Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:13]=1[N:14]1[CH2:42][CH2:41][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([F:40])[CH:26]=[CH:27][C:28]=2[CH2:29][O:30][CH2:31]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([F:40])[CH:26]=[CH:27][C:28]=2[CH2:29][O:30][CH2:31]3)[CH2:41][CH2:42]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCc1cc(F)ccc1COC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCc1cc(F)ccc1COC3
Yield: 74.5 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{16-fluoro-4,24-dimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetate (28 mg, 0.047 mmol) and NaOH (1.877 mg, 0.047 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then cooler to rt and purified by preparative HPLC to obtain (2S)-2-(tert-butoxy)-2-{16-fluoro-4,24-dimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetic acid (20 mg, 0.035 mmol, 75.0% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.46-7.32 (m, 1H), 7.08-6.91 (m, 2H), 6.50 (s, 1H), 5.79 (s, 1H), 4.83 (q, J=12.1 Hz, 2H), 4.75 (d, J=12.5 Hz, 1H), 4.61 (d, J=12.5 Hz, 1H), 4.49 (t, J=11.7 Hz, 1H), 3.69-3.32 (m, 3H), 3.07 (br. s., 1H), 2.69 (br. s., 2H), 2.56 (d, J=9.5 Hz, 1H), 2.51 (br. s., 3H), 1.87-1.50 (m, 8H), 1.18 (s, 3H), 1.16 (s, 9H). LCMS (M+1)=569.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:39])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]CC3C=CC=CC=3)[NH:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:39])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[NH:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1
Reactant: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: [Pd]
Solvent: CO
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2O)[nH]n1
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a stirred solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide (0.2 g, 0.00039 mole) in methanol (60 mL), added 10% Pd/C (0.04 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 2 hours. The mixture was then filtered through celite, the celite was washed with methanol and the organic layers were concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and methanol to afford 0.055 g (32%) of 5-(2-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 454.16 (M+1)+, 94.65%. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 10.4 (s, 1H), 8.0 (s, 1H), 7.6 (d, 1H), 7.2 (m, 4H), 7.0 (d, 1H), 6.8 (m, 2H), 6.6 (t, 1H), 4.9 (d, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.8 (d, 1H), 3.6 (m, 1H), 3.2 (t, 1H), 2.7 (t, 1H), 1.9 (m, 2H), 1.3 (m, 2H).
Reaction SMILES: [CH:1]1([CH:7]([NH:30][C:31]([C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)=[O:32])[C:8]([NH:10][CH:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:12]([N:14]2[CH:22]3[CH:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:16][CH:15]2[C:23](O)=[O:24])=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.[CH2:80]([O:82][C:83](=[O:91])[CH:84]([OH:90])[CH:85]([NH2:89])[CH2:86][CH2:87][CH3:88])[CH3:81]>O.ClCCl.CN(C)C=O>[CH2:80]([O:82][C:83](=[O:91])[CH:84]([OH:90])[CH:85]([NH:89][C:23]([CH:15]1[CH2:16][CH:17]2[CH:22]([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:14]1[C:12](=[O:13])[CH:11]([NH:10][C:8](=[O:9])[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[NH:30][C:31]([C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1)=[O:32])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:86][CH2:87][CH3:88])[CH3:81]
Reactant: CC(C)(C)C(NC(=O)C(NC(=O)c1cnccn1)C1CCCCC1)C(=O)N1C(C(=O)O)CC2CCCCC21
Reactant: CCCC(N)C(O)C(=O)OCC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC(NC(=O)C1CC2CCCCC2N1C(=O)C(NC(=O)C(NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C)C(O)C(=O)OCC
Temperature: 0 °C
Yield: 81.9 %

