Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[NH:6][C:5]2([CH2:17][NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:13]([F:16])([F:15])[F:14].CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[NH:6][C@@:5]2([CH2:17][NH:18][C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:13]([F:16])([F:14])[F:15]
Reactant: O=C1Nc2ccc(Cl)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C1Nc2ccc(Cl)cc2[C@](CNC(=O)c2ccc(F)cc2)(C(F)(F)F)N1

Procedure:
N-{[6-chloro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}4-fluorobenzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=N)[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.C(=O)(O)[O-:23]>Cl>[CH3:1][C:2]1([CH3:21])[C:6](=[O:23])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1
Reactant: O=C([O-])O
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=N
Agent: Cl
Product: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Yield: 95 %

Procedure:
A suspension of the compound 10a in 6N HCl (25 mL) was refluxed for 35 min. The cooled solution was poured in a 10% bicarbonate solution, extracted using ethyl acetate (3×25 mL). The organic layer was washed with brine, and finally dried over magnesium sulphate to give of desired compound 11a (950 mg, 95%) which was used as such in the next step. 1H NMR (300 MHz, Acetone-d6) δ: 1.54 (s, 6H), 7.81 (broad s, 1H), 8.17 (m, 2H), 8.26 (s, 1H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH:11]([CH3:13])[CH3:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.Cl.Cl.[CH2:16]([O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=1[NH2:28])[CH2:17][CH2:18][CH3:19].N.OO.[CH2:32](O)C>O>[ClH:1].[CH2:16]([O:20][C:21]1[C:22](=[NH:28])[CH:23]=[C:24]([NH2:27])[CH:25]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:2][CH3:32])[CH:11]([CH3:13])[CH3:12])=[CH:5][CH:6]=2)[CH:26]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCO
Reactant: CC(C)N(C)c1ccc(N)cc1
Reactant: CCCCOc1ccc(N)cc1N
Agent: Cl
Agent: N
Agent: OO
Solvent: O
Product: CCCCOC1=CC(Nc2ccc(N(CC)C(C)C)cc2)C(N)=CC1=N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 0.003 mol of N-methyl-N-isopropyl-4-aminoaniline hydrochloride and 0.003 mol of 4-butoxybenzene-1,3-diamine dihydrochloride in 2 ml of water and 6 ml of ethanol, brought to pH 9.5 with 20% aqueous ammonia solution, are added 10.2 ml of 20-V 6% aqueous hydrogen peroxide solution; after stirring for 24 hours at room temperature, a gum forms. The supernatant is removed and the gum is washed with three times 50 ml of water, 4 ml of ethyl acetate and then with isopropyl ether. After drying, 260 mg of 4-butoxy-6-[4-(ethylisopropylamino)phenylamino]-3-iminocyclohexa-1,4-dienylamine hydrochloride 1 are obtained in the form of a black powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:7]=1.[C:8](=[S:10])=[S:9].C(OCC)(=O)C.[CH2:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]>CCCCCC>[N:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:8](=[S:9])[S-:10].[CH2:17]([NH+:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]
Reactant: CCN(CC)CC
Reactant: S=C=S
Reactant: Nc1cnccn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC[NH+](CC)CC
Product: S=C([S-])Nc1cnccn1
Reaction time: 8 h
Yield: 31.6 %

Procedure:
In a 100-ml flask, 4.9 g (50 mmol) of 3-aminopyrazine, 4.5 g (59 mmol) of carbon disulfide and 50 ml of ethyl acetate were placed, and 6.5 g (64 mmol) of triethylamine was added dropwise with stirring over a 5-min period on a water bath. After the mixture was stirred at 60° C. for 5 hr. 10 ml of hexane was added to the mixture, which was allowed to stand overnight at room temperature to precipitate yellow crystals. The crystals were separated from the solution by filtration, and washed with 5 ml of ethyl acetate to obtain 4.3 g of triethylammonium N-(2-pyrazinyl)-dithiocarbamate (Intermediate II-1). Yield 31%. Mp 113°-116° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:56][O:57][CH2:58][CH2:59][CH2:60][NH2:61]>CN(C=O)C>[CH3:56][O:57][CH2:58][CH2:59][CH2:60][NH:61][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32]
Reactant: COCCCN
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 3-methoxy-propylamine (42 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 10 days, the reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and purified on a silica gel column to give the titled compound as a pale orange waxy solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1>C(N)C1C=CC=CC=1>[CH2:14]([NH:13][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Nc1cccc(Br)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Solvent: NCc1ccccc1
Product: O=C(Nc1cccc(NCc2ccccc2)n1)c1cc(-c2ccc(F)cc2)n(C2CCCCO2)n1
Temperature: 130 °C
Yield: 118.4 %

Procedure:
N-(6-Bromopyridin-2-yl)-5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide 3 (300 mg, 0.67 mmol) was dissolved in benzylamine (3 ml). The reaction mixture was heated for 24 hrs at 130° C. Then the reaction mixture was purified on a silica gel column (1:5 EtOAc:Pet-ether) to give N-(6-(benzylamino)pyridin-2-yl)-5-(4-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxamide 4 as a white solid (187 mg, 59%). Mp. 139-140° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][CH:10]=1)=[O:8])C.[OH-].[Na+].[CH3:20][NH:21][S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2)(=[O:24])=[O:23].N1CCCCC1>CO.C(O)C>[CH3:14][C:13]1[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:3])=[O:17])=[O:8])=[CH:10][NH:11][C:12]=1[CH:15]=[C:28]1[C:27]2[C:31](=[CH:32][CH:33]=[C:25]([S:22](=[O:23])(=[O:24])[NH:21][CH3:20])[CH:26]=2)[NH:30][C:29]1=[O:34]
Reactant: CCOC(=O)CNC(=O)c1c[nH]c(C=O)c1C
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc(C(=O)NCC(=O)O)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
A mixture of [(5-formyl-4-methyl-1H-pyrrole-3-carbonyl)-amino]-acetic acid ethyl ester (0.142 g, 0.59 mmol) and 1N NaOH (1.2 mL) in methanol (10 mL) was stirred at room temperature for 1 hr. The reaction was concentrated and the residue was condensed with 5-methylaminosulfonyl-2-oxindole (0.13 g, 0.48 mmol) and piperidine (0.12 mL) in ethanol (12 mL) to give 0.11 g (52%) of the title compound.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:30]Br.[N:36]#[C:37]Br>>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:30][N:10]1[CH2:9][CH2:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:37]1=[NH:36]
Reactant: NCCNc1ccccc1
Reactant: N#CBr
Reactant: Fc1ccc(CBr)cc1F
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Product: N=C1N(Cc2ccc(F)c(F)c2)CCN1c1ccccc1

Procedure:
The title compound was prepared from N-phenylethylenediamine in four steps by Procedure A. In the first step, one equivalent of Boc2O was used and, similarly, one equivalent of 3,4-difluorobenzyl bromide was used as benzylating reagent in the second step. After reacting with cyanogen bromide, the crude product was isolated upon aqueous work-up and purified by preparative LCMS to give the title compound as the free base. MS (ES+) m/z 288 ([M+1]+, 100); HR-MS: 288.1316 ([M+1]+, C16H16F2N3; calc. 288.131228).
Reaction SMILES: CC1C=CC([C:8]([OH:10])=[O:9])=CC=1.[C:11](O)(=[O:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1>>[C:8](=[O:10])=[O:9].[C:16]([C:15]1[CH:19]=[CH:20][C:12]([CH:11]=[O:21])=[CH:13][CH:14]=1)([OH:18])=[O:17]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: O=C=O
Product: O=Cc1ccc(C(=O)O)cc1

