0.072 mol) of N,N,N',N'-tetramethylethylenediamine in 100 ml of anhydrous tetrahydrofuran. The mixture was stirred for one hour and then 18.9 g (0.070 mol) of 2,4-dichloro-4'-fluorobenzophenone in 100 ml of anhydrous tetrahydrofuran were added at -60° C. The solution was stirred for one hour at -60° C. and kept standing overnight at room temperature. Then 50 ml of water were added and the solid matter formed was filtered off. The filtrate was extracted with tetrahydrofuran and diethyl ether. The organic phase was dried over sodium sulphate and the solvents were distilled off. Diethyl ether was added to the semisolid residue and the solid matter was filtered off. This product was combined with the solid matter obtained after the addition of water. The substance was twice crystallised from acetone with a small amount of dimethylformamide. α-(2,4-Dichlorophenyl)-α-(p-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol was obtained. Melting point 179° C.
Reaction SMILES: CCOC(C)=O.[O:7]=[C:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]3)=[CH:13][CH:14]=2)[NH:9]1.Cl.CCOC(C)=O.C(Cl)(Cl)Cl>O>[NH2:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][C:8](=[O:7])[NH:9]3)=[CH:14][CH:13]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc3c(c2)NC(=O)CC3)CC1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: NC1CCN(Cc2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an EtOAc (130 mL) solution of the compound (37.8 g) obtained in Step 1-5, 4 M HCl/EtOAc solution (263 mL) was added under ice cooling and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc (200 mL) and filtrated to obtain a solid. To the solid, CHCl3 (200 mL) and H2O (200 mL) were added and the mixture was stirred for 15 minutes. After a water layer and an organic layer were separated, the water layer was washed with CHCl3 twice. To the water layer, a 2 M aqueous NaOH solution was added to adjust to pH 10 and thereafter the solution was extracted 30 times with CHCl3. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Chromatorex NH, mobile phase: MeOH/CHCl3=1/4; v/v) to obtain 7-[(4-aminopiperidin-1-yl)methyl]-3,4-dihydroquinolin-2(1H)-one (17.9 g, a colorless solid).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[C:11]3[CH:15]=[CH:14][S:13][C:12]=13)[N+:9](CCCS([O-])(=O)=O)=[C:8]([CH3:23])[C:7]2([CH3:25])[CH3:24])([OH:3])=[O:2].C1CS(=O)(=O)OC1.[OH-].[Na+]>S1(CCCC1)(=O)=O.Cl>[CH3:23][C:8]1[C:7]([CH3:24])([CH3:25])[C:6]2[C:10](=[C:11]3[CH:15]=[CH:14][S:13][C:12]3=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[N:9]=1
Reactant: CC1=[N+](CCCS(=O)(=O)[O-])c2c(cc(C(=O)O)c3sccc23)C1(C)C
Agent: Cl
Agent: O=S1(=O)CCCO1
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: CC1=Nc2c(cc(C(=O)O)c3sccc23)C1(C)C
Temperature: 25 °C

Procedure:
Synthesis of 5-carboxy-2,3,3-trimethyl-1-(3-sulfonatopropyl)-3H-thieno[2,3-g]indol-1-ium BE: A solution of BD (210 mg, 0.81 mmole) and 1,3-propanesultone (530 mg, 4.3 mmole) in 0.4 mL sulfolane was heated at 180° C. for 1 hr and cooled down to 25° C. The reaction was diluted with 0.5 mL 6 N HCl and heated to 80° C. for 1 hr and cooled down to to 25° C. The solution was neutralized with 2N NaOH solution to pH 9. The product was purified by reverse phase HPLC eluted with a gradient of CH3CN over 0.1 N TEAB buffer. The yield of the desired product BE was 172 mg (44%).