Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.N1C=CC=CC=1>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[CH:6]=1
Reactant: Brc1c[nH]cn1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Fc1ccc(-n2cnc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 44 h
Yield: 36.8 %

Procedure:
A mixture of 4-bromo-1H-imidazole (223 mg, 1.52 mmol), 4-fluorophenylboronic acid (425 mg, 3.03 mmol), copper(II) acetate (413 mg, 2.28 mmol), pyridine (0.25 mL) and powdered 4 Å molecular sieves (1 g) in 1,2-dichloroethane (7 mL) was stirred at room temperature under a slow stream of air for 44 hours. The reaction mixture was filtered through Celite®, washing with ethyl acetate. The filtrate was concentrated and the residue purified by flash column chromatography on silica eluting with 10 to 20% ethyl acetate/isohexane to give the product as a white solid (135 mg, 37%).
Reaction SMILES: [CH2:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[NH:8][C:7]2[C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2]>CO>[CH2:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[NH:8][C:7]2=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=[C:6]2[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Solvent: CO
Product: CCC1(c2ccccn2)COc2cccc(N)c2N1
Reaction time: 2 h
Yield: 6.5 %

Procedure:
3-Ethyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine (10 mg, 0.3 mmol) was dissolved in methanol (10 mL) in a Parr bottle, degassed with nitrogen, and palladium (10% on carbon) (10 mg) was added. The reaction vessel was pressurized to 50 PSI with hydrogen and shaken for 2 h. The reaction mixture was filtered and concentrated to give crude 3-ethyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (0.005 g, 40%). LCMS calculated for C15H18N3O (M+H)+: m/z=256.1. found: 256.0.
Reaction SMILES: C(OC([NH:8][C:9]([C:11]1[CH:38]=[CH:37][C:14]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)=[NH:10])=O)(C)(C)C.Cl.CCOCC>C(OCC)(=O)C>[ClH:36].[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=4)[CH:27]=3)(=[O:24])=[O:25])[CH2:21][CH2:22]2)=[O:16])=[CH:37][CH:38]=1)(=[NH:8])[NH2:10]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N=C(N)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Reaction time: 5 h
Yield: 153.5 %

Procedure:
To 1-(4-tert-butoxycarbonylamidino benzoyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine (150 mg) was added 4 N hydrochloric acid in ethyl acetate solution (15 ml) and the solution was allowed to stand at room temperature for 5 hours, to which was added ether. The precipitate was filtered, washed with ether and dried to give a colorless solid of the title compound (102 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH2:30])[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.C(OC([NH:38][C:39](N1C=CC=N1)=[N:40]C(OC(C)(C)C)=O)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[NH4+].[Cl-]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:30][C:39]([NH2:40])=[NH:38])[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCc1ccccc1CN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: N=C(N)NCc1ccccc1CN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of (1H-Benzimidazol-2-ylmethyl)-(2-Aminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (see AMD9720) (50 mg, 0.125 mmol) in THF (5 mL) was added added N,N′-di-t-butoxycarbonyl-pyrazole-1-carboxamidine (60 mg, 0.187 mmol) and potassium carbonate (35 mg, 0.25 mmol) and the mixture stirred overnight. The reaction was diluted with aqueous NH4Cl (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic fractions were dried (Na2SO4), concentrated and purified by chromatography on silica gel (5% MeOH/CH2Cl2) to give the desired product as a pale foam (51 mg, 64%). 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.48 (s, 9H), 1.81 (m, 1H), 2.00 (m, 2H), 2.26 (m, 2H), 2.71–2.88 (m, 2H), 3.89–4.05 (m, 5H), 4.73 (dd, 1H, J=15.5, 5.1 Hz), 4.96 (dd, 1H, J=15.5, 5.7 Hz), 7.12 (m, 7H), 7.36–7.44 (m, 3H), 7.55 (br s, 1H (NH)), 8.55 (m, 1H (NH)), 8.66 (d, 1H, J=5.1 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(O)C>O>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: Fc1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
A mixture of 9.0 g of 4-chloro-6-fluoro-2-phenylquinoline prepared according to the procedure described in example 9(b) and 18 ml of ethyl isonipecotate was stirred and heated in an oil bath at 160°-165° for 2 hr. It was then cooled and diluted with water. Addition of ethanol caused a solid to form which was collected to give 7.2 g of product as white prisms, mp 120°-124°.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[Si:18]([O:35][CH:36]1[CH2:39][C:38](=O)[CH2:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Si:18]([O:35][CH:36]1[CH2:37][C:38](=[CH:9][C:7]#[N:8])[CH2:39]1)([C:31]([CH3:33])([CH3:34])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](OC1CC(=O)C1)(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 1.0M potassium tert-butoxide in tetrahydrofuran (5.95 mL, 5.95 mmol) at 0° C. was added diethyl cyanomethylphosphonate (1.05 g, 5.95 mmol). The bath was removed and reaction allowed to warm to room temperature for 1 hour. The reaction was cooled to 0° C. and a solution of 3-{[tert-butyl(diphenyl)silyl]oxy}cyclobutanone (1.95 g, 6.01 mmol) in THF (10 mL) was added. Upon complete addition, the bath was removed and the reaction was allowed to warm to room temperature and stir overnight. The reaction solution was diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated. The crude was purified silica gel column to give the desired product (2.07 g, 90%) as an oil. LCMS (M+H)+: 348.2.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[C:15]([O:21][CH3:22])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[CH:19]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[C:32]([O:31][CH3:30])=[CH:37][N:36]([CH3:38])[C:35](=[O:39])[CH:34]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:15]([O:21][CH3:22])=[N:16][CH:17]=1
Reactant: COc1ncc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Reactant: COc1cn(C)c(=O)cc1B1OC(C)(C)C(C)(C)O1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1cn(C)c(=O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)cnc1OC)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(5-chloro-2-methoxy-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate BF) and 5-methoxy-1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (Intermediate AR) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. ESI-MS: tR=1.09 min, [M+H]+ 553/555/557 (LC-MS 1).
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].C1N2CCN(CC2)C1.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:2]([CH3:20])([NH:1][S:36]([CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:38])=[O:37])[C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4])=[CH:16][CH:15]=1)[CH3:19]
Reactant: C#CCNC(=O)C(C)(N)COc1ccc(OCC)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: C#CCNC(=O)C(C)(COc1ccc(OCC)cc1)NS(=O)(=O)Cc1ccccc1
Reaction time: 20 h

Procedure:
0.880 g 2-Amino-3-(4-ethoxy-phenoxy)-2methyl-N-prop-2-ynyl-propionamide and 0.233 g DABCO are dissolved in 8 ml tetrahydrofurane. After addition of 0.232 phenyl-methansulfonyl chloride the mixture is stirred for 20 hours. This mixture is then subjected to flash chromatography without further work-up to yield 320 mg of a white solid. M.p. 155-156° C.
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:23])/[CH:11]=[CH:12]/[C:13]1[C:18]([CH3:20])([CH3:19])[C:17](=[O:21])[CH2:16][CH2:15][C:14]=1[CH3:22])=[CH:3]/[C:4]([OH:6])=[O:5].[BH4-].[Na+].Cl>C(O)C>[OH:21][CH:17]1[C:18]([CH3:20])([CH3:19])[C:13](/[CH:12]=[CH:11]/[C:10](/[CH3:23])=[CH:9]/[CH:8]=[CH:7]/[C:2](/[CH3:1])=[CH:3]\[C:4]([OH:6])=[O:5])=[C:14]([CH3:22])[CH2:15][CH2:16]1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)C(C)(C)C(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C\C(=O)O)C(C)(C)C(O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
0.5 g of (2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-5-oxo-cyclohex-1-enyl)-nona-2,4,6,8-tetraenoic acid was dissolved in 25 ml of ethanol while warming slightly and treated with 100 mg of sodium borohydride while cooling with ice. After stirring at 0° C. for 1 hour the reaction mixture was poured on to ice-water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phases were washed (H2O), dried (Na2SO4) and evaporated. The amorphous residue was filtered over a small column (silica gel, hexane/ethyl acetate=1:1) and recrystallized from hexane/ethyl acetate. 0.35 g of (2Z,4E,6E,8E)-9-(5-hydroxy-2,6,6-trimethyl-cyclohex-1-enyl)-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid was obtained in yellow crystals, m.p. 152-154° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:47]=[CH:46][C:19]([CH2:20][NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:25]=[C:24]([NH:34][C:35]3[CH:45]=[CH:44][C:38]([C:39]([O:41]CC)=[O:40])=[CH:37][CH:36]=3)[N:23]=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.Cl>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:47]=[CH:46][C:19]([CH2:20][NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:25]=[C:24]([NH:34][C:35]3[CH:45]=[CH:44][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)[N:23]=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCCCCNC(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCCCCCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 110 °C
Yield: 75.2 %

