Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]3[N:27]=[C:28]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[O:29][C:25]=3[CH3:24])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:23])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 63. 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, 1H, J=3.52 Hz, J=1.17 Hz), 7.36 (dd, 1H, J=5.08 Hz, J=1.17 Hz), 7.18 (d, 2H, J=8.60 Hz), 7.06 (dd, 1H, J=5.08 Hz, J=3.91 Hz), 6.93-6.85 (m, 4H), 6.82 (d, 2H, J=8.60 Hz), 4.18 (t, 2H, J=6.65 Hz), 3.21 (d, 1H, J=13.69 Hz), 3.13 (d, 1H, J=13.69 Hz), 2.96 (t, 2H, J=6.65 Hz), 2.35 (s, 3H), 1.36 (s, 3H); HRMS (ES+) m/z exact mass calcd for C26H25NO5FS 482.1437, found 482.1451.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=3)[N:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:15]=2[CH2:30][CH3:31])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:30]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]2[C:22]([C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH3:31]
Reactant: CCc1c(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(F)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(C2CCNCC2)c2ccc(F)cc2n1-c1ccccc1
Reaction time: 15 h
Yield: 76.4 %

Procedure:
To a stirred solution of 4-(2-ethyl-6-fluoro-1-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.12 g) in DCM (20 ml) at r.t., is added trifluoroacetic acid (0.5 ml). After 15 h, the mixture is concentrated in vacuo. Flash chromatography (DCM:MeOH, gradient elution) of the resulting liquid gives 70 mg pure product (57%, TFA salt) as a beige solid after trituration with diethylether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[C:32]([N+:40]([O-:42])=[O:41])=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[C:4]([O:30][C:31]1[C:32]([N+:40]([O-:42])=[O:41])=[C:33]3[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]3)[N:3]=[CH:2]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: O=[N+]([O-])c1c(O)ccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2cnc(Oc3ccc4[nH]ccc4c3[N+](=O)[O-])nc2cc1OCCCN1CCCCC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
Nitrogen was bubbled through a mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (114 mg, 0.34 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (141 mg, 1.02 mmol), 5-hydroxy-4-nitroindole (60.5 mg, 0.34 mmol) and DMA (8.5 ml) for 5 minutes at ambient temperature. This mixture was then stirred at 90° C. for 4 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica column chromatography using gradient elution with dichloromethane/methanol (100/0 to 95/5) followed by dichloromethane/methanolic ammonia (7M) (95/5) to give a partially purified oil. This oil was further purified by silica column chromatography, gradient elution with ethyl acetate/methanolic ammonia (95/5 to 80/20) to give 6-methoxy-(4-nitroindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (63 mg, 39%).
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.[Li]CCCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]([C:37](=[O:46])[C:38]2[CH:43]=[CH:42]C(C#N)=[CH:40][CH:39]=2)[CH3:36])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]([CH3:36])[C:37](=[O:46])[C:38]2[CH:39]=[CH:40][C:15]([C:14]3[NH:3][C:4](=[O:13])[C:5]4[C:6]([CH:12]=3)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=4)=[CH:42][CH:43]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1ccc(C#N)cc1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)CC4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
N,N-Diethyl-2,3-dimethyl-benzamide (200 mg, 0.97 mmol) was dissolved in anhydrous THF (4 mL) under a N2 and cooled to −78° C. n-BuLi (2.5M in n-hexanes, 0.82 mL, 2.04 mmol) was added dropwise to yield a deep red coloured solution and the reaction mixture was stirred at −78° C. for 30 minutes. 4-{[(4-Cyano-benzoyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (348 mg, 0.97 mmol) was dissolved in anhydrous THF (4 mL) and added dropwise, and the reaction stirred at −78° C. for 2 h. The reaction mixture was quenched with ice/water, allowed to warm to RT and extracted with CH2Cl2 and EtOAc. The combined organic phase was passed through a phase separation cartridge and concentrated in vacuo. The crude compound was triturated with isohexane/diethyl ether (80:20), the solid filtered and dried in vacuo to give 4-({methyl-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a light beige solid (171 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[Li].Cl.[CH3:16][O:17][C:18](=[O:23])[C@H:19]([CH2:21][OH:22])[NH2:20].CCN(CC)CC>O=S(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:20][C@H:19]([C:18]([O:17][CH3:16])=[O:23])[CH2:21][OH:22])=[O:13])[S:10][C:3]=12
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Agent: Cl
Agent: [Li]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)c1cc2nccc(Cl)c2s1
Yield: 54.2 %

