Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[Li+].[OH-].[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CO.CN(C=O)C.O.C1COCC1>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([S:18]([NH:17][CH:14]2[CH2:13][CH2:12][CH:11]([C:9]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[O:8])[CH2:16][CH2:15]2)(=[O:19])=[O:20])=[CH:26][CH:25]=1)#[N:28]
Reactant: N#Cc1ccc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)OCc3ccccc3)CC2)cc1
Reactant: C1CNCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1ccc(S(=O)(=O)NC2CCC(C(=O)N3CCNCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.9 g (4.7 mmol) trans-4-(4-cyano-benzenesulfonylamino)-cyclohexanecarboxylic acid benzyl ester and 0.8 g (1.9 mmol) LiOH in a mixture of methanol, THF and water was stirred at room temperature for 2 h. The mixture was evaporated to dryness and 10 mL DMF, 0.7 g (8.1 mmol) piperazine, 2.87 g (8.9 mmol) TBTU and 2.26 g (22 mmol) NEt3 was added. The mixture was stirred at room temperature for 1 h and evaporated to dryness. The residue was purified by column chromatography on silica obtaining 0.3 g (16%) of the title compound. MS (m/e): 377.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: S=C1CCc2cc(Br)c(Cl)cc2N1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1cc(Cl)c(Br)cc1CC2

Procedure:
To a stirred solution of 6-bromo-7-chloro-3,4-dihydroquinoline-2(1H)-thione (110-3; 1.8 g, 0.0065 mol) in n-butanol (80 mL) was added acetic hydrazide (1.2 g, 0.0162 mol). Reaction mass was refluxed for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel (60-120 mesh) column chromatography using 0-5% methanol in dichloromethane to afford title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.81 (s, 1H), 2.96 (bs, 4H), 2.66 (s, 3H). MS (M+1): 296.0.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:10]1([C:15]2[N:20]=[C:19]([CH:21]3[CH:25]([C:26](=[S:28])[NH2:27])[CH2:24][CH2:23][N:22]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:18]=[C:17]([CH3:36])[N:16]=2)[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:7]([O:6][C:4]([C:3]1[N:27]=[C:26]([CH:25]2[CH2:24][CH2:23][N:22]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:21]2[C:19]2[CH:18]=[C:17]([CH3:36])[N:16]=[C:15]([N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[N:20]=2)[S:28][CH:2]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1cc(C2C(C(N)=S)CCN2C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)C2c2cc(C)nc(-n3ccnc3)n2)n1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
Ethyl 3-bromo-2-oxopropanoate (350 mg, 1.79 mmol) was added to a solution of tert-butyl 2-(2-(1 H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-carbamothioylpyrrolidine-1-carboxylate (700 mg, 1.80 mmol) in DCM (20 mL) at rt under an atmosphere of N2. The reaction mixture was heated to 100° C. for 2 h then cooled to rt. Sodium bicarbonate (20 mL, sat. aq.) was added and the mixture extracted with DCM (2×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was then purified using column chromatography (DCM to 9:1 DCM/MeOH) to afford 500 mg (80%) of 2-[1-tert-butoxycarbonyl-2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-3-yl]-thiazole-4-carboxylic acid ethyl ester as a yellow oil.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)O)([O-:3])=[O:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[N+:1]([CH2:4][CH2:5][CH2:6][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCc1ccc(C(O)CC[N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(CCC[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Nitro-1-(4-octylphenyl)propan-1-ol (30 g) and trifluoroacetic acid (47 mL) are charged into a round bottom flask equipped with a calcium chloride guard tube. The mixture is cooled to 0° C., triethylsilane (32.5 mL) is added, and the mixture is stirred overnight at room temperature. The mass is poured onto crushed ice (200 g) and the mixture is extracted with ethyl acetate (2×200 mL). The combined organic layer is dried over sodium sulphate and concentrated under reduced pressure, to give the crude as a color liquid. The crude obtained is purified by silica gel column chromatography (100-200 mesh, 500 g) using 5% ethyl acetate in hexane as the eluent, and the eluted fraction containing the desired compound are pooled, evaporated under reduced pressure to give the title compound. Yield: 19.8 g.
Reaction SMILES: [CH2:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([CH2:13][NH2:14])[C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:21][CH2:22][C:23](Cl)=[O:24].O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:21][CH2:22][C:23]([NH:14][CH2:13][C:7]1[C:6]2[NH:5][C:4]3[CH2:3][CH2:2][CH2:1][C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:24]
Reactant: NCc1cccc2c3c([nH]c12)CCC3
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(CCl)NCc1cccc2c3c([nH]c12)CCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution of 1,2,3,4-tetrahydrocyclopenta[b]indol-5-ylmethylamine (100 mg, 0.538 mmol) and pyridine (0.1 mL, 1.23 mmol) in CH2Cl2 (2 mL) was cooled to 0-5° C. in an ice-bath under Ar before chloroacetyl chloride (62 μL, 0.59 mmol) was added. After 1 h, the ice-bath was removed to allow the reaction to warm to rt. After an additional 12 h, H2O (3 mL) and CHCl3 (3 mL) were added. The two layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification on SiO2, eluted with (40:1) CHCl3:CH3OH gave 80 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:22])[CH2:16][C:17](OCC)=[O:18])[CH2:11][CH2:10]1.O.[NH2:24][NH2:25]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:22])[CH2:16][C:17]([NH:24][NH2:25])=[O:18])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CC(C)N1CCN(c2ccccc2OC)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccccc1N1CCN(C(C)CC(=O)NN)CC1
Yield: 76 %

