Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:21]([F:22])=[CH:20][C:5]2[O:6][CH2:7][CH:8]([N:17]([CH3:19])[CH3:18])[C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>>[CH3:18][N:17]([CH3:19])[CH:8]1[C:9]2[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=2[C:4]2[CH:3]=[C:2]([C:32]#[C:31][C:29]([OH:33])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[CH3:30])[C:21]([F:22])=[CH:20][C:5]=2[O:6][CH2:7]1
Reactant: C#CC(C)(O)c1ccccn1
Reactant: CN(C)C1COc2cc(F)c(Br)cc2-c2nc(C(N)=O)sc21
Product: CN(C)C1COc2cc(F)c(C#CC(C)(O)c3ccccn3)cc2-c2nc(C(N)=O)sc21

Procedure:
Similar to as described in General Procedure G, racemic 9-bromo-4-(dimethylamino)-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with racemic 2-(pyridin-2-yl)but-3-yn-2-ol to give an isomeric mixture of the titled compound. The mixture (80 mg) was separated by Chiral-Prep-HPLC with the following conditions (2#-Gilson Gx 281(HPLC-09)): Column, CHIRALPAK AD-H SFC, 5*25 cm, 5 um; mobile phase, Hex (0.2% TEA) and ethanol (0.2% TEA) (hold 30.0% ethanol (0.2% TEA) in 30 min); Detector, UV 220/254 nm to give 1st 3.7 mg (2%) of Compound 1, then 10.2 mg (4%) of Compounds 2 and 18.6 mg (8%) Compound 3. The stereochemistry of these compounds has not been assigned.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=1.CCN(CC)CC.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:24]([O:14][C:9]1[C:8]([O:15][CH3:16])=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:11][C:10]=1[O:12][CH3:13])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc(-c2ccco2)cc(OC)c1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2ccco2)cc(OC)c1OC(=O)c1ccccc1
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of 4-(furan-2-yl)-2,6-dimethoxyphenol (1.3 g, 5.9 mmol) in anhydr CH2Cl2 (20 mL) under argon was added Et3N (1.6 mL, 11.5 mmol) then the mixture was cooled over an ice bath. Benzoyl chloride (0.75 mL, 6.4 mmol) was added dropwise and the reaction was stirred for 3 hrs. 10% aqueous NaHCO3 and CH2Cl2 were added, stirred, and the layers were separated. The organics were washed with H2O and saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. Purification by chromatography (0-25% EtOAc-hexanes) gave 4-(furan-2-yl)-2,6-dimethoxyphenyl benzoate as a light yellow solid (0.54 g isolated from chromatography of approximately half of the crude product; 57% yield).
Reaction SMILES: CC1CC[N:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[C:10]3[C:18]([F:21])([F:20])[F:19])[N:3]=1.[CH3:22][CH:23]=[CH:24][C:25](=O)[CH2:26][CH3:27]>>[CH2:26]([C:25]1[CH2:24][CH:23]([CH3:22])[N:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[C:10]3[C:18]([F:19])([F:20])[F:21])[N:3]=1)[CH3:27]
Reactant: CC=CC(=O)CC
Reactant: CC1=NN(c2ccc3[nH]c(=O)cc(C(F)(F)F)c3c2)CC1
Product: CCC1=NN(c2ccc3[nH]c(=O)cc(C(F)(F)F)c3c2)C(C)C1

Procedure:
This compound was prepared from the condensation of Compound 793 (Structure 159 of Scheme XXXIII) and 2-hexen-4-one as yellow solid. 1H NMR (500 MHz, DMSO-d6) 12.1 (bs, 1H), 7.41 (dd, J=8.8, 2.4, 1H), 7.34 (d, J=8.8, 1H), 7.21 (bs, 1H), 6.92 (s, 1H), 4.37-4.28 (m, 1H), 3.12 (dd, J=17.1, 10.2, 1H), 2.53 (dd, J=17.1, 4.9, 1H), 2.37 (q, J=7.3, 2H), 1.12 (t, J=7.3, 3H), 1.12 (d, J=5.9, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[NH:20][CH2:19][C:18](=[O:21])[NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:22]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1>>[NH:33]1[CH:32]=[C:31]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[NH:20][CH2:19][C:18](=[O:21])[NH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:22]=2)[CH:35]=[N:34]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C1CNC(c2cc3c(s2)-c2ccc(Br)cc2OCC3)=NN1
Product: O=C1CNC(c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)=NN1