Procedure:
The reaction was conducted in the same manner as in Example 16 except that Ru(acac)3 was used instead of ruthenium chloride as a catalyst starting material. Consequently, the conversion of p-toluic acid was 95%, and the selectivity for terephthalic acid relative to p-toluic acid reacted was 76%. As the other products, carbon dioxide and 4-carboxybenzaldehyde were formed in the selectivities of 17%, and 2.2% respectively.
Reaction SMILES: [ClH:1].N[C@H]1CCC[C@@H]1NC(=O)C1C=CC=CC=1[Cl:16].[NH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:24][C:25](=[O:31])OC(C)(C)C.[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[C:34]=1C(O)=O.O1POPOP1>>[ClH:16].[ClH:1].[NH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:24][C:25](=[O:31])[C:34]1[C:38]([O:42][CH3:43])=[CH:39][CH:40]=[CH:41][C:33]=1[F:32]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: COc1cccc(F)c1C(=O)O
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1Cl
Agent: Cl
Agent: O1POPOP1
Product: COc1cccc(F)c1C(=O)N[C@H]1CCC[C@@H]1N

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-aminocyclopentyl]-2-chlorobenzamide hydrochloride (Intermediate 19) from tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 500 mg, 2.50 mmol), 2-fluoro-6-methoxybenzoic acid (CAS number 137654-21-8; 637 mg, 3.74 mmol) and 1,3,5,2,4,6-trioxatriphosphorinane, 2,4,6-tripropyl-, 2,4,6-trioxide (CAS number 68957-94-8; 50% in ethyl acetate, 2.2 ml, 3.74 mmol). Subsequent deprotection with HCl afforded the title compound.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1>CN(C=O)C>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([NH:6][CH:1]2[CH2:7][CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CCCC1
Reactant: N#Cc1ccc(Br)cc1F
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1NC1CCCCC1
Temperature: 60 °C

Procedure:
Cyclopentylamine and potassium carbonate were added to a DMF solution of 4-bromo-2-fluorobenzonitrile, followed by stirring at 60° C. By post-treating the reaction liquid, 4-bromo-2-(cyclohexylamino)benzonitrile was obtained. By making reference to the method described in J. Am. Chem. Soc.; 1996; 118; 7215-7216, this was allowed to react with piperidine to obtain 2-(cyclohexylamino)-4-piperidin-1-ylbenzonitrile.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)=[O:28]>CC#N>[Cl-:25].[C:19]1([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N+:1]([CH2:26][C:27](=[O:28])[NH:29][C:30]5[CH:35]=[CH:34][N:33]=[CH:32][N:31]=5)([CH2:6][CH2:5]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CCl)Nc1ccncn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ccncn1
Product: [Cl-]
Yield: 61 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (0.44 mmol) and 2-chloro-N-pyrimidin-4-yl-acetamide (Example 22a) (0.48 mmol) in anhydrous MeCN (2 mL) were stirred together at room temperature for 2.5 days. The reaction mixture was concentrated in vacuo and the residue purified by flash silica gel chromatography (2-10% MeOH/dichloromethane) to give the title compound as a light yellow solid (134 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)([O:12][CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:38]=[N+:39]=[N-:40].[Na+]>C(OCC)(=O)C.O>[N:38]([CH2:14][CH2:13][O:12][C@:8]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][CH2:10][CH3:11])=[N+:39]=[N-:40]
Reactant: CCC[C@](OCCOS(C)(=O)=O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCC[C@](OCCN=[N+]=[N-])(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Yield: 99.3 %

Procedure:
(R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(methylsulfonyloxy)ethoxy)butyl)piperidine-1-carboxylate (900 mg, 1.82 mmol) was dissolved into anhydrous DMF (15 mL), solid NaN3 (230 mg, 3.51 mmol) was added and the reaction mixture was heated to 70° C. overnight. The reaction mixture was cooled to rt and then was diluted with ethyl acetate (110 mL), and water (30 mL), the organic phase was washed with water (3×20 mL), dried over Na2SO4 and evaporated to give (R)-tert-butyl 3-((R)-1-(2-azidoethoxy)-1-(3-chlorophenyl)butyl)piperidine-1-carboxylate (790 mg, 99%).
Reaction SMILES: CC1(C)CO[C:5]2([CH2:11][CH2:10][C:8](=[O:9])[CH2:7][CH2:6]2)[O:4][CH2:3]1.COC1C=CC(O)=CC=1.[Li].N>C(O)C>[CH3:3][O:4][C:5]1[CH2:11][CH2:10][CH:8]([OH:9])[CH2:7][CH:6]=1
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Agent: COc1ccc(O)cc1
Agent: N
Agent: [Li]
Solvent: CCO
Product: COC1=CCC(O)CC1

