Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:37])([CH2:31]OS(C)(=O)=O)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10].[NH:38]1[CH:42]=[N:41][CH:40]=[N:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.C(OC(C)C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]([OH:37])([CH2:31][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10]
Reactant: c1nc[nH]n1
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@@](O)(Cn1cncn1)c1ccccc1F
Temperature: 80 °C
Yield: 76 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (2.2 g) was dissolved in 40 ml of dimethylformamide, to which 1.39 g of 1H-1,2,4-triazole and 5.55 g of potassium carbonate were added. The mixture was heated at 80° C. for 4 hours. The reaction solution was diluted with a mixture of 150 ml of ethyl acetate and 50 ml of diisopropyl ether, and washed with water (40 ml×2), 1N-hydrochloric acid (40 ml×2) and 20 ml of aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=1:1 to 1:2). The desired fraction was concentrated and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1.59 g of 1-[(1R,2S)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (yield: 75%) as colorless powdery crystals.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[CH:8]([NH2:13])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:5])([CH3:4])[CH3:3].[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=O.C(N(CC)CC)C>ClCCl>[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=[N:13][CH:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7]([O:6][C:2]([CH3:3])([CH3:5])[CH3:4])=[O:14]
Reactant: CC(C)CC(N)C(=O)OC(C)(C)C
Reactant: O=Cc1nccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(N=Cc1nccs1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A stirred mixture of 2-amino-4-methyl-pentanoic acid tert-butyl ester, hydrochloride salt (5.00 g, 22.34 mmol), 1,3-thiazole-2-carboxaldehyde (2.53 g, 22.34 mmol) and triethylamine (3.10 mL, 22.3 mmol) in dichloromethane (60 mL) was heated under reflux under nitrogen for 19 hours. The reaction mixture was allowed to cool to room temperature, washed twice with water, dried over Na2SO4 and evaporated to give the title compound as an oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:19][N:18]=[CH:17]2)=[CH:11][CH:10]=1)#[N:8].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:20]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:19][N:18]=[CH:17]2)=[CH:13][CH:14]=1)#[N:8]
Reactant: N#Cc1ccc(Cn2cncc2CCCO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1ccc(Cn2cncc2CCC=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.14 ml of dimethylsulfoxide in 5 ml of methylene chloride is cooled to -78° under N2 and 0.1 ml of oxalyl chloride is added dropwise. After 30 min, a solution of 0.24 g of 1-(p-cyanophenylmethyl)-5-(3-hydroxypropyl)-1H-imidazole in 1 ml of methylene chloride and 0.2 ml of dimethylsulfoxide is added slowly. The reaction mixture is stirred at -78° for 2 h and 1 ml of triethylamine is added slowly. The reaction mixture is allowed to warm slowly to room temperature, diluted with 30 ml of methylene chloride and washed three times with 10 ml of water. The organic phase is dried over sodium sulfate and evaporated to yield the title compound (a) as an oil, NMR (60 MHZ): δ5.15 (s, 2H), 9.65 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH:30]([OH:33])([CH3:32])[CH3:31]>O1CCOCC1.CN(C=O)C>[CH:30]([O:33][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])([CH3:32])[CH3:31]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OC(C)C)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and isopropanol in dioxane and DMF. ES-MS m/e (%): 429 (M+H+, 100).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[CH:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C([O-])=O.[OH-].[Na+]>C(O)C>[C:26]([OH:28])(=[O:27])[CH3:25].[CH:1]1[C:14]2[C:13](=[CH:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][CH:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:22][CH2:23]3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCC1CCN(CCC=C2c3ccccc3Sc3ccccc32)CC1
Agent: O=C([O-])C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)O
Product: O=C(O)CCC1CCN(CCC=C2c3ccccc3Sc3ccccc32)CC1
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of ethyl 3-(1-(3-(thioxanthen-9-ylidene)-1-propyl)piperidin-4-yl)propionate (as the free base released from the above hydrogen oxalate; 3.71 g, 0.0088 mol), 4 N sodium hydroxide (10 ml) and 96% ethanol (70 ml) was stirred at room temperature overnight. Ethanol was evaporated in vacuo, the residue was dissolved in water (50 ml) and the aqueous solution was washed with diethyl ether (50 ml). The aqueous phase was neutralised with acetic acid and extracted with dichloromethane (3×150 ml). The combined dichloromethane extracts were dried (MgSO4) and evaporated in vacuo. The residue was dissolved in acetone (30 ml), the solution was diluted with diethyl ether (30 ml) and the mixture was stirred for 1 h. The precipitated solid was filtered off, washed with acetone and dried in vacuo, affording 2.24 g (56%) of the title compound.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(C1CCC(=[O:28])CC1)CC.C(C1CCC([Mg]Br)CC1)CC>C1CCCCC1>[CH2:16]([C@H:13]1[CH2:14][CH2:15][C@H:10]([C:7]2([OH:28])[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]2)[CH2:11][CH2:12]1)[CH2:17][CH3:18]
Reactant: CCCC1CCC(=O)CC1
Reactant: CCCC1CC=C([C@H]2CC[C@H](CCC)CC2)CC1
Agent: CCCC1CCC([Mg]Br)CC1
Solvent: C1CCCCC1
Product: CCCC1CCC(O)([C@H]2CC[C@H](CCC)CC2)CC1

