Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7]O)[CH3:5].[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][N:16]2S(C)(=O)=O)=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][N:16]2[CH2:7][CH2:6][N:4]([CH3:5])[CH3:3])=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)n1ccc2ccc(Br)cc21
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN(C)CCn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
To a powdered suspension of NaH (55 mg, 4.8 mmol) in toluene (4 mL) was added 2-(N,N-dimethylamino)ethanol (321 mg, 3.6 mmol). The mixture was stirred for 10 minutes, after which compound (i), above, (751 mg, 2.4 mmol) was added and the mixture refluxed 16 h. The mixture was allowed to cool to room temperature and then diluted with CH2Cl2. The organic extract was washed with water and brine and dried over anhydrous Na2SO4. The crude residue was purified by flash chromatography to give the title product as a white solid (390 mg, 61% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)[CH3:2].[CH:21]1([CH2:24][O:25][C:26]2[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[CH2:23][CH2:22]1.[O-]CC.[Na+]>C(O)C>[CH:21]1([CH2:24][O:25][C:26]2[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:27]=2/[CH:28]=[CH:20]/[C:11]2[N:12]=[C:13]3[S:19][CH:18]=[CH:17][N:14]3[C:15](=[O:16])[C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=2)[CH2:22][CH2:23]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(-c2c(/C=C/c3cccc(OC)c3OCC3CC3)nc3sccn3c2=O)cc1
Yield: 40.3 %

Procedure:
The title compound was prepared by condensation of Intermediate 10 (300 mg, 1.047 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (302 mg, 1.466 mmol) in presence of sodium ethoxide (142 mg, 2.090 mmol) in ethanol (10 ml) according to the procedure of Example 24 to afford 200 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.25-0.27 (m, 2H), 0.49-0.51 (m, 2H), 1.03-1.05 (m, 1H), 3.67-3.70 (m, 2H), 3.77-3.81 (m, 3H), 6.89-6.91 (m, 2H), 6.98-7.02 (m, 4H), 7.23-7.26 (m, 2H), 7.47-7.49 (m, 1H), 7.96-8.10 (m, 1H), 8.10-8.15 (m, 1H); ESI-MS (m/z) 461.39 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>CC(O)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C(=O)O)c1ccc(N)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 2-(4-Aminophenyl)propanoic acid (8.45 g, 51.2 mmol) in AcOH (70 mL) was added HNO3 (60%, 5.66 g) at room temperature. The reaction mixture was refluxed for 4 hrs then cooled to room temperature. The mixture was poured into iced water (200 mL), and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[C:18]23[O:29][CH2:28][CH2:27][CH2:26][O:25]2)(=[O:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:31][CH2:32][CH:33]([Br:35])[CH3:34].O>CS(C)=O>[N:7]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:32]([CH3:31])[CH:33]([Br:35])[CH3:34])[C:19](=[O:24])[C:18]23[O:29][CH2:28][CH2:27][CH2:26][O:25]2)(=[O:13])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(Br)CCBr
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C12OCCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(Br)C(C)N1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Reaction time: 0.17 h

Procedure:
To a solution of potassium t-butoxide (0.12 g, 1 mmol, 1 eq) in anhydrous DMSO (5 mL) at room temperature under dry N2 atmosphere was added 5′-{[pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (previously described in step 2, Example 12) (0.33 g, 1 mmol). After stirring for 10 minutes, 1,3-dibromobutane (0.22 g, 1 mmol, 1 eq) was added dropwise to the reaction over a 5 minute period. The reaction mixture was stirred at room temperature for one hour. The mixture was poured into H2O (20 ml) and exhaustively extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using 30% EtOAc/hexane to give the title compound as an off white solid (0.23 g, 50% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (API-ES+) m/z 474 [M+H].
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([O:25]C)[CH:13]=[C:14]3[C:22]=2[N:21]([CH:23]=1)[C:20]1[CH:19]=[C:18]([Br:24])[CH:17]=[CH:16][C:15]3=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.Br>[CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([OH:25])[CH:13]=[C:14]3[C:22]=2[N:21]([CH:23]=1)[C:20]1[CH:19]=[C:18]([Br:24])[CH:17]=[CH:16][C:15]3=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(=O)c(Cc3ccccc3)cn3c4cc(Br)ccc4c(c1)c23
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=c1c(Cc2ccccc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Yield: 58.2 %

