Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([Br:14])=[N:10][N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21]C)[C:8]2=[O:23])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([Br:14])=[N:10][N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])[C:8]2=[O:23])=[CH:24][CH:25]=1
Reactant: COc1ccccc1-n1nc(Br)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(Br)nn(-c2ccccc2O)c(=O)n1Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
According to Scheme 9 Step 1: To a solution of 4-(4-chlorobenzyl)-6-bromo-2-(2-methoxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione (150 mg, 0.35 mmol) in DCM (2 ml) cooled at −78° C. was added dropwise BBr3 (0.710 mL, 0.710 mmol). The reaction mixture was stirred 1 h at −78° C. and was quenched with MeOH. The mixture was allowed to reach room temperature. Water was added and the aqueous layer was extracted with DCM (×3). The combined organic layers were successively washed with water, brine, dried over MgSO4, filtered and concentrated. 131 mg (yield=90%) of 4-(4-chlorobenzyl)-6-bromo-2-(2-hydroxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione were recovered as a beige solid which was used in the next step without any purification.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH3:17])[C:3](=[O:6])[CH:4]=[CH2:5].[NH2:18][C:19]1[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:18][C:19]1[N:24]=[CH:23][C:22](/[CH:5]=[CH:4]/[C:3]([N:2]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH3:17])[CH3:1])=[O:6])=[CH:21][N:20]=1
Reactant: C=CC(=O)N(C)Cc1c(C)[nH]c2ccccc12
Reactant: Nc1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c2ccccc2c1CN(C)C(=O)/C=C/c1cnc(N)nc1
Yield: 128.8 %

Procedure:
A solution of N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide (1.18 g, 6.5 mmole), 2-amino-5-bromopyrimidine (0.5 g, 2.9 mmole), Pd(OAc)2 (0.11 g, 0.49 mmole), tri-ortho-tolylphosphine (0.17 g, 0.55 mmole), and diisopropylethylamine (1.5 mL, 8.6 mmole) in propionitrile (100 mL) and DMF (10 mL) was heated at reflux overnight. The dark mixture was filtered through Celite®, and the filtrate was concentrated. Flash chromatography on silica gel (9:1 CHCl3/CH3OH containing 5% NH4OH) gave the title compound (1.2 g, 65%): MS (ES) m/e 372 (M+H)+.
Reaction SMILES: O[CH2:2][CH:3]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>ClCCl.CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[N:40]([CH2:2][CH:3]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:41]=[N-:42]
Reactant: [N-]=[N+]=[N-]
Reactant: NS(=O)(=O)c1ccc(NC(CO)CSc2ccccc2)c([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: [N-]=[N+]=NCC(CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of Example 434B (1.01 g, 2.6 mmol) and N,N-diisopropylethylamine (0.70 mL, 4.0 mmol) in dichloromethane (5 mL) and DMF (5 mL) at room temperature was treated with methanesulfonyl chloride (0.22 mL, 2.90 mmol), stirred for 1 hour, and concentrated to remove the dichloromethane. The resulting DMF solution was treated with sodium azide (1.95 g, 30 mmol) and tetrabutylammonium iodide (100 mg), heated to 50° C. for 16 hours, diluted with ethyl acetate (200 mL), washed with water (100 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16]CC3C=CC=CC=3)[C:10]2=[O:24])=[CH:5][CH:4]=1.FC(F)(F)C1C=CC(N2CCN(CCOCC3C=CC=CC=3)C2=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[C:10]2=[O:24])=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(CCOCc3ccccc3)C2=O)cc1
Agent: O=C1N(CCOCc2ccccc2)CCN1c1ccc(C(F)(F)F)cc1
Product: COc1ccc(N2CCN(CCO)C2=O)cc1
Yield: 91 %

Procedure:
In a similar manner to Referential Example 5 except that a reaction was conducted using α-{2-[1-(4-methoxyphenyl)-2-imidazolidinon-3-yl]ethoxy}toluene in lieu of α-{2-[1-(α,α,α-trifluoro-4-tolyl)-2-imidazolidinon-3-yl]ethoxy}toluene, the title compound was obtained in a yield of 91%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([O-:12])(=O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Na+].P(Cl)(Cl)([Cl:16])=O>S1(CCCC1)(=O)=O.C(#N)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([Cl:16])(=[O:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])Cc1cccc(I)c1
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Product: O=S(=O)(Cl)Cc1cccc(I)c1
Temperature: 0 °C

