Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:39]=[CH:38][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:29]([N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])=[O:30])=[C:18]([CH:28]=2)[O:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:41][OH:42].[O-]CC.[Na+]>C(O)C>[NH2:2][C:1](=[N:41][OH:42])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:29](=[O:30])[N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:33])[CH3:34])=[C:18]([CH:28]=2)[O:19][C:20]([CH3:26])([CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:38][CH:39]=1
Reactant: NO
Reactant: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(C(N)=NO)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A stirred solution of ethyl 2-[5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]-2-methylpropanoate (1.2 g, 2.3 mmol) in 30 mL of anhydrous ethanol is treated with hydroxylamine hydrochloride (480 mg, 6.8 mmol) and 21% sodium ethoxide solution in ethanol (2.6 mL, 6.8 mmol) and stirred at 50° C. overnight. The reaction is concentrated in vacuo and purified by chromatography on silica gel (20 g) with 80% ethyl acetate/hexane as the eluent to afford ethyl 2-[5-[5-[4-[amino(hydroxyimino)methyl]-phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxy]-2-methylpropanoate as a colorless foam;
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH2:13][CH:14]1[CH:19]2[CH:15]1[CH2:16][N:17]([C:20]1[N:25]=[CH:24][C:23]([C:26]([O:28]CC)=[O:27])=[CH:22][N:21]=1)[CH2:18]2.[OH-].[Na+].Cl>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH2:13][CH:14]1[CH:15]2[CH:19]1[CH2:18][N:17]([C:20]1[N:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][N:21]=1)[CH2:16]2
Reactant: CCOC(=O)c1cnc(N2CC3C(CNCc4ccc5ccccc5c4)C3C2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N2CC3C(CNCc4ccc5ccccc5c4)C3C2)nc1
Yield: 25.3 %

Procedure:
Ethyl 2-(6-{[(naphthalen-2-ylmethyl)amino]methyl}-3-aza-bicyclo[3.1.0]hex-3-yl)-pyrimidine-5-carboxylate (0.76 mmol) was stirred in THF (6 ml) and 1M NaOH (6 ml) at r.t. for 16 h. The reaction was then acidified to pH˜3 with 2M HCl, causing a solid to precipitate. This was collected and dried to give the title compound as a white solid (72 mg, 25% over two steps) which was used in the next step without further purification. LCMS purity 96%, m/z 375 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:13][CH:12]3[CH2:14][CH:9]([CH2:10][N:11]3C(OC(C)(C)C)=O)[CH:8]=2)[CH:2]=1.N1C=CC=C(C2CC3CC(C=2)N(C(OC(C)(C)C)=O)C3)C=1>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:13][CH:12]3[CH2:14][CH:9]([CH2:10][NH:11]3)[CH2:8]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC2C=C(c3cccnc3)CC1C2
Agent: [Pd]
Agent: CC(C)(C)OC(=O)N1CC2CC(c3cccnc3)=CC1C2
Solvent: CO
Product: c1cncc(C2CC3CNC(C3)C2)c1
Reaction time: 48 h

Procedure:
To a solution of a mixture of t-butyl 3-(3-pyridinyl)-6-azabicyclo[3.2.1]oct-2-ene-6-carboxylate and t-butyl 3-(3-pyridinyl)-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate (150 mg) in methanol (5 ml) was added catalytic 10% Pd/C and the mixture was subjected to hydrogenolysis (45 psi) for 48 h. The reaction was filtered through Celite and concentrated by rotary evaporation, and then the residue was taken up in dichloromethane (1 ml) and treated with trifluoroacetic acid (2 ml). After 3 h, the mixture was concentrated to dryness by rotary evaporation, partitioned between water and dichloromethane, and the organic layer discarded. The aqueous layer was made basic with sodium hydroxide and extracted with dichloromethane. After drying over sodium sulfate, the filtered solution was concentrated to dryness by rotary evaporation and the residue purified by column chromatography, using a methanol/dichloromethane gradient (0-10% methanol with 1% ammonium hydroxide) as eluent. The product fractions were pooled and concentrated to give the desired product (20 mg). It was then re-chromatographed (same conditions) to give the free base (10 mg) as a brown oil.
Reaction SMILES: [CH2:1]([OH:11])[C@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.C(Cl)Cl>[C:12]1([C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:10][CH2:9][C@H:7]2[O:8][C@H:2]([CH2:1][O:11][C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:3]([OH:4])[C@@H:5]2[OH:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O[C@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
a mixture of 2.35 g (14.33 mmol) of 2,5-anhydro-D-mannitol and 8.79 g (31.53 mmol) of triphenylmethyl chloride in 38 ml of pyridine was stirred at 100° C. for 12 hours. After cooling, the mixture was diluted with CH2Cl2, and washed with aq.HCl (0.78 mol/l), the organic phase was dried over Na2SO4 and the solvent was subsequently removed under reduced pressure. The crude product was purified by means of column chromatography (hexane/ethyl acetate 2:1). Yield: 5.57 g (60% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:27]=[CH:26][C:10]([CH2:11][CH2:12][O:13][C:14]3[NH:15][CH:16]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:18](=[O:20])[N:19]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[CH3:34]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:27]=[CH:26][C:10]([CH2:11][CH2:12][O:13][C:14]3[N:15]([CH3:34])[CH:16]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:18](=[O:20])[N:19]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:30]([F:31])([F:33])[F:32]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CC(F)(F)F
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(CC(F)(F)F)c(=O)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
To a solution of 2-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenethoxy)-5-(2,2,2-trifluoroethyl)pyrimidin-4(1H)-one (66 mg, 0.134 mmol) in DCM (10 mL) was added DIPEA (0.070 mL, 0.402 mmol) and MeI (0.013 mL, 0.201 mmol). The mixture was stirred at room temperature for 3 h. Purification via reverse phase flash chromatography then afforded the title compound (28 mg, 41.3% yield). LCMS: rt=3.73 min, [M+H+]=507
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH:28][CH2:29][CH2:30][NH2:31])[CH3:27]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][CH2:30][CH2:29][NH:28][CH2:26][CH3:27])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CCNCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: CCNCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-ethylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J=7.2 Hz, 1 H), 7.99-7.97 (m, 2 H), 7.81 (d, J=8.4 Hz, 1 H), 7.67 (t, J=7.2 Hz, 1 H), 7.51-7.46 (m, 2 H), 6.08 (s, 1 H), 5.37 (s, 2 H), 4.57 (s, 2 H), 3.91 (t, J=6.4 Hz, 2 H), 3.69 (t, J=4.8 Hz, 2 H), 3.37 (t, J=6.4 Hz, 2 H), 3.15 (q, J=7.2 Hz, 2 H), 2.43 (s, 3 H), 1.35 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C@@H:16]([NH2:21])[CH2:15]2>>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C@@H:16]([NH:21][C:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=1)=[O:10])[CH2:15]2
Reactant: O=C(O)c1ccc(O)cn1
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Product: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(O)cn1

Procedure:
According to method C, 5-hydroxypyridine-2-carboxylic acid was reacted with (R)-5-bromo-indan-2-ylamine. This afforded the product with the molecular weight of 333.19 (C15H13BrN2O2); MS (ESI); 333 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH2:19][CH2:20][C:21](Cl)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:13]1([CH2:19][CH2:20][C:21]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8]2)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: c1ccc(C2CNCCO2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.4 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenylpropionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 3-phenyl-1-(2-phenylmorpholin-4-yl)propan-1-one are collected and the solvent is removed in vacuo to give 528 mg of colorless oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.33 h
Yield: 35.5 %

Procedure:
Methanesulphonyl chloride (2.5 g) was added dropwise to a stirred solution of 1-benzyl-4-aminopiperidine (4 g) and triethylamine (4 ml) in chloroform (40 ml) at room temperature. After 20 minutes, water (40 ml) was added, the organic layer separated, dried (MgSO4), and evaporated in vacuo to give an oil which crystallized from ether to give N-(1-benzylpiperid-4-yl)methanesulphonamide (2 g, m.p. 135°-6°).
Reaction SMILES: [CH2:1]1[CH2:19][O:18][CH:17]2[CH:3]([C@@H:4]([C@@H:15]([CH:20]=[CH:21][C:22](=[O:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:16]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:2]1>C(O)C.[Ni]>[CH2:1]1[CH2:19][O:18][CH:17]2[CH:3]([C@@H:4]([C@@H:15]([CH2:20][CH2:21][C:22](=[O:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])[CH2:16]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:2]1
Reactant: COC(=O)CCCCCC[C@H]1C2OCCOC2C[C@@H]1C=CC(=O)CCC=C(C)C
Agent: [Ni]
Solvent: CCO
Product: COC(=O)CCCCCC[C@H]1C2OCCOC2C[C@@H]1CCC(=O)CCC=C(C)C
Yield: 88.2 %

Procedure:
To the solution of 4.4 g of 9-ethylenedioxy-15-keto-19-methyl-prost-13,18-dienoic acid, methyl ester, in ethanol (60 ml.) are added 0.8 g of Raney-nickel washed with ethanol and the mixture is hydrogenated at room temperature under pressure. After absorption of the theoretical quantity of hydrogen the catalyzer is separated by filtration and the solvent evaporated in vacuo, to yield 3.9 g of 9-ethylenedioxy-15-keto-19-methyl-prost-18-enoic acid, methyl ester.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH2:17][C:18]([CH:20]=[CH2:21])=[O:19]>C(O)C>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][CH:18]([C:17]([CH:1]([OH:8])[CH2:2][CH2:3][N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)=[O:16])[OH:19])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)CO
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CCO
Product: O=C(NC1CCN(CCC(O)C(=O)C(O)CCN2CCC(NC(=O)c3ccccc3)CC2)CC1)c1ccccc1

Procedure:
4-Benzamidopiperidine (2.4 g.) in ethanol (15 ml.) was added to hydroxymethylvinyl ketone (2.0 g.). An exothermic reaction occured and crystallisation occurred on cooling to give 2-(4-benzamidopiperidino)ethylhydroxymethyl ketone, m.p. 154°-155° C. (Found: C, 65.9; H, 7.7; N, 9.5; C16H22N2O3 requires C, 66.2; H, 7.6; N, 9.65%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[CH:10]=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=1.[H-].[Na+]>CN(C=O)C>[C:20]1([C:9]2[N:8]=[C:7]([N:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][CH:16]([OH:19])[CH2:17][CH2:18]3)[CH:10]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(Cl)n2)CC1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1CCN(c2cc(-c3ccccc3)nc(-n3cccc3)n2)CC1

Procedure:
The title compound was prepared from pyrrole (0.072 g, 1.07 mmol) and compound 1-(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol (0.31 g, 1.07 mmol) in the presence of 60% NaH (0.039 g, 1.6 mmol) in DMF by a procedure analogous to that disclosed in Example 93.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]4([OH:18])[CH2:17][CH2:16]4)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]4([O:18][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])[CH2:17][CH2:16]4)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C3(O)CC3)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1(c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(Br)c23)CC1
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Step 2 A solution of 4-bromo-7-(1-hydroxycyclopropyl)-9H-carbazole-1-carboxamide (0.151 g, 0.436 mmol), tert-butylchlorodimethylsilane (0.079 g, 0.524 mmol) and imidazole (0.074 g, 1.091 mmol) in DMF (2.2 mL) was stirred at rt for 18 h. Additional tert-butylchlorodimethylsilane (0.079 g, 0.524 mmol) and imidazole (0.074 g, 1.091 mmol) were added and stirring was continued for 1 h. The mixture was diluted with EtOAc (75 mL) and washed seven times with brine. The organic layer was dried and concentrated and the residue was purified by column chromatography (eluting with a gradient from 90:10 to 50:50 hexane-EtOAc) to give 4-bromo-7-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-9H-carbazole-1-carboxamide (0.144 g, 67%).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][NH:39]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][OH:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][NH2:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][OH:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCO)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCO)CS[C@H]12)c1csc(N)n1
Yield: 68.6 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.5 g.), conc. hydrochloric acid (1.9 g.) and methanol (40 ml.) were treated in a similar manner to that of Example 6-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)(C)(C)C>Cl>[CH3:30][S:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13]([C:9]3[C:8]([NH2:7])=[CH:12][O:11][N:10]=3)=[CH:18][CH:17]=2)=[CH:26][CH:25]=1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCc2ccc(S(C)(=O)=O)cc2)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(COc2ccc(-c3nocc3N)cc2)cc1
Temperature: 25 °C

Procedure:
{3-[4-(4-Methanesulfonyl-benzyloxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (20.5 mg, 0.046 mmol) was dissolved in a 2M HCl in dioxanes (5 mL, 10 mmol) and stirred at rt until no starting material remained. Removal of volatiles under reduced pressure and workout according to Example 2 provided 3-[4-(4-methanesulfonyl-benzyloxy)-phenyl]-isoxazol-4-ylamine (14.5 mg, 91%). HRMS (M+1)=345.09
Reaction SMILES: C(N1C2C(=CC(Br)=CC=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C.[CH:22]1([C:25]([N:27]2[C:36]3[C:31](=[CH:32][C:33]([C:37]4[CH:38]=[N:39][NH:40][CH:41]=4)=[CH:34][CH:35]=3)[N:30]([C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])[CH2:29][C@@H:28]2[CH3:48])=[O:26])CC1>>[C:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([C:37]3[CH:41]=[N:40][NH:39][CH:38]=3)=[CH:34][CH:35]=2)[N:30]([C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])[CH2:29][C@@H:28]1[CH3:48])(=[O:26])[CH3:22]
Reactant: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(-c3cn[nH]c3)cc21
Agent: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
Isopropyl (S)-4-acetyl-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1 (2H)-carboxylate was synthesized from (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure outlined above for (S)-isopropyl 4-(cyclopropanecarbonyl)-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 343 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.[F:17][C@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[F:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCl)cn1
Reactant: F[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CC[C@H](F)C2)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A mixture of tert-butyl 5-(chloromethyl)pyridin-2-ylcarbamate 117(9.5 g, 39.1 mmol), (S)-3-fluoropyrrolidine 118 (4.19 g, 47.0 mmol), potassium carbonate (16.2 g, 117 mmol) and sodium iodide (0.586 g, 3.91 mmol) in DMF (150 mL) was stirred at 60° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. H2O (250 mL) was added and the resulting solid was collected by filtration, rinsed with H2O and dried to give 119 (7.00 g, 61% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([N+:15]([O-])=O)[C:13]=2[NH2:14])[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]([NH2:14])=[C:12]([NH2:15])[CH:11]=[N:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cncc([N+](=O)[O-])c2N)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2cncc(N)c2N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine (CXVII) (382 mg, 1.61 mmol) in MeOH (11 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 4 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 5-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (CXVIII) as purple solid (330 mg, 1.59 mmol, 99% yield). 1H NMR (DMSO-d6, 500 MHz,): δ 2.18 (s, 3H), 2.34-2.36 (m, 4H), 3.13-3.16 (m, 4H), 3.89 (s, 2H), 5.20 (s, 2H), 5.94 (s, 1H), 7.31 (s, 1H); ESIMS found C10H17N5 m/z 208 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:19])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:2]1.[C:20]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:19])[CH2:11][CH:12]([CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]([O:28][CH2:29][CH3:30])=[O:27])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:2]1
Reactant: O=C(C=Cc1ccccc1)c1c[nH]c2ccccc12
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1c[nH]c2ccccc12)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(1H-indol-3-yl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(1H-indol-3-yl)-3-oxo-1-phenylpropyl]malonate was obtained as yellowish solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[CH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B]1OC2C(=CC=CC=2)O1.Br[C:22]1[S:26][C:25]([CH2:27][CH2:28][C:29]2([CH3:35])[CH2:33][O:32][C:31](=[O:34])[NH:30]2)=[CH:24][CH:23]=1.[O-]CC.[Na+].[OH-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:35][C:29]1([CH2:28][CH2:27][C:25]2[S:26][C:22]([CH:11]=[CH:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:23][CH:24]=2)[CH2:33][O:32][C:31](=[O:34])[NH:30]1
Reactant: C#CCCCc1ccccc1
Reactant: CC1(CCc2ccc(Br)s2)COC(=O)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CC1(CCc2ccc(C=CCCCc3ccccc3)s2)COC(=O)N1
Temperature: 60 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
To 5-phenylpent-1-yne (0.38 ml, 2.58 mmol) was added catecholborane (500 mg, 1.72 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. After the reaction solution was cooled down to room temperature, toluene (5.0 ml), 4-[2-(5-bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one (500 mg, 1.72 mmol) obtained in Example 1 (f), bis(triphenylphosphine)palladium chloride (119 mg, 0.17 mmol), and sodium ethoxide (0.83 ml, 20% ethanol solution) were added thereto at room temperature. The reaction mixture was stirred for 2 hours at 60° C., cooled down to room temperature, and then 1N sodium hydroxide was added thereto. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with water and then with a saturated aqueous sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (378 mg, 68% yield).