Procedure:
A mixture of ethyl 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.0 g) and K2CO3 (1.25 g) in acetone (12 mL)/water (12 mL) was heated at 110° C. for 24 hours. After cooling to room temperature, the mixture was acidified with 1N HCl to pH=3. The white precipitate was collected, washed with water (20 mL) and dried under vacuum to give 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (0.72 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(=O)CC>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCOC(=O)CCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
A solution of 4-hydroxybenzaldehyde (15.0 g, 0.122 mole) in butanone (200 ml) was treated with anhydrous potassium carbonate (18.55 g, 0.134 mole), and the mixture stirred at room temperature for 20 mins. Ethyl 4-bromobutanoate, (24.0 g, 0.122 mole), dissolved in butanone (10 ml), was added dropwise to the stirred mixture over a period of 1 h. The reaction was stirred and refluxed for 6 h, then cooled and partitioned between water and butanone. The organic phase was separated, washed with dilute sodium hydroxide, water, brine and dried, (MgSO4). Evaporation of the solvent in vacuo gave a red oil, which was distilled at 0.05 mm/Hg to yield 19.31 g (67%) of a colourless oil, bp 152°-6° C. υmax (film) 1730, 1685, 1600, 1580, 1508 cm-1 δ (CDCl3) 1.25 (3H, t, J 7 Hz, ester CH3) 2.18 (2H, bt, J6 Hz, OCH2CH2), 2.49 (2H, bt, J6 Hz, CH2CO2), 4.09 (2H, t, J6 Hz, OCH2), 4.11 (2H, q, J7 Hz, ester CH2), 7.38 (4H, ABq, Δυ75 Hz, J9 Hz, C6H4), 9.90 (1H, s, CHO)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[C:34]([Cl:35])=[C:33]([CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[C:34]([Cl:35])=[C:33]([CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: CCc1ccnc(C(=O)CBr)c1Cl
Agent: Br
Product: CCc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)OC)c1Cl

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-3-chloro-4-ethylpyridine hydrobromide*.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:6]1.O[Li].O>C1COCC1.CO>[F:17][C:2]([F:1])([F:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1
Reactant: CCOC(=O)C1CCN(CCC(F)(F)F)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1CCN(CCC(F)(F)F)CC1
Reaction time: 15 h
Yield: 99.1 %

