Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O-].[Na+].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7]([O-])=[O:8].[CH3:14][O:15][CH2:16][CH2:17][N:18]1[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21](=O)[O:20]C1=O.Cl>>[CH2:12]([O:11][C:5]([C:6]1[C:7](=[O:8])[N:18]([CH2:17][CH2:16][O:15][CH3:14])[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21]=1[OH:20])=[O:10])[CH3:13]
Reactant: COCCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O

Procedure:
50 ml. of NaOEt (0.5 g. Na--0.021 mole) was added to 3.4 g. (0.021 mole) of ethyl malonate and stirred 10 minutes, then evaporated to dryness. DMF was added until a solution was achieved and then 3.2 g. (0.011 mole) of 1-(2-methoxyethyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and this mixture refluxed 2 hours. The chilled reaction was poured into dilute HCl and the ensuing precipitate filtered off and rinsed with water. Recrystallization from ethyl acetate gave 3.5 g. of the title product--m.p. 178°-179° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:25]2[O:26][C:27](=[O:31])[N:28]([CH3:30])[N:29]=2)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(O[C:35](=O)[C:36]1[CH:41]=C(Br)C=NC=1C1C=CC(NC(=O)C2C(F)=CC=CC=2F)=CC=1)C>>[CH:41]1([C:2]2[CH:3]=[C:4]([C:25]3[O:26][C:27](=[O:31])[N:28]([CH3:30])[N:29]=3)[C:5]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:24])[C:16]4[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=4[F:22])=[CH:12][CH:13]=3)=[N:6][CH:7]=2)[CH2:36][CH2:35]1
Reactant: CCOC(=O)c1cc(Br)cnc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Reactant: Cn1nc(-c2cc(Br)cnc2-c2ccc(NC(=O)c3c(F)cccc3F)cc2)oc1=O
Product: Cn1nc(-c2cc(C3CC3)cnc2-c2ccc(NC(=O)c3c(F)cccc3F)cc2)oc1=O

Procedure:
Step-4: N-(4-(5-Bromo-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-2-yl)phenyl)-2,6-difluorobenzamide: The title compound was prepared from ethyl-5-bromo-2-(4-(2,6-difluorobenzamido)phenyl)nicotinate by following the similar procedure sequentially as described in step-2, step-3, and step-4 of Intermediate-1a. ESI-MS (m/z) 487, 489 [(MH)+, Br79,81].
Reaction SMILES: Cl.C([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17][C:16]3[CH:24]=[CH:25][C:26]([Br:28])=[CH:27][C:15]=3[CH2:14]2)[CH2:9][CH2:8]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[Br:28][C:26]1[CH:25]=[CH:24][C:16]2[S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:13]([N:10]3[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]3)[CH2:14][C:15]=2[CH:27]=1
Reactant: CCOC(=O)N1CCN(C2Cc3cc(Br)ccc3Sc3ccccc32)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Brc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2

Procedure:
47.2 g of 1-carbethoxy-4-(2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine hydrochloride, 585 ml of ethylene glycol, 32.8 g of potassium hydroxide and 1.95 ml of water are heated to 160° C for 90 minutes. Then the mixture is poured on to water and extracted with chloroform. The organic solution is extracted with 2-N hydrochloric acid. The hydrochloric acid solution is made alkaline, extracted with chloroform, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. There is obtained crystalline 1-(2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine of melting point 112°-115° C.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C([O:6][C:7]([NH:9][N:10]([CH2:13][CH3:14])[C:11]#[N:12])=O)C>C(O)(=O)C>[CH2:13]([N:10]1[C:11]([S:3][CH2:1][CH3:2])=[N:12][C:7]([OH:6])=[N:9]1)[CH3:14]
Reactant: CCS
Reactant: CCOC(=O)NN(C#N)CC
Solvent: CC(=O)O
Product: CCSc1nc(O)nn1CC
Yield: 75.1 %

