Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14]N(C2C=CC(Cl)=CC=2C)CN(C2C=CC(Cl)=CC=2C)[CH2:10]1.ClC(OC(Cl)(Cl)Cl)=[O:33].[CH:39]([NH:42][C:43]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[S:44])([CH3:41])[CH3:40].[OH-].[Na+]>>[C:46]([N:45]=[C:43]1[N:42]([CH:39]([CH3:41])[CH3:40])[C:14](=[O:33])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[CH3:1])[CH2:10][S:44]1)([CH3:47])([CH3:49])[CH3:48]
Reactant: Cc1cc(Cl)ccc1N1CN(c2ccc(Cl)cc2C)CN(c2ccc(Cl)cc2C)C1
Reactant: CC(C)NC(=S)NC(C)(C)C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)ccc1N1CSC(=NC(C)(C)C)N(C(C)C)C1=O
Yield: 20.2 %

Procedure:
In a similar manner, 3.3 g (0.007 mole) of 1,3,5-tris(2-methyl-4-chlorophenyl)-hexahydro-s-triazine, 2.0 g (0.01 mole) of trichloromethyl chloroformate, 3.2 g (0.018 mole) of 1-isopropyl-3-t-butylthiourea, and 18 g of a 10% aqueous sodium hydroxide solution were used to obtain 0.5 g (7% yield) of 2-t-butylimino-3-isopropyl-5-(2-methyl-4-chlorophenyl)-tetrahydro-1,3,5-thiadiazin-4-one (compound No. 387) of the formula, ##STR178## as white crystals melting at 122°-123° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][S:10][C:6]=2[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+].O.S(=O)(=O)(O)[OH:18]>C(O)C>[N+:11]([C:5]1[C:6]2[S:10][N:9]=[CH:8][C:7]=2[C:2]([OH:18])=[CH:3][CH:4]=1)([O-:13])=[O:12]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(Cl)c2cnsc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(O)c2cnsc12
Yield: 86 %

Procedure:
43 g of 4-chloro-7-nitro-1,2-benzisothiazole and 16 g of sodium hydroxide powder in 400 ml of ethanol are stirred for 1 hour at 70° C. When the mixture has cooled, 500 ml of water are added, the batch is neutralized with dilute sulfuric acid whilst cooling with ice, and the product which has precipitated is filtered off. The filter cake is then washed with a little ice-cold methanol, and dried. 34 g (86% of theory) of 7-nitro-4-hydroxy-1,2-benzisothiazole are obtained, melting at 284° C. (with decomposition) after one recrystallization from n-butanol.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]([CH3:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:15][C:16](=[N:18]O)[NH2:17].C(N(CC)CC)C>C1C=CC=CC=1.CCOCC.C(=O)(O)[O-].[Na+]>[Cl:1][CH2:2][C:3]1[O:4][N:17]=[C:16]([CH2:15][S:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:20])[CH3:6])[N:18]=1
Reactant: CN(C)c1ccccc1SCC(N)=NO
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CCOCC
Product: CN(C)c1ccccc1SCc1noc(CCl)n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Chloroacetylchloride (2.64 ml, 3.74 g, 3.3×10-2 mol) in benzene (10 ml) was added dropwise to a stirred solution of 2-(2-dimethylaminophenylthio)acetamidoxime (6.75 g, 0.03 mol) and triethylamine (4.17 ml) in benzene (20 ml). The mixture was stirred at ambient temperature for 10 hours then refluxed for 1 hour. The cooled mixture was taken up in ether and 5% aqueous sodium bicarbonate solution. The organic layer was washed with water and saturated aqueous sodium chloride solution dried and evaporated to dryness to give a brown oil. Chromatography on silica gel (135 g), eluting with hexane:ether (3:1) gave 5-(chloromethyl)-3-(2-dimethylaminophenylthiomethyl)-1,2,4-oxadiazole as a colourless oil, nmr δ(CDCl3) 2.78(6H, CH3), 4.20(2H, ,--CH2 --), 4.65 (2H, ,--CH2 --), 6.8-7.4 (4H, m, aromatic hydrogens).
Reaction SMILES: [N+]([O-])(O)=O.C(O)C.[C:8](=[O:10])=O.[Cl:11][C:12]1[C:17](C)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19]>>[Cl:11][C:12]1[C:17]([CH3:16])=[C:8]([OH:10])[CH:15]=[CH:14][C:13]=1[CH3:19]
Reactant: O=C=O
Reactant: Cc1cccc(C)c1Cl
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: Cc1ccc(O)c(C)c1Cl
Reaction time: 0.17 h

