Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23]Cl>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][O:22][CH3:23])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: COCCl
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
1.9 G. of 1-acetamido-4-hydroxy-2-nitrobenzene, and 10 g. anhydrous potassium carbonate were stirred at room temperature in 75 ml. acetone and treated with 5 ml. chloromethyl methyl ether over 10 minutes. After a further 10 minutes, the mixture was filtered, evaporated to dryness, and the product filtered through silica gel eluting with 1% methanol to afford 1-acetamido-4-methoxymethoxy-2-nitrobenzene.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:3][CH2:2]1.C[O-].[Na+].[CH2:23]([O:25][C:26](=[O:34])[C:27]([S:30]C(=O)C)([CH3:29])[CH3:28])[CH3:24]>C(O)C>[CH2:23]([O:25][C:26](=[O:34])[C:27]([CH3:29])([S:30][CH2:8][CH2:7][CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH3:28])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCOCC2)cc1
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCCC1CCOCC1
Temperature: 130 °C
Yield: 108.9 %

Procedure:
To a solution of 1.9 g (6.7 mmol) of toluene-4-sulfonic acid 2-(tetrahydro-pyran-4-yl)-ethyl ester in ethanol (20 mL) are added 1.4 g (26.8 mmol) of sodium methoxide, followed by 1.27 g (6.7 mmol) of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester. The reaction mixture is heated in a microwave at 130° C. for 0.5 h. The solvent is removed under reduced pressure. The residue is partitioned between saturated aqueous NaHCO3 solution (25 mL) and DCM (25 mL). The layers are separated and the aqueous phase extracted with DCM (2×25 mL). The combined organic extracts are dried over Na2SO4, filtered and the solvent is removed under reduced pressure to afford 1.9 g of 2-methyl-2-[2-(tetrahydro-pyran-4-yl)-ethylsulfanyl]-propionic acid ethyl ester. Yield: 100%; ES-MS: m/z 261 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.15-1.38 (5H, m), 1.42-1.70 (12H, m), 2.59-2.71 (1H, m), 3.37 (2H, td, J=11.73, 1.98 Hz), 3.95 (2H, ddd, J=11.04, 3.88, 0.91 Hz), 4.18 (2H, q, J=7.16 Hz)
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]([NH2:13])=[S:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=1)=O>C(O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:13]=[C:11]([NH:10][S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:14])=[CH:6][CH:5]=3)(=[O:9])=[O:8])[S:12][CH:16]=2)=[CH:20][C:21]=1[CH3:26]
Reactant: Cc1cc(C(=O)CBr)ccc1O
Reactant: Cc1ccc(S(=O)(=O)NC(N)=S)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(O)c(C)c3)cs2)cc1
Reaction time: 72 h
Yield: 24.8 %

Procedure:
A solution of 26 g of 4-toluenesulfonyl-thiourea in 225 ml of ethanol was treated with 25.9 g of 2-bromo-1-(4-hydroxy-3-methyl-phenyl)-ethanone, left to stand at room temperature for 3 days and then boiled for a brief period. The reaction mixture was evaporated to dryness in a vacuum and subsequently partitioned between water and ethyl acetate. The aqueous phase was extracted once with ethyl acetate, the organic phases were combined, dried with sodium sulphate and concentrated. The residue was chromatographed on 500 g of Kieselgel 60 with ethyl acetate/hexane (1:1) as the eluent. The product-containing fractions were concentrated and, after recrystallization from 50% ethanol, yielded 10.1 g of N-[4-(4-hydroxy-3-methyl-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as colourless crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][O:4][C:3]1=[O:8].[Li+].[CH3:10]C([N-]C(C)C)C.CC(C)=O.C(=O)=O.CI>C1COCC1>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][O:4][C:3]1=[O:8]
Reactant: CC1CCCOC1=O
Reactant: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1(C)CCCOC1=O
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
The 3-methyltetrahydro-2H-pyran-2-one from Example 4(a) (5.6 g, 49.0 mmol) was slowly added to a cold (-78° C.) THF solution (50 ml) of LDA (54 mmol) so that the internal temperature did not exceed -65° C. After stirring for an additional 30 minutes, the acetone/CO2 bath was replaced with a CH3CN/CO2 bath and CH3I (10.4 g, 73.5 mmol) was added at a rate sufficient to maintain the internal temperature at -45° C. After stirring at 31 45° C. for an additinal hour the reaction was allowed to warm to -30° C. and quenched by the dropwise addition of 10% HCl (21 ml). The resulting mixture was poured into ether (300 ml) and the ether layer was washed with saturated brine (50 ml), saturated NaHCO3 solution (20 ml), saturated brine (2×25 ml), dried (MgSO4) and evaporated to provide a pale yellow oil. This oil was distilled to give the title compound as a colorless liquid. b.p.0.2 54° C. NMR (CDCl3) δ4.34 (2H, m), 1.89 (2H, m), 1.75 (2H, m), 1.30 (6H, s).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][S:5]([CH3:8])(=[O:7])=[O:6].[CH3:11][NH2:12].C1COCC1>CO>[CH3:8][S:5]([NH:4][C:3]([S:2][CH3:1])=[N:12][CH3:11])(=[O:7])=[O:6]
Reactant: CSC(=NS(C)(=O)=O)SC
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CN=C(NS(C)(=O)=O)SC
Temperature: 50 °C
Yield: 70 %