Procedure:
To an ethanolic solution of sodium ethylate produced from 4.6 g of sodium and 100 ml of absolute ethanol there is firstly added dropwise 14.9 g of ethyl mercaptan and subsequently 31.4 g of 2-ethyl-2-cyanohydrazinecarboxylic acid ethyl ester is added dropwise. There is formed a crystalline precipitate, which is refluxed for 3 hours. The cooled suspension is freed, after the addition of 12 g of glacial acetic acid, by filtration from the precipitated sodium acetate, and the filtrate is concentrated in vacuo to dryness. 200 ml of chloroform is added to the residue and filtration is performed. The filtrate is again concentrated to dryness. The residue is recrystallised with cyclohexane. There is obtained 26 g (75% of theory) of 1-ethyl-5-ethylthio-3-hydroxy-1,2,4-triazole, m.p. 65°-68° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].O>CCOCC>[NH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCCCCN
Reaction time: 2 h

Procedure:
To a solution of lithium aluminium hydride (600 mg, Aldrich) in ether (50 mL) was added dropwise the product (3.8 g) from Example 4 in ether (50 mL). After 1-3 h, the mixture was poured into water and stirred for 30 min. The insoluble aluminum hydroxide was filtered through a celite pad, and the aqueous layer was extracted with ether three times. The ether extracts were washed with brine solution, dried and concentrated. The crude product was distilled at 0.25 Torr and 82° C. High resolution mass spectrum for C13 H31 O N Si: calculated 245.2175, found 245.2159.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:5][C:4]([CH2:12][F:13])([C:6]([O:8]C(C)C)=[O:7])[CH2:3]1.[OH-].[Na+]>C(O)C>[F:1][C:2]1([F:14])[CH2:3][C:4]([CH2:12][F:13])([C:6]([OH:8])=[O:7])[CH2:5]1
Reactant: CC(C)OC(=O)C1(CF)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(CF)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of Intermediate 302D (0.25 g, 1.189 mmol) in ethanol (5 mL) was added NaOH (1.189 mL, 5.95 mmol, 5 M in water) and the reaction mixture was stirred at RT for 8 h. The reaction mixture was concentrated in vacuo, dissolved in water and extracted with diethyl ether. The pH of the aq. solution was adjusted to 7 using a 2N aq. solution of HCl and extracted with DCM (3×10 mL) The combined organic layer was dried over Na2SO4, filtered, and the filtrate concentrated to afford Intermediate 302E as a pale yellow liquid (0.12 g, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.02-13.40 (br. s., 1H), 4.53-4.76 (m, 2H), 2.95 (q, J=13.22 Hz, 2H), 2.59-2.78 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17]([NH:19][C@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=1)[C:21](OC)=[O:22])=[O:18].Cl>CN(C)C=O.ClCCl>[CH2:1]([N:8]1[CH2:16][C:17](=[O:18])[NH:19][C@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH3:33])[CH:27]=2)[C:21]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(C)c1)NC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@H]2NC(=O)CN(Cc3ccccc3)C2=O)cc1C
Temperature: 35 °C
Reaction time: 3 h