Procedure:
Following the procedure in Example 44 for 134, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4,5-dihydro-1,2,4-triazin-6(1H)-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 212. MS: (ESI+) 366.2
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1([CH3:22])[O:14][CH:13]([CH2:15][O:16][C:17]2[N:18]=[CH:19][S:20][CH:21]=2)[CH2:12][O:11]1>CC#N>[Br:8][C:21]1[S:20][CH:19]=[N:18][C:17]=1[O:16][CH2:15][CH:13]1[CH2:12][O:11][C:10]([CH3:22])([CH3:9])[O:14]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OCC(COc2cscn2)O1
Solvent: CC#N
Product: CC1(C)OCC(COc2ncsc2Br)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., NBS (11.94 g, 67.1 mmol) was added over 90 min to a soln. of 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)thiazole (13.75 g, 63.9 mmol) in MeCN (320 mL). The mixture was further stirred at 0° C. for 30 min, then, it was quenched by the addition of aq. 5% NaHCO3 and extracted with EtOAc. The comb. org. layers were washed with aq. 5% NaHCO3 and brine, dried over MgSO4, and conc. in vacuo.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:25]C(=O)C)=[CH:18][C:17]=2[OH:29])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH2:25])=[CH:18][C:17]=2[OH:29])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Yield: 101.2 %

Procedure:
A mixture of N-(1-benzylpiperid-4-yl)-2-hydroxy-4-acetamido-5-nitrobenzamide (1 g; 0.0024 moles) [prepared as described in Example 2], sodium hydroxide (0.2 g; 0.0048 moles), water (25 ml) and ethanol (12.5 ml) was boiled under reflux for 3 hours. Then the mixture was diluted with water, neutralized with diluted hydrochloric acid and the precipitate collected by filtration. This precipitate was washed with water and then with diethyl ether to give 0.9 g of N-(1-benzylpiperid-4-yl)-2-hydroxy-4-amino-5-nitrobenzamide. This compound was treated with a saturated solution of hydrogen chloride in methanol to give the hydrochloride which was recrystallized from ethanol. N-(1-Benzylpiperid-4-yl)-2-hydroxy-4-amino-5-nitrobenzamide hydrochloride was obtained, m.p. 248°-250° C. (dec).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[CH:35][N:36]=[C:10]23)=[CH:6][CH:5]=1)[CH3:3].N1C(C)=CC=CC=1C.O1CCCC1.FC(F)(F)S(O[Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])(=O)=O>C(OCC)(=O)C>[Si:58]([O:1][CH:2]([C:4]1[CH:38]=[CH:37][C:7]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[CH:35][N:36]=[C:10]23)=[CH:6][CH:5]=1)[CH3:3])([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(C)O)cc2)c2ncnn12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(C)O[Si](C)(C)C(C)(C)C)cc2)c2ncnn12
Reaction time: 3 h
Yield: 100 %

Procedure:
To a mixture of 4′-({4-[4-(1-hydroxyethyl)benzyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.2 g), 2,6-lutidine (0.41 mL) and tetrahydrofuran (30 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.79 mL) at 0° C., and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.4 g, 100%).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([Cl:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:15])[CH:2]=[CH2:3].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:13]=[C:12]([Cl:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:15][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(Cl)c2ccccc2c1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cc(Cl)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 2-allyl-4-chloro-1-naphthol (20.0 g, 0.091 mol) in N,N-dimethylformamide (700 mL) was added sodium hydride (60 wt. %, 4.39 g, 0.11 mol) and the reaction mixture was allowed to stir at room temperature for 30 min. Benzyl bromide (18.8 g, 0.11 mol) was then added and the reaction mixture was allowed to stir at room temperature for 2 h. The solvent was removed in vacuo to provide a crude oil. The residue was re-dissolved in ethyl acetate (500 mL) and the organic layer was washed with water (2×250 mL), saturated aqueous sodium chloride (250 mL), dried (sodium sulfate) and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, dichloromethane:hexanes 1:4) provided 23.0 g (82%) of 2-allyl-1-(benzyloxy)4-chloronaphthalene as a light brown oil. Treatment of the benzyl ether with AD-mix-α (104.3 g) generally according to the procedure described for Intermediate 2 afforded 24.0 g (94%) of (±)-3-[1-(benzyloxy)-4-chloro-2-naphthyl]propane-1,2-diol as a white solid. mp 69-71° C.; Anal. calcd. for C20H19ClO: C, 70.07; H, 5.59. Found: C, 68.01; H, 5.47.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1)[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([C:25]2[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=2)[CH:29]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CNCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Product: CN(CC1(c2nc(-c3ccccc3)cs2)CCOCC1)C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 14 %