Procedure:
Nitration of 2-chloro-m-xylene. Nitric acid (90%, 50 mL) was cooled to −35° C. (ethanol-dry ice bath). 2-Chloro-m-xylene (10 mL) was added dropwise over 1 h keeping the temperature between −30° C. and −35° C. The reaction mixture was poured onto ice, stirred for 10 min, precipitate formed was collected by filtration, washed with water, dried. The crude product was purified on SiO2 (50 g), hexane-EtOAc (0 to 2% v/v). The product—yellow solid, 12.8 g, as a mixture of 2-chloro-1,3-dimethyl-4-nitro-benzene and chloro-1,3-dimethyl-5-nitro-benzene (4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCOCC>[ClH:1].[C:18]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[N:7]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccccc3)c3cc(Cl)ccc23)CC1
Product: Cl
Temperature: 100 °C
Yield: 56 %

Procedure:
A mixture of 3.0 g of 6-chloro-3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of benzoyl chloride was heated at 100° C. on a steam bath for 4 hrs. The reaction mixture was cooled to ambient temperature and ether was added. The precipitate was filtered, washed with ether and dried. Recrystallization from ethanol (twice) yielded 2.6 g (56%) of product, mp 248°-250° C.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CO>C(Cl)Cl>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][O:8][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)O[C@]1(C(=O)COC(=O)c2ccccc2)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
In 4 ml of methylene chloride was dissolved 208 mg of 17α-acetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione obtained according to the method described in Example 6. To this solution was added 202 mg of triethylamine, and the mixture was ice-cooled. Next, 140 mg of benzoyl chloride was directly added to the solution and the mixture was stirred for one hour. To the solution was further added 1 ml of methanol, and the mixture was stirred for one hour. The reaction liquid was concentrated under reduced pressure and the resultant residue was directly subjected to preparative thin layer chromatography (silica gel) for purification whereby 204 mg (yield: 78.5%) of the title compound was obtained as a colorless amorphous solid. The structure of this compound was confirmed by the following physical properties and results of various analyses:
Reaction SMILES: [CH2:1]([C:3]1([CH2:19][CH3:20])[C:15]2[CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH3:2].C(P(CCCC)CCCC)CCC.[I-:34].[K+].CN(C=O)C>C1(C)C=CC=CC=1.[Ni](Br)Br>[CH2:1]([C:3]1([CH2:19][CH3:20])[C:15]2[CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([I:34])=[CH:7][CH:8]=2)[CH3:2]
Reactant: [I-]
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Agent: Br[Ni]Br
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC1(CC)c2cc(I)ccc2-c2ccc(C=O)cc21
Yield: 75 %

Procedure:
A mixture of 9,9-diethyl-7-bromofluorene-2-carboxaldehyde, (28.8 g., 0.0875 mol.), nickel (II) bromide (2.1 g., 9.6 mmol.), tri-n-butyl phosphine (4m1, 16 mmol.), potassium iodide (52.0 g., 0.3132 mole, 3.6 equivalents), and DMF (125 ml), was held at reflux under an atmosphere of nitrogen for 15 hours, cooled, diluted with toluene (450 ml), and filtered. The filtrate was washed with water in several portions, dried, and concentrated. The residual solids were recrystallized from toluene-heptane (1:2, 150 ml); 24.79 g., m.p. 138-140° C., (75% yield). When the reaction was run longer, 24 and 34 hours, the yields fell to 61 and 59% respectively. Mass Spec (m/z): 376 (M+), not contaminated with the bromo aldehyde. Anal.Calcd. for C18H17Ol: C, 57.46; H, 4.55; and l, 33.73%. Found: C, 58.04 and 58.02; H, 4.72 and 4.66; and l, 32.62 and 32.89.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH:7]=[CH:8][CH:9]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][CH:11]([CH3:12])[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)=[O:13]
Reactant: CCC(=O)c1cccc(Cl)c1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)c1cccc(Cl)c1
Yield: 60 %