Procedure:
Benzylamine (5.4 ml) and potassium carbonate (4.08 g) were added successively to a solution of methyl (2R)-2-(2-chloroacetylamino)-3-(3,4-dimethylphenyl)propionate (5.33 g) in N,N-dimethylformamide (25 ml) at 20° C. After 3 hours of stirring at 35° C., the mixture was poured into a mixture of ice-water (40 ml) and dichloromethane (40 ml). After the mixture was adjusted to pH 6 with concentrated hydrochloric acid (ca. 1.4 ml), the organic layer was separated, washed with brine (20 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was triturated with n-hexane and filtered to give colorless powders of (3R)-1-benzyl-3-(3,4-dimethylbenzyl)-2,5-piperazinedione (1.51 g). The filtrate was evaporated under reduced pressure to give an oil of methyl (2R)-2-[(2-benzylaminoacetyl)amino]-3-(3,4-dimethylphenyl)propionate (5.67 g).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:16])=[C:7]([CH2:12][CH2:13][CH2:14][OH:15])[CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)C1C=CC=CC=1.[C:26]([C:30]1[CH:31]=[C:32]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH2:47][CH2:48][S:49][CH2:50][CH2:51][C:52](Cl)=[O:53])=[O:44])[CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])([CH3:29])([CH3:28])[CH3:27].S(=O)(=O)(O)O>C(OCC)C>[C:26]([C:30]1[CH:31]=[C:32]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH2:47][CH2:48][S:49][CH2:50][CH2:51][C:52]([O:15][CH2:14][CH2:13][CH2:12][C:7]2[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=2[OH:16])=[O:53])=[O:44])[CH:33]=[C:34]([C:37]([CH3:38])([CH3:40])[CH3:39])[C:35]=1[OH:36])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cc(CCC(=O)OCCCSCCC(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Cc1cc(CCCO)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: Cc1cc(CCCOC(=O)CCSCCCOC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c(C(C)(C)C)c1
Yield: 66.7 %

Procedure:
Into a 50 ml reactor were charged 3.40 g (15.29 mmol) of 3-(3-tert-butyl-2-hydroxy-5-methylphenyl)-1-propanol, 20 ml of diethyl ether and 1.94 g (16.00 mmol) of N,N-dimethylaniline. The atmosphere in the reactor was replaced with dry nitrogen. To the reactants was added dropwise 7.09 g (16.00 mmol) of 3-[3-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyloxy]propylthio]propionyl chloride. The reactants were heated and refluxed for 6 hours in the nitrogen stream. After the completion of the reaction, diethyl ether was added and the reaction product was neutralized with 10% sulfuric acid. After liquid separation, washing with saturated aqueous solution of sodium chloride and dehydration with anhydrous sodium sulfate, the organic solvent was removed under reduced pressure. After separation by silica gel chromatography (solvent: chloroform), 6.42 g (10.20 mmol) of the desired product was obtained. The yield was 67%. The physical properties of the product are shown below.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].[CH3:8][C:9]1[N:10]=[C:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[S:12][C:13]=1[CH3:14]>CS(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([C:15]([C:11]2[S:12][C:13]([CH3:14])=[C:9]([CH3:8])[N:10]=2)([OH:20])[C:16]([F:19])([F:18])[F:17])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(C(=O)C(F)(F)F)sc1C
Reactant: Cc1ncsc1C
Solvent: CS(C)=O
Product: Cc1nc(C(O)(c2nc(C)c(C)s2)C(F)(F)F)sc1C

Procedure:
From 4,5-dimethylthiazole and 4,5-dimethyl-2-trifluoroacetylthiazole. M.p. 122°-123.5° C. 13C Nmr (d6 -DMSO) 10.5, 14.4, 76.9 (g, J 30 Hz) 123.1 (q, J 286Hz), 129.0, 147.9 and 161.0 ppm.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][NH2:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:36][N:35]2[C:32]2[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:34][CH:33]=2)=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-n2nc(-c3ccc(O)cc3O)c3ccc(O)cc32)cc1
Yield: 59.6 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.400 g, 1.60 mmol), sodium acetate (0.267 g, 3.3 mmol) and (4-methanesulfonyl)phenylhydrazine hydrochloride (0.454 g, 2.5 mmol) to give 0.378 g of product as a tan solid.
Reaction SMILES: [C:1]1([S:7][S:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][NH:11][C:12]([F:14])=[O:13]>>[CH3:10][N:11]([S:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([F:14])=[O:13]
Reactant: CNC(=O)F
Reactant: ClSSc1ccccc1
Product: CN(SSc1ccccc1)C(=O)F

