Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC([N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=O)(C)(C)C>C1COCC1>[C:1]([C:5]1[O:6][C:7]2[C:13]([S:14]([N:33]3[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)N3CCCNCC3)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (5.54, 18 mmol) and triethylamine (2.51 mL, 18 mmol) in THF (100 mL) at 0° C. was added homopiperazine-carboxylic acid tert-butyl ester (3.0 g, 15 mmol). The reaction was warmed to room temperature and allowed to stir overnight. The solution was concentrated and then diluted with water and extacted with ethyl acetate (3 times). The combined organic layers were dried with MgSO4, filtered, and concentrated. Flash chromatography (80% ethyl acetate/20% Ethanol) on silica gel gave the title compound (4.0 g, 61%). LC-MS m/z 473.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH3:12])[C:7]=1[C:13]([OH:15])=O)=[O:5])[CH3:2].S(Cl)([Cl:18])=O>>[Cl:18][C:13]([C:7]1[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:15]
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1cnn(CC)c1C(=O)Cl
Yield: 100.1 %

Procedure:
2-Ethyl-2H-pyrazole-3,4-dicarboxylic acid 4-ethyl ester (example 62, step 3, 1.47 g, 6.93 mmol) and thionyl chloride (19.0 g, 11.6 ml, 159 mmol) were combined to give a light yellow solution. The reaction mixture was stirred at reflux for 5 h. Excess thionyl chloride was removed under reduced pressure, and residual thionyl chloride was removed under vacuum. The title compound (1.6 g, estimated purity 37%, 37% yield) was used without further purification in the next step. MS (m/e)=390.3 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=2)=[N:7][CH:8]=1)#[N:2].Cl>C1COCC1.CCO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: N#Cc1ccc(Oc2ccc(C(N)=O)cc2)nc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1ccc(Oc2ccc(C(N)=O)cc2)nc1
Yield: 36 %

Procedure:
Combine 4-(5-cyano-pyridin-2-yloxy)-benzamide (202 mg, 0.844 mmol), 5% Pd/C (80 mg) and conc. HCl (0.423 mL) in THF (4 mL) and EtOH (4 mL). Run the reaction under hydrogen atmosphere (1 atm) at rt overnight. Add NaOH (5 N, 2 mL) and filter the reaction mixture through Celite®. Concentrate the filtrate. Wash the residue with H2O (5 mL) and extract with CH2Cl2 (3×5 mL). Combine the organic layers and purify through an SCX column eluting with 2M ammonia in methanol. Concentrate the fractions to give the title compound (74 mg, 36%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(F)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J15) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) according to the general procedure M. Obtained as a light yellow solid (126 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:23][CH3:24])[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[CH:26]([CH3:41])[CH2:27][CH2:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([O:12][C:5]1[C:4]([O:23][CH3:24])=[CH:3][C:2]([NH:1][CH:26]([CH3:41])[CH2:27][CH2:28][CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCOc1c(OC)cc(N)c2ncccc12
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCOc1c(OC)cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2ncccc12
Yield: 49.8 %

Procedure:
A stirred mixture of 3.65 g of 8-amino-5-decoxy-6-methoxyquinoline and 3.5 g of 4-bromo-1-phthalimidopentane was maintained at 140°-145° while 1 g of triethylamine was added in portions during 1.5 hr. Five more increments of 4-bromo-1-phthalimidopentane (3 g) and triethylamine (1 g) were added at 1.5 hr intervals in the usual manner. The mixture was allowed to cool and extracted with diethyl ether (ca. 300 ml). Treatment of the extract with diethyl ether-hydrochloric acid gave a red oil. The oil was dissolved in chloroform (200 ml) washed with dilute sodium hydroxide (2×30 ml) and water, dried (potassium carbonate) passed through a silica column and concentrated to give 3 g of phthalimide derivative as a red oil. This material was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[I-:13].[Na+]>CC(C)=O>[I:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: BrCCCCCC1CCCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCC1CCCCC1
Temperature: 60 °C