Procedure:
A solution of ethyl 3-[4-(2-methoxyphenyl)piperazin-1-yl]butanoate D11 (2.75 g, 8.97 mmol) and hydrazine monohydrate (2.7 g, 53.85 mmol) in ethanol (40 mL) was refluxed for 48 hrs. The solvent was evaporated under reduced pressure, toluene (50 mL) was added and the solvent was evaporated and the resulting light yellow oil was triturated with 50% AcOEt in hexane (10 mL). The resulting white solid was filtered, washed with hexane and dried to afford 2 g (76%) 3-[4-(2-methoxyphenyl)piperazin-1-yl]butanohydrazide D12.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12]([OH:22])[C:11]1=[O:23])=[O:4].O[Li].O.Cl.[CH2:34]1COCC1.O.CO>>[CH3:28][C:26]([CH3:29])([CH3:27])[C:25]#[C:24][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]2[C@H:15]([CH:16]([CH2:21][CH3:20])[CH2:17][CH2:18][CH2:19][CH3:34])[CH2:14][CH2:13][C@H:12]([OH:22])[C:11]2=[O:23])[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](O)CC[C@H]1C1CCCCC1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCCCC(CC)[C@@H]1CC[C@H](O)C(=O)N1c1cc(C#CC(C)(C)C)sc1C(=O)O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a solution of 3-((3S,6S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (1.5 g, 3.59 mmol, 1 equiv.) in THF/H2O/MeOH (5.0 mL/5.0 mL/1.0 mL) was added LiOH.H2O (0.79 g, 17.56 mmol, 5.0 equiv.) at room temperature. The reaction mixture was stirred at 50° C. for 20 minutes. The reaction was then acidified to pH=5 by addition of 3.0 N HCl aq. solution and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC (XBridge Prep C 18 5 um, 30×50 mm) in basic condition (0.1% NH4OH, 10%˜45% CH3CN/H2O, 10 min run, 40 ml/min) to give 850 mg of product (yield 57%). MS: 404 [M+H+]. 1H-NMR (400 MHz, MeOD): δ 6.95 (s, 1H), 4.09 (m, 1H), 3.74 (m, 1H), 2.09 (m, 1H), 1.94-1.67 (m, 8H), 1.38 (m, 1H), 1.33 (s, 9H), 1.17 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.Br[CH2:10][CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH2:10][CH:11]([CH3:13])[CH3:12])[N:3]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Cn1cc(C#N)c(N)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
3-Amino-4-pyrazolecarbonitrile 1 (Aldrich, 24.0 g, 0.222 mole), 1-bromo-2-methyl-propane (Lancaster, 36.48 g, 0.266 mole) and anhydrous potassium carbonate (Acros, 36.8 g, 0.266 mole) were suspended in 240 mL reagent grade acetonitrile and heated at 80° C. under nitrogen for 22 hours. LC/MS indicated 1 remained. Therefore, added an additional 3 mL (0.027 mole) 1-bromo-2-methylpropane and 4.25 g (0.031 mole) K2CO3. After 24 hours, the reaction was filtered and the filtrate concentrated in vacuo. The solid was stirred in 250 mL of water for 3.5 hours at room temp. The solid was filtered, washed with 50 mL diethyl ether, and dried to yield 16.28 g (45%) of a tan powder which was seen by 1H NMR to contain a mixture of 255 and 256 in approximately a 2:1 ratio. This mixture was used without further purification. Mixture of 255 and 256: mp 91.3-106; MS (ES+ calculated: 164.21; found: 165.28 M+H). HPLC (99% purity, retention times 6.920 and 7.086 minutes—Method B); 1H NMR (400 MHz, DMSO-d6) δ 8.05 and 7.51 (s, 1H), 6.50 and 5.49 (s, 2H), 3.68 (t, 2H), 2.05 (m, 1H), 0.82 and 0.81 