Procedure:
A solution in 300 ml of cyclohexane of 24.8 g of 1-(trans-4-propylcyclohexyl)-4-propylcyclohexene [obtainable by reacting 4-propylcyclohexanone with 4-propylcyclohexylmagnesium bromide to give 1-(trans-4-propylcyclohexyl)-4-propylcyclohexanol and dehydrating the latter] is hydrogenated over 4 g of 10% PdC at 20° and 1 bar until absorption of H2 ceases. The mixture is filtered and worked up analogously to Example 3 via the thiourea adduct to give trans,trans-4,4'-dipropylbicyclohexyl, c.p. 41°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)(O)=[O:22]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:21](=[O:22])[C:24]3[CH:29]=[CH:28][C:27]([S:30](=[O:32])(=[O:31])[NH2:33])=[CH:26][CH:25]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Product: NS(=O)(=O)c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-4-sulfamoyl-benzamide was prepared starting from intermediate D and 4-carboxybenzenesulfonamide. MS calcd. for C23H18ClN3O4S [(M+H)+] 467.9, obsd. 468.0.
Reaction SMILES: [Na].[CH2:2]([S:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(O)(=[O:28])C.OO.[OH2:32]>>[CH2:2]([S:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])(=[O:28])=[O:32])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCSc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O
Agent: OO
Agent: [Na]
Product: CCCCCCCCCCS(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 6 h
Yield: 99.3 %

Procedure:
After adding 1 g of sodium tungstenate to a mixture of 86 g of 4-decylthio-3-nitrobenzotrifluoride obtained in the above step and 300 ml of acetic acid, the resultant mixture was heated to 70° C. Then, 46 ml of an aqueous 35% hydrogen peroxide solution was added dropwise to the mixture while maintaining it at 80° to 85° C. Thereafter, the reaction was performed for 6 hours at the same temperature. After the reaction was over, water was added to the reaction mixture and crystals thus deposited were recovered by filtration and dried to provide 93.1 g of the desired product with a yield of 99.3%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:12])[N:9]=2)[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(Br)c2[nH]ncc12
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: Cc1ccc(Br)c2nn(C)cc12