Procedure:
This compound was synthesized from N-methyl-1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 14%). 1H NMR (400 MHz, CDCl3) δ 8.13-8.09 (m, 2H), 7.96-7.94 (m, 2H), 7.57-7.55 (m, 2H), 7.48-7.41 (m, 3H), 7.36-7.32 (m, 1H), 3.99-3.96 (m, 2H), 3.92 (s, 2H), 3.66-3.60 (m, 2H), 2.53 (s, 3H), 2.48-2.44 (m, 2H), 2.23-2.16 (m, 2H). MS (ESI) m/z: Calculated for C26H23F3N4O3S: 528.14. found: 529.2 (M+H)+.
Reaction SMILES: C(Cl)CCl.[CH3:5][NH:6][CH2:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]=[CH2:18])=[CH:14][CH:13]=[CH:12][CH:11]=2.Cl.[O:20]=[C:21]1[CH2:26][O:25][C:24]2[CH:27]=[C:28](/[CH:31]=[CH:32]/[C:33](O)=[O:34])[CH:29]=[N:30][C:23]=2[NH:22]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:5][N:6]([CH2:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]=[CH2:18])=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:33](=[O:34])/[CH:32]=[CH:31]/[C:28]1[CH:29]=[N:30][C:23]2[NH:22][C:21](=[O:20])[CH2:26][O:25][C:24]=2[CH:27]=1
Reactant: C=Cc1c(CNC)[nH]c2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: C=Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)[nH]c2ccccc12
Reaction time: 8 h
Yield: 23.1 %

Procedure:
EDC (73 mg, 0.3 mmol) was added to a solution of N-methyl(3-vinyl-1H-indol-2-yl)methanamine (54.7 mg, 0.29 mmol), (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid hydrochloride (79 mg, 0.3 mmol), HOBT.H2O (39 mg, 0.29 mmol) and DIPEA (0.21 mL, 1.1 mmol) in dry DMF (5 mL). After stirring overnight, water was added. The precipitate that formed was washed with ethyl acetate and dried to afford the title compound (26 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 11.20-11.05 (rotamers, s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.22 (d, J=15.6 Hz, 1H), 7.10 (t, J=7.1 Hz, 1H), 7.07-6.98 (m, 2H), 5.62 (d, J=17.9 Hz, 1H), 5.12 (d, J=11.0 Hz, 1H), 5.03 (s, 2H), 4.68 (s, 3H), 3.09 (s, 2H); MS (ESI): m/e 389.1 (C22H20N4O3+H)+.
Reaction SMILES: [ClH:1].[N:2]1([C:7]([C@@H:9]2[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1>O1CCOCC1>[ClH:1].[NH:11]1[CH2:12][CH2:13][O:14][C@@H:9]([C:7]([N:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:8])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)N2CCCC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C([C@H]1CNCCO1)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of hydrogen chloride in 1,4-dioxane (20 mL) was added to a solution of (R)-tert-butyl 2-(pyrrolidine-1-carbonyl)morpholine-4-carboxylate (0.62 g, 2.1 mmol) in \ 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the resulting crude material was triturated with diethyl ether to afford (R)-morpholin-2-yl(pyrrolidin-1-yl)methanone hydrochloride (0.4 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)CCCCCCCCCCCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCC(C)C)cc1

Procedure:
A mixture of 5 g. of 15-methylhexadecyl bromide and 5.2 g. of ethyl 4-aminobenzoate in 50 ml. hexamethylphosphoramide is heated for 17 hours at 120° C. The cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered, washed with 100 ml. of 50% ethanol, dried, and crystallized from ethanol to yield a colorless crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[CH2:31]1[C:34]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33][CH2:32]1.C(N(CC)CC)C.O>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([N:37]2[CH2:38][CH2:39][C:34]3([CH2:31][CH2:32][CH2:33]3)[CH2:35][CH2:36]2)[N:8]=1
Reactant: C1CC2(C1)CCNCC2
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CNc2nc(N3CCC4(CCC4)CC3)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 8 h
Yield: 36.3 %