Procedure:
Prepared by the procedure of Example II by reacting phenylthiosulfenyl chloride with methylcarbamoyl fluoride. b.p. 100°-110° C/0.3 Torr ND22.5 1.5770.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N+:14]([C:6]1[CH:5]=[CH:4][C:3]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:8][C:7]=1[N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)([O-:16])=[O:15]
Reactant: COc1ccc([N+](=O)[O-])c(-n2cccn2)c1
Reactant: C1COCCN1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1-n1cccn1
Yield: 8.5 %

Procedure:
Under N2 a solution of 1-(5-Methoxy-2-nitro-phenyl)-1H-pyrazole (3.00 g, 13.7 mmol), of Example 611a, in Morpholine (100 mL, 1000 mmol; Acros) was warmed to 120° C. for 100 h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between 10% Na2CO3 and EtOAc. The aqueous phase was washed with a second portion of EtOAc, then the organics were combined, dried over Na2SO4, filtered and concentrated to yield 1.46 g of crude product 4-(4-Nitro-3-pyrazol-1-yl-phenyl)-morpholine (26% by LC). An initial purification by normal phase chromatography eluting with a gradient of 100% CH2Cl2 to 10:1 CH2Cl2:MeOH met with limited success. The purest fractions were concentrated and rerun on another normal phase column eluting with a gradient of 10% EtOAc/Hexane to 65% EtOAc/Hexane. The purest fractions were combined and concentrated under reduced pressure to give 0.48 g of purer material. This material was crystallized from Et2O and the resulting solid was filtered and rinsed with a small amount of Et2O to yield 318 mg (9%) of 4-(4-Nitro-3-pyrazol-1-yl-phenyl)-morpholine, which was carried on without further purification.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:9][CH3:10])[CH3:7].[C:28]1(=[O:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[Cl-].[NH4+]>O1CCCC1>[CH2:6]([C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:28]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:13]([CH3:19])[CH:12]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Reactant: O=C1CCCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.9 %

Procedure:
n-Butyllithium (1.59 M solution in hexane, 5.4 mL, 8.59 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 1.00 g, 3.42 mmol) in tetrahydrofuran (15 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred for 15 minutes. Then, cycloheptanone (0.81 mL, 6.87 mmol) was added to the reaction mixture, which was stirred at 0° C. for one hour, heated to room temperature and further stirred for one hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=90:10 to 50:50) to give the target compound as a colorless oil (829 mg, 60%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[SH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([S:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)O)cc1C(C)(C)C
Reactant: O=C(O)c1ccc(S)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Sc2ccc(C(=O)O)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Crude 3-(tert.butyl)-4-methoxybenzoic acid, prepared starting with 1.04 g (5 mmoles) of 3-(tert.butyl)-4-methoxybenzoic acid, described in Example 35 of French Patent No. 85 13747 (2.570.377), is dissolved in 15 ml of dichloromethane. The solution is slowly added to a mixture of 771 mg (5 mmoles) of 4-mercaptobenzoic acid and 8 ml of pyridine. The reaction mixture is stirred at ambient temperature for 8 hours, evaporated to dryness, taken up in water, acidified to pH 5 with 1N HCl and extracted with ethyl ether. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting residue is purified by chromatography on a silica column (eluant: ethyl ether). The solvent is evaporated and 530 mg (32% yield) of 4-[3-tert.butyl-4-methoxybenzoylthio]benzoic acid whose melting point is 220°-221° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:4].O.[NH2:18][NH2:19].O>O1CCCC1>[NH:18]([C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=1)=[S:13])[NH2:19]
Reactant: NN
Reactant: COC(=O)c1ccc(N=C=S)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(NC(=S)NN)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 84.7 %

Procedure:
A solution of the above synthesized 4-methoxycarbonyl-3-nitrophenyl isothiocyanate (149 mg, 0.62 mmol) in tetrahydrofuran (2.2 ml) was added dropwise to a solution of hydrazine monohydrate (94 mg, 1.87 mmol) in tetrahydrofuran (4.0 ml) at 0° C. over 20 minutes. After stirring at 0° C. for further 40 minutes, water was added, and the precipitated solid was filtered to obtain 142 mg of the desired product as a colorless solid (yield 85%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]=[C:14]=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[NH2:18][C:19]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:21]([O-])=[O:22]>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[C:5]([N:13]2[C:21](=[O:22])[CH:20]=[C:19]([C:24]([F:27])([F:26])[F:25])[NH:18][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Cl)ccc(N=C=O)c1C
Reactant: NC(=CC(=O)[O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1C
Yield: 58.9 %