Procedure:
To a solution of N-methanesulfonylcarbonimidodithioic acid dimethyl ester (1.5 g, 8.02 mmol) in MeOH (15 ml) was added a solution of methylamine in THF (2.0 M, 4.8 ml, 9.6 mmol) and the reaction heated to 50° C. for 2.5 h before another portion of methylamine was added (4.8 ml, 9.6 mmol) and the reaction heated to 50° C. for an additional 1 h. The mixture was concentrated and purified by column chromatography on silica gel (EtOAc/Hexanes, 1:1) to afford S-methyl N-methanesulfonyl-N′-methylcarbamimidothioate (0.95 g, 70%) as a clear oil. 1H NMR (CDCl3) δ 2.40 (s, 3H), 2.96 (d, 3H, J=6 Hz), 3.01 (s, 3H), 7.95 (br s, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14](N)=[O:15]>>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[NH:13][C:14]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(N)=O
Reactant: O=C(O)CNCc1ccccc1
Product: O=C1CN(Cc2ccccc2)C(=O)N1
Yield: 42.7 %

Procedure:
The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.4 %

Procedure:
0.574 g (0.003 mol) of 1-benzyl-4-hydroxypiperidine dissolved in 5 ml of dimethylformamide was added dropwise at 0° to a suspension of 0.14 g (0.0035 mol) of sodium hydride in 5 ml of dimethylformamide. The mixture was left to warm to room temperature and was stirred for 1.5 hrs. Then, 0.39 ml (0.0033 mol) of benzyl bromide was added dropwise. The mixture was stirred at 40° for 18 hrs. The solvent was removed, the residue was taken up in water, adjusted to pH 11 with 2N aqueous NaOH and extracted with ether. The organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.333 g (40%) of 1-benzyl-4-benzyloxypiperidine was obtained as a yellow oil. MS: me/e=282 (C9H24NO+).
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[N:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1[C:41]([OH:43])=O.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)[C:41]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][N:35]=2)=[O:43])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1cnccn1)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
To a stirred solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (183 mg, 0.40 mmol) in dry CH2Cl2 (5 mL) was added 2-pyrazinecarboxylic acid (68 mg, 0.55 mmol), N,N -diisopropylethylamine (0.21 mL, 1.21 mmol), 1-hydroxybenzotriazole hydrate (81 mg, 0.60 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (115 mg, 0.60 mmol) and the mixture was stirred at room temperature for 20 hours. Following standard work-up procedures, the crude material was purified by column chromatography on silica gel (CH2Cl2/MeOH, 98:2 followed by 95:5) to give the desired amide (131 mg, 58%) as a colorless oil.
Reaction SMILES: N12CCN(CC1)CC2.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][OH:16])=[CH:12][CH:11]=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].O>ClCCl>[CH3:26][C:25]1[CH:27]=[CH:28][C:22]([S:19]([O:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:10]([Br:9])=[CH:11][CH:12]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc(Br)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,4-Diazabicyclo[2.2.2]octane (5.61 g, 0.050 mol) and 4-bromophenethyl alcohol (5.0 g, 0.025 mol) were combined in dichloromethane (100 mL). The resulting mixture was cooled to 0° C. in an ice bath and a solution of tosyl chloride (5.67 g, 0.029 mol) in dichloromethane (50 mL) was added via an addition funnel over 15 min. After stirring for about 1 h at 0° C., water (30 mL) was added and stirring was continued for another 30 min. The aqeuous layer was then separated and discarded. The organic layer was dried (NaSO2), filtered, and concentrated under reduced pressure to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][N:58]([CH3:60])[CH3:59])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:60][N:58]([CH3:59])[CH2:57][CH2:56][O:55][C:53](=[O:54])[CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3=[C:6]([CH:37]=2)[N:7]=[C:8]([NH:29][C:30]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:36])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:22])[CH3:23])[CH2:14][CH2:15][CH3:16])=[CH:11]3)=[CH:47][CH:48]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CN(C)CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCN(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, 2-(dimethylamino)ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded 2-(dimethylamino)ethyl-2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[F:16][C:17]1[C:22]([F:23])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[Si:33]([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+].CC#N>CCOC(C)=O.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.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:21]2[CH:20]=[CH:19][C:18]([Si:33]([CH3:34])([CH3:36])[CH3:35])=[C:17]([F:16])[C:22]=2[F:23])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Reactant: CC1(C)OB(c2ccc([Si](C)(C)C)c(F)c2F)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2F)c(F)c(N)c1OC
Temperature: 115 °C
Yield: 75.5 %