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:31])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH:23]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)O)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(CC)CC)C.CS(Cl)(=O)=O.O>C(Cl)Cl>[F:31][C:2]([F:1])([O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19](/[CH:22]=[CH:23]/[CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)(=[O:20])=[O:21])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=S(=O)(CC(O)C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(/C=C/C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazin-1-yl}sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)ethanol (3.6 g, 0.008M) was dissolved in DCM (100 ml) and triethylamine (5.58 ml, 0.04 mol) was added. The mixture was cooled to 0° C. and methane sulphonyl chloride (0.94 ml, 0.012M) added with stirring at room temperature overnight. Water was added and the organic phase separated off, dried over MgSO4, filtered and evaporated to dryness to yield 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-{[(E)-2-(tetrahydro-2H-pyran-4-yl)vinyl]sulfonyl}piperazine. Yield (3.15 g, 86.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.Br[CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(S(C)(=O)=O)cc1
Reactant: COCCOCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: COCCOCCn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)pyridin-2(1H)-one was reacted with 1-bromo-2-(2-methoxyethoxy)ethane in the presence of potassium carbonate and a catalytic amount of tetrabutylammonium iodide to give the title compound as a light brown oil, MS (ESI+): m/z=532.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1Cl)(=[O:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:23]([SH:25])[CH3:24]>>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH2:24][CH2:23][SH:25])(=[O:6])=[O:5]
Reactant: CCS
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1ccc(CCS)c(S(=O)(=O)CCO)c1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
132.85 g of 2-chloro-5-nitrophenyl hydroxyethyl sulfone are suspended together with 69.1 g of potassium carbonate in 500 ml of ethylmercaptan, and the reaction is allowed to proceed at 30° C. for 2 hours. The ethylmercaptan excess is distilled off under a high vacuum, the residue is taken up in ethanol, and the product is crystallized by pouring into ice-water. After filtration this gives 140.5 g of 2-mercaptoethyl-5-nitrophenyl hydroxyethyl sulfone having a melting of 112°-114° C. (purity >95%), which corresponds to a yield of 91.5% of theory, relative to starting 2-chloro-5-nitrophenyl hydroxyethyl sulfone.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>O.C1(C)C=CC=CC=1>[CH2:11]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
A mixture of 13.11 g (0.1 mole) of 2-methylindole, 13.92 g (0.11 mole) of benzyl chloride, 33 g (0.5 mole) of 85% KOH, 14 mL of H2O, 2.5 g (2.5 mmoles) of PEG-1000, and 100 mL of toluene was stirred and heated at 60° for 23 hours. After cooling to room temperature, 100 mL of H2O was added. The layers were separated. The aqueous layer was extracted with 100 mL of toluene. The combined toluene phases were washed 2N HCl (2×50 mL), H2O (2×50 mL), and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 26.98 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 20-22 were combined giving 2.08 g (9%) of 1-benzyl-2-methylindole as a yellow oil which solidified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:37])[CH2:25][N:26]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O.NN>C(O)C>[OH2:8].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:37])[CH2:25][NH2:26])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1nnc(CNC(=O)CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nnc(CNC(=O)CN)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 94 %