Procedure:
A stirred mixture of sodium (3-iodophenyl)methanesulfonate (3.6 g) and phosphoryl chloride (10 ml) in sulpholane (20 ml) and acetonitrile (30 ml) was heated at 70° for 2 h. The mixture was poured onto crushed ice (200 ml) and the precipitated product was collected and dried to give the title product (2.8 g) LCMS RT=3.47 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[F:12].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>C1COCC1>[F:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2cc([N+](=O)[O-])ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of ˜80% pure 2-(bromomethyl)-1-fluoro-4-nitrobenzene (0.956 g, 3.27 mmol) in THF (10 mL) was added slowly drop-wise to a −20° C. solution of 1-methylpiperazine (0.393 g, 3.92 mmol) and DIEA (1.142 mL, 6.54 mmol) in THF (20 mL), the mixture allowed to warm slowly to RT and stirred overnight. The resulting solid was removed via filtration and the filtrate was concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford 1-(2-fluoro-5-nitrobenzyl)-4-methylpiperazine (577 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.28 (dd, J=6.2, 3.0 Hz, 1H), 8.21 (ddd, J=9.0, 4.4, 3.0 Hz, 1H), 7.47 (t, J=9.1 Hz, 1H), 3.60 (s, 2H), 2.48-2.25 (br m, 8H), 2.14 (s, 3H); MS (ESI) m/z: 254.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=2[Cl:21])[NH:14][C:13]=1[C:23]([O:25]CC)=[O:24])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=2[Cl:21])[NH:14][C:13]=1[C:23]([OH:25])=[O:24])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1
Temperature: 50 °C
Yield: 81.9 %

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (800 mg, 2.04 mmol) in tetrahydrofuran (5 mL) and water (5 mL). Add lithium hydroxide monohydrate (252 mg, 6 mmol) and stir at room temperature overnight. Warm to 50° C. in an water bath for several hours, dilute with water (10 mL) and ethyl acetate (25 mL). Stir and acidify with 1N hydrochloric acid. Separate the organic phase and dry. Evaporate the solvent in vacuo and recrystallize (ethyl acetate/hexane) to give the title compound as a white powder (630 mg, 85%); mp 275° C. (dec).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].S(Cl)([Cl:14])=O>N1C=CC=CC=1.ClCCl>[Cl:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: O=S(Cl)Cl
Reactant: C=CCCCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCCCCCCCCCl
Reaction time: 8.5 h
Yield: 95.3 %

Procedure:
10 drops of pyridine was added to 26.0 g of 9-decene-1-ol and the mixture was placed in an eggplant type flask. Into the flask was then dropped 24.0 g of thionyl chloride while cooling with ice. After dropping thionyl chloride, reaction was carried out for 8.5 hours at 70° C. After the reaction, the resulting reaction solution was diluted with dichloromethane and was washed with an aqueous potassium hydroxide solution. The organic phase was dried over magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain 27.7 g of 10-chloro-1-decene. (Yield: 95%).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([NH:33][C:34](=[O:37])[O:35][CH3:36])[C:4](=[O:32])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[N:11]=1)=[CH:19][C:18](B1OC(C)(C)C(C)(C)O1)=[CH:17][CH:16]=3.Br[C:40]1[CH:45]=[CH:44][C:43]([C:46]2[NH:50][C:49]([C@@H:51]3[C@@H:56]4[CH2:57][C@@H:53]([CH2:54][CH2:55]4)[N:52]3[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:48][CH:47]=2)=[CH:42][CH:41]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:36][O:35][C:34]([NH:33][C@@H:3]([CH:2]([CH3:38])[CH3:1])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[N:11]=1)=[CH:19][C:18]([C:40]1[CH:41]=[CH:42][C:43]([C:46]2[NH:50][C:49]([C@@H:51]4[C@@H:56]5[CH2:57][C@@H:53]([CH2:54][CH2:55]5)[N:52]4[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:48][CH:47]=2)=[CH:44][CH:45]=1)=[CH:17][CH:16]=3)=[O:32])=[O:37]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 82.8 %