Procedure:
This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid (2.69 g, 12.25 mmole), SOCl2 (10 ml), L-serine methyl ester hydrochloride (2.86 g, 18.4 mmole) and Et3N (5.12 ml, 37.7 mmole) in a manner as previously described for example 9d to give a white solid (2.09 g, 54%). 1H NMR (300 MHz, CDCl3) δ8.61 (1H, d, J=5.1 Hz), 8.02 (1H, s), 7.35 (1H, d, J=5.1 Hz), 4.89 (1H, m), 4.15 (2H, m), 3.84 (3H, m).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:18].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([F:11])([F:12])[F:10])=[CH:4][N+:3]=1[O-:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(F)(F)F)cnc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)c[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.1 %

Procedure:
A mixture of 2,3-dimethyl-5-trifluoromethyl-pyridine (0.700 g, 4.00 mmol), 3-chloroperoxybenzoic acid (77%, 2.8 g, 12 mmol) in CH2Cl2 (20 mL) was stirred at room temperature for 20 h. After that period of time saturated aqueous NaHCO3 (5 mL), and the mixture was extracted with CH2Cl2 (5×20 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed, and the residue was purified on silica gel column (EtOAc), affording 2,3-dimethyl-5-trifluoromethyl-pyridine 1-oxide as a pale yellow solid (0.620 g, 81%).
Reaction SMILES: Cl.Cl.O[C:4]1[N:16]=[CH:15][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:4]1[N:16]=[CH:15][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN1CCc2cnc(O)cc2CC1
Agent: Cl
Product: CCN1CCc2cnc(Cl)cc2CC1

Procedure:
Prepared from 3-hydroxy-7-ethyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine dihydrochloride by reaction with phosphorus oxychloride at 130° C.
Reaction SMILES: [C:1]([CH:11]([CH:27]1[NH:32][CH2:31][CH2:30][NH:29][CH2:28]1)[N:12]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:13]([CH:15]1[CH2:18][CH2:17][CH2:16]1)=[O:14])(OCC1C=CC=CC=1)=O.C(Br)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+]>CO.CC#N.[Pd]>[CH2:1]([CH:11]([CH:27]1[NH:32][CH2:31][CH2:30][NH:29][CH2:28]1)[N:12]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:13]([CH:15]1[CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccccc1NN(C(=O)C1CCC1)C(C(=O)OCc1ccccc1)C1CNCCN1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: Cc1ccccc1NN(C(=O)C1CCC1)C(CCc1ccccc1)C1CNCCN1
Reaction time: 12 h
Yield: 41.5 %

Procedure:
A solution of 213 (0.302 mmol, 127 mg) in CH3OH (1 mL) at 25° C. was treated with 30% Pd—C (25 mg) and then placed under a hydrogen atmosphere. The reaction mixture stirred for 12 h and then was filtered through a pad of celite. The solvents were removed in vacuo and the resulting oil was then treated with phenethyl bromide (1.5 equiv, 0.453 mmol, 62 μL) and K2CO3 (2.0 equiv, 0.604 mmol, 83 mg) in CH3CN (1.0 mL). The reaction mixture stirred for 12 h at 65° C. The reaction mixture was then purified directly by chromatography (PTLC, SiO2, 20 cm×20 cm, 1 mm, EtOAc-10% CH3OH) which provided 214 (51 mg, 118 mg theoretical, 43%) as colorless oil: Rf 0.45 (SiO2, EtOAc-10% CH3OH); LRMS m/z 390 (M+, C26H34N2O, requires 390).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][OH:14].Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1sc(-c2ccccc2)nc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a mixture of (5-methyl-2-phenyl-4-thiazolyl)methanol (5.0 g), 6-chloro-3-cyanopyridine (3.38 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 1.07 g) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (5.55 g, 74%) of 6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 124-125° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(NCc2cccnc2)cc1
Reactant: Oc1ccccc1F
Product: Fc1ccccc1Oc1ccc(NCc2cccnc2)cc1