Procedure:
A mixture of (5-bromopentyl)cyclohexane (2 gm, 8.6 mmol) in acetone (20 ml), and sodium iodide (2.57 g, 17.1533 mmol) was heated for 60° C. for 12 hrs. The mixture was allowed to cool to room temperature and the solvent was evaporated. The residue was diluted with EtOAc (30 ml), H2O (20 ml) was added, separated and the organic phase was washed with brine (30 ml). The organic layer was dried over anhydrous Na2SO4; solvent was evaporated under reduced pressure and the crude product was purified by column chromatography using hexane as eluent. The pure product was an oily liquid (1.36 gm).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][NH:28]2)=[CH:24][C:23]=1[O:31][CH3:32].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[CH:27][NH:28]5)=[CH:24][C:23]=4[O:31][CH3:32])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc2cc[nH]c2cc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Solvent: O
Product: COc1cc2cc[nH]c2cc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 90.8 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.5 mmol), 6-(3-chloropropoxy)-5-methoxyindole (2.5 g, 10.4 mmol), K2 CO3 (1.6 g, 11.5 mmol), KI (200 mg) and acetonitrile (100 ml) was stirred at reflux under nitrogen for 40 hours. The cooled reaction was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, washed with brine, dried with MgSO4 and concentrated to yield 4.0 g of a solid. The compound was recrystallized from ethanol to afford 3.3 g. Another recrystallization from ethanol (utilizing a charcoal treatment) provided 2.9 g (66%) of 6-fluoro-3-[1-[3-[(5-methoxy-1 H-indol-6-yl)oxy]-propyl]piperdinyl]-1,2-benzisoxazole as a beige solid, m.p.=156°-158° C.
Reaction SMILES: C[O:2][C:3]1([CH3:10])O[CH:8]2[CH:5]([CH2:6][CH2:7]2)[O:4]1.C[Si](C)(C)[I:13]>C(Cl)Cl>[I:13][C@@H:8]1[CH2:7][CH2:6][C@H:5]1[O:4][C:3](=[O:2])[CH3:10]
Reactant: C[Si](C)(C)I
Reactant: COC1(C)OC2CCC2O1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CC[C@H]1I
Yield: 76.5 %

Procedure:
73.4 g (0.51 mol) of 3-methoxy-3-methyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) and 102.0 g (0.51 mol) of trimethyliodosilane in 300 ml of methylene chloride are heated to the reflux for 15 hours. Working up by distillation gives 93.6 g (82%) of trans-1-iodo-2-acetoxy-cyclobutane. Boiling point12 94°-95°, nD20 1.5203.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#[CH:3].[CH2:6]=[C:7]=[CH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>CCOCC>[OH:14][C:9]([CH:1]=[C:2]=[CH2:3])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][C:7]#[CH:6]
Reactant: C#CC[Mg]Br
Reactant: C=C=CC(=O)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCC(O)(C=C=C)CCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 125 mmol. of propargylmagnesium bromide in 85 ml. of ether at -20° C. is added a solution of 11.7 g. (95 mmol.) of 1,2-octadien-4-one in 30 ml. of ether during 30 minutes. After the addition, the solution is stirred at 25° C. overnight, cooled to 0° C., and treated dropwise with 18 ml. of saturated ammonium chloride solution. The mixture is filtered, and the filtrate is washed with brine, dried over magnesium sulfate, and concentrated. The product is distilled from anhydrous potassium carbonate to provide the title compound as a colorless liquid, b.p. 84°-87° C. (7 mm.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C[O:27][B:28](OC)[O:29]C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:28]([OH:29])[OH:27])=[C:11]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: FC(F)(F)Oc1cc(OCc2ccccc2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCc2ccccc2)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 135.8 %

Procedure:
To a mixture of 4-(benzyloxy)-1-bromo-2-(trifluoromethoxy)benzene (1.8 g, 5.19 mmol) in THF (20 mL) was added butyllithium (2.5 M in THF, 2.28 mL, 5.70 mmol) at −78° C. dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 1 h, then trimethylborate (1.73 mL, 15.6 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated from diethyl ether three times and the residue was dried on high vacuum to provide the title compound as a gummy solid (2.2 g, 61% pure, 83% yield). The crude material was carried on without further purification. MS (M−1)=311.3
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([CH3:10])[CH2:7][CH2:8][OH:9])[CH:2]=[CH2:3].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1COCC1.[OH-].[Na+]>>[CH2:11]([O:9][CH2:8][CH2:7][C:6](=[N:5][O:4][CH2:1][CH:2]=[CH2:3])[CH3:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCON=C(C)CCO
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCON=C(C)CCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A reactor was charged with 0.1 mole of 3-allyloxyiminobutanol, 0.12 mole of benzyl chloride and 2 moles of THF. The mixture was cooled to 0° C., and 0.11 mole of sodium hydroxide was added little by little. The temperature of the mixture was returned to room temperature, and it was stirred for 2 hours. After the reaction, the product was isolated in a customary manner to give 3-allyloxyiminobutyl benzyl ether in a yield of 95 mole %.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C-]#N.[Li+].[CH3:18][N:19](C=O)C>>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][C:18]#[N:19])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CCCCBr)CCCC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Li+]
Product: COC(=O)C1(CCCCC#N)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-bromobutyl)cyclopentane carboxlic acid methyl ester was treated with a solution of 0.5 molar lithium cyanide in DMF (5 mmol, 10 mL) and stirred overnight at room temperature followed by heating at 75° C. for two hrs. The reaction mixture was evaporated to dryness, the residue was dissolved in ethyl acetate (30 mL) and washed with sat'd sodium bicarbonate (2×10 mL), and brine (5 mL) and dried over magnesium sulfate to give a yellow oil (860 mg). Silica gel chromtography eluting with 1:3 ethyl acetate:hexane yielded a pale oil (83%, 693 mg). LR MS (C12H19NO2): Obs mass, 227 (M+NH4), 248 (M+K).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:8])=[CH:13][CH:12]=1)=[O:10]
Reactant: Clc1ccccc1Br
Reactant: O=Cc1ccc(B(O)O)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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccccc2Cl)cc1