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (396 mg, 0.761 mmol), (1R,3S,4S)-tert-butyl 3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (382 mg, 0.913 mmol), Pd(PPh3)4 (88 mg, 0.0761 mmol) and K2CO3 (2M in H2O, 0.95 mL, 1.9 mmol) were suspended in DME (4 mL). The reaction mixture was degassed with N2 for 6 min then heated to reflux. After 6.5 h, the reaction mixture was cooled to RT, diluted with MeOH, filtered over a thiol SPE column and concentrated. The crude residue was purified by column chromatography (0% to 30% MeOH/EtOAc) to afford the title compound (461 mg, 83%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:7][C:8]([CH3:14])([CH3:13])[C:9]([O:11][CH3:12])=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C)CC(CCCCN)CCCc1cccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of 0.34 g methyl 8-amino-2,2-di-methyl-4-[3-(3-pyridyl)propyl]octanoate in 5 mL dry methylene chloride is added a catalytic amount of 4-dimethylaminopyridine followed by 0.2 mL triethylamine and the mixture is cooled to 0° C.; 0.208 g (0.96 mmol) p-chlorobenzenesulfonyl chloride is added, the reaction is allowed to warm to room temperature and stirred for 48 hours. The mixture is diluted with methylene chloride and washed with saturated sodium bicarbonate, water and brine. The organic phase is dried, filtered and evaporated to yield an amber oil which is purified by flash chromatography using 1:1 ethyl acetate,hexane to yield methyl 8-(p-chlorophenylsulfonamido)-2,2-dimethyl-4-[3-(3-pyridyl)-propyl]-octanoate; IR (CH2Cl2): 3381, 1729, 1164 cm-1 ; NMR (CDCl3): delta 3.57 (s,3H), 2.9 (q,2H), 2.53 (t,2H), 1.12 (s,6H).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[C:8]([NH2:13])[CH:9]=[CH:10][C:11]=1[CH3:12].C([O:16][C:17]([C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[C@H:20]1[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:36][CH:35]=1)=O)C>ClC(Cl)C.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:17]([C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[C@H:20]2[C:34]2[CH:39]=[CH:38][C:37]([NH:40][CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:36][CH:35]=2)=[O:16])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(N)cc1Cl
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(NC2CCCC2)cc1
Agent: C[Al](C)C
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)[C@H]2CCCN(C(=O)c3ccccc3C)[C@H]2c2ccc(NC3CCCC3)cc2)cc1Cl
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Me3Al (290 μL, 0.57 mmol, 2M in toluene) was added to a solution of the 3-Chloro-4-methylphenylamine (65 mg, 0.46 mmol) in dry dichloroethane (1 mL) at ambient temperature. Stirred for 20 minutes, then (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (100 mg, 0.23 mmol) dissolved in dry dichloroethane (1 mL) was added to it. The reaction mixture was then heated to 85° C. for 3 h, cooled to r.t, diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined organic layer was dried (MgSO4) and concentrated. The residue was purified by reverse phase preparative HPLC (20-95% gradient of CH3CN—H2O with 0.1% TFA as additive), the product containing fractions were pooled together and concentrated. The residue was diluted with CH2Cl2 (30 mL), washed with saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4) and concentrated to get the pure (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid (3-chloro-4-methylphenyl)amide in 50% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23][N:24]2C(=O)C3=CC=CC=C3C2=O)=[N:21][N:20]=[C:19]1[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38].NN>C(O)C>[CH3:39][N:37]([CH3:38])[CH2:36][CH2:35][C:19]1[N:18]2[C:10]3[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:24][CH2:23][C:22]2=[N:21][N:20]=1
Reactant: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Product: CN(C)CCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1C, 2'-chloro-5-nitro- 2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is refluxed with hydrazine to give 1-[2-(dimethylamino)ethyl]-8-nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. This compound is converted to its hydrochloride by treating it with ethereal hydrogen chloride.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([O:19][CH3:20])(=[O:18])[C:15]([CH3:17])=O.C([O-])(=O)C.[Na+]>CO>[CH3:20][O:19][C:14](=[O:18])[C:15](=[N:10][NH:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:17]
Reactant: COC(=O)C(C)=O
Reactant: NNc1ccc(Cl)cc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)=NNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
(4-Chloro-2-nitro-phenyl)hydrazine hydrochloride (30 g, 0.14 mol) prepared in Step A and methyl pyruvate (14.4 mL, 0.16 mol) were dissolved in methanol (300 mL), and sodium acetate (14.2 g, 0.17 mol) was added thereto. The reaction solution was stirred for 8 h at room temperature, and the resulting yellow solid was filtered, washed with water and methanol, and dried to give the title compound (30 g, Yield 82%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][S:10](=[S:13])([O-:12])=[O:11].[Na+]>CCO>[CH3:9][S:10](=[S:13])([O:12][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: CS(=O)([O-])=S
Reactant: BrCc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=S)OCc1ccccc1