Procedure:
Using the method of Example 342 using N-(4-bromophenyl)pyridin-3-ylmethylamine and 2-fluorophenol (Aldrich)and purifying via preparative HPLC eluting with 90:10 to 80:20 DCM/ethyl acetate gave N-(4-(2-fluorophenoxy)phenyl)pyrid-3-ylmethylamine. Anal Calcd for C18H15FN2O: C, 73.45; H, 5.14; N, 9.52. Found: C, 73.36; H, 5.22; N, 9.35. MS found 295.1 [M+H]+
Reaction SMILES: [Si]([N:8]1[C:16]2[C:11](=[C:12](B3OC(C)(C)C(C)(C)O3)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C(C)(C)C)(C)C.Cl[C:28]1[N:29]=[C:30]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:31]2[N:37]=[C:36]([CH2:38][N:39]3[CH2:44][CH2:43][CH:42]([C:45]([OH:48])([CH3:47])[CH3:46])[CH2:41][CH2:40]3)[CH:35]=[CH:34][C:32]=2[N:33]=1>>[F:17][C:13]1[C:12]([C:28]2[N:29]=[C:30]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[C:31]3[N:37]=[C:36]([CH2:38][N:39]4[CH2:44][CH2:43][CH:42]([C:45]([OH:48])([CH3:47])[CH3:46])[CH2:41][CH2:40]4)[CH:35]=[CH:34][C:32]=3[N:33]=2)=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[CH:10]2
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure A, 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 105. LCMS (MH+)=505.2. 1H-NMR (DMSO-d6): δ 11.2 (s, 1H), 8.15 (d, 1H), 7.87 (d, 1H), 7.47 (m, 1H), 7.44 (s, 1H), 7.01 (m, 1H), 6.75 (s, 1H), 4.49 (s, 4H), 4.02 (s, 1H), 3.80 (m, 4H), 3.73 (s, 2H), 2.93 (m, 2H), 1.99 (m, 2H), 1.66 (m, 2H), 1.28 (m, 3H), 1.04 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[C:18]([Cl:26])[CH:17]=4)[CH2:14][C:13](=[O:27])[NH:12][CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[C:18]([Cl:26])[CH:17]=4)[CH2:14][C:13](=[O:27])[NH:12][CH:11]3[C:28](=[CH2:31])[CH2:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)OC)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)O)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.9 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-methoxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.6 g, 33 mmol) prepared in example 92c in the mixture of tetrahydrofuran (60 mL) and methanol (30 mL) was added the solution of sodium hydroxide (1N, 30 mL). After the reaction mixture was stirred at room temperature for 2 h, the crude was concentrated. The residue was neutralized to “pH”-4 with the dilute hydrochloride solution, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-hydroxycarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 1.5 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8]1=[O:17])[C:5]#[N:6].[C-:19]#[N:20].[K+].O>CO>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:7]1([C:19]#[N:20])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8]1=[O:17])[C:5]#[N:6]
Reactant: COC(=O)C(C#N)=C1C(=O)Nc2ccc(Cl)cc21
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)C(C#N)C1(C#N)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 86 %

Procedure:
A stirred suspension of crude (5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-cyanoacetic acid methyl ester, intermediate 1 (56.0 g, 0.21 mol) in methanol (750 ml) was treated, in portions, with potassium cyanide (13.8 g, 0.21 mol) followed by water (45 ml). The mixture was stirred at ambient temperature for 7 hours and the resultant black solution was left to stand overnight. The solvent was removed in vacuo, water (500 ml) was added and the mixture acidified by the addition of 2M hydrochloric acid [CAUTION: TRACES OF CYANIDE MAY STILL BE PRESENT!]. The mixture was extracted with dichloromethane (3×300 ml). The combined extracts were washed with water (2×300 ml) and dried (MgSO4). The solvent was removed in vacuo to give the crude (5-chloro-3-cyano-2-oxo-2,3-dihydro-1H-indol-3-yl)-cyanoacetic acid methyl ester as a pale-brown solid (53.3 g, 86%). This was a mixture of diastereomers, which was sufficiently pure by 1H NMR for subsequent reaction.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([NH2:4])=[O:3].CN1CCOCC1.ClC(OCC)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][OH:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[Cl-].[NH4+]>COCCOC>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][N:32]([OH:33])[C:1]([C:2]([NH2:4])=[O:3])=[O:6])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCNO)cc1OC
Reactant: NC(=O)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: COc1ccc(CCN(O)C(=O)C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-hydroxamide. To a suspension of oxamic acid (195 mg, 2.21 mmol) in 1,2-dimethoxyethane (7 mL) under an argon atmosphere was added dropwise N-methylmorpholine (0.27 mL, 2.42 mmol), followed by ethyl chloroformate (0.23 mL, 2.42 mmol). After stirring for 1 h at room temperature, a solution of N-[2-(3,4-dimethoxyphenyl)ethyl]-N-hydroxyamine (417 mg, 2.10 mmol) in 1,2-dimethoxyethane (5 mL) was added, and the resulting mixture was stirred for 4 h. Saturated aqueous ammonium chloride was added, and the mixture was extracted with methylene chloride (2×). The combined organic extracts were washed successively with 10% hydrochloric acid and water and dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 5% methanol/methylene chloride, and recrystallized from methanol/methylene chloride to provide the oxamide (98 mg, 17%): m.p. 143°-144° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([NH2:21])[CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([NH:21][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:13]=1
Reactant: O=C(Cl)CCCCCl
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)CCCCCl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124.6 %