Procedure:
To a solution of ethyl 1-(3,3,3-trifluoropropyl)piperidine-4-carboxylate (3.30 g, 13.0 mmol) in THF (40 mL) and MeOH (40 mL) was added LiOH—H2O (1.64 g, 39.1 mmol). The reaction was allowed to stir for 15 h at which time the solution was filtered to remove undissolved solids and the filtrate concentrated. The resulting material was diluted with water (10 mL), made to pH 5 with HCl (conc), then concentrated in vacuo to yield a white solid (2.9 g, 150%). Mass Spectrum: Calcd for C9H15NF3O2(M+H): 226. Found: 226.
Reaction SMILES: C[Si](C#C[C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)(C)C.CO.C(=O)([O-])[O-].[K+].[K+].O1CC[CH2:24][CH2:23]1>>[C:23]([NH:13][C:10]1[CH:9]=[CH:8][CH:7]=[CH:12][N:11]=1)#[CH:24]
Reactant: C1CCOC1
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CNc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 5-trimethylsilanylethynyl-pyridin-2-ylamine (26 mg, 137 μmol) described in Manufacturing Example 28-1-2 in tetrahydrofuran (1 mL) and methanol (1 mL) was added potassium carbonate (37.9 mg, 274 μmol) at room temperature, which was stirred for 1 hour at room temperature. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (16 mg, 99%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(OC([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([NH:27][C@H:28]([C:32](OC)=O)[CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:20][CH2:19]1)=O)(C)(C)C>C1(C)C=CC=CC=1.ClCCl>[CH:29]([C:28]1[NH:27][C:25](=[O:26])[N:24]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:23][CH2:22]2)[CH:32]=1)([CH3:30])[CH3:31]
Reactant: COC(=O)[C@@H](NC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)c1cn(C2CCNCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminum hydride (1M, 0.520 mL, 0.520 mmol) was added to a solution of methyl N-{[(1-tert-butoxycarbonylpiperidin-4-yl)amino]carbonyl}valinate (155 mg, 0.434 mmol) in toluene (3 mL) and dichloromethane (3 mL) at −78° C. and stirred for 30 min and then warmed to ambient temperature. After 1 h, the reaction was quenched with 1 N saturated potassium sodium tartrate solution (3 mL) and extracted with dichloromethane (2×). The combined organic extracts were dried over sodium sulfate, filtered, concentrated. The crude material was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (5 mL). After 30 min, the reaction was concentrated to give the title compound. MS 210.1 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([O:18][C:19](=[O:33])[CH2:20][C@@H:21]([C:30](O)=[O:31])[NH:22]C(OC(C)(C)C)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[NH2:22][C@H:21]([C:30](=[O:31])[NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:20][C:19]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:33].[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 0.214 g (1.55 mmol) of p-nitroaniline and 0.50 g (1.55 mmol) of N-(t-butyloxycarbonyl)-L-aspartic acid 4-benzyl ester (111) in 10 mL of dichloromethane at 25° C. under argon, was added a solution of 0.383 g (1.86 mmol) of DCC in 20 mL of dichloromethane via cannula. The reaction mixture was stirred for 24 h, filtered, concentrated, and column chromatographed on silica gel using a mixture of hexane, methanol, and dichloromethane (40:4:1) as eluant to give 0.45 g of the amide (85% yield; based on reacted p-nitroaniline) and 0.05 g (23% recovery) of p-nitroaniline. Mp 47-50° C.; [α]20D=−36.5° (c 1.3, CHCl3); 1H NMR δ 9.18 (s, 1H, NH), 8.20 (d, J=7 Hz, 2H, Ar), 7.66 (d, J=7 Hz, 2H, Ar), 7.36 (s, 5H, Ar), 5.86 (s, 1H, NH), 5.20 (d, J=12.4 Hz, 1H, OCH2), 5.16 (d, J=12.4 Hz, 1H, OCH2), 4.67 (m, 1H, CHN), 3.09 (dd, J=17, 4 Hz, 1H, CH2CO), 2.82 (dd, J=17, 6 Hz, 1H, CH2CO), 1.49 (s, 9H, t-Bu); 13C NMR δ, 171.6, 169.4, 153.1, 143.4, 135.2, 128.6, 128.5, 128.47, 128.2, 125.0, 119.2, 67.1, 65.8, 51.6, 35.4, 28.2. A solution of 0.15 g (0.34 mmol) of the above amide and 0.85 mL (3.39 mmol) of 4 M HCl in dioxane was stirred at 25° C. for 2 h, neutralized with 10 mL of aqueous NaHCO3, and extracted three times with dichloromethane. The combined organic layer was washed with brine, dried (MgSO4), and concentrated to give 0.122 g of 110 (100% yield): [α]22D=−19° (c, 0.15, CHCl3; 1H NMR δ 10.00 (s, 1H, CONH), 8.22 (d, J=7 Hz, 2H, Ar), 7.75 (d, J=7 Hz, 2H, Ar), 7.34 (s, 5H, Ar), 5.18 (d, J=12.4 Hz 1H, OCH2), 5.14 (d, J=12.4 Hz, 1H, OCH2), 3.83 (dd, J=6.8, 4.4 Hz, 1H, CHN), 3.02 (dd, J=17, 4.4 Hz, 1H, CH2), 2.96 (dd, J=17, 6.8 Hz, 1H, CH2); 13C NMR δ, 174.4, 172.0, 143.4, 135.1, 128.7, 128.5, 128.4, 128.3, 125.1, 118.9, 66.9, 52.4, 38.9. HRMS calcd for C17H18N3O5 (M+1) 344.1169, found 344.1150.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:3]1=2.C(Cl)Cl.CN(CCN(C)C)C.[Si]([I:33])(C)(C)C.II>>[I:33][CH:7]1[CH2:8][C:2]([CH3:17])([CH3:1])[C:3]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=2[NH:5][C:6]1=[O:9]
Reactant: C[Si](C)(C)I
Reactant: CC1(C)CCC(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: CN(C)CCN(C)C
Agent: II
Solvent: ClCCl
Product: CC1(C)CC(I)C(=O)Nc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5,5-Dimethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (4.00 g, 0.0171 mol) in Methylene chloride (54 mL, 0.84 mol) was cooled to 0° C., treated with TMEDA (7.73 mL, 0.05 mol) then treated dropwise with TMSI (7.29 mL, 0.05 mol). The mixture was stirred at 0° C. for 60 min after which solid Iodine (6.50 g, 0.0256 mol) was added in one portion and the mixture stirred at 0° C. for 60 min. The reaction was quenched with 10% Na2S2O3. Title compound isolated as a beige solid. (5.43 g, 88%) LCMS 361 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]2[C:16](=[O:17])[C:15]([CH3:18])=[N:14][C:13]3[CH:19]=[CH:20][CH:21]=[N:22][C:12]2=3)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:23][CH2:18][C:15]1[C:16](=[O:17])[N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[C:12]2[N:22]=[CH:21][CH:20]=[CH:19][C:13]=2[N:14]=1
Reactant: COC(=O)c1cccc(-n2c(=O)c(C)nc3cccnc32)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1
Yield: 74.7 %

Procedure:
A mixture of 4-(3-methoxycarbonylphenyl)-2-methyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (5.02 g), N-bromosuccinimide (4.0 g) and benzoyl peroxide (0.50 g) in chloroform (60 ml) was stirred under reflux for 2 hours. The mixture was concentrated and chromatographed on silica gel column (1% methanol in chloroform) to give 2-bromomethyl-4-(3-methoxycarbonylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (4.75 g).