Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[NH2:26][C:27]1[CH:28]=[C:29]([C:33]2[N:38]=[C:37]([NH:39][C:40]3[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=3)[C:36]3=[C:52]([CH3:56])[N:53]=[C:54]([CH3:55])[N:35]3[N:34]=2)[CH:30]=[CH:31][CH:32]=1>>[CH3:56][C:52]1[N:53]=[C:54]([CH3:55])[N:35]2[C:36]=1[C:37]([NH:39][C:40]1[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([O:46][CH3:47])[CH:45]=1)=[N:38][C:33]([C:29]1[CH:28]=[C:27]([NH:26][C:1](=[O:4])[CH3:2])[CH:32]=[CH:31][CH:30]=1)=[N:34]2
Reactant: COc1cc(Nc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1cc(Nc2nc(-c3cccc(NC(C)=O)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
14 mg (0.21 mmol) of acetic acid, 31 mg (0.23 mmol) of HOBt, 63 mg (0.62 mmol) of 4-methylmorpholine, 44 mg (0.23 mmol) of EDC and 87 mg (0.21 mmol) of 3-[5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)imidazo[5,1-f][1,2,4]triazin-2-yl]-aniline from example 7 are reacted analogously to example 2.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)OC)#[N:2].[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:1]([NH:3][C:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[N:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2]
Reactant: COC(=NC#N)c1ccco1
Reactant: NCCc1ccccc1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Methyl N-cyano-2-furancarboximidate (0.30 g, 2.0 mmol) was dissolved in methanol (2 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether-hexane to give the title compound (0.46 g, 1.93 mmol, yield: 97%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:36]2[CH2:38][CH2:37]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[I-].[Na+]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)c(F)c1
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c(F)c1

Procedure:
In analogy to the procedure described in example 101A], 2-(3-fluoro-4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in the presence of catalytic amount of sodium iodide to give 2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-3-fluoro-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101B] to yield the title compound as white crystals of mp. 177.5–178.0° C.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[C:11]3=[CH:12][C:13]4[O:17][CH:16]=[N:15][C:14]=4[C:18]([F:19])=[C:10]3[N:9]([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[F:27])C2=O)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[F:19][C:18]1[C:14]2[N:15]=[CH:16][O:17][C:13]=2[CH:12]=[C:11]([NH:7][S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:5])=[O:6])[C:10]=1[NH:9][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27]
Reactant: O=c1n(-c2ccc(I)cc2F)c2c(F)c3ncoc3cc2n1S(=O)(=O)C1CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc2ocnc2c(F)c1Nc1ccc(I)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution of 7-(cyclopropylsulfonyl)-4-fluoro-5-(2-fluoro-4-iodo phenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (30 mg, 0.06 mmol) in THF (3 mL) was added potassium trimethylsilanolate (12 mg, 0.09 mmol). After stirring at room temperature for 1 h, the reaction was quenched with saturated NH4Cl (aq.). The aqueous layer was extracted with ethyl acetate (5 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residual crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1-3:1, v/v) to give the corresponding product as a white solid (10 mg, 35.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 7.88 (s, 1H), 7.46 (dd, 1H), 7.33 (s, 1H), 7.23 (dd, 1H), 6.15 (m, 1H), 5.49 (s, 1H), 2.55 (m, 1H), 1.01 (m, 2H), 0.92 (m, 2H). MS APCI (+) m/z: 492.5, [M+H].
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:40]2[N:41]=[N:42][NH:43][N:44]=2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C:40]4[N:41]=[N:42][NH:43][N:44]=4)=[C:33]4[C:37]=3[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]4)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CN1Cc2c(-c3nn[nH]n3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4nn[nH]n4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-amino-2-methyl-4-(2H-tetrazol-5-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 181A).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:13][C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([CH2:27][CH2:28][C:29]4[CH:34]=CC(O)=[CH:31][CH:30]=4)=[CH:21][CH:22]=3)[CH2:17][C:16]=2[CH:15]=1)[CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1>O>[C:5]([O:4][C:1]1[CH:31]=[CH:30][C:29]([CH2:28][CH2:27][C:20]2[CH:19]=[C:18]3[C:23]([C:24]4[CH:25]=[CH:26][C:14]([O:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][C:16]=4[CH2:17]3)=[CH:22][CH:21]=2)=[CH:34][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCOc1ccc2c(c1)Cc1cc(CCc3ccc(O)cc3)ccc1-2
Solvent: O
Solvent: c1ccncc1
Product: CCCCCOc1ccc2c(c1)Cc1cc(CCc3ccc(OC(C)=O)cc3)ccc1-2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (5 mL) was slowly added to a mixture of 4-(2-(2-pentyloxyfluorene-7-yl)ethyl)phenol (5 g) produced according to the first to ninth steps in Example 1 and pyridine (100 mL) while maintaining 0° C., and the solution was stirred at the same temperature for 2 hours. The reaction mixture was poured into ice and water (200 mL), and the product was extracted with toluene (50 mL). The toluene layer was dried on anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by means of column chromatography (silica gel, eluting solvent: toluene) to obtain 4-(2-(2-pentyloxyfluorene-7-yl)ethyl)phenyl acetate (5.1 g).
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7](Cl)[C:6]([CH:10]([CH3:12])[CH3:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[CH:15]=2)[N:4]=1.[CH2:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:3]1[N:8]=[C:7]([O:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:14][CH:15]=2)[C:6]([CH:10]([CH3:12])[CH3:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[CH:15]=2)[N:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc(Oc2nc(Cl)nc(Cl)c2C(C)C)cc(C2OCCO2)c1
Agent: [Na]
Product: Cc1cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)cc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred anhydrous benzyl alcohol (10 ml) under nitrogen atmosphere at room temperature, was added sodium metal (285 mg, 12.41 mmol). After 1 hr., 2,4-dichloro-6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-pyrimidine (1.91 g, 5.17 mmol) in anhydrous benzyl alcohol (7 ml) was added. After stirring for overnight at room temperature, the mixture was evaporated in vacuo. The residue was dissolved in dichloromethane, filtered through a celite pad and the pad was washed with dichloromethane. The combined filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:10)) to afford 1.52 g (57%) of a colorless syrup. 1H NMR (200 MHz, CDCl3) δ 1.30 (6H, d, J=7.2 Hz), 2.39 (3H, s), 3.43 (1H, m), 4.02-4.13 (4H, m), 5.12 (2H, s), 5.42 (2H, s), 5.81 (1H, s), 6.92 (1H, s), 7.07 (1H, s), 7.16 (1H, s), 7.20-7.43 (10H, m).
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])[CH:8]=1)C.[OH-].[Na+].Cl>CO>[CH3:41][C:5]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])[CH:8]=1)[C:4]([OH:42])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1cccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)c1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1cccc(CC(C)(Oc2ccccc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the ester obtained from Step A (72 mg, 0.12 mmol) in methanol (2 ml) is added 5N NaOH (0.5 ml, 2.5 mmol), and the mixture stirred for 20 hours at ambient temperature. The mixture is poured into 1N HCl (20 ml), then extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil (64 mg, 94%) (diastereomer 4).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[CH3:24][O:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:28]2[CH2:29][CH2:30][CH:26]([O:25][CH3:24])[CH2:27]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: COC1CCNC1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Temperature: 65 °C
Yield: 42.9 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 3-methoxypyrrolidine hydrochloride (0.056 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.33 g, 1.0 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated under reduced pressure. The residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give the desired product (44.5 mg, 43%). LCMS calculated for C16H18ClN2O2 (M+H)+: m/z=305.1; Found: 305.1.
Reaction SMILES: [OH-].[NH4+:2].F[C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([CH:11]=1)[C:9]#[N:10]>O1CCOCC1>[NH2:2][C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cc(F)ccc1C(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1cc(N)ccc1C(F)(F)F

Procedure:
Ammonium hydroxide solution (50 mL) was added to a stirred solution of 5-fluoro-2-(trifluoromethyl)benzonitrile (commercially available, for example from Alfa Aesar, Ward Hill, Mass., USA, 2.0 g, 10.6 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was heated to 130° C. for 20 h under 200 psi pressure in a steel bomb. The reaction mixture was evaporated to dryness, and the residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% EtOAc/petroleum ether, to give the title compound (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:23])[CH:9]=[C:10]([CH:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(N)ncnn23)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)C1
Temperature: 25 °C
Yield: 188.1 %

Procedure:
A solution of tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate (1.2 g, 3.96 mmol) in DMF (20 mL) was cooled to 40° C. and treated with 1,3-dibromo-5,5-dimethylhydantoin (508 mg, 1.78 mmol). The reaction was allowed to warm slowly to rt over a 2 h period and was then partitioned between EtOAc and bicarbonate solution. After concentration, the residue was triturated with EtOAc to yield the desired product (1.28 g, 85%). 1H-NMR (DMSO): δ 7.86 (s, 1H), 6.69 (s, 1H), 3.68 to 3.80 (m, 2H), 3.36 to 3.46 (m, 1H), 3.20 to 3.30 (m, 2H), 2.16 to 2.30 (m, 1H), 1.98 to 2.08 (m, 1H), 1.37 (s, 9H); MS: LC/MS (+esi), m/z=382.1 [M+H]; LC/MS rt=3.08 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH3:25][NH2:26]>>[CH3:25][NH:26][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23]
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)Cl)c(C)c1C
Reactant: CN
Product: CNC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride is reacted with methyl-amine to produce 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid methyl amide, m.p. 206° C.;
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][CH2:13]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CN1CCNCC1
Product: CN1CCN(c2c([N+](=O)[O-])cnn2C)CC1
Yield: 65 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and N-methyl piperazine gave 1-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazine as an oil (0.18 g, 65%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 3.77 (s, 3H), 3.26 (t, J=4.6 Hz, 4H), 2.60-2.53 (m, 4H), 2.38 (s, 3H)
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH:4]3[CH:5]([CH2:6]2)[CH:3]13.[C:9](Cl)(Cl)=[S:10]>C(Cl)(Cl)Cl>[N:1]([CH:2]1[CH:7]2[CH2:8][CH:4]3[CH:5]([CH2:6]2)[CH:3]13)=[C:9]=[S:10]
Reactant: NC1C2CC3C(C2)C13
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: S=C=NC1C2CC3C(C2)C31
Reaction time: 2 h

Procedure:
3-Aminotricyclo[2,2,1,02,6 ]heptane (21 g.) (prepared as described in U.K. Patent Specification No. 1,051,319), was dissolved in chloroform (25 ml.) and added slowly, below 10°, to a stirred solution of thiophosgene (22 g.) in chloroform (20 ml.). When addition was complete the mixture was allowed to attain ambient temperature and stirred a further 2 hours. The chloroform solution was consecutively washed with 20 ml. portions of water, 1N NaOH, and water again, dried over anhydrous MgSO4, filtered and the chloroform evaporated in vacuo. The residual oil was fractionally distilled in vacuo to give 3-isothiocyanatotricyclo[2,2,1,02,6 ]heptane, b.p. 70°-76° at 0.4 mm. Hg. pressure.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)CCl.[CH:23]1[CH:24]=CC2N(O)N=[N:29][C:27]=2[CH:28]=1.N1CCCC1>CN(C=O)C.O.C(=O)(O)[O-].[Na+]>[CH2:4]([O:3][C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([N:29]1[CH2:24][CH2:23][CH2:28][CH2:27]1)=[O:15])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C([C@H]1CCCN1C(=O)OCc1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (+)-carbobenzyloxy-D-proline (1.5 g, 6 mmol), EDC (2.3 g, 12 mmol), HOBt (800 mg, 6 mmol), TEA (1.5 mL) and pyrrolidine (853 mg, 12 mmol) in DMF (20 mL) was stirred at rt for 18 hr. The reaction was diluted with water and sodium bicarbonate, extracted with dichloromethane (3×). The combined DCM was concentrated and purified on a silica gel column to give (R)-2-(pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester. (R)-2-(pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester was hydrogenated using Pd/C in methanol at ambient temperature for 20 hr to provide pyrrolidin-1-yl-(R)-pyrrolidin-2-yl-methanone. To a solution of pyrrolidin-1-yl-(R)-pyrrolidin-2-yl-methanone (1.2 g, 7.1 mmol) in THF (10 mL) at 0° C. was added B2H6 (10 mL, 10 mmol). The mixture was heated to reflux for 16 hr. The reaction was acidified with HCl and concentrated. The residue was basified to pH 10 with 2N NaOH and extracted with 5% methanol in DCM. The organic layer was concentrated and purified on a silica gel column to give 800 mg (73%) of (R)-2-pyrrolidin-1-ylmethyl-pyrrolidine.
Reaction SMILES: Br[C:2]1[C:3]([O:37][CH3:38])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.CC(C)([O-])C.[Na+].C(=[NH:58])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[F:36][C:32]1[CH:31]=[C:30]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH2:58])[C:3]=3[O:37][CH3:38])[N:7]([C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:6]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1c(Br)ccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1c(N)ccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A total of 810 mg of 5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1-trityl-1H-indazole obtained in Production Example II-18-a was dissolved in 7.2 ml of toluene, 194 mg of sodium t-butoxide, 0.29 ml of benzophenoneimine, 135 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 74.5 mg of tris(dibenzylideneacetone)bispalladium were added, and the mixture was stirred at 80° C. in an atmosphere of nitrogen gas for 8 hours. The reaction mixture was cooled to room temperature, and diethyl ether was added. The mixture was filtrated through Celite, and the filtrate was evaporated. The resulting residue was dissolved in 7.2 ml of tetrahydrofuran and 0.36 ml of 2 N hydrochloric acid was added, followed by stirring at room temperature for 3 hours. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was extracted with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:3), to give 426 mg of the title compound as reddish brown crystals.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][CH2:2]1.[Br:12][CH2:13][C:14](Br)=[O:15]>>[Br:12][CH2:13][C:14]([N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3][CH2:4]1)=[O:15]
Reactant: O=C(Br)CBr
Reactant: c1ccc2c(c1)NCCCO2
Product: O=C(CBr)N1CCCOc2ccccc21

Procedure:
2,3,4,5-tetrahydro-1,5-benzoxazepine [E. K. Orlova et al.; Kim. Geterotsikl. Soedin.,9, 1296 (1975): Chem. abstra., 84, 59411] and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[P:6](=[S:12])(Cl)([O:9][CH3:10])[O:7][CH3:8]>ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[P:6](=[S:12])([O:9][CH3:10])[O:7][CH3:8])[CH3:2]
Reactant: CCNCC
Reactant: COP(=S)(Cl)OC
Solvent: ClCCl
Product: CCN(CC)P(=S)(OC)OC
Reaction time: 1 h

Procedure:
A solution of diethylamine (7.31 g, 100 mmol) in dichloromethane (250 ml) at 5° C. was treated with O,O-dimethyl phosphorochloridothioate (8.03 g, 50 mmol) in dichloromethane (50 ml) in a dropwise fashion. The resulting mixture was stirred 1 h and then washed with 1N HCl (2X 100 ml) and water (100 ml). The dichloromethane solution was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give an oil. Distillation employing a Kugelrohr apparatus at 45°-50° C. and less than 1 mm Hg pressure gave 5.27 g (53 percent of theory) of the desired product; nD25 1.4735.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:12]3[N:11]=2)=[CH:6][CH:5]=1.[S:28]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])(=[O:30])[NH2:29]>>[S:28]([C:32]1[CH:33]=[C:34]([NH:38][C:23]([C:22]2[CH:21]=[N:20][N:13]3[C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:26])([F:27])[F:1])=[CH:9][CH:8]=4)=[N:11][C:12]=23)=[O:25])[CH:35]=[CH:36][CH:37]=1)(=[O:30])(=[O:31])[NH2:29]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-trifluoromethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.19) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 544.2 [(M−H)−]; mp 257° C.