Procedure:
Bromine (6.07 ml, 0.12 mol) was added to a solution of 3′-chloropropiophenone (20 g, 0.12 mol) in chloroform (250 ml) at room temperature. The reaction was followed by TLC in DCM. When all of the starting material was consumed the mixture was washed with a saturated solution of sodium bicarbonate. The organic phase was dried over magnesium sulphate, filtered and evaporated. Recrystallisation from chloroform gives the desired compound in 60% yield as a pale yellow solid (18 g, 73 mmol).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=O)[CH2:3][CH2:2]1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[N:23][N:24]([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:25]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH:7]([NH:32][C:29]2[CH:30]=[N:31][C:26]([N:24]3[CH:25]=[C:21]([C:20]([F:34])([F:33])[F:19])[CH:22]=[N:23]3)=[CH:27][CH:28]=2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1
Reactant: COC(=O)c1ccc(C(=O)C2CCOCC2)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)c1ccc(C(Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)C2CCOCC2)cc1
Yield: 0.1 %

Procedure:
A round bottom flask was charged with methyl 4-(tetrahydro-2H-pyran-4-carbonyl)benzoate (150 mg, 572 mmol), 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine (130 mg, 572 mmol) and MeOH (1.2 mL). Decaborane reagent (26.4 mg, 229 mmol) was added in one portion and the reaction stirred over the week-end. The reaction mixture was quenched with HCl solution (1 N, aq.) and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) provide (±)-methyl 4-((tetrahydro-2H-pyran-4-yl)((6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)amino)methyl)benzoate (206 mg, 78%) as a colorless gum. MS (M+1): 461.3.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=1[O:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=4[O:30][CH3:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCN1CCC(c2noc3cc(Cl)ccc23)CC1
Yield: 98.2 %