Procedure:
5-Chlorovaleryl chloride (2.64 g, 17 mmol, 1.1 equiv) in CH2Cl2 (5 ml) was added over 2 min to a stirred solution of 3-amino-5-nitro-benzoic acid methyl ester (D1) (3 g, 15.3 mmol, 1 equiv) and NEt3 (2.6 ml, 18 mmol, 1.2 equiv) in CH2Cl2 (30 ml). The resulting mixture was stirred for 1 h at room temperature then washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with CH2Cl2 to give 3-(5-Chloro-pentanoylamino)-5-nitro-benzoic acid methyl ester D3 (6 g, 112%) as a brown oil.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)=[CH:18][CH:19]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: COc1ccccc1CN
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3ccccc3OC)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-methoxybenzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 450.5. HPLC (Condition A), Rt: 4.70 min (HPLC purity: 92.7%).
Reaction SMILES: C(OC(=O)[N:7]([CH:25]([CH3:27])[CH3:26])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:25]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:29][CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:26])[CH3:27]
Reactant: NC1CCOCC1
Reactant: CSc1nccc(-c2cnc3c(N(C(=O)OC(C)(C)C)C(C)C)nccn23)n1
Product: CC(C)Nc1nccn2c(-c3ccnc(NC4CCOCC4)n3)cnc12

Procedure:
Isopropyl-{3-[2-(tetrahydro-pyran-4-ylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine was prepared by a process analogous to that described in Example 12 starting from isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 11 supra), and 4-amino-tetrahydropyran. LC-MS: [M+H]+ 354.3.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][NH:11]2)=[CH:7][C:6]=1[S:14][C:15]#[N:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18].N1C=CC=CC=1>C(Cl)Cl>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[CH:7][C:6]=1[S:14][C:15]#[N:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(cc1SC#N)CCN2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc2c(cc1SC#N)CCN2S(=O)(=O)c1ccc(C#N)cc1
Reaction time: 8 h

Procedure:
6-tert-Butyl-5-thiocyanato-2,3-dihydro-1H-indole (prepared in Example JJ; 4.5 g, 19 mmol) was taken in CH2Cl2 (50 mL) and treated with 4-cyanophenylsulfonyl chloride (3.91 g, 19.4 mmol) and pyridine (5 mL). The reaction mixture was stirred overnight, quenched with saturated NaHCO3 solution, and diluted with EtOAc. The organic layer was separated, dried (MgSO4), and concentrated. The crude product was purified by flash chromatography (20%-75% EtOAc in hexanes as eluents). MS(APCI): 397 (M+).
Reaction SMILES: [Na+].[Br:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1Br)NC(=O)CN2
Temperature: 25 °C
Yield: 38.4 %

Procedure:
A solution of N-(4′-bromo-5′-methyl-2′-nitrophenyl)glycine sodium salt (0.200 g, 0.692 mmol, as prepared above) and tin (II) chloride dihydrate (0.468 g, 2.07 mmol, Aldrich, used as received) in ethanol (2.0 mL) was refluxed for 30 min. It was then cooled to room temperature. The precipitated solid was filtered and dried under vacuum to yield 0.064 g (38%) of the title compound as a yellow powder; 1NMR (DMSO-d6): δ 2.130 (s, 3H), 3.674 (s, 21), 6.120 (s, 1H), 6.583 (s, 1H), 6.868 (s, 1H), 10.284 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3](C)[CH2:4][C:5](=[CH:9][CH:10]=1)[C:6](Cl)=[O:7].CN.[CH2:14]([N:16](CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH3:14])=[O:7])=[CH:4][N:3]=1
Reactant: CN1CC(C(=O)Cl)=CC=C1Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Cl)nc1
Yield: 91 %

Procedure:
To a solution of 6-chloro-N-methylnicotinoyl chloride (7.39 g, 42.0 mmol) in tetrahydrofuran (50 mL), methylamine (42 mL, 84.0 mmol) and triethylamine (6.4 mL, 46.2 mmol) were added under ice-cold conditions, and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated in vacuo, then filtered, and washed with tetrahydrofuran. The obtained residue was recrystallized (ethyl acetate/hexane) and 6-chloro-N-methylnicotinamide (6.52 g, yield 91%) was obtained as a white crystal.