Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]([CH2:16][OH:17])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]([CH2:16][O:17][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)C=Cc1ccccc1C2CO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)C=Cc1ccccc1C2COS(=O)(=O)c1ccc(C)cc1
Yield: 79.8 %

Procedure:
To a solution of 2-methoxy-5-hydroxymethyldibenzo[a,d]cycloheptene (10.5 g) in dry dichloromethane (150 ml) was added p-toluenesulphonyl chloride (8.1 g), pyridine (6.6 g) and 4-dimethylamino pyridine (300 mg). The reaction mixture was refluxed for 15h, cooled, washed with water (2×200 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica chromatography using 15% ethyl acetate in hexane as eluent to give the title compound as an oil (13.5 g). δ(360 MHz, CDCl3), 2.44 (3H, s, Ar--CH3), 3.78 (3H, s, OCH3), 4.19-4.31 (3H, m CH-CH2 --OSO2Ar). 6.58 (1H, d, J=11.9 Hz, Ar--CH=CH--Ar), 6.65 (1H, d, J=11.9 Hz, Ar--CH=CH--Ar), 6.68 (1H, d, J=2.7, CH=C(OCH3)--CH), 6.85 (1H, dd, J=8.4 and 2.7 Hz, CH=C(OCH3)--CH) and 7.16-7.42 (9H, m, aromatics). m/e 406 (M+).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:27][CH:28]3[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]3)[CH:9]=[C:10]([N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH:42]1(B(O)O)[CH2:44][CH2:43]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:42]1([C:2]2[N:6]3[N:7]=[C:8]([NH:27][CH:28]4[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]4)[CH:9]=[C:10]([N:11]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:5]3=[N:4][CH:3]=2)[CH2:44][CH2:43]1
Reactant: OB(O)C1CC1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(NC3CCC(NC(=O)OC(C)(C)C)CC3)nn3c(Br)cnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2ccccc2)c2cc(NC3CCC(NC(=O)OC(C)(C)C)CC3)nn3c(C4CC4)cnc23)cc1
Temperature: 120 °C
Yield: 15.4 %

Procedure:
tert-Butyl 4-(3-bromo-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate (30 mg, 0.048 mmol) from (1a) and cyclopropylboronic acid (10 mg, 0.090 mmol) in toluene were purged with argon for 15 min, then aq. K3PO4 (2M, 0.06 mL), EtOH (0.04 mL) and tetrakis(triphenylphosphine)palladium(0) were added sequentially. The mixture was heated at 120° C. for 20 h. After cooling to room temperature, the mixture was partitioned between EtOAc (20 mL) and water (5 mL) and the organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by reverse phase preparative HPLC to provide tert-butyl 4-(3-cyclopropyl-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate as a cream colored oil (4.3 mg, 15%) LCMS [M+H]+ 583.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:11][C:10]([C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([Cl:1])[CH:7]=1)=[O:12]
Reactant: COc1ccccc1Cl
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)cc1Cl
Yield: 96.2 %

Procedure:
A mixture of 30 grams (210 millimoles) of orthochloroanisole and 19.8 grams (252 millimoles) of acetyl chloride was dissolved in 400 milliliters of methylene chloride, and then 33.6 grams (252 millimoles) of anhydrous aluminum chloride was gradually added thereto while cooling with ice and stirring. The resulting mixture was further stirred for 3 hours while cooling with ice. The reaction mixture was allowed to stand to room temperature and stirred for 2 hours at room temperature. Then the reaction mixture was added to 1,200 milliliters of 5% hydrochloric acid, which was then allowed to separate into aqueous and organic layers. The organic layer thus obtained was washed with a 5% aqueous solution of sodium carbonate and dried over anhydrous sodium sulfate and, thereafter, the methylene chloride was distilled away under reduced pressure. Thus, as a product, 37.4 grams (202 millimoles) of 3-chloro-4-methoxyacetophenone was obtained (yield, 97%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.C([CH:22]1[CH2:25][NH:24][C:23]1=[O:26])(=O)C1C=CC=CC=1>CCCCCC.C1COCC1>[C:3]1([C:1]#[C:2][CH:22]2[CH2:25][NH:24][C:23]2=[O:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1NCC1C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1NCC1C#Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 500 mL, three necked round bottomed flash with a stirring bar, low temperature thermometer, argon inlet and a septum was added dry THF (100 mL) and ethynylbenzene (60 mmol, 6.1 mL). This solution was cooled to -78° C. and n-butyllithium (60 mmol, 24 mL of a 2.5M solution in hexane) was added with a syringe at such a rate that the temperature was maintained below -50° C. When the addition was complete, the solution was aged 30 min then a solution of 3(R,S)-benzoylazetidinone (15 mmol, 2.87 g) in THF (50 mL) was added slowly with a syringe, maintaining the temperature below -60° C. The resulting solution was aged 1 h at -78° C. then warmed to 0°C. The reaction was quenched at 0°C. by addition of saturated, aqueous NH4Cl solution. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with H2O and brine. Drying (MgSO4), filtration and removal of the solvents in vacuo gave 3(R,S)-phenylethynylazetidinone (15-2) as a crystalline solid, which was used in Step B without further purification. ##STR139##
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]2[C:17](=[CH:18][CH:19]=1)[C:9]1[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=1[CH2:7]2)[CH3:2].C(O[C:24](=[O:26])[CH3:25])(=O)C>O>[C:24]([N:3]([C:4]1[CH:5]=[C:6]2[C:17](=[CH:18][CH:19]=1)[C:9]1[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=1[CH2:7]2)[CH2:1][CH3:2])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Solvent: O
Product: CCN(C(C)=O)c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Reaction time: 1 h
Yield: 90 %

Procedure:
5,10-Dihydro-2-(N-Ethylamino)indeno[1,2-b]indole (0.47 g, 1,90 mM) and acetic anhydride (4 cm3) were heated to 90°-95° C. for 4 hours. Water (30 cm3) was added to the cold solution and the mixture was stirred vigorously for 1 hour. The solid product which formed was then collected and washed with a few drops of cold ethanol to afford the title compound 0.5 g, 90% as a colourless solid, M.p. 232° C. 1H NMR (CDCl3) δ: 1.16 (3H, t, J=7.0 Hz), 1.90 (3H, s), 3.73 (2H, s), 3.81 (2H, q, J=7.0 Hz), 7.05-7.20 (4H, m), 7.46 (1H, d, J=7.5 Hz), 7.57 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=7.0 Hz, 10.36 (1H, s)).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC1C[O:46][CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH:14]3[CH2:45][O:46][CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: BrC1COC1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(C3COC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromooxetane and isolated as light-yellow gum. MS (m/e): 339.3 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=[O:19])[CH:13]([CH3:18])[CH2:14][C:15]([OH:17])=[O:16])=[CH:11][C:5]=2[O:4][CH2:3]1.[C:20](Cl)(=O)C>CO>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=[O:19])[CH:13]([CH3:18])[CH2:14][C:15]([O:17][CH3:20])=[O:16])=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)OCC(=O)N2
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)OCC(=O)N2

Procedure:
4-(3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-Oxo-3-methylbutyric acid (5 g) was suspended in methanol (50 ml) and acetyl chloride (0.5 ml) added. The mixture was heated on a steam bath until all of the solid dissolved. The solvent was evaporated at reduced pressure providing the ester as a white foam which was recrystallized from ethyl acetate-methanol to give the product as white crystals, yield 5 g, mp 95°-98° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)#[N:2].C(=O)([O-])[O-:20].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[CH3:18][C:15]([S:13]([NH:12][C@H:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:20])[CH:8]=1)[CH2:10][CH3:11])=[O:14])([CH3:17])[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C#N)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a chilled (10° C.) rapidly stirred solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-cyano-pyridin-4-yl)-propyl]-amide (4.4 g, 16.58 mmol) in DMSO (70 mL) was added potassium carbonate (3 g, 21.72 mmol) portionwise followed by a 30% aqueous solution of hydrogen peroxide (6.16 mL, 54.38 mmol) dropwise. The reaction was stirred at room temperature for 3.5 hours. The reaction was cooled to 5° C., diluted with EtOAc (100 mL), quenched with 10% aqueous sodium thiosulfate solution (25 mL), and stirred for 1 hour. The organic layer was separated, and the aqueous layer was extracted with EtOAc (4×100 mL). The combined organic layers were washed with water (3×50 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford 4-[(S)-1-(2-methyl-propane-2-sulfinylamino)-propyl]pyridine-2-carboxylic acid amide as a thick colorless oil.
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
Temperature: 80 °C