Procedure:
To a 20 mL microwave vial were added methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.80 g, 3.41 mmol), (2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)trimethylsilane (1.28 g, 4.09 mmol), sodium carbonate (Na2CO3; 0.36 g, 3.41 mmol), and PdCl2(PPh3)2 (0.24 g, 0.34 mmol). Subsequently, CH3CN (5.7 mL) and H2O (5.7 mL) were added, and the reaction vial was sealed and heated in a Biotage microwave to 115° C. for 20 min. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (2×2 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using a Teledyne ISCO purification system with a gradient eluent system of EtOAc and hexanes to yield methyl 4-amino-6-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-fluoro-3-methoxypicolinate (0.99 g, 75%) as a white solid: mp 123-125° C.; 1H NMR (400 MHz, CDCl3) δ 7.32 (ddd, J=7.6, 5.5, 1.1 Hz, 1H), 7.20 (ddd, J=7.7, 4.5, 1.4 Hz, 1H), 4.60 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 0.41-0.28 (m, 9H); 19F NMR (376 MHz, CDCl3) δ −127.39, −127.45, −127.46, −137.48, −137.56, −140.78, −140.85, −140.86, −140.92; ESIMS m/z 383.20 ([M−H]−).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11]>CO.O1CCCC1.[Pd]>[NH:22]1[CH2:21][CH2:20][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10]([N:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:1]3)=[O:11])=[CH:14][CH:15]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C2CCNCC2)cc1)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 4-(4-(isoindoline-2-carboxamido)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 2.38 mmol) in 20 ml of 1:1 methanol/tetrahydrofuran was added to 5% Pd on carbon (wet) (0.200 g) in a 50 ml pressure bottle and stirred for 16 hours at 30 atm and room temperature. The mixture was filtered through a nylon membrane and concentrated. The residue was suspended in dichloromethane, stirred 1 hour and filtered with dichloromethane washes to provide the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40][CH3:41])=[O:39])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:42]#[N:43].[Na+]>CN(C=O)C>[C:42]([CH2:26][CH:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:38]([O:40][CH3:41])=[O:39])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)#[N:43]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(COS(=O)(=O)c1ccc(C)cc1)COc1ccccc1-3
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CC#N)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of methyl 14-cyclohexyl-7(R,S)-({[(4-methylphenyl)sulfonyl]oxy}methyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.35 M) in DMF was treated with NaCN (1.2 eq.) and the resulting mixture was stirred overnight at RT. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted into EtOAc. The combined organic layers were washed with brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 90:10) affording the product as a yellow foam (90%). (ES+) m/z 429 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][S:15]([C:18]3[S:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=3)(=[O:17])=[O:16])[C:10]2=[O:25])[CH:4]=1)#[N:2].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:15]([C:18]3[S:19][C:20]([Cl:24])=[C:21]([Cl:23])[CH:22]=3)(=[O:17])=[O:16])[C:10]2=[O:25])[CH:4]=1)#[N:2]
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3cc(Cl)c(Cl)s3)C2=O)cs1
Product: N#Cc1cc(CN2CC[C@H](N(Cc3ccccc3)S(=O)(=O)c3cc(Cl)c(Cl)s3)C2=O)cs1