Procedure:
5-benzyl-9-bromo-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (137 mg) produced in Example 121 was dissolved in acetic acid (7 ml) and 48% HBr (7 ml), and the solution was stirred at room temperature for 30 hours. The reaction mixture was poured into water and the crystals precipitated were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (77 mg, 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:29]=1)[C:7]([N:9]=[S@@:10]([CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:30]([C:32]1[CH:33]=[C:34]([NH:38][C:39]([C:41]2[N:45]([CH3:46])[N:44]=[C:43]([CH3:47])[CH:42]=2)=[O:40])[CH:35]=[CH:36][CH:37]=1)#[CH:31]>>[Si:22]([O:21][CH2:20][CH2:19][CH2:18][S@:10](=[O:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N:9][C:7](=[O:8])[C:6]1[CH:29]=[C:2]([C:31]#[C:30][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C:39]([C:41]3[N:45]([CH3:46])[N:44]=[C:43]([CH3:47])[CH:42]=3)=[O:40])[CH:33]=2)[CH:3]=[N:4][CH:5]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Reactant: CC(C)(C)[Si](C)(C)OCCC[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CCCO[Si](C)(C)C(C)(C)C)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described in Example 506 (step 3), (S)-5-bromo-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl--sulfanylidene]nicotinamide and N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide are converted to the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH2:11][CH3:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=1)=[O:4].C(O)C.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(N(CC)CC)C>[CH2:11]([N:10]1[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:9]1)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: CCn1nc(-c2ccncc2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)nn1CC
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a 25 ml flask was added (S)-2-amino-N-(1-ethyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-phenylpropanamide 101.1.B (132 mg, 0.39 mmole), 3 ml of ethanol and 0.08 ml of triethylamine. The reaction mixture was cooled to 0° C., and then ethyl bromoacetate (48 μl, 0.43 mmole) was added to the mixture. The reaction was stirred at 50° C. for 1 hour and at room temperature overnight. After then, the solution was concentrated, and dissolved in ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 101.1.C (45 mg, 27% yield) as colorless amorphous. 1H NMR (400 MHz, CDCl3) δ ppm 9.73 (s, 1H), 8.61 (d, J=5.9 Hz, 2H), 7.69 (d, J=6.3 Hz, 2H), 7.38-7.26 (m, 5H), 6.87 (s, 1H), 4.19-4.04 (m, 4H), 3.54 (dd, J=8.4, 4.5 Hz, 1H), 3.42 (d, J=17.6 Hz, 1H), 3.32 (d, J=17.6 Hz, 1H), 3.35 (dd, J=14.1, 4.5 Hz, 1H), 3.00 (dd, J=14.1, 8.2 Hz, 1H), 2.05 (brs, 1H), 1.43 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=2[CH:9]=O)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=3[CH2:9][NH:19][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: COc1ccc(C=O)c(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)Oc1ccc(Cl)cc1NC2
Yield: 60.1 %

Procedure:
3.50 g of 2-(4-chloro-2-nitrophenoxy)-4-methoxybenzaldehyde, prepared as described above in Example 5, in tetrahydrofuran (THF) (35 mL) was shaken in a Parr hydrogenator at 5 psi hydrogen with Raney nickel at 25° C. for 6 hours. The catalyst was filtered from the reaction and the solution evaporated in vacuo. The crude product was chromatographed, as described above in Example 2, through silica gel 60 using hexane:ethyl acetate (2:1), and recrystallized from ethanol (3A) to yield 1.79 g (60.1%) of product as white crystals. Melting Point: 113°-115° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:31][C:32]1[N:33]=[CH:34][N:35]([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][C:38]=2[O:44][CH3:45])[CH:36]=1>>[Cl:31][C:32]1[N:33]=[CH:34][N:35]([C:37]2[CH:43]=[CH:42][C:40]([NH:41][C:2]3[N:3]=[C:4]([N:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:22][CH2:23]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:39][C:38]=2[O:44][CH3:45])[CH:36]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Product: COc1cc(Nc2nc3c(c(N4CCN(C(=O)OC(C)(C)C)CC4)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Yield: 62.1 %

Procedure:
tert-butyl 4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (Preparation Hl) (117 mg, 0.270 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (60.4 mg, 0.270 mmol) were combined as per Example 26 to give tert-butyl 4-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (104 mg, 0.168 mmol, 62.1% yield) crude without purification. LC-MS (M+H)+=620.4.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([O:15][CH3:16])(=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11]>CC(O)(C)C>[CH3:13][O:12][C:10]([CH:9]([C:8]([O:15][CH3:16])=[O:14])[C@@H:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)=[O:11]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C1C=CCCC1
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=O)OC)[C@@H]1CCCC(=O)C1
Temperature: 30 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C=100) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 194 μL (2.0 mmol) of 2-cyclohexenone, 228 μL (2.0 mmol) of dimethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 30° C. for 72 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 443 mg (97% yield) of the title compound. The optical rotation [α]D23 was +3.45 (c 2.44, CHCl3). The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=85:15, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 98% ee.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].Cl[C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>O>[C:22]([CH2:21][NH:20][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])([OH:24])=[O:23]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNc1cc(Cl)ccc1C(=O)O
Temperature: 30 °C
Yield: 87.7 %