Procedure:
To a solution of 5-chloro-2-[3-(2-phthalimidoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (2.3 g) in ethanol (20 ml), hydrazine hydrate (0.92 g) is added, and the resultant mixture is refluxed for 1 hour. The precipitated phthalylhydrazide is filtered off, and the filtrate is evaporated under reduced pressure. The residue is dissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate and water in order, dried over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on a column of silica gel, and the product obtained from the eluate by evaporation is recrystallized from ethyl acetate to give 5-chloro-2-(3-glycylaminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone hydrate as crystals melting at 110° to 113° C. The yield is 94%.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23]C)[C:12]2=[O:25])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:5]1([N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[C:12]2=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccccc1CC1CCN(C2CCCCC2)C1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C(Cc2ccccc2O)CCN1C1CCCCC1
Reaction time: 0.33 h
Yield: 57.6 %

Procedure:
Add boron tribromide (0.21 mL, 2.2 mmol) to a solution of 1-cyclohexyl-3-(2-methoxy-benzyl)-pyrrolidin-2-one (210 mg, 0.73 mmol) in dichloromethane (5 mL). Stir 20 minutes. Pour mixture onto a mixture of ice and saturated sodium bicarbonate. Stir 5 minutes. Wash the organic layer with water, brine, dry, concentrate, and purify the residue on a Biotage cartridge, eluting with 4:1 hexanes:ethyl acetate to afford the title compound (115 mg): MS (APCI-pos mode) m/z (rel intensity) 274 (100).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2[S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2].[CH2:29]([O:31][C:32](=[O:38])[C:33](OCC)=O)[CH3:30].CCOCC.C(O)(=O)C>CN(C)C=O.[Cl-].[Na+].O.O1CCOCC1>[CH3:21][O:20][C:18]([C:9]1[CH:8]=[C:7]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]3[O:14][C:33]([C:32]([O:31][CH2:29][CH3:30])=[O:38])=[CH:2][C:1](=[O:3])[C:4]=3[CH:5]=2)[N:10]=1)=[O:19]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Sc3ccccc3)cc(C(=O)OC)nc12
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCCc1c2nc(C(=O)OC)cc(Sc3ccccc3)c2cc2c(=O)cc(C(=O)OCC)oc12
Yield: 31.1 %

Procedure:
A solution of the product of step (a) (4.0 g) and diethyloxalate (13.0 g) in dry dimethylformamide (275 ml) was slowly added to a stirred suspension of ether washed sodium hydride (50% dispersion in oil, 2.1 g) in dry dimethylformamide (225 ml) under an atmosphere of nitrogen. The resulting suspension was stirred for 1 week then poured into water (1000 ml). The solution formed was acidified with glacial acetic acid, made saline with brine, extracted with ethyl acetate (2×500 ml), washed with water, dried and evaporated to give a brown oil. This oil was dissolved in dry dioxan and dry hydrogen chloride gas was bubbled through it for 15 minutes. The solution was then poured into water, extracted with ethyl acetate (2×300 ml), dried and evaporated to give a yellow brown solid which gave the sub-title compound (1.5 g) after chromatography (SiO2 /3:2 40°-60° petroleum ether/ether) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:25])[O:4][N:3]=1.C(OCC)(=O)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[CH3:1][C:2]1[C:6]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of tert-butyl 9-(3,5-dimethylisoxazol-4-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (120 mg, 0.348 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (2 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (67.4 mg, 69.0%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[C:25](=[CH:20][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])[C:26](=[O:32])[NH:27]2
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 93.6 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-bromo-1,3-dihydro-indol-2-one (prepared according to US20030225127) as starting materials to give 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (74 mg, 93.6%) as a yellow solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]([O:9][B:10](OC(C)C)[O:11][CH:12]([CH3:14])[CH3:13])([CH3:8])[CH3:7]>>[CH2:1]([B:10]([O:11][CH:12]([CH3:14])[CH3:13])[O:9][CH:6]([CH3:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Product: CCCCB(OC(C)C)OC(C)C

Procedure:
Following the method of Example 1, reaction of n-butyllithium (115 mL, 218 mmol) and triisopropoxyborane (41 g, 218 mmol) yielded n-butyldiisopropoxyborane, 37.3 g, (291 mmol, 93%). Proton NMR (neat) δ4.20 (septet, J=18 Hz, 2H), 1.23-0.63 (m, 9H) overlap with isopropyl doublet at 0.98 (d, J=18 HZ, 12H); boron NMR (neat) δ+30.2 ppm (s).
Reaction SMILES: Cl[C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]=1[CH:9]=O.C(N(CC)CC)C.[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>ClCCl>[CH3:8][C:5]1([CH3:7])[CH2:6][C:2]2[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9][C:3]=2[CH2:4]1
Reactant: CC1(C)CC(Cl)=C(C=O)C1
Reactant: CCOC(=O)CS
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(s1)CC(C)(C)C2
Yield: 50.2 %

Procedure:
To a solution of 282b (33.0 g, crude) in dichloromethane (400 mL) and triethylamine (60 g, 600 mmol) was added ethyl 2-mercaptoacetate (19.2 g, 160 mmol). The reaction mixture was heated at reflux for 6 h. It was then concentrated under reduced pressure. The residue was dissolved in ethanol (400 mL) and triethylamine (60 g, 600 mmol). The mixture was heated at reflux for 12 h. It was concentrated again under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 40:1 petroleum ether/ethyl acetate to afford 282c as yellow solid (18.0 g, 32%, over two steps). MS-ESI: [M+H]+ 225.3. 1H NMR (500 MHz, DMSO-d6) δ 7.49 (s, 1H), 4.32 (q, J=7.0 Hz, 2H), 2.72 (s, 2H), 2.56 (s, 2H), 1.35 (t, J=7.0 Hz, 3H), 1.22 (s, 6H).