Procedure:
Benzyl bromide (9.07 g, 0.053 mol) was slowly added to a suspension of sodium methanethiosulfonate (7.10 g, 0.0530 mol) in absolute EtOH (100 mL) and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled with an ice bath and the solid (sodium bromide and sodium methanethiosulfonate) was filtered off. The filtrate was concentrated to give a crude product which was mainly the desired product. Pure product was obtained by flash chromatography on silica gel with EtOAc-hexanes (1:6) (7.92 g, 74%). The product was further purified by recrystallization from absolute ethanol. mp 39.5-40.2° C. (lit. 40-42.5° C.) IR (KBr): 3089, 3068, 3017, 3000, 2981, 2936, 2918, 1602, 1582, 1496, 1305, 1131, 960, 771, 741, 702 cm−1. 1H NMR (200 MHz, CDCl3): δ 7.38 (m, 5H, phenyl), 4.38 (s, 2H, SCH2), 2.91 (s, 3H, CH3SO2). 13C NMR (50 MHz, CDCl3): δ 135.12, 129.14, 129.03, 128.26, 51.09, 40.79.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[C:13](=O)[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:20]1([CH3:24])[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][CH2:16][O:15][CH2:14][C:13]2[NH:6][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[N:1]=2)[CH:19]=1
Reactant: COC(=O)COCCc1cccc(C)c1
Reactant: NC(=O)c1cccnc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CCOCc2nc3ncccc3c(=O)[nH]2)c1

Procedure:
In analogy to example 91.3, 2-amino-nicotinamide and (2-m-tolyl-ethoxy)-acetic acid methyl ester (prepared from 2-m-tolyl-ethanol [1875-89-4] in analogy to example 91.1-91.2) reacted in the presence of LiHMDS in THF to yield after purification of the crude product with column chromatography (silica gel, EtOAc) and crystallization from EtOAc/heptane 2-(2-m-tolyl-ethoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one as white solid. MS (m/e): 296.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([NH:25][C:26]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2)CCCCC1.CN(C)C(=O)C>[C:17]([NH:25][C:26]1[CH:38]=[C:37]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1NC(=O)c1ccccc1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
44 mp of 3-chlorophenylboronic acid, 49 mg of sodium carbonate and 6 mg of polymer supported di(acetato)dicyclohexylphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 15 hours. After the reaction mixture was cooled to room temperature, 5.1 mg of polymer supported di(acetato) dicyclohexylphenylphosphine palladium(II) was added and stirred at 110° C. for 9 hours and 30 minutes. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Tribonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(benzamido)-4-(3-chlorophenyl)benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=O)[C:5]#[N:6].[CH3:12][C:13](=[O:18])[CH2:14][C:15](=[O:17])[CH3:16].C(O)(=O)C.N1CCCCC1>ClCCl>[C:15]([C:14]([C:13](=[O:18])[CH3:12])=[CH:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[CH3:1])(=[O:17])[CH3:16]
Reactant: Cc1cc(C#N)ccc1C=O
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc(C#N)cc1C)C(C)=O

Procedure:
950 mg (6.54 mmol) of 3-methyl-4-formylbenzonitrile [S. Levesque et al., Bioorg. Med. Chem. Lett. 11, 3161-3164 (2000], 655.2 mg (6.544 mmol) of 2,4-pentanedione, 589.5 mg (9.82 mmol) of acetic acid and 111.5 mg (1.31 mmol) of piperidine are dissolved in 35 ml of dichloromethane and heated under reflux with an inverse water trap overnight. Cooling is followed by washing twice with water, and the organic phase is dried with magnesium sulfate. The solvent is removed in a rotary evaporator and the residue is purified by column chromatography (silica gel, mobile phase: initially dichloromethane, then isohexane/ethyl acetate 3:1). After concentration of the product fractions, the residue is crystallized from diethyl ether and dried under high vacuum. 1.12 g (75.3% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([O-:19])=[O:18].[OH-].[Na+]>CO>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=[O:18]
Reactant: Nc1onc(-c2ccccc2C(F)(F)F)c1C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Yield: 71.2 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), 5-amino-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylate (6.0 g, 20.96 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (4.06 g, 14.92 mmol, 71%) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][N:5]([CH3:7])[CH:6]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.C(Cl)Cl>CN(C)C1C=CN=CC=1>[Br:1][C:2]1[C:3]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cn1cc(Br)c(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (4-bromo-1-methyl-1H-pyrazol-3-yl)methanol (100.0 mg, 0.5235 mmol), tert-butyldimethylsilyl chloride (236.7 mg, 1.570 mmol), 4-dimethylaminopyridine (12.79 mg, 0.1047 mmol), 1H-Imidazole (106.9 mg, 1.570 mmol) and DCM (40 mL, 700 mmol) was stirred at rt for 1 h. The material was transferred to a separatory funnel and partitioned between DCM and water. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 2% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. MS (ES+): m/z=305.06/307.06 (100/100) [MH+]. HPLC: tR=1.82 min (polar—3 min, UPLC-ACQUITY).