Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[N:11]=1)=[CH:6]N(C)C)[CH3:2].[H][H]>CCO.[Ni]>[CH2:1]([O:3][C:4]([C:5]1[C:10]2=[N:11][C:12]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:13][CH:14]=[C:15]2[NH:16][CH:6]=1)=[O:27])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=CN(C)C)c1nc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2ccc(OC3CCN(C)CC3)nc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 3-dimethylamino-2-[6-(1-methyl-piperidin-4-yloxy)-3-nitro-pyridin-2-yl]-acrylic acid ethyl ester (3.69 g, 9.76 mmol), RANEY 2400 nickel (3.7 g wet) in EtOH (100 mL) is shaken at room temperature under an atmosphere of hydrogen (50 psi) for a period of 7 h. During this time period, the pressure dropped to 20 psi. The reaction vessel is recharged with hydrogen (50 psi) and shaken at room temperature for a period of 17 h. The reaction mixture is filtered through celite and the filtrate washed with EtOH (300 mL) taking care to never allow the filtrate to become dry. The filtrate is concentrated and purified by chromatography on silica (gradient elution with 10% MeOH/CHCl3 with 0.1% NH4OH to 14% MeOH/CHCl3 with 0.1% NH4OH) to give the title compound as a yellow solid: m.p=231.9° C.; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.64 (d, 1H, J=8.7 Hz), 6.51 (d, 1H, J=8.7 Hz), 5.36-5.28 (m, 1H), 4.26 (q, 2H, J=7.1 Hz), 3.15-3.06 (m, 2H), 3.00-2.90 (m, 2H), 2.61 (s, 3H), 2.30-2.20 (m, 2H), 2.18-2.08 (m, 2H), 1.30 (t, 3H, J−7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 165.0, 159.3, 140.5, 133.7, 125.8, 123.7, 107.3, 106.6, 66.1, 60.0, 51.6, 44.2, 28.5, 14.6; MS (CI) m/z 304.3 (M+1).
Reaction SMILES: CC([N:5](C(O)=O)[NH:6][C:7](=[O:23])[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)(C)C.Cl.[OH-].[Na+]>O1CCCC1.O>[CH3:22][C:19]([C:10]1[CH:9]=[C:8]([CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]=1[OH:18])[C:7]([NH:6][NH2:5])=[O:23])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cc(C(=O)NN(C(=O)O)C(C)(C)C)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)NN)cc(C(C)(C)C)c1O
Reaction time: 0.33 h
Yield: 65.3 %

Procedure:
1,1-Dimethylethyl 2-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]hydrazine carboxylic acid (4.0 g , 0.011 mole) in tetrahydrofuran (100 ml) is treated with a mixture of water (12 ml) and concentrated hydrochloric acid (30 ml). The resulting mixture is heated on a steam-bath. After 20 minutes the mixture is stripped of volatiles under reduced pressure. The residue is dissolved in water (100 ml) and treated with 1M NaOH until the solution is slightly basic. The product is extracted into ether (600 ml) and the organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration provides a solid which is recrystallized from isopropyl ether/hexane to yield 1.9 g (2.9 g theor., 66%) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, hydrazide, mp 187°-188° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=1.CN(C)C=O>O>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nc(NCCN)nc(N)c2cc1OC
Reactant: c1ccc(OCC2CO2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nc(NCCNCC(O)COc3ccccc3)nc(N)c2cc1OC
Reaction time: 48 h

Procedure:
3.8 g. Phenyl glycidyl ether and 10 g. 2-(2-aminoethylamino)-4-amino-6,7-dimethoxyquinazoline are dissolved in 5 ml. dimethylformamide and left to stand for 48 hours at ambient temperature. The reaction mixture is then poured into water, filtered with suction and purified chromatographically on a silica gel column in the manner described in Example 24. There are obtained 2.5 g. (24% of theory) of the desired product in the form of colorless crystals; m.p. 122°-124° C., after recrystallization from isopropyl alcohol.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([C:25](=[O:28])[CH2:26][CH3:27])[N:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[OH:22][C:20]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]([CH3:11])[C:25](=[O:28])[C:26]=1[CH3:27]
Reactant: CCOC(=O)C(=NN(C)C(=O)CC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(C)c(=O)c(C)c1O
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a solution of LiHMDS (0.78 mL, 0.78 mmol, 1 M solution in THF) in THF (1 mL) at −78° C. was added a solution of diethyl 2-(2-methyl-2-propionylhydrazono)malonate (50 mg, 0.19 mmol) in THF (1 mL). The resulting mixture was slowly warmed to −40° C. and stirred for 1.5 hours al −40° C. The reaction mixture was quenched with 10% aqueous HCl and diluted with water. The resulting mixture was extracted with EtOAc (2×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 20% EtOAc in hexanes) to afford 25 mg (61%) of the desired product.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].C(O)C.C(O[C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:13]([C:16]#[N:17])[C:14]#[N:15])C>O>[NH2:15][C:14]1[O:3][N:2]=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[C:16]#[N:17]
Reactant: CCOC(=C(C#N)C#N)c1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1c(-c2ccccc2)noc1N