Procedure:
To a solution of potassium carbonate (50.7 g), potassium hydroxide (47.3 g), 2,4-dichlorobenzoic acid (VI) (70 g) and glycine (VII) (96.3 g) in water (700 ml) was added cupric chloride (0.7 g) and the resulting solution was refluxed for 4 hours. After this reaction solution was cooled to 30° C., the copper salt was removed by filtration and concentrated hydrochloric acid (288 g) was added to the resultant filtrate at temperature of not more than 40° C. Then, the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 73.8 g of 2-carboxymethylamino-4-chlorobenzoic acid (yield, 87.7%).
Reaction SMILES: [ClH:1].Cl.[Cl:3]C1C=C[C:7]([C:10]2O[C:13]([CH:15]=[C:16]3[CH2:21][CH2:20][CH2:19][N:18]=[C:17]3[C:22]3[CH:23]=NC=CC=3)=[CH:12][CH:11]=2)=[C:6]([N+:28]([O-])=O)C=1.Cl.[C:32]1([CH:42]=O)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>C(O)(C)C>[ClH:3].[ClH:1].[C:32]1([CH:42]=[C:11]2[CH2:10][CH2:7][CH2:6][N:28]=[C:12]2[C:13]2[CH:15]=[C:16]3[C:17](=[CH:22][CH:23]=2)[N:18]=[CH:19][CH:20]=[CH:21]3)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1-c1ccc(C=C2CCCN=C2c2cccnc2)o1
Reactant: O=Cc1cccc2ccccc12
Agent: Cl
Solvent: CC(C)O
Product: C(=C1CCCN=C1c1ccc2ncccc2c1)c1cccc2ccccc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
Intermediate 15 (196 mg, 0.93 mmol) (prepared as described in Example 55) was dissolved into isopropanol (6 mL) in a reaction vessel and treated with 6 N HCl(aq) (310 μL, 1.9 mmol). 1-Naphthaldehyde (219 mg, 1.4 mmol) was added, the reaction vessel was sealed, and the reaction heated to 85° C. with stirring overnight. The reaction was cooled to room temperature, concentrated under reduced pressure, treated with saturated NaHCO3(aq), and extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The recovered material was eluted through a 20 gram column of silica gel with a 10.5:7:7:0.3:0.03 (750 mL) and 7:7:7:0.5:0.05 (300 mL) Hexane:MtBE:CH2Cl2:MeOH:NH4OH step gradient. The material recovered from this column was then further purified by preparative HPLC using the same conditions and method described for Example 47. The recovered material was dissolved into MeOH and treated with 2 eq. of 6 N HCl(aq). This solution was then concentrated under reduced pressure and the recovered material dissolved into hot isopropanol. After this solution had cooled to room temperature, ether was added until the solution became cloudy. This mixture was cooled to −20° C. Crystals did form and were recovered by vacuum filtration, washed with fresh ether, and dried under vacuum giving 31 mg (6.9%) of a brown solid. LC-MS: RT=5.45 min, [M+H]+=349.0.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH:22]=[O:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH2:22][OH:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C=O)cc2ccccc2c1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(CO)cc2ccccc2c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-formylnaphthalen-2-yl)acetate (12 mg, 0.0283 mmol) in DCM/EtOH (1/1, 1 mL) at 0° C., was added NaBH4 (2 mg, 0.053 mmol) and the reaction mixture stirred at 0° C. for 2 h. The reaction was quenched by adding sat. NH4Cl. The resulting mixture was extracted with DCM, dried over MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 8 mg of the desired product. 1H-MNR 400 MHz (CDCl3) δ: 7.85 (s, 1H), 7.78 (d, J=4.0 Hz, 1H), 7.46-7.38 (m, 4H), 7.30-7.26 (m, 1H), 7.20-7.15 (m, 2H), 5.13 (s, 1H), 5.02 (d, J=6.2 Hz, 1H), 4.54 (d, J=6 Hz, 1H), 4.12-4.02 (m, 2H), 3.82 (bs, 1H), 1.14 (t, J=7 Hz, 3H), 1.01 (s, 9H).
Reaction SMILES: [C-]#N.[K+].[CH3:4][N:5](C=O)C.[C:9]([O:12][CH2:13][C:14]1([CH2:17]Br)[CH2:16][CH2:15]1)(=[O:11])[CH3:10].O>C1(C)C=CC=CC=1>[C:9]([O:12][CH2:13][C:14]1([CH2:17][C:4]#[N:5])[CH2:16][CH2:15]1)(=[O:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CC(=O)OCC1(CBr)CC1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)OCC1(CC#N)CC1
Temperature: 80 °C
Yield: 119.5 %