Procedure:
A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2 benzisoxazole (4.6 g, 19 mmol), l-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (4.3 g, 19 mmol), K2CO3 (2.8 g), a few crystals of KI and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to yield 8.0 g of yellow solid. The solid was chromatographed on a Waters Prep 500 LC (silica columns, eluting with methylene chloride/methanol, 5%). Concentration of the appropriate fractions yielded 3.2 g of a light yellow solid, which upon recrystallization from ethyl acetate afforded 2.3 g (28%) of 1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenylethanone as a pale yellow solid, m.p.=133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[S:47]1[C:56]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51][C:50]=2[NH:49][C:48]1=[O:57]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:53]3[CH2:54][CH2:55][C:56]4[S:47][C:48](=[O:57])[NH:49][C:50]=4[CH2:51][CH2:52]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: O=c1[nH]c2c(s1)CCNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2[nH]c(=O)sc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 0.25 mmol 6-chloro-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid, 0.30 mmol HATU, 1.52 mmol DIPEA and 0.51 mmol 3,4,5,6,7,8-hexahydro-thiazolo[4,5-d]azepin-2-one in 1 mL DMF. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 20 mg (23% of theory). ESI-MS: m/z=350 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[C:38]([NH:45][C@H:46]([C:50](O)=[O:51])[CH:47]([CH3:49])[CH3:48])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(N(CC)CC)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([C:50](=[O:51])[C@@H:46]([NH:45][C:38](=[O:39])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH:47]([CH3:49])[CH3:48])[CH2:35][CH2:36]6)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCNCC5)cn4)sc23)c(F)c1)NC1CC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of compound 49 (150 mg, 0.289 mmol, scheme 15), Boc-L-valine (94 mg, 0.43 mmol) and triethylamine (120 μL, 0.87 mmol) in DMF (5 mL) under nitrogen were added HOBT monohydrate (49 mg, 0.32 mmol) and EDC hydrochloride (139 mg, 0.72 mmol) reagents, and the reaction mixture was stirred at RT overnight. The reaction mixture was then partitioned between AcOEt and a saturated aqueous solution of sodium bicarbonate. The organic layer was successively washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product was purified by Biotage (Snap 25 g; MeOH/DCM: 1/99 to 10/90 over 20 CV), to afford the title compound 75 (171 mg, 0.238 mmol, 82% yield) as a colorless sticky film. MS (m/z): 718.4 (M+H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]([C:15]1([CH3:39])[C:19](=[O:20])[NH:18][C:17]([C:21]2[N:30]=[CH:29][C:28]([CH2:31][S:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[N:16]1)([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C(Cl)Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[CH:12]([C:15]1([CH3:39])[C:19](=[O:20])[NH:18][C:17]([C:21]2[N:30]=[CH:29][C:28]([CH2:31][S:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:6])=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[N:16]1)([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cc(CSc2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc(CS(=O)c2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
3-Chloroperoxybenzoic acid (20 mL, 0.00252 mol) is added dropwise to a -78° C. solution of 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-[(phenylthio)methyl]nicotinic acid, methyl ester (1.0 g, 0.00252 mol) and sodium bicarbonate (0.2 g, 0.00238 mol) in methylene chloride. The reaction mixture is stirred at -78° C. for 30 minutes and then at room temperature for 24 hours. The reaction mixture is diluted with 5% sodium metabisulfite solution. The methylene chloride layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow oil. The oil is chromatographed using silica gel and hexanes/ethyl acetate (1:1) to (1:2) to (1:9) and finally 100% ethyl acetate as eluant to give the title compound as a yellow solid (0.97 g, 90%), mp 132°-136° C., identified by IR and NMR spectral analyses.
Reaction SMILES: C([O:3][PH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])C.[CH2:12]=[O:13].Cl>>[OH:13][CH2:12][P:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[OH:3]
Reactant: CCO[PH](=O)c1ccccc1
Reactant: C=O
Agent: Cl
Product: O=P(O)(CO)c1ccccc1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
100 g (0.5 moles) of phenylphosphinic acid ethyl ester are heated to 80° C., and 15 g (0.52) of paraformaldehyde are added in small portions. The paraformaldehyde addition is regulated so that the temperature does not exceed 110° C. by virtue of the exothermic nature of the reaction. When the addition is complete, the mixture is kept for about one hour under agitation at 110° C., and the termination of the reaction can be seen by gas chromatography or thin layer chromatography. 100 cc of a 10% HCl solution are then added, and the mixture kept at 80° C. for 30 min. The water and hydrochloric acid are then evaporated under vacuum, and the mixture taken up in isopropanol. On cooling, 69.3 g of hydroxymethylphenylphosphinic acid are obtained with a yield of 80.5% and a melting point of 138°-9° C.
Reaction SMILES: C([CH:4]([CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:5]([CH3:9])(O)[C:6]#[CH:7])(C)=C.O1C[CH2:23][CH2:22][CH2:21]1.[N+]([O-])([O-])=O.[K+].[OH2:30]>[N+]([O-])([O-])=O.[Ag+]>[CH3:9][C:5](=[CH:4][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18])[CH2:6][CH:7]=[CH:21][C:22](=[O:30])[CH3:23]
Reactant: C1CCOC1
Reactant: O
Reactant: C#CC(C)(O)C(CC=C(C)CCC=C(C)C)C(=C)C
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: CC(=O)C=CCC(C)=CCC=C(C)CCC=C(C)C