Procedure:
Journal of Synthetic Communications 9(2), 123–127 (1979) disclosed a process for the preparation of 1,4-cyclohexane dione mono-2,2-dimethyl trimethylene ketal using Birch reduction of 4-methoxy phenol with lithium and ammonia in presence of ethanol to yield 4-methoxy-3-cyclohexene-1-ol, which is further reacted with neopentyl glycol using PTSA in benzene medium gave 2,3-dimethyl-1,3-dipropylene ketal of 4-hydroxycyclohexanone. Oxidation of the resulting ketal with pyridinium chlorochromate yields the 1,4-cyclohexanedione mono-2,2-dimethyl trimethylene ketal. Journal of Synthetic Communications, 14 (1), 39–44 (1984) disclosed a process for preparation of 1,4-cyclohexanedione mono-2,2-dimethyl trimethylene ketal that includes continuous extraction of an aqueous solution of 1,4-cyclohexane dione containing 2,2-dimethyl-1,3-propane diol in molar excess and sulfuric acid as the catalyst to afford the 1,4 cyclohexanedione mono-2,2-dimethyl trimethylene ketal. Nevertheless, there is still a need for an improved process suitable for a commercial scale production of 1,4-cyclohexanedione mono-2,2-dimethyl trimethylene ketal
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:28]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])([C:12]([F:14])([F:15])[F:13])[C:6]=2[CH:28]=1
Reactant: O=C(NCC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21)Nc1ccc(F)cc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=C(NC[C@@]1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21)Nc1ccc(F)cc1

Procedure:
N-{[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-N′-(4-fluorophenyl)urea was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8](=[S:28])[NH:9][C:10]=2[C:11]2[C:20]([F:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.Br[C:30]1[S:31][CH:32]=[N:33][N:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[F:21][C:20]1[C:11]([C:10]2[N:9]=[C:8]([S:28][C:30]3[S:31][CH:32]=[N:33][N:34]=3)[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=23)=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:16]=[CH:15]2
Reactant: Brc1nncs1
Reactant: Nc1nccn2c(=S)[nH]c(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nccn2c(Sc3nncs3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Temperature: 100 °C

Procedure:
A 10 mL microwave vessel was charged with a solution of 8-amino-1-(8-fluoro-2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazine-3-thione (20 mg, 0.00005 mol), 2-bromo-1,3,4-thiadiazole (0.017 g, 0.00010 mol) and potassium carbonate (0.021 g, 0.00015 mol) in DMF (1.4 mL, 0.018 mol). The reaction mixture was heated in the microwave at 100° C. for 10 min. The reaction mixture was concentrated in vacuo and purification by Gilson HPLC eluting with 10→65% acetonitrile: H2O afforded the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ=7.31 (d, J=5.05 Hz, 1H), 7.47-7.58 (m, 3H), 7.69-7.80 (m, 3H), 8.05 (d, J=8.84 Hz, 1H), 8.24 (dd, J=8.34, 1.52 Hz, 2H), 8.32 (dd, J=8.72, 1.39 Hz, 1H), 9.07 (s, 1H). MS(ES+): m/z 472.13 (100)[MH+]. HPLC: tR=2.9 min (Open Lynx polar—5 min).
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH2:10][O:11][CH2:12][C:13]2([CH2:20][CH3:21])[CH2:18][O:17][P:16](Cl)[O:15][CH2:14]2)([CH2:8][CH3:9])[CH2:4][O:3]1.[CH2:22]([NH:26][CH:27]1[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:26]([P:2]1[O:7][CH2:6][C:5]([CH2:10][O:11][CH2:12][C:13]2([CH2:20][CH3:21])[CH2:18][O:17][P:16]([N:26]([CH:27]3[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30][C:31]([CH3:33])([CH3:34])[CH2:32]3)[CH2:22][CH2:23][CH2:24][CH3:25])[O:15][CH2:14]2)([CH2:8][CH3:9])[CH2:4][O:3]1)[CH:27]1[CH2:28][C:29]([CH3:35])([CH3:36])[NH:30][C:31]([CH3:34])([CH3:33])[CH2:32]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCC1(COCC2(CC)COP(Cl)OC2)COP(Cl)OC1
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Product: CCCCN(C1CC(C)(C)NC(C)(C)C1)P1OCC(CC)(COCC2(CC)COP(N(CCCC)C3CC(C)(C)NC(C)(C)C3)OC2)CO1