Procedure:
In a dry flask charged with a 1:1 mixture of dichloromethane-dimethylformamide (100 ml) was placed 1-(2-{2-Cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic acid 32a (2.0 g, 4.28 mmols), PyBOP (2.5 g, 4.7 mmol), and N-methyl-morpholine (2.4 ml, 21.4 mmol) and the reaction placed under an atmosphere of nitrogen. In a 100 mL addition funnel was placed a solution of the amine 14(1.0 g, 4.7 mmols) and N-methyl-morpholine (0.60 ml, 5.35 mmol) in a 1:1 mixture of dichloromethane-dimethylformamide (10 ml). The reaction was cooled to 0° C., and the amine was added while maintaining the temperature at 0° C. The reaction was allowed to warm to ambient temperature as it was stirred over night. HPLC analysis showed the reaction to be complete, and then the reaction was diluted with water to 500 mL. After stirring the precipitate was filtered and dried to give 2.4 g (82% yield) of 32 as a beige solid. This material was used as is in the next step without further purification. HPLC: RT=5.66 min, (10-90% acetonitrile-water over 7 minutes); LC/MS: retention time 3.94 min (10-90% acetonitrile-water over 5 minutes); M+H+=685.5.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([O:5][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][C:18](=O)[C:12]=3[CH:13]=2)[N:8]=1)=[O:4].[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1.[B][B][B][B][B][B][B][B][B][B]>CO.C(Cl)Cl>[CH3:22][C:2]([CH3:23])([CH3:1])[C:3]([O:5][CH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][C:11]3[CH2:20][CH2:19][CH:18]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=4)[C:12]=3[CH:13]=2)[N:8]=1)=[O:4]
Reactant: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)C(=O)CC3
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc4nc(COC(=O)C(C)(C)C)[nH]c(=O)c4cc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
A suspension of 2-(2,2-dimethylpropionyloxymethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione (0.47 g, 1.50 mmol) in anhydrous methanol (33 ml) and anhydrous CH2Cl2 (5 ml) was treated with tert-butyl 4-aminobenzoate (0.34 g, 1.78 mmol) followed by decaborane (0.07 g, 0.58 mmol) and the mixture stirred at room temperature under argon for 18 h. The solvent was removed in vacuo and the residue purified by column chromatography (50 g of silica gel) eluting with 30% ethyl acetate in CH2Cl2 to yield the desired product as a white solid (0.43 g, 58%); m.p. 231° C.; 1H-NMR (CDCl3) δ 1.26 (s, 9H, CMe3), 1.58 (s, 9H, CO2CMe3), 2.00 (m, 1H, 7-H), 2.72 (m, 1H, 7-H), 3.08 (m, 2H, 8-H), 5.10 (s, 2H, 2-CH2), 5.15 (m, 1H, 6-H), 6.67 (d, J=8.8 Hz, 2H, 3′-H, 5′-H), 7.58 (s, 1H, 9-H), 7.87 (d, J=8.8 Hz, 2H, 2′-H, 6′-H), 8.24 (s, 1H, 5-H); MS (FAB, m/z): Found 491 [(M+H)+, 25%], 514 [(M+Na)+, 100%]; Found C, 68.37; H, 6.86; N, 8.35. C28H33N3O5 requires C, 68.41; H, 6.77; N, 8.55%.
Reaction SMILES: C(OC(=O)[C:5](=[O:22])[C:6]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[CH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)C.[NH2:24][NH2:25]>C(O)C>[Cl:21][C:16]1[CH:15]=[C:14]([CH:6]2[CH:7]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[NH:25][NH:24][C:5]2=[O:22])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CCOC(=O)C(=O)C(=Cc1ccncc1)c1ccc(Cl)c(Cl)c1
Reactant: NN
Solvent: CCO
Product: O=C1NNC(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C

Procedure:
To a solution of 3-(3,4-Dichloro-phenyl)-2-oxo-4-pyridin-4-yl-but-3-enoic acid ethyl ester 11.4 g in ethyl alcohol 50 mL was added hydrazine 1.68 mL. The reaction was heated to 50° C. for 15 hours. All solvent was removed after under reduced pressure to afford the title compound 10.8 g as light yellow solid. MS (ES+): 308 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[H-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]I)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.Cl>CN(C=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH:5]([S:6]([CH3:9])(=[O:8])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:10])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: Fc1ccc(-c2ccc(CCI)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccc(-c2ccc(F)cc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A mixture of ethyl(methylsulphonyl)acetate (330 mg, 1.99 mmol) in 4 mL of DMF was treated with sodium hydride (88 mg, 60% dispersion in mineral oil, 2.19 mmol), until effervescence ceased in an ice bath under nitrogen. To this was added 4-fluoro-4′-(2-iodoethyl)biphenyl (650 mg, 1.99 mmol) as a solid and the residual material was dissolved by the addition of DMF (2 mL). The mixture was warmed to room temperature, then heated at 50° C. for 2 hours. The mixture was then cooled to room temperature, poured into 60 mL of 0.5N aqueous HCl and extracted 2×60 mL with ethyl acetate. The organic phase was dried over sodium sulfate filtered and concentrated in vacuo to yield a light yellow oil with some white solid particulates. The crude yield was 840 mg. The material was purified by flash chromatography on a 40 mm flash column using 120 g silica gel eluting with 0-50% ethyl acetate/heptane. This afforded the title compound as an oil (510 mg, 70.2%). MS (LC/MS) m/z 365.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:26](Cl)(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:26]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(C(=O)C=Cc4ccccc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and cinnamoyl chloride (65 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.[CH2:17]([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[C:43]([Cl:51])[CH:42]=2)=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:48])[F:50])=[C:43]([Cl:51])[CH:42]=2)=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1Cl
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(CCc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1Cl
Yield: 17 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{2-[3-chloro-4-(trifluoromethyl)phenyl]-ethynyl}pyridazine (Intermediate 75) except that THF was used as the solvent. The crude product was purified by reverse phase chromatography (eluting with 5-100% acetonitrile in water with acid modifier) to give a pale yellow solid. The solid was recrystallised from a mixture of methyl tert-butyl ether and ethyl acetate to afford 3,4-bis(benzyloxy)-6-((3-chloro-4-(trifluoromethyl)phenyl)ethyl)-pyridazine as a white solid (0.182 g, 17%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].C1(S([N:20]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[C:22]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=3)=[CH:21]2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:31]2[N:30]=[C:29]([C:22]3[C:23]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:20][CH:21]=3)[CH:34]=[CH:33][N:32]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: CCOc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 30.8 %