Procedure:
Hydroxylamine hydrochloride was suspended in water (30 ml) and added sodium hydroxide (4.4 g, 0.11 mole), then ethanol (40 ml) followed by batchwise addition of 2-(Ethoxy-phenyl-methylene)-malononitrile(21.7 g, 0.11 mole). Heated reaction mixture to 50° C. for 2 hours. Removed ethanol under vacuum and filtered precipitate. Redissolved precipitate in 50% ethyl acetate/hexanes and chromatographed on silica gel to give 8.2 g product after removal of solvent (yield: 40%).
Reaction SMILES: [CH3:1][P:2]([O:6][CH3:7])(=[O:5])[O:3][CH3:4].C([Li])CCC.[C:13]([Si:17]([CH3:28])([CH3:27])[O:18][CH2:19][C:20](OCCCC)=O)([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([Si:17]([CH3:28])([CH3:27])[O:18][CH2:19][CH2:20][CH2:1][P:2](=[O:5])([O:6][CH3:7])[O:3][CH3:4])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCCOC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CCCO[Si](C)(C)C(C)(C)C)OC
Temperature: -30 °C
Reaction time: 2 h

Procedure:
Dimethyl methanephosphonate (70 ml; 634.8 mmol) was placed in tetrahydrofuran (1.6 l) at −75° C. and treated at this temperature with 1.6M n-butyllithium in tetrahydrofuran (437 ml; 700 mmol). After 1.5 hours at −75° C. n-butyl (t-butyl-dimethyl-silanyloxy)-acetate (52.1 g; 211.6 mmol) in tetrahydrofuran (110 ml) was added and the batch was stirred for 2 hours at −30° C. The reaction mixture was subsequently poured into 1N ice-cold aqueous hydrochloric acid (800 ml) and extracted rapidly with ethyl acetate (2×1 l). The combined organic phases were washed in succession with water (2×1 l) and saturated aqueous sodium chloride solution (500 ml), dried over magnesium sulphate and concentrated. The residue was azeotroped with toluene (2×300 ml) and distilled (b.p.: 89-95° C.; 0.42 mm Hg). Yield: 57.2 g (92%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.O>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH:9]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of ethyl 3-(3-fluorophenyl)-3-oxopropionate (20 g, 95 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 3.80 g, 95 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (22.7 g, 95 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 4 hrs. The reaction solution was poured into water (300 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) and recrystallized from ethyl acetate-hexane to give ethyl 3-(3-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (28.8 g, 82%).
Reaction SMILES: [C:1]1(/[CH:11]=[CH:12]\[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P([O-])([O-])(O)=[O:15].[Na+].[Na+]>C(Cl)Cl>[C:1]1([C@H:11]2[O:15][C@H:12]2[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C/C=C\c1cccc2ccccc12
Reactant: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1O[C@@H]1c1cccc2ccccc12
Temperature: 6 °C
Reaction time: 6 h