Procedure:
To a solution of 2-bromochlorobenzene (0.24 mL, 2 mmol) and 4-formylbenzeneboronic acid (0.35 g, 2.2 mmol) in toluene (20 mL) were added 2M aq. sodium carbonate (2.6 mL) followed by (Ph3P)4Pd (0.34 g, 0.3 mmol). The resulting reaction mixture was refluxed for 3 h, cooled and diluted ethyl acetate. The organic phase was washed with water, saturated aq. sodium bicarbonate, brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the residue obtained was purified by chromatography (hexane:ethyl acetate; 4:1) to yield the title product.
Reaction SMILES: [F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1.O.NN>CO.[Ni]>[F:1][CH:2]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)C(F)C1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(N)cc23)C(F)C1
Yield: 44.9 %

Procedure:
A solution of compound 132 (0.175 g, 0.635 mmol) in dry methanol (5 mL) was treated with hydrazine hydrate (0.198 mL, 6.357 mmol) followed by Ra—Ni (˜0.05 g) at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 2 min. The reaction was brought to room temperature, filtered through celite bed, washed with methanol (3×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 133 (0.07 g, 45%) as a solid. mp 176-178° C.; 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 2.40-2.56 (m, 1H), 2.73-2.83 (m, 1H), 2.99-3.08 (m, 1H), 3.30-3.42 (m, 1H), 4.51 (s, 2H), 5.37 (d, 1H, J=48.9 Hz), 6.22-6.26 (m, 1H), 6.51 (dd, 1H, J=1.8, 8.5 Hz), 6.97 (d, 1H, J=1.8 Hz), 7.08 (d, 1H, J=8.4 Hz), 7.27 (t, 1H, J=1.8 Hz), 10.72 (s, 1H); ESI-MS m/z (%): 246 (MH+, 12), 203 (100).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([NH:19][C:20]1[CH:28]=[N:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].[NH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[OH:40]>N1C=CC=CC=1>[C:12]([O:16][C:17]([NH:19][C:20]1[CH:28]=[N:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:29][C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][C:31]=1[OH:40])=[O:24])=[O:18])([CH3:13])([CH3:14])[CH3:15]
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cnccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
To a mixture of 1.15 g of WSC and 8 ml of pyridine, 1.43 g of 3-tert-butoxycarbonylamino isonicotinic acid was added and stirred at room temperature for 15 minutes. To the reaction mixture, 1.06 g of 2-amino-4-(trifluoromethyl)phenol was added and stirred while heating at 60° C. for two hours. Thereafter, the mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 1.79 g of 3-tert-butoxycarbonylamino-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:15]([CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:14][CH2:13]2)[CH:16]([CH3:18])[CH3:17])[CH:26]=1
Reactant: CC(C)NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Reactant: COC(=O)Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CN(C(C)C)C2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A mixture of [1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]isopropylamine (159 mg), (3-bromomethylphenyl)acetic acid methyl ester (138 mg), potassium carbonate (107 mg) and dimethylformamide (2 mL) was stirred at 80° C. for 8 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (90 mg). Yield: 37%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=1>>[Cl:31][C:30]1[C:25]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[N:26][C:27]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:28][CH:29]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2Cl)n1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4Cl)n3)cc2CC1