Procedure:
Using the procedure of example 1, 4-ethoxyaniline (222 mg) was reacted with compound 1f (200 mg) to provide compound 40 (55 mg, 31%). 1H NMR (400 MHz, DMSO) δ 8.90 (d, J=8.0 Hz, 1H), 8.45 (s, 1H), 8.30 (d, J=5.6 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.25 (d, J=5.6 Hz, 1H), 7.20 (m, 1H), 6.90 (d, J=8.0 Hz, 2H), 4.05 (q, J=8.0 Hz, 2H), 1.36 (t, J=8.0 Hz, 3H). MS (ESI) m/z: 332 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A suspension of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Step 8.3) (1.26 g, 4.1 mmol) and palladium on carbon (200 mg) in MeOH (30 mL) was stirred for 30 min at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and concentrated to afford 1.1 g of the title compound as a pink solid: ESI-MS: 278.2 [M+H]+; tR=2.85 min (System 1).
Reaction SMILES: Cl.I[As:3]([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5]>[Zn].O>[F:5][C:4]([AsH:3][C:8]([F:11])([F:10])[F:9])([F:7])[F:6]
Reactant: FC(F)(F)[As](I)C(F)(F)F
Agent: Cl
Agent: [Zn]
Solvent: O
Product: FC(F)(F)[AsH]C(F)(F)F
Yield: 43.1 %

Procedure:
The trifluoromethyl arsine hydrides can be made via direct reaction of the tris-trifluoromethyl arsenic iodides with zinc and hydrochloric acid. For instance, 10 g of zinc, 10 ml of water, and 15 ml of 5N HCl are shaken with 3.80 g of iodo bis-trifluoromethylarsine to give 1.03 g of bistrifluoromethylarsine (b.p. 19° C.), a 43% yield. Trifluoromethylarsine can be made by a similar method (b.p. -12.5° C.).
Reaction SMILES: [C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH2:12])[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:5]=1)(=O)[CH3:2].Cl.[CH3:26][NH:27][OH:28].N1C=CC=CC=1>CO>[CH3:26][N+:27]([O-:28])=[C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH2:12])[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:5]=1)[CH3:2]
Reactant: CNO
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O)=[N+](C)[O-]
Temperature: 20 °C
Reaction time: 68 h
Yield: 36.8 %

Procedure:
A mixture of 2.0 grams (0.005 mole) of 3-acetyl-5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole, 0.83 gram (0.01 mole) of N-methylhydroxylamine hydrochloride, 1.21 ml (0.015 mole) of pyridine and 150 ml of methanol was stirred 68 h at 20° C. The mixture was successively evaporated, washed with CH2Cl2 and water; filtered; washed in hot acetonitrile, acetone, hot methanol; and dried so as to give 0.79 gram of Compound No. 4 (m.p. about 228° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25](=[O:35])[NH:26][O:27]CC2C=CC=CC=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:41])[NH:7][CH:8]([C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25](=[O:35])[NH:26][OH:27])=[CH:14][CH:15]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccccc2CCC(=O)NOCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccccc2CCC(=O)NO)cc1)NC(=O)OC(C)(C)C
Yield: 119.1 %