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° C. 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: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4].[OH-].[Na+].Cl>O.CO>[Br:14][C:12]1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH:7]=[N:8][N:9]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester (1.7 g, 4.8 mmol) in water (15 mL) and methanol (15 mL) was added a solution of 2 N aqueous sodium hydroxide (10 mL, 20 mmol). The solution was warmed at reflux for 1 hour. The reaction mixture was cooled to room temperature and acidified with 1 N aqueous HCl (pH=3-4) to afford a precipitate which was collected by filtration, washed with MeOH and air dried to afford 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[OH:20]>>[OH:20][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[CH2:18][NH:17][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and N-[5-((1R)-2-amino-1-hydroxy- ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a white solid; ; mp >85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.60-3.00 (m, 5H), 2.92 (s, 3H), 3.75-3.85 (m, 2H), 4.53 (dd, J=8.3, 4.0 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 7.01 (dd, J=8.3, 2.0 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.9 Hz, 2H); MS (ES) m/z: 449.9 (MH+); HRMS Calcd. for C21H26N3O6S(M−H)−: 448.1549. Found: 448.1541.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[S:18])[CH:13]=[CH:14][CH:15]=1)#[N:9].[C:19]([O:23][C:24](=[O:27])[CH2:25][NH2:26])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:8]([C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH:26][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])=[S:18])[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: N#Cc1cccc(N=C=S)c1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=S)Nc1cccc(C#N)c1
Temperature: 20 °C
Reaction time: 12 h
Yield: 88.7 %

Procedure:
2.8 cm3 (20 mmol) of triethylamine and 3.2 g (20 mmol) of 3-cyanophenyl isothiocyanate are added at 0° C. to a solution of 3.35 g (20 mmol) of glycine t-butyl ester in 150 cm3 of dichloromethane. The mixture is stirred at 20° C. for 12 hours before being concentrated under vacuum and then taken up with a mixture of water and ethyl ether (300:300). The ether phase is separated off and washed with a 1N hydrogen chloride solution (200 cm3), and then with a saturated sodium chloride solution. After drying with magnesium sulfate and concentration under vacuum, 5.17 g (89% yield) of a yellow solid is obtained, whose melting point is 131°-132° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N:24]=[C:25]=[S:26])[O:5][CH2:6][C:7]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].I.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1.[OH-].[Na+].O1CCCC1>O>[N:28]1([C:25]([NH:24][C:23]2[CH:22]=[CH:21][C:4]([O:5][CH2:6][C:7]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:8]=3[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:3][C:2]=2[F:1])=[S:26])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1
Reactant: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(N=C=S)c(F)c1
Reactant: C1CCNNC1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(NC(=S)N2CCCCN2)c(F)c1
Yield: 81.2 %

Procedure:
By the method of Example 1, Step C, of U.S. Pat. No. 4,906,281, 1.50 g (0.004 mole) of methyl 2-[2-(3-fluoro-4-isothiocyanatophenoxymethyl)-5-methyl-phenoxy]propionate and 1.07 g (0.005 mole) of perhydropyridazine monohydroiodide (prepared by the method of Example 1, Step B, of U.S. Pat. No. 4,906,281) were reacted in the presence of 0.20 g (0.0050 mole of sodium hydroxide in 40 mL of water and 10 ML of tetrahydrofuran, yielding 1.50 g of methyl 2-[2-[4-(perhydropyridazin-1-ylthiocarbonylamino)-3-fluorophenoxy-methyl]-5-methylphenoxy]propionate as a syrup. The NMR spectrum was consistent with proposed structure.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:13])(=O)=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Na+].S(Cl)([Cl:17])=O>CN(C)C=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([Cl:17])(=[O:13])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C

Procedure:
A suspension of 100 g. of sodium 4-acetylbenzenesulfonate in 225 ml. of dimethylformamide is treated with 31 ml. of thionyl chloride and the mixture is stirred at room temperature for 5 minutes, then poured into 1 l. of ice water. The resulting precipitate of 4-acetylbenzenesulfonyl chloride is collected by filtration and washed with ice water. The still-damp product may be used as such without further purification. However, if purification is desired, the following procedure may be used: The product is dissolved in methylene chloride and the solution is dried and evaporated at reduced pressure. Th residual sulfonyl chloride is crystallized from benzene/hexane; m.p. 83°-85° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Brc1ccc(I)nc1
Product: CN1CCN(c2ccc(Br)cn2)CC1

Procedure:
The product is obtained analogously to Example 3.24a is from 1.5 g (5.28 mmol) 5-bromo-2-iodopyridine and 1.3 mL (11.7 mmol) N-methylpiperazine.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1)[CH3:2].[N+:19]([O-])(O)=O.O.N>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[NH:10][N:9]=1)[CH3:18]
Reactant: CCN(CC)CCCNc1n[nH]c2ccccc12
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1n[nH]c2ccc(N)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
In 2.58 ml of sulfuric acid was dissolved 1.5 g of 3-(3-diethylaminopropylamino)indazole. To the solution were added dropwise 0.41 ml of nitric acid(d=1.42) and 0.41 ml of sulfuric acid(sp. gr. 1.84) under cooling with ice, and the solution was stirred for 2 hours at 5°-10° C. To 12.1 ml of ice and water was added the solution, and the pH of the solution was adjusted to at least 11 with an aqueous ammonia solution. Then the solution was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue was dissolved in 50 ml of anhydrous benzene. To the solution were added 10 g of iron powder and 2 ml of hydrochloric acid, and the solution was stirred for 30 minutes at 80° C. The reaction solution was added with 0.5 ml of water and stirred for 10 hours at 80° C. After cooling, the solution was filtered. The benzene layer of the filtrate was extracted three times with 20 ml of lN hydrochloric acid. The pH of the hydrochloric acid layer was adjusted to at least 11 and the alkali layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 100 g) using chloroform as the developing solvent to give 0.69 g of 3-(3-diethylaminopropylamino)-5-aminoindazole having the following analytical values in a yield of 44%.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.[C:13](OCC)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)(=O)C>[O:20]=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCCCC(=O)OCC
Reactant: COP(C)(=O)OC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCC(=O)CP(=O)(OC)OC

Procedure:
n-Butyllithiium (130 ml. of 1.6 M. solution) is slowly added to a solution of dimethyl methylphosphonate (25.6 g.) in 475 ml. of tetrahydrofuran (THF) at about -65° C. To the mixture is added a solution of ethyl heptanoate (18.4 g.) in 50 ml. of THF, annd the resulting mixture is stirred at about -70° C. for 2 hrs. Then, 16 ml. of acetic acid is added, and the mixture is concentrated under reduced pressure. The residue is mixed with dichloromethane (about 400 ml.) and water (about 50 ml.) shaken, and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation yields the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](O)=[O:14])[CH:9]=2)[N:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:26])=O>ClCCl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([Cl:26])=[O:14])[CH:9]=2)[N:4]=1
Reactant: O=C(O)c1ccc2nc(C(F)(F)F)ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2nc(C(F)(F)F)ccc2c1
Reaction time: 2 h

Procedure:
2-(Trifluoromethyl)quinoline-6-carboxylic acid (0.20 g) was dissolved in dichloromethane. To this solution, a small amount of N,N-dimethylformamide (300 μL) and oxalyl chloride (0.17 g) were added at room temperature and stirred for two hours. After refluxing for 20 minutes, the solvent was distilled off under the reduced pressure and 2-(trifluoromethyl)quinoline-6-carbonyl chloride was obtained as a crude product. To this crude product, 4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylaniline (0.49 g) dissolved in pyridine was added and refluxed for 5 hours. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by column chromatography to obtain N-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylphenyl]-2-(trifluoromethyl)quinoline-6-carboxamide (0.10 g, yield 24%).
Reaction SMILES: [CH:1]([NH:3][NH:4][CH:5]=O)=O.C[Si](Cl)(C)C.CCN(CC)CC.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1>N1C=CC=CC=1>[N:4]1[N:3]=[CH:1][N:19]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=2)[CH:5]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=CNNC=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)Cc1ccc(-n2cnnc2)cc1
Temperature: 100 °C
Yield: 92.9 %

Procedure:
Adapting a protocol by Catarzi et al (J. Med Chem., 2001, 44, 3157–3165), diformylhydrazine (352 mg, 4.0 mmol) and then dropwise trimethylsilyl chloride (2.53 mL, 20 mmol) and Et3N(1.30 mL, 9.3 mmol) were added to a suspension of 4-aminophenylacetic acid (201 mg, 1.33 mmol) in anhydrous pyridine. The mixture was heated at 100° C. overnight, volatiles were removed at reduced pressure and the resulting solid was treated with water (6 mL), collected, washed with H2O and dried in vacuo to provide 251 mg (93%) of 141JP01 as a light brown solid. LCMS m/z 204[M+H]+. 1H-NMR (DMSO-d6) δ 9.05 (s, 2H), 7.62 (d, 1H, J=8.6), 7.40 (d, 1H, J=8.2), 3.61 (s, 2H).