Procedure:
A 12 L 4-neck round bottle flask was equipped with mechanical stirrer, a thermometer, a condenser, a nitrogen inlet and an additional funnel. To the flask was charged 1335 mL of and 667 g of potassium cyanide and kept stirring to complete dissolution. 1417 g of DMF and 1417 g of crude [1-(bromomethyl)cyclopropyl]methyl acetate were added from the addition funnel over 30 min. When the addition was complete, the reaction mixture was heated to 80° C. with stirring about 1 hour. The resulting mixture was cooled to about 20˜25° C. 3500 mL of water and 3500 mL of toluene were added to the reaction mixture with stirring over 30 min. The layers were separated and the aqueous layer was back extracted with 3500 mL of toluene. Combined the organic layer and then concentrated to obtain 1253 g dark brown liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].O1CCCC1.CC(C)([O-])C.[K+:20].[C:21](=[S:23])=[S:22]>CCOCC>[O:1]([CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[C:21]([S-:23])=[S:22].[K+:20]
Reactant: S=C=S
Reactant: O=C1CCCN1CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCCN1CCOC(=S)[S-]
Reaction time: 1 h

Procedure:
To a stirred solution of 5.16 g. of N-(2-hydroxyethyl)-2-oxo-pyrrolidine in 200 ml. of anhydrous tetrahydrofuran at room temperature was added 4.48 g. of potassium t-butoxide. A gummy precipitate formed. The mixture was stirred for 1 hour, and then 3.6 ml. of carbon disulfide was added. The mixture was stirred for 2 hours, and then 100 ml. of anhydrous ether was added, causing the formation of a gummy precipitate. The solvent was decanted from the gummy precipitate, and the gummy precipitate was dried under high vacuum to give a foam (5.0 g.) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([CH3:15])([C:6]1[CH:7]=[N:8][C:9]([N+:12]([O-])=O)=[CH:10][CH:11]=1)[CH3:5].[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:6]1[CH:7]=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=1)([CH3:15])[CH3:5]
Reactant: [H][H]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccc(N)nc1
Yield: 91.9 %

Procedure:
2-Methyl-2-(6-nitropyridin-3-yl)-propionic acid methyl ester (1.88 g, 8.4 mmol) was dissolved in THF and 200 mg of 10% palladium on carbon was added. The reaction was exposed to hydrogen at a pressure of 50 psi for 5 hrs. NMR showed the reduction was incomplete. More palladium on carbon was added and the reaction was exposed to hydrogen again at 50 psi for several hrs. The reaction was filtered through celite and concentrated to give 1.5 g (92%) of 2-(6-amino-pyridin-3-yl)-2-methyl-propionic acid methyl ester which was used without purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][C:34]#[N:35])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:36]O.[OH-].[Na+]>CO>[NH2:35][C:34](=[O:36])[CH2:33][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13]([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:11][CH2:12]2)=[O:14])=[CH:21][C:20]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=1
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CC#N)cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide (58 mg, 0.12 mmol), H2O2 (30 wt % solution in water, 36 μL, 1.2 mmol), and NaOH (10 wt % in water, 0.15 mL, 0.42 mmol) were dissolved in MeOH (1.2 mL) and stirred at 25° C. for 2 hours. The reaction was filtered and purified by reverse phase HPLC to yield 2′-(2-amino-2-oxoethyl)-5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,N-dimethylbiphenyl-4-carboxamide (14 mg, 23%). ESI-MS m/z calc. 485.2, found 486.5 (M+1)+; Retention time 2.54 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH:16]([CH2:20][OH:21])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:29]([C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH:16]([CH2:20][O:21][S:38]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=4)(=[O:39])=[O:40])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: OCC1CN(C2CCN(c3ccc(Cl)cc3)CC2)CCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CN(C3CCN(c4ccc(Cl)cc4)CC3)CCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of {4-[1-(4-chlorophenyl)-4-piperidinyl]-2-morpholinyl}methanol obtained from step (vi) (125 mg, 0.384 mmol) in dichloromethane (CH2Cl2) (2 mL) was added triethylamine (0.240 mL, 1.72 mmol) followed by 3-nitrobenzenesulfonyl chloride (127.5 mg, 0.575 mmol) and the reaction mixture kept on stirring at room temperature overnight. The volatiles were removed in vacuo, residue dissolved in chloroform, washed sucessively with saturated aqueous sodium hydrogen carbonate (NaHCO3) and water (H2O). The organic layer was dried over sodium sulphate (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash chromatography to give the subtitled compound (163 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH3:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:36][CH2:37][N:32]([C:26]3[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:25]=3[CH3:24])[CH2:33][CH2:34]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2cccc(C)c2C)CC1
Yield: 78.7 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.