Procedure:
The title compound is prepared as in EXAMPLE 126, Part A using 4,5-dichlorothiophene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide in place of 7-methoxynaphthalene-2-sulfonic acid [1-(5-cyanothiophen-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide and benzyl bromide in place of MeI to give the title compound as a white foam.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:9]=1.C[OH:25]>>[C:6]([OH:25])(=[O:5])[CH3:2].[OH:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[N:9]=1
Reactant: CO
Agent: O[C@@H]1COC[C@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Product: CC(=O)O

Procedure:
4-[(3R,4R)-(4-Hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline (cf. Example 19) (758 mg) is dissolved in methanol, and the mixture is evaporated to dryness under reduced pressure. The residue is dissolved in acetone (15 ml), and the mixture is filtered, and to the filtrate is added acetic acid (202 mg), and the mixture is allowed to stand at room temperature. The precipitated crystals are separated by filtration to give 4-[(3R,4R)-(4-hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl) quinazoline monoacetate (796 mg) as crystals.
Reaction SMILES: [ClH:1].I[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH:12]([CH3:25])[N:13]([CH3:24])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:26]1([C:32]#[CH:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[ClH:1].[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:33]#[C:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([CH2:11][CH:12]([CH3:25])[N:13]([CH3:24])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1
Reactant: C#Cc1ccccc1
Reactant: COc1ccc(I)c(CC(C)N(C)CCCCc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2)c(CC(C)N(C)CCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 33.1 %

Procedure:
The free base of 2-iodo-5-methoxy-N,alphadimethyl-N-[(phenyl)butyl]benzeneethanamine hydrochloride (1.66 g, 3.1 mmole) was dissolved in 10 ml of triethylamine and 0.68 ml (6.2 mmole) of phenylacetylene, 11 mg (0.015 mmole) of bis(triphenylphosphine) palladium (II) chloride and 6 mg (0.03 mmole) copper (I) iodide were added. The mixture was stirred under argon at room temperature for 20 hours. An additional 6 mg copper (I) iodide and 11 mg bis(triphenylphosphine) palladium (II) chloride were added. The mixture was stirred for 20 hours. The solvent was evaporated in vacuo. The residue was taken up in CH2Cl2. The CH2Cl2 was washed with dilute HCl and dilute NaOH solution, dried (K2CO3) and the solvent evaported in vacuo. A hydrochloride salt was prepared from ethereal hydrogen chloride and recrystallized twice from 2-propanolether to give 0.46 g of 5-methoxy-N,alphadimethyl-N-[(phenyl)butyl]-2-[(phenyl)ethynyl]benzeneethanamine hydrochloride, mp 133°-135° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[CH2:8][N:9]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:11][C:12]\1=[O:13].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:38]([O:37][C:35]([CH2:34][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[CH2:8][N:9]([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:11][C:12]\1=[O:13])=[O:36])[CH3:39]
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccc[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cccc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of (E)-3-[(pyrrol-2-yl)methylidene]-1-(triphenylmethyl)piperidin-4-one (7.16 g) and ethyl bromoacetate (8.60 g) in N,N-dimethylformamide (80 ml) were added potassium carbonate (7.10 g) and potassium iodide (8.50 g) with stirring at room temperature, and the resulting mixture was stirred at 80° C. for 4 hours. After filtration, the reaction mixture was diluted with dichloromethane, subsequently washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane, and dichloromethane (1:2:1) as the eluent to afford the title compound (7.13 g, yield: 83%) as a yellow amorphous solid.