Procedure:
To a solution of 7-bromo-4-methyl-1H-indazole (1 equiv.) in acetonitrile, Cs2CO3 (1.3 equiv.) and MeI (3 equiv.) was added and reaction was heated at 80 oC for 1.5 h. On completion, it was cooled and quenched by addition of water. Extraction was carried out using ethyl acetate. Organic layer was dried over Na2SO4 and crude compound was column purified to afford the title compound. (Polar isomer confirmed as N-2-Methyl and non-polar isomer confirmed as N-1-Methyl by NOE experimentation).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21](=[O:23])[O:22][CH2:26][C:27]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
To a stirred solution of 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid (6.0 g, 0.01 mol) in acetonitrile (50 mL) were added TEA (2.58 mL, 0.02 mol) and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (6.16 g, 0.02 mol) at RT under an inert atmosphere. The reaction mixture was stirred for 30 minutes, cooled to 0° C., and then DBU (5.5 mL, 0.03 mol) was added. The reaction was stirred for an additional 15 minutes and then quenched with HCl (1 N) and extracted with DCM (2×300 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (500 mg) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.64 (d, J=7.8 Hz, 2H), 8.50-8.44 (m, 1H), 8.04-7.98 (m, 2H), 7.8 (t, J=7.2 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.50 (s, 1H), 7.38-7.32 (m, 3H), 7.26-7.22 (m, 1H), 5.55 (s, 2H), 5.38 (s, 2H). MS: M+H: m/z=429.1. HPLC: 90%, (Condition-I).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[O:38][CH3:39].[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:48](=[O:49])[CH2:47][N:44]3[C:45]([CH3:46])=[C:41]([Cl:40])[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43]3)[CH2:36][CH2:37]2)=[CH:28][C:27]=1[O:38][CH3:39]
Reactant: COc1cc(N2CCNCC2)ccc1Br
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Br

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Bromo-3-methoxyphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.34 (d,1H), 6.71 (s, 1H), 6.52 (d, 1H), 5.39 (s, 2H), 3.82 (s, 3H), 3.62 (m, 4H), 3.30 (m, 2H), 3.20 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=495.0, found=495.0.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[N:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[N:36]1[N:28]2[C:27]([CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29]2)=[CH:38][CH:37]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine. The mixture is stirred at room temperature for 5 hours and is then washed with water, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid, m.p. 142°-146° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.C(N(CC)C(C)C)(C)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[N:40]1([C:8]([C@@H:4]2[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]2)=[O:10])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1
Reactant: C1COCCN1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: O=C1CCC[C@@H](C(=O)O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC[C@@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 107.2 %

Procedure:
(1R)-3-Oxo-cyclohexanecarboxylic acid was prepared according to the procedure described by R. D. Allan et al. in Aust. J. Chem., 1981, 34, 2231. A solution of (1R)-3-oxo-cyclohexanecarboxylic acid (1 eq, 2.52 g, 18.1 mmol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT, H. Li et al. Organic Letters, 1999, 1, 91) (1.05 eq, 19.0 mmol, 5.68 g) and N,N-diisopropylethylamine (15 eq, 27.1 mmol, 4.7 mL) in anhydrous dichloromethane (70 mL) was allowed to stir at room temperature for 75 minutes. Morpholine (1.2 eq, 21.72 mmol, 1.9 mL) was added and the solution was stirred at ambient temperature for 16 h. The mixture was concentrated under vacuum to an oil which was purified by flash chromatography eluting with a 2.5% methanol-dichloromethane gradient on silica gel to give (3R)-3-(morpholine-4-carbonyl)-cyclohexanone (2.05 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:23][C:19]1[O:18][CH:22]=[CH:21][CH:20]=1)[CH3:15]
Reactant: O=Cc1ccco1
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Product: CC(C)(COc1ccc2ccccc2c1Cl)NCc1ccco1
Yield: 34 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and furan-2 carbaldehyde in 34% yield as a pale oil.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][CH:40]=3)[CH:32]=2)[C@@H:11]([OH:47])[C@@H:10]1[CH2:48][O:49]CC1C=CC=CC=1)C1C=CC=CC=1.CO.ClC1C=CC=CC=1Cl.[H][H]>O1CCCC1.[Pd]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@@H:12]2[C@@H:11]([OH:47])[C@H:10]([CH2:48][OH:49])[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@H:13]2[OH:23])=[CH:32][C:33]=1[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH3:46])=[CH:43][CH:44]=1
Reactant: [H][H]
Reactant: CCc1ccc(Cc2cc([C@@H]3[C@@H](O)[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)[C@@H]3O)ccc2Cl)cc1