Procedure:
5-Chloro-N(4)-(2-chloro-phenyl)-N(2)-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-pyrimidine-2,4-diamine was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2-chloro-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine in an analogous manner to Example 308c. Product isolated as a pale yellow foam (109 mg, 52%). m.p.=85-92° C.; LCMS (m/e) 458 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.47 (d, 1H, J=8.3 Hz), 8.12 (s, 1H), 7.73 (s, 1H), 7.45 (d, 1H, J=8.0 Hz), 7.33 (s, 1H), 7.30-7.20 (m, 2H), 7.11-7.02 (m, 2H), 6.92 (s, 1H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.97-2.87 (m, 4H), 2.80-2.70 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N+:11]([O-])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:21]#[N:22])(C)C.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]([C:21]#[N:22])=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cc(Br)cc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncc(OCc2ccccc2)cc1Br
Temperature: 100 °C

Procedure:
To a solution of 53-(benzyloxy)-5-bromopyridine 1-oxide (from step 2) (1.0 eq.) in acetonitrile (0.2 M) was added trimethylsilyl cyanide (TMSCN) (4.0 eq.) and triethylamine (3.0 eq.). The reaction was heated at 100° C. overnight. After cooling to room temperature, the solvent was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in hexane to give a mixture of two benzoxy regioisomers, one of which was the desired product. The mixture was carried onto the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].C1(C)C=CC=CC=1>CN(C)C=O>[CH3:29][Si:27]([CH3:30])([C:23]([CH3:26])([CH3:25])[CH3:24])[O:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2COc2ccc(O)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 10 g of 2-hydroxy-6,11-dihydrodibenz[b,e]oxepin-11-one in 50 ml of dimethylformamide are added 6.5 g of imidazole and 7 g of t-butyldimethylchlorosilane and the mixture is stirred for 1 hour. After adding 300 ml of toluene, successively washing with water and a saturated saline solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure to give 13 g of 2-(dimethyl-t-butylsilyloxy)-6,11-dihydrodibenz[b,e]oxepin-11-one (oil). Mass spectrum m/z: 340(M+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.[Cl:18][C:19]1[CH:39]=[CH:38][C:22]([CH2:23][NH:24][C:25]([CH:27]([C:33](OCC)=[O:34])[C:28](OCC)=[O:29])=[O:26])=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[Cl:18][C:19]1[CH:39]=[CH:38][C:22]([CH2:23][NH:24][C:25]([C:27]2[C:28](=[O:29])[N:17]=[C:14]3[CH:13]=[CH:12][C:11]([C:10]#[C:9][CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[CH:16][N:15]3[C:33]=2[OH:34])=[O:26])=[CH:21][CH:20]=1
Reactant: Nc1ccc(C#CCOC2CCCCO2)cn1
Reactant: CCOC(=O)C(C(=O)NCc1ccc(Cl)cc1)C(=O)OCC
Solvent: Cc1ccccc1C
Product: O=C(NCc1ccc(Cl)cc1)c1c(O)n2cc(C#CCOC3CCCCO3)ccc2nc1=O

Procedure:
5-(3-(Tetrahydro-2H-pyran-2-yloxy)-1-propynyl)-2-pyridinylamine (Preparation 6, 30 mg) and diethyl 2-(((4-chlorobenzyl)amino)carbonyl)malonate (Preparation 5, 50 mg) are dissolved in xylene and heated to reflux for 3 h. The solvent is evaporated and the residue is crystallized from ether/hexanes and dried to afford 20 mg of the a brown solid. Physical characteristics: MS (ESI+) m/z 470 (M+H)+. 1H NMR (CDCl3) δ9.80, 9.12, 7.80, 7.52, 7.32, 7.27, 4.86, 4.65, 4.51, 3.90, 3.5-3.6, 1.55-1.9.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][N:3]1[CH2:13][C:14]([O:16]C)=O.[CH3:18][C@H:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([CH3:25])[N:20]1[CH2:26][CH2:27][NH2:28]>>[CH3:18][C@H:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([CH3:25])[N:20]1[CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][N:3]1[CH2:4][CH:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][C:2]1=[O:1]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: COC(=O)CN1CC(c2ccccc2)CC1=O
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CC(c2ccccc2)CC1=O

Procedure:
From 7.0 g. of methyl 2-oxo-4-phenyl-1-pyrrolidineacetate and 5.0 g. of cis-2-(2,6-dimethyl-1-piperidinyl)-ethylamine, following the procedure of Example 9, there is obtained cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-oxo-4-phenyl-1-pyrrolidineacetamide; m.p. 115°-116° C. after recrystallization from cyclohexane.