Procedure:
If 1,3-bis(2-chloro-5-ethyl-1,3,2-dioxaphosphorinan-5-yl)-2-oxapropane is reacted with 4-butylamino-2,2,6,6-tetramethylpiperidine in a procedure analogous to Example 2, 1,3-bis[2-(N-butyl-N-(2,2,6,6-tetramethyl-4-piperidyl)amino)-5-ethyl-1,3,2-dioxaphosphorinan-5-yl]-2-oxapropane is obtained as a viscous resin (Compound No. 22, formula below, R3 =H); FD-MS: 730 (M+).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:16](=O)[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2].Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+]>CO>[C:1]([NH:4][CH:5]([C:16](=[N:35][OH:36])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)NC(Cc1csc2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC(Cc1csc2ccccc12)C(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=NO
Reaction time: 16 h

Procedure:
The compound of Example 4 (0.5 g) was dissolved in methanol followed by hydroxylamine hydrochloride (0.220 g) and sodium acetate (0.7 g). The reaction was stirred for 16 hours, the solvent was removed and the residue was dissolved in ethyl acetate (100 ml), washed with water (100 ml), dried (MgSO4), filtered and evaporated to yield an oil which was purified by chromatography on silica using dichloromethane/Et2O (3:1) to yield the title compound isomer A as a white solid, mp=200°-201° C.; found: C, 54.79; H, 4.24; N, 5.19; C23H20F6N2O2S requires C, 54.98; H, 4.01; N, 5.58%. Further elution yielded the title compound isomer B as a white solid, mp=200°-203° C.; found: C, 55.13; H, 4.14; N, 5.45; C23H20F6N2O2S requires C, 54.98; H, 4.01; N, 5.58 %.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: CCS(=O)(=O)Nc1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL) was added ethanesulfonyl chloride (25 mg, 0.19 mmol) and the reaction mixture was stirred at room temperature for about 3 hours. Additional sulfonyl chloride (25 mg, 0.19 mmol) was added and the reaction mixture was stirred for about 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in dichloromethane (10 mL) and washed with 1 N aqueous hydrochloric acid (10 mL). The organic portion was separated, dried under reduced pressure, and treated with hydrochloric acid (4 N in dioxane, 5 mL) and stirred at room temperature for about 12 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.12 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.29-7.48 (m, 5H), 5.64 (s, 2H), 3.29 (d, J=9.2 Hz, 2H), 1.31 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 383 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:8]([C:6]3[S:7][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[O:10])=[N:13]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: CSc1ccc(C(=O)O)s1
Solvent: O
Product: CSc1ccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)s1
Yield: 75.9 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5-methylthio-2-thiophenecarboxylic acid (5.6 g), N,N'-carbonyldiimidazole (5.2 g) and 2-amino-7-chloro-1,8-naphthyridine (4.3 g). The product obtained by precipitation in water is purified by recrystallization in a dimethylformamide/methanol (5:5 by volume) mixture (200 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-5-methylthio-2-thiophenecarboxamide (6.1 g), m.p. 235° C., is thereby obtained.