Procedure:
This compound was prepared in a manner analogous to the second part of Step D, Example 1. Here, 16.7 grams (0.074 mole) of methyl 6-chloro-3-isocyanato-2-methylbenzoate was combined with 4.4 grams (0.110 mole) of 60% sodium hydride and 14.2 grams (0.076 mole) of 3-amino-4,4,4-trifluoro-2-butenoate in 600 mL of THF. The reaction product was purified by column chromatography on silica using a 1:1 mixture of EtOAc and hexane as eluant. The fractions containing product were combined and concentrated under reduced pressure, yielding 15.8 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([I:12])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].O>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[C:3]2[N:4]([C:9]([I:12])=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Reactant: CC(C)(O)CN
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)CNc1cc(Cl)nn2c(I)cnc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 1.20 g (3.35 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c in 24 mL N,N-dimethylformamide were added 895 mg 1-amino-2-methylpropan-2-ol and the mixture was stirred at 40° C. overnight. Water was added and the mixture was extracted with dichloromethane and methanol. The organic phase was washed with water and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 798 mg (65%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32]O)[CH2:27][CH2:26]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12
Reactant: Fc1cccc(-c2n[nH]c3nnc(-c4ccccc4)c(Cl)c23)c1
Reactant: CN1CCN(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN1CCN(CCn2nc(-c3cccc(F)c3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
A mixture of 4-chloro-3-(3-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), 2-(4-methylpiperazin-1-yl)ethanol (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 8.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO[CH:15](OC)[CH2:16][CH:17](OC)OC.Cl>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:17]=[CH:16][CH:15]=[N:12]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2cccn2)cc1
Temperature: 0 °C
Yield: 79 %

Procedure:
To a solution of 4-(methylsulfonyl)phenylhydrazine (5.0 g, 26.8 mmol, 1.00 equiv) and 1,1,3,3-tetramethoxypropane (4.4 mL, 26.8, 1.0 equiv) in ethanol (37 mL) at rt was added concentrated HCl (2.8 mL). The resulting solution was heated at reflux for 1 hr, cooled to 0° C. and filtered to give 1-(4-methanesulfonyl-phenyl)-1H-pyrazole as a yellow solid (4.73 g, 79%). LCMS: (MH)+=223.1 (1.19 min).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:22][CH3:23]>CC(C)=O>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)[CH3:23]
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(C2CCC(=O)CC2)cc1
Temperature: 65 °C
Yield: 100 %

Procedure:
A solution of 4-(4-hydroxyphenyl)cyclohexanone (5.0 g, 26.3 mmol) in acetone (100 mL) was treated with K2CO3 (14.5 g, 105 mmol, 4 equiv) and iodoethane (10.5 mL, 20.5 g, 131 mmol, 5 equiv.). The reaction was heated at 65° C. overnight. After the solvent was removed, the residue was treated with H2O and extracted with EtOAc. The organic extracts were combined and washed with brine, dried over Na2SO4 and concentrated in vacuum to give the spectroscopically pure 4-(4-ethoxyphenyl)-cyclohexanone (5.74 g, 100%). 1H NMR (CDCl3) 7.15 (dt, 2H), 6.86 (dt, 2H), 4.02 (q, 2H), 2.99 (tt, 1H), 2.46-2.54 (m, 4H), 2.16-2.24 (m, 2H), 1.83-2.00 (m, 2H) and 1.41 (t, 3H); MS (electrospray) m/e, 219 (M+1)+, Calcd for C14H18O2, 218. Step 2: