Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[S:12][C:13]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])=[CH:4][N:3]=1.[OH2:29]>N1CCOCC1>[C:21]([C:13]1[S:12][C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:3]3[CH2:4][CH2:5][O:29][CH2:7][CH2:2]3)=[N:3][CH:4]=2)=[O:9])=[N:15][C:14]=1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1)c1ccc(Cl)nc1
Reactant: O
Solvent: C1COCCN1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1)c1ccc(N2CCOCC2)nc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Compound 147 (100 mg, 0.244 mmol) was dissolved in morpholine (1 mL), followed by stirring at 80° C. for 1 hour. Water was added to the reaction system, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 148 (81.0 mg, 72%).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[N+:5]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)([O-:7])=[O:6].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([N:11]1[CH:12]=[C:8]([N+:5]([O-:7])=[O:6])[N:9]=[CH:10]1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Yield: 69.1 %

Procedure:
In PATENT DOCUMENT 4, 98 mass % nitric acid is added dropwise to 4-nitroimidazole dissolved in glacial acetic acid and acetic anhydride is further added dropwise thereto to perform nitration reaction, and then the reaction solution is added into crushed ice and 1,4-dinitroimidazole is produced at a yield of 69.1% by performing filtration and drying.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:17]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:34]([CH3:35])[S:33][C:32](=[O:36])[NH:31][N:30]=3)=[CH:26][CH:27]=2)[C:22]([CH3:38])([CH3:37])[CH2:21][CH2:20]1)=[O:18].N1C=CC=CC=1>ClCCl>[CH2:8]([N:7]([CH2:6][CH2:5][O:4][C:2]([N:31]1[N:30]=[C:29]([C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[N:19]([C:17](=[O:18])[C:16]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:20][CH2:21][C:22]3([CH3:37])[CH3:38])[CH:34]([CH3:35])[S:33][C:32]1=[O:36])=[O:3])[CH2:10][CH3:11])[CH3:9]
Reactant: COc1ccc(C(=O)N2CCC(C)(C)c3cc(C4=NNC(=O)SC4C)ccc32)cc1OC
Reactant: CCN(CC)CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)C(C)(C)CCN3C(=O)c2ccc(OC)c(OC)c2)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
6 g of 2-(N,N-diethylamino)ethyl chloroformate dissolved in 50 ml of dichloromethane are added dropwise with stirring to a solution of 10 g of 3,6-dihydro-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-6-quinolyl]-6-methyl-2H-1,3,4-thiadiazin-2-one ("B") and 9.8 ml of pyridine in 100 ml of dichloromethane and the mixture is subsequently stirred at 20° C. for one hour. The solvent is removed and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; Rf (THF) 0.65.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:11][N:12](C(OC(C)(C)C)=O)[CH:13]([CH2:15][CH:16]=[CH2:17])[CH3:14].FC(F)(F)C(O)=O>[Pd]>[CH3:11][NH:12][CH:13]([CH2:15]/[CH:16]=[CH:17]/[C:2]1[CH:3]=[C:4]2[O:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1)[CH3:14]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: Brc1cnc2ncoc2c1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C/C=C/c1cnc2ncoc2c1

Procedure:
In another example, 6-bromooxazolo[4,5-b]pyridine, when submitted sequentially to palladium catalyzed coupling to N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine and deprotection with trifluoroacetic acid, gives (4E)-N-methyl-5-(6-oxazolo[4,5-b]pyridinyl)-4-penten-2-amine. The requisite 6-bromooxazolo[4,5-b]pyridine can be produced from 2-amino-5-bromo-3-pyridinol by condensation with formic acid or a trialkyl orthoformate, using methodology similar to that of M-C. Viaud et al., Heterocycles 41: 2799-2809 (1995). The use of other carboxylic acids produces 2-substituted-6-bromooxazolo[4,5-b]pyridines, which are also substrates for the Heck reaction. The synthesis of 2-amino-5-bromo-3-pyridinol proceeds from furfurylamine (Aldrich Chemical Company). Thus, 5-bromo-3-pyridinol (produced from furfurylamine according to U.S. Pat. No. 4,192,946) can be chlorinated, using methods described by V. Koch et al., Synthesis, 499 (1990), to give 2-chloro-5-bromo-3-pyridinol, which in turn can be converted to 2-amino-5-bromo-3-pyridinol by treatment with ammonia.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([CH3:13])=[CH:15][CH:16]=1.[C:9]([NH2:8])(=[O:19])[C:10]1[CH:5]=[CH:6][CH:7]=[CH:12][CH:11]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CNCCC#Cc1ccccn1
Product: Cc1ccc(C(=O)N(C)CCC#Cc2ccccn2)cc1
Product: NC(=O)c1ccccc1
Yield: 36 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 4-methylbenzoyl chloride (58 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 31 mg of N,4-dimethyl-N-(4-pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 36%).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Cl:23])=[CH:21][CH:22]=1.[CH3:35][C:36]([O:39][C:40]([N:42]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:43]1[NH:44][CH:45]=[C:46]([C:48](O)=[O:49])[N:47]=1)=[O:41])([CH3:38])[CH3:37].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:38][C:36]([O:39][C:40]([N:42]([C:43]1[NH:44][CH:45]=[C:46]([C:48]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:18]=2[F:34])=[O:49])[N:47]=1)[C:51]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])=[O:41])([CH3:35])[CH3:37]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C(=O)O)c[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (0.035 g, 0.183 mmol) and HOBT (0.025 g, 0.183 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.048 g, 0.153 mmol) and 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-imidazole-4-carboxylic acid (0.050 g, 0.153 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. Saturated aqueous sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give crude bis(1,1-dimethylethyl)(4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate as an oil. Trifluoroacetic acid (0.3 mL, 3.89 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (0.066 g, 0.106 mmol) in dichloromethane (2 mL). The mixture was stirred at RT overnight, concentrated and purified by reverse phase HPLC (acetonitrile:water with 0.1% formic acid) to give the title compound (0.017 g, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09-8.18 (m, 2H), 7.81 (s, 1H), 7.51 (s, 1H), 7.44-7.50 (m, 2H), 7.30 (t, 1H), 7.10 (s, 1H), 5.45 (br. s., 2H), 4.44 (d, 2H). MS m/z 420 (M+1).
Reaction SMILES: [C:1](CCCC(Cl)=S)(=[O:3])[CH3:2].[C:10]([CH2:13][CH2:14][C:15](Cl)=[S:16])(=[O:12])C.SCC(SC)C([N:23]1[CH2:30][C:29](=[O:31])[CH2:28][C@H:24]1[C:25]([OH:27])=[O:26])=O>>[C:1]([S:16][CH2:15][CH2:14][CH2:13][C:10]([N:23]1[CH2:30][C:29](=[O:31])[CH2:28][C@H:24]1[C:25]([OH:27])=[O:26])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)CCC(=S)Cl
Reactant: CC(=O)CCCC(=S)Cl
Reactant: CSC(CS)C(=O)N1CC(=O)C[C@H]1C(=O)O
Product: CC(=O)SCCCC(=O)N1CC(=O)C[C@H]1C(=O)O

Procedure:
Following the procedure of Example 1 but substituting 4-acetylthiobutyroyl chloride for the 3-acetylthiopropionyl chloride in part (d), one obtains 1-[4-(acetylthio)-1-oxobutyl]-4-oxo-L-proline.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].O.[OH-].[Li+]>CS(C)=O>[CH3:20][C:18]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:19]=1
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C#N)c(Nc2ccccc2[N+](=O)[O-])c1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
Combine 1-fluoro-2-nitro-benzene (5.34 g, 37.83 mmol), 2-amino-4-methyl-benzonitrile (5.00 g, 37.83 mmol), lithium hydroxide monohydrate (3.17 g, 75.66 mmol) and DMSO (70.0 ml). Stir the mixture at 55° C. for 16 hours then cool it to ambient temperature. Pour the mixture onto ice chips and stir for 1 hour. Remove the resulting yellow precipitate by vacuum filtration. Dry the precipitate under vacuum then recrystallize it in ethanol to give 5.15 g (54%) of fine, amber colored needles: mp 162–164°; mass spectrum (ion spray): m/z=254.0 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].CN1CCOCC1.Cl.[CH3:20][O:21][C:22](=[O:26])[CH2:23][CH2:24][NH2:25].O>ClCCl>[CH3:20][O:21][C:22](=[O:26])[CH2:23][CH2:24][NH:25][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-formyl-benzoic acid (20 g, 133 mmol), CDMT (24 g, 137 mmol), and 4-methyl-morpholine (15.4 mL, 140 mmol) are combined in anhydrous dichloromethane (DCM) (300 mL) under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. Beta-alanine methyl ester hydrochloride (20.4 g, (147 mmol) is then added to the reaction mixture, followed by 4-methylmorpholine (15.4 mL, 140 mmol), and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction is diluted with DCM. The reaction is diluted with water and extracted with 1N HCl. The organic layer is washed with water and brine, followed by drying over anhydrous sodium sulfate. The solution is filtered and concentrated and further purified using flash column chromatography (30 g, 128 mmol).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:37])([F:36])[CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]3[N:22]=[CH:23][C:24]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([O:31]C)=[O:30])=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:9].C1COCC1.Cl>CO.O>[F:37][C:5]([F:4])([F:36])[CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]3[N:22]=[CH:23][C:24]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([OH:31])=[O:30])=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: COC(=O)c1cccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)O)c4)cnn23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium hydroxide monohydrate (40. mg, 0.96 mmol) was added to a mixture of methyl 3-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}benzoate (0.090 g, 0.19 mmol) in methanol (2.0 mL)/THF (1.0 mL)/water (0.5 mL) and then the reaction was stirred at r.t. for 4 h. The mixture was adjusted with conc. HCl to PH˜3, and then concentrated under reduced pressure to give the crude product which was directly used in the next reaction without further purification. LCMS (M+H)+: m/z=456.1
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[CH2:6](Cl)/[CH:7]=[C:8](/[CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:19])[CH3:14])\[CH3:9]>CN(C)C=O.C(OCC)(=O)C>[CH2:6]([S:5][CH2:3][CH3:4])/[CH:7]=[C:8](/[CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:19])[CH3:14])\[CH3:9]
Reactant: CCS
Reactant: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
0.84 g of sodium hydride was added to a solution of 2.40 g of ethylmercaptan dissolved in 30 ml of N,N-dimethylformamide. Thereinto was dropped 10.00 g of phytyl chloride at 40° C. The resulting mixture was stirred at the same temperature for 3 hours. After the completion of the reaction, the resulting mixture was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid, 3% aqueous sodium hydrogencarbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane:ethyl acetate=9:1) to obtain 10.00 g (yield: 92%) of oily ethyl phytyl thioether.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[O:12][CH2:13][CH3:14].[Li][N:17]([Si](C)(C)C)[Si](C)(C)C.B(F)(F)F.[CH3:30][S:31]([CH3:34])(=[O:33])=[O:32]>CO.C1COCC1>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]([NH2:17])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:6][C:5]=1[O:12][CH2:13][CH3:14]
Reactant: CS(C)(=O)=O
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: CCOc1cc(C=O)ccc1OC(F)F
Agent: FB(F)F
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
To the THF solution (100 ml) of 4-difluoromethoxy-3-ethoxy-benzaldehyde (21.0 g, 0.1 mol) was added dropwise LiN(TMS)2 (1M in THF, 100 ml, 0.1 mol) at 0° C. After 15 minutes of stirring, BF3.THF complex (22 ml, 0.2 mol) was added to the reaction mixture (1). To the THF solution (100 ml) of methyl sulfone (9.4 g, 0.1 mol) was added LiN(TMS)2 (1M in THF, 100 ml, 0.1 mol) at −78° C. The mixture (2) was stirred at −78° C. for 1 hour. Mixture (1) was added to the mixture (2) via a 2-way needle. The mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. MeOH (20 ml) was added to quench the reaction. The mixture was concentrated in vacuo until there was one-fourth left. To the resulted mixture was added HCl aqueous solution (20%, 150 ml) followed by concentrated HCl until pH=3. The mixture was extracted with ether (100 ml×3). The aqueous layer was neutralized with NaOH (15 M) till pH=8. The mixture was extracted with methylene chloride (100 ml×3). The combined organic layer was washed with water (100 ml×2), brine (100 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel column to give 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (2.8 g, 10%) as yellow oil. 1H NMR (CDCl3) δ 1.41 (t, J=6.8 Hz, 3H, OCH2CH3), 3.30–3.40 (m, 2H, CH2SO2), 3.45 (s, 3H, CH3), 4.58–4.64 (m, 1H, CHN), 6.53 (t, J=75 Hz, 1H, CF2H), 6.84–7.12 (m, 3H, Ar).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]3[S:11][C:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)=[C:13]([O:14]C)[C:9]=3[C:8](=[O:27])[N:7]([CH3:28])[N:6]=2)[CH2:3][CH2:2]1.B(Br)(Br)Br.O>ClCCl>[CH:1]1([CH2:4][C:5]2[C:10]3[S:11][C:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)=[C:13]([OH:14])[C:9]=3[C:8](=[O:27])[N:7]([CH3:28])[N:6]=2)[CH2:2][CH2:3]1
Reactant: COc1c(Cc2cccc(C(F)(F)F)c2)sc2c(CC3CC3)nn(C)c(=O)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1nc(CC2CC2)c2sc(Cc3cccc(C(F)(F)F)c3)c(O)c2c1=O
Temperature: -15 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
7-Cyclopropylmethyl-3-methoxy-5-methyl-2-[(3-trifluoromethylphenyl)methyl]-thieno[2,3-d]pyridazin-4(5H)-one (8.8 g) was dissolved in dichloromethane (250 ml) and cooled to −15° C. Boron tribromide in dichloromethane (1M, 24 ml) was added. The reaction was allowed to warm to room temperature and left to stir for 72 hours. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate was dried, filtered and concentrated. The residue was purified by chromatography, eluting with 1:1 isohexane:ether, and then recrystallised from isohexane to give the sub-title compound (4.5 g).
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][C:7]([N:9]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][O:11][C:10]1=[O:21])=[O:8])C.BrC[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[CH2:12]([O:11][C:10](=[O:21])[CH:6]([C:7]([N:9]1[CH:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][O:11][C:10]1=[O:21])=[O:8])[CH2:5][CH2:4][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:13]
Reactant: CCOC(=O)CCC(=O)N1C(=O)OCC1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(=O)OC(C)(C)C)C(=O)N1C(=O)OCC1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of the compound of example 67 (5.0 g, 16.38 mmol) in anhydrous THF (160 mL) was cooled to −78° C. A solution of NaHDMS in THF (1M, 16.4 mL, 16.4 mmol) was injected over 10 minutes. The reaction mixture was stirred for an additional 20 minutes, after which time, a solution of tert-butyl bromoacetate in anhydrous THF (10 mL) was slowly injected. After stirring for 1 h at −78° C. and 3 h at −48° C., the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted several times with ethyl acetate. The recombined organic layer was successively extracted with brine, a saturated sodium hydrogen carbonate solution, brine and water. The solvent was evaporated following drying over sodium sulfate and filtration. The resultant crude product was flashed with 20% ethyl acetate in hexanes to give the product as a white solid. 1H-NMR(CDCl3, 400 MH: 1.24(t, J=7.2, 3H); 1.44(s, 9H); 2.54(m, 2H); 2.77(m, 3H); 3.31(m, 1H); 4.14(m, 4H); 4.43(m, 1H); 4.69(m, 1H); 7.26(m 5H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[N:22]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:21]=2)[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.Cl>[CH2:1]([O:8][CH2:9][C:10]1([C:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[N:22]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:21]=2)[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(C3(COCc4ccccc4)CCC4(CC3)OCCO4)cc2-c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C3(COCc4ccccc4)CCC(=O)CC3)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.2 %

Procedure:
To a solution of 3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazole (Reference Example 90) (458 mg, 0.872 mmol) in tetrahydrofuran (2.2 mL), 6 M hydrochloric acid (4.4 mL) was added, and the obtained solution was stirred at room temperature for 15 hours. The reaction solution was cooled in ice and 50% aqueous sodium hydroxide solution was added dropwise thereto at 0° C. until basic. Thereafter, the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (387 mg, 0.804 mmol, 92%) as a white amorphous product,
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:16])([CH3:15])[CH:13]=O.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:13]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]([Cl:16])([Cl:11])[CH3:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: CC(Cl)(Cl)C=O
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(Cl)(Cl)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
4-Chlorobenzamide, the product from Example 24A, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 1C to provide the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].[OH-].[Na+]>C1COCC1>[CH3:25][S:26]([NH:11][C:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=1)(=[O:28])=[O:27]
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.0 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 10 ml of THF, 0.56 ml (4.0 mmol) of triethylamine and 230 mg (2.0 mmol) of methanesulfonyl chloride are added. The mixture is stirred overnight at RT, the solvent is removed in vacuo and the crude product is subjected to an aqueous work-up and extracted with dichloromethane. The isolated product is dissolved in 10 ml of DMF, 8 mmol 12.5 mmol of 1M NaOH solution are added and the mixture is stirred overnight at RT. The solvent is removed in vacuo and the crude product subjected to HPLC chromatography. Yield after two steps: 170 mg, 30%
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=[O:11])[CH:3]=[CH:2]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:13]([O:11][C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1cccc2cc[nH]c12
Yield: 83.4 %

Procedure:
A solution of 0.68 g (4.2 mmol) of indole-7-carboxylic acid, 0.9 g (8.4 mmol) of benzylalcohol 1.03 g (8.4 mmol) of DMAP and 1.6 g (8.4 mmol) of 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (Aldrich) in 30 mL of CH2Cl2 was stirred at rt for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, hexanes:ethyl acetate 30:1) to give 0.88 g of the title compound.