Procedure:
To a solution of (1R,2S,3R,4R,5S,6R)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)cyclohexanol (60 g, purity of 98%, 0.077 mol, 1 eq) in tetrahydrofuran:methanol (v/v=2:1) (600 mL) was added 1,2-dichlorobenzene (21.5 g, 16.54 mL, 0.82 mol, 2 eq), palladium on carbon (10%, 4.8 g) and was stirred for 4 h under an atmospheric pressure of hydrogen at room temperature (about 25° C.). The mixture was filtered and the filtrate was evaporated to dryness to give a yellow oil (80% pure).
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:21]([C:24]([NH2:26])=[NH:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.C[I:28]>CN(C)C=O>[ClH:1].[I-:28].[NH+:2]1([CH2:7][CH:8]([N:10]2[C:23]3[CH:22]=[C:21]([C:24]([NH2:26])=[NH:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=N)N)cc21
Reactant: CI
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C[NH+]1CCCC1)N1c2ccccc2Sc2ccc(C(=N)N)cc21
Product: [I-]
Yield: 71.5 %

Procedure:
In manner analogous to that described in Example 9 (sic), but starting with D series 10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamidine hydrochloride (2 g) in dimethylformamide (20 cc) and with methyl iodide (0.75 g), D series 10-[1-(1-pyrrolidinio)-2-propyl]-2-phenothiazinecarboxamidine iodide hydrochloride (1.9 g) is obtained in the form of a yellow powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CCCCCCC(=O)Cl
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCCCC(=O)NCc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added heptanoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give heptanoic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amide as a light yellow solid (280 mg, 47% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.10 min (97.8%); mp, 208-210° C.; 1HNMR (DMSO-d6) 0.86 (t, J=6 Hz, 3H, CH3), 1.25-2.21 (m, 11H, CH2CH2CH2CH2CH2, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.68-4.84 (m, 2H, CH2NH), 5.23 (dd, J=6, 12 Hz, 1H, Ch), 7.29-7.75 (m, 3H, Ar), 8.18 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.87, 20.77, 21.98, 23.27, 25.22, 28.31, 30.59, 31.96, 35.37, 38.68, 38.96, 39.23, 39.51, 39.79, 40.07, 40.35, 41.39, 56.47, 117.63, 124.30, 125.39, 133.78, 141.23, 148.44, 154.75, 160.95, 169.51, 172.29, 172.59. LCMS MH=413; Anal Calcd For C22H28N4O4: C, 64.06; H, 6.84; N, 13.58. Found: C, 64.05; H, 6.80; N, 13.58.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[Cl:15][C:16]1[CH:27]=[C:26]([F:28])[C:25]([N:29]=[C:30]=[O:31])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>CCCCCC.CN(C)C=O>[Cl:15][C:16]1[CH:27]=[C:26]([F:28])[C:25]([NH:29][C:30]([NH:1][C:2]([C:9]([F:10])([F:11])[F:12])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:31])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C=C(NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of 3.55 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 50 ml of n-hexane is added dropwise with stirring and at 0°-3° C. during 15 minutes to 0.85 g of a 55% sodium hydride dispersion in 50 ml of dimethylformamide, and the mixture is stirred for a further 30 minutes. Then a solution of 5.0 g of isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate in 100 ml of n-hexane is added dropwise during 5 minutes with stirring and cooling. The temperature of the reaction mixture rises to 10° C., and the mixture is thereafter stirred for one hour at room temperature. The isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-trifluoromethyl-vinyl]ureido}benzoate which is formed as an intermediate is not isolated.