Procedure:
4-Isopropenyl-3,7,11-trimethyl-6,10-dodecadien-1-yn-3-ol (0.260 g; 10-3 mole) is kept at the reflux temperature of tetrahydrofuran and protected from light, in the presence of silver nitrate (0.017 g; 10-4 mole) and potassium nitrate (0.101 g; 10-3 mole) in a mixture (6 cc) of tetrahydrofuran and water (2:1 by volume). After being heated under reflux for 15 hours, the reaction mixture is treated under the conditions described in Example 1. 6,10,14-Trimethyl-3,6,9,13-pentadecatetraen-2-one (0.120 g) is thus obtained, with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([C:16](O)=O)[CH:12]=[N:11]1.S(Cl)(Cl)=O.S(N)([NH2:26])(=O)=O>S1(CCCC1)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([C:16]#[N:26])[CH:12]=[N:11]1
Reactant: NS(N)(=O)=O
Reactant: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(Cl)cc1Cl
Solvent: O=S1(=O)CCCC1
Solvent: O=S(Cl)Cl
Product: Cc1c(C#N)cnn1-c1c(Cl)cc(Cl)cc1Cl
Yield: 76 %

Procedure:
By the method of Example 1, Step E, 25.6 g (0.0838 mole) of 1-(2,4,6-trichlorophenyl)-4-carboxy-5-methyl-1H-pyrazole, 114.3 g (0.961 mole) of thionyl chloride, and 12.7 g (0.132 mole) of sulfamide were reacted in 100 mL of sulfolane, yielding 18.25 g of 1-(2,4,6-trichlorophenyl)-4-cyano-5-methyl-1H-pyrazole as an oil which subsequently solidified. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH2:20][C:19]([CH3:22])([CH3:21])[O:18][N:17]=1.O>CN(C)C=O>[CH2:1]([S:8][C:16]1[CH2:20][C:19]([CH3:22])([CH3:21])[O:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: CC1(C)CC(Cl)=NO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(SCc2ccccc2)=NO1
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of 2.8 g (22.5 mmoles) of benzylmercaptan dissolved in 50 ml of dimethylformamide were added, in a nitrogen current, 3.2 g (23.2 mmoles) of anhydrous potassium carbonate and 3.0 g (22.5 mmoles) of 3-chloro-5,5-dimethyl-2-isoxazoline. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, and the residue was purified by silica gel column chromatography to obtain 3.1 g (yield: 62.0%) of 3-benzylthio-5,5-dimethyl-2-isoxazoline as a yellow oily substance (refractive index nD20=1.5521).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1[F:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:12][C:10]1[N:11]=[C:3]2[C:2]([O:1][CH2:19][C:20]3[C:21]([F:28])=[CH:22][CH:23]=[C:24]([F:27])[C:25]=3[F:26])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]2[C:9]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reactant: Fc1ccc(F)c(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)ccc(F)c3F)cc(C)cn12
Reaction time: 0.5 h

Procedure:
10 g (42.69 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 87A, 10.9 g (46.96 mmol) of 2-(bromomethyl)-1,3,4-trifluorobenzene and 30.6 g (93.91 mmol) of caesium carbonate were initially charged in 611 ml of DMF, and the mixture was heated in an oil bath, preheated to 60° C., for 30 min. The reaction mixture was poured into about 5 l of water and stirred for 30 min, and the solid formed was filtered off with suction, washed with water and dried under high vacuum. This gave 14.1 g of the target compound (86% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:16][CH2:17]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:16][CH3:17])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A mixture of 2-(4-fluorophenyl)acetic acid (23.5 g, 152 mmol) in thionyl chloride 56 mL, 762 mmol) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 200 mL DCM, and stirred at 0° C. The mixture was treated with EtOH (9.8 mL, 168 mmol) and TEA (26 mL) dropwise. The mixture was then stirred for 2 hours. The mixture was quenched with 20 mL H2O and extracted with DCM (3×50 mL). The combined organics were washed with H2O (3×50 mL) and brine 20 mL, dried over anhydrous Na2SO4, and concentrated in vacuo to give 24.7 g of a pale yellow oil.