Procedure:
(ref. E. Jacobsen, el al; JACS 1991, 7064.) The (Z)-1-(1-naphthyl)-propene (2.06 g, 0.012 mol) was dissolved in methylene chloride, and (R, R)-Jacobsen's catalyst (0.168 g) was added, then cooled to 6° C., and a bleach solution (10 mL, buffered to pH=11.3 with disodium hydrogen phosphate) was added. After 6 h at 6° C., the layers were separated, and the aqueous layer washed with ether. The combined organic layers were washed with water, then brine, dried over magnesium sulfate, filtered and rotovapped. The crude product was chromatographed on silica using 5% ether/pentane, to give the desired (1R, 2S)-1-(1-naphthyl)-1-propene oxide (0.421 g). NMR (CDCl3) 8.1-7.7 (3H, m), 7.6-7.3 (4H, m), 4.6-4.5 (1H, m), 3.7-3.5 (1H, m), 1.0 (3H, d, J=5.3 Hz).
Reaction SMILES: C[O:2][C:3](=[O:27])/[C:4](/[CH:10]([P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]\[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[CH2:22]([O:21][P:19]([CH:10]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])/[C:4](=[CH:5]/[C:6]([OH:8])=[O:7])/[C:3]([OH:27])=[O:2])([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: CCOP(=O)(OCC)C(/C(=C/C(=O)OC)C(=O)OC)P(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOP(=O)(OCC)C(/C(=C/C(=O)O)C(=O)O)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
A solution of 12.7 g of 2-[bis(diethoxyphosphoryl)methyl]maleic acid dimethyl ester in 76.8 ml of 1 N sodium hydroxide is kept under stirring for 96 hours, then the reaction mixture is washed twice with ethyl ether and is brought to pH 8.5 with 37% hydrochloric acid. The mixture is then concentrated to dryness and redissolved in 50 ml of methanol. After filtration of the formed sodium chloride, the solvent is evaporated under reduced pressure. The residue is treated with 125 ml of acetone, to give, after filtration, 11.5 g of the product as disodium salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-])=[CH:4][CH:3]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: [O-][n+]1ccccc1C=Cc1ccc(F)cc1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: N#Cc1cccc(C=Cc2ccc(F)cc2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(4-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a yellow crystalline material. MS: m/e=224 (M+).
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][C:3](=[O:23])[C:2]=1[S:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Sc1ccccc1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Sc1ccccc1

Procedure:
The title compound was prepared as described in General Method 6 from 1.50 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 1.60 mmol of benzenethiol, and 1.60 mmol of piperidine in 30 mL of dichloromethane. The product was triturated with hexane:ether (1:1) to afford a solid. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 58°-60° C.). 1H NMR (DMSO-d6)δ2.22-2.39 (m, 3H), 2.62 (m, 1H), 3.46 (q, 2H), 6.48 (m, 2H), 6.98 (m, 3H), 7.15 (m, 3H), 7.25 (m, 2H), 7.46 (m, 5H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[CH3:31])(=O)=O.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]1>CN(C=O)C>[F:30][CH:28]([F:29])[O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[N:20][C:15]([NH:14][C:12]3[CH:11]=[CH:10][C:9]([CH3:31])=[C:8]([CH:13]=3)[CH2:7][CH2:6][N:32]3[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]3)=[N:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1CCOS(C)(=O)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCc2cc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)ccc2C)CC1
Temperature: 90 °C

Procedure:
5-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl methanesulfonate 51b (0.9 mmol), ethyl piperidine-4-carboxylate (2.2 mmol) are dissolved in DMF (10 mL) and heated to 90° C. for 4 h then cooled to rt. The reaction mixture is partitioned with EtOAc and water. The organic layer is washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude material is purified by column chromatography on silica with hexane:EtOAc=1:1 to 100% EtOAc as eluant to yield ethyl 1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylate 52 as clear viscous oil. MS (m/z) (M+1)+: 511.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: Nc1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2ccccn2)cc1[N+](=O)[O-]

Procedure:
4-methoxy-3-nitrobenzoyl chloride (1.08 g, 0.005 mol), 2-aminopyridine (0.94 g, 0.01 mol) and DIPEA (1.8 mL, 0.01 mol) were allowed to stir in DCM (10 mL) for 48 h to form 4-methoxy-3-nitro-N-(pyridin-2-yl)benzamide. Intermediate was purified via silica column chromatography using 0 to 100% EtOAc in hexane.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][N:5]=1)=O.[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])[CH3:28]>O1CCOCC1.O>[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:4]2[N:9]=[C:8]([N:10]3[C:18]4[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11]3)[CH:7]=[CH:6][N:5]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CS(=O)c1nccc(-n2ccc3c(OCCCS(C)(=O)=O)cccc32)n1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 110 °C
Yield: 99.7 %

Procedure:
A mixture of 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (25 g, 64 mM) and 4-amino-cyclohexanecarboxylic acid ethyl ester (16.3 g, 95.3 mM) in dioxane (400 mL) and heated at 110° C. for approximately 5 h. The solution was concentrated in vacuo to give a white residue. The residue was suspended in H2O, filtered and washed in H2O, and dried at 60° C. in vacuo to yield 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (31.7 g, 99.7%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[Br:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([Br:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Product: CC(C)OC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Br)cc1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 4-bromobenzenesulfonic acid chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[NH2:11][C:12]1[N:16]([CH3:17])[N:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=1.C(O)CCC.Cl>O1CCOCC1>[Cl:10][C:5]1[C:6]([NH:8][CH3:9])=[N:7][C:2]([NH:11][C:12]2[N:16]([CH3:17])[N:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)=[N:3][CH:4]=1
Reactant: CNc1nc(Cl)ncc1Cl
Reactant: COC(=O)c1cc(N)n(C)n1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc(C(=O)OC)nn2C)ncc1Cl
Temperature: 130 °C
Yield: 64.6 %

Procedure:
To a 30 mL microwave vial was added 0.98 g of 2,5-dichloro-N-methylpyrimidin-4-amine, 0.78 g of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate, 10 mL of 1-butanol and 0.13 mL of 4M hydrogen chloride in dioxane. The vial was capped and the reaction was heated in a microwave for 30 minutes at 130° C. As the reaction cooled, a precipitate fell out. Filter the precipitate and rinse with a small amount of n-butanol. Drying the cake yielded 0.964 g of methyl 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylate which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].[Br:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[N:28][C:29](Cl)=[N:30]2>>[Br:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[N:28][C:29]([NH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11])=[N:30]2
Reactant: Clc1ncc2c(Br)cccc2n1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3c(Br)cccc3n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 5-bromo-2-chloroquinazoline. ESI-MS (m/z): 520, 522 [M]+, [M+2]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[N:12]=[CH:11][C:10]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH:22]=3)[C:19]([OH:21])=[O:20])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].[CH3:23][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:23][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:14]([C:10]2[CH:11]=[N:12][C:13]3[N:4]([C:1](=[O:3])[NH2:2])[CH2:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)[CH:15]=[N:16][CH:17]=1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(C(=O)O)c3)cnc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
To the solution of 5-(8-Carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-nicotinic acid (100 mg, 0.33 mmol) in 12 mL of toluene/MeOH 3:1 mixture is added 2.0 M trimethylsilyl-diazomethane (0.20 mL, 0.40 mmol) under N2 atmosphere. The reaction solution is stirred at room temperature for 16 hrs. The solvents are removed in vacuo and the residue is purified by preparative HPLC to give 33 mg of the titled product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[C:22]([C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:27]([O:36][CH3:37])[CH:26]=1)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:32][CH2:31][CH2:30][O:29][C:28]3[CH:34]=[CH:35][C:25]([C:22](=[O:24])[CH3:23])=[CH:26][C:27]=3[O:36][CH3:37])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: OC(c1ccccc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(O)(c2ccccc2)c2ccc(F)cc2)CC1
Yield: 27.4 %

Procedure:
A mixture of 6.5 g (0.023 mole) of α-(p-fluorophenyl)-α-phenyl-4-piperidinemethanol, 5.5 g (0.023 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.92 g (0.023 mole) of sodium bicarbonate in 80 ml of dimethylformamide was heated at 100°-110° C. for 2 hrs. The reaction mixture was cooled and filtered and the dimethylformamide was removed at reduced pressure. The residual oil was dissolved in chloroform and filtered. The chloroform was removed at reduced pressure. The solid residue which remained weighed 8.6 g (77%) and was recrystallized from ethanol to give 3.1 g of material melting at 147°-148° C. A sample was dried over refluxing toluene and submitted for analysis. (See Ex. 14, U.S. Pat. No. 3,956,296).
Reaction SMILES: [OH:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:3][O:4][NH2:5].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[C:13]1([NH:19][C:20]([NH:5][O:4][CH2:3][CH:2]([OH:1])[CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NOCC(O)CN1CCCCC1
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NOCC(O)CN1CCCCC1)Nc1ccccc1

Procedure:
O-(2-hydroxy-3-piperidino-propyl)-hydroxylamine (1,74 g, 0,01 mol) was dissolved in 40 ml chloroform and 1,09 ml (0,01 mol) phenyl isocyanate was added thereto while stirring. The reaction was monitored by chromatography. After the end of reaction the solution was evaporated and the oily residue was purified by column chromatography. The oil thus obtained was crystallized from diethyl ether. Yield: 0,6 g (20%). Mp: 101-103° C.