Procedure:
Palladium on BaSO4 (5%, 0.24 g) was added to a degassed solution of the benzyl hydroxamate 63 (0.7 g) in MeOH (20.0 mL) and the suspension was treated with hydrogen at atmospheric pressure for 6 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 64 (0.7 g, 97%). 1H NMR (DMSO-d6): 10.37 (s, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.23-7.16 (m, 3H), 7.06 (t, J=8.4 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.76 (d, J=7.6 Hz, 1H), 4.53 (m, 1H), 2.80 (s, 3H), 2.79-2.75 (m, 7H), 2.23 (t, J=2.0 Hz, 2H), 1.30 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][S:16][C:14]=2[N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:9][C:10]1[N:11]=[C:12]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][S:16][C:14]=2[N:15]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: OCC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCC1CCN(c2nc(Cl)nc3scc(-c4ccccc4)c23)CC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
4-Piperidinemethanol (987 mg, 8.57 mmol) was added to a stirred suspension of 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (2 g, 7.14 mmol) and triethylamine (2.18 ml, 15.7 mmol) in dry ethanol (ml) at room temperature. Reaction was warmed to 40° C. and the resulting solution stirred for ˜2 h. Reaction was allowed to cool to room temperature and poured onto ice/water (50 ml). The resulting suspension was filtered and the solid dried in a vacuum oven at 40° C. The desired compound was obtained as a pale yellow solid (2.4 g, 93%). LCMS: (M+1) 360, RT=4.69 min.
Reaction SMILES: C([N:8]1[C@H:13]2[CH2:14][CH2:15][C@@H:9]1[CH:10]([C:17]([O:19][CH3:20])=[O:18])[C:11](=[O:16])[CH2:12]2)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[O:16]=[C:11]1[CH2:12][C@H:13]2[NH:8][C@H:9]([CH2:15][CH2:14]2)[CH:10]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1C(=O)C[C@@H]2CC[C@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1C(=O)C[C@@H]2CC[C@H]1N2
Reaction time: 10 h
Yield: 97.9 %

Procedure:
To a solution of methyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b) (818 mg, 2.99 mmol) in acetic acid (10 ml) was added 10% Pd-C (a catalyst), and the resulting mixture was stirred under a hydrogen atmosphere for 10 hours. After completion of the reaction, the mixture was filtered with Celite and the filtrate was concentrated in vacuo. The residue was adjusted to pH 8.0-8.5 with a saturated aqueous sodium hydrogen-carbonate solution and extracted with chloroform. The extract was dried over Na2SO4, filtered and then concentrated in vacuo, and the thus obtained crude product was purified by a silica gel column chromatography (CHCl3:MeOH=30:1) to obtain 536.5 mg of methyl (1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. In this case, the yield was 98 mol %. Then, to a methanol (20 ml) solution of this compound (281 mg, 1.54 mmol) were added a 37% formaldehyde solution (213 μl, 7.67 mmol), formic acid (579 μl, 15.4 mmol) and paraformaldehyde (200 mg), and the resulting mixture was refluxed for 17 hours. After completion of the reaction, the reaction mixture was adjusted to pH 8.0-8.5 with a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over Na2SO4, filtered and then concentrated in vacuo, and the thus obtained crude product was purified by a silica gel column chromatography (CHCl3:MeOH=50:1) to obtain 274 mg of methyl (1R,5S)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. The yield from the above two steps was 88 mol %.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C1COCC1>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: C1COCCN1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)N3CCOCC3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 14.2 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.060 g, 0.152 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.098 g, 0.304 mmol), TEA (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and morpholine (0.062 g, 0.304 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.41 (s, 6H), 2.96 (s, 2H), 3.37 (s, 4H), 3.56 (s, 4H), 6.64 (s, 1H), 8.40 (s, 2H), 10.82 (s, 1H), 11.26 (s, 1H); MS [M+H]+: 462.23.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Br:16])[C:5]2[N:6]([CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH:7]=1.CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([Br:16])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cn2cc(Br)nc(Br)c2n1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: OCc1cn2cc(Br)nc(Br)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a stirred solution of ethyl 6,8-dibromoimidazo[1,2-a]pyrazine-2-carboxylate (13.95 g, 40 mmol) in toluene (558 mL) at 0° C. was added 80 mL DIBAH (120 mmol, 3 eq, 1.5M in toluene) dropwise. After stirring overnight at rt, the solution was poured on 1M HCl, extracted with ethyl acetate and the organic phase was washed with water, sole, dried over sodium sulphate and filtered. Removal of the solvent and recrystallyzation from DCM yielded 5.55 g (45.2%) (6,8-dibromoimidazo[1,2-a]pyrazin-2-yl)methanol: 1H-NMR (300 MHz, d6-DMSO): δ=8.93 (s, 1H), 8.05 (s, 1H), 5.46 (bs, 1H), 4.63 (s, 2H) ppm. UPLC-MS: RT=0.73 min; m/z 308.0 [MH+]; required MW=307.0.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7]Br)=[CH:3][CH:2]=1.[H-].[Na+].CN([CH:14]=[O:15])C>>[CH3:5][C:4](=[CH2:3])[CH2:7][CH2:14][O:15][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: C=C(C)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BnBr was added to the mixture of alcohol and NaH in DMF cooled in an ice bath. The mixture was stirred at room temperature overnight and the solid was filtered. The solvent was removed and the residue was purified by column chromatography to give compound 1.