Procedure:
In THF (20 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (201 mg, 0.45 mmol) and 7-azaspiro[3.5]nonane (62 mg, 0.5 mmol). Triethylamine (137 mg, 1.35 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 8 h, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=50/1) to give a white solid (83 mg, 36% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][NH:24][CH3:25]>C(#N)C>[CH3:23][N:24]([CH3:25])[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CCC(CC)Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(CC)Nc1nc(N(C)C)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 52.4 %

Procedure:
To a room-temperature mixture containing 6-chloro-3-nitro-N-(pentan-3-yl)pyridin-2-amine (250 mg, 0.90 mmol) and potassium carbonate (250 mg, 1.8 mmol) in acetonitrile (2 mL) was added dimethylamine (1.35 mL, 1.0 M, 1.35 mmol) by syringe. After 3 h, the reaction mixture was concentrated in vacuo and then re-dissolved in EtOAc and water. The organic layer was washed twice with water and once with brine, dried over sodium sulfate, filtered and concentrated In vacuo. Silica gel chromatography (5%-20% EtOAc/Hexanes) provided the title compound as a yellow solid (119 mg, 52%). m/z=253.2 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:39])[C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[C:28]([C:33]2[CH2:37][CH2:36][CH2:35][C:34]=2Br)[CH:27]=1)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:39])[C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[C:28]([C:33]2[CH2:37][CH2:36][CH2:35][C:34]=2[C:10]2[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:27]=1)[CH3:23]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1cc(C2=C(Br)CCC2)ccc1N
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)ccc1N

Procedure:
Prepared by general procedure C(iii) but using 2-benzyloxy-5-trifluoromethylphenylboronic acid instead of 2-benzyloxy-5-chlorophenylboronic acid and 3-(2-bromocyclopent-1-enyl)-6-aminobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.CO.[NH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1.[BH4-].[Na+]>C(OCC)(=O)C.O>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: O=Cc1ccncc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNCc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
4-Pyridinecarbaldehyde (0.64 ml, 6.8 mmol) was added to a methanol solution (10 ml) of 7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.18 g, 6.8 mmol), and stirred under a nitrogen atmosphere at room temperature for 1.5 hours. The reaction mixture was cooled in an ice water bath, and sodium borohydride (257 mg, 6.8 mmol) was added thereto at 0° C. The mixture was then stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→3:2). The purified product was concentrated under reduced pressure to thereby obtain 2.35 g (yield: 84%) of 1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[CH:6]=[C:7]=[CH2:8])[CH3:2].[H][H].C(OC(=O)C(C)/C=C\C)C.C(OC(=O)C(C)CC=C)C>[Pd].[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: [H][H]
Reactant: C=C=CC(C)C(=O)OCC
Agent: [Pd]
Agent: C/C=C\C(C)C(=O)OCC
Agent: C=CCC(C)C(=O)OCC
Solvent: CCO
Product: CCCC(C)C(=O)OCC

Procedure:
The resulting ethyl-2-methyl-3,4-pentadienoate is then reacted with hydrogen in the presence of a palladium-on-carbon catalyst or a "Lindlar" catalyst (palladium-on-calcium carbonate). The percentage of palladium on carbon or on calcium carbonate varies from about 2% up to about 7% with a percentage of palladium-on-carbon or on calcium carbonate being preferred to be about 5%. The temperature of reaction for this hydrogenation may vary from about 10° C up to about 50° C with a preferred reaction temperature of 25°-35° C. Since the reaction is exothermic, it is usually necessary to provide external cooling to the reaction mass during the course of the reaction. The pressure of hydrogen over the reaction mass may vary from about 5 psig up to about 50 psig, with the most preferred pressure being 20 psig. It has been found that pressures above 20 psig give rise to larger amounts of undesired side products. The hydrogenation reaction may be carried out in the presence of or in the absence of a solvent. When a solvent is used, it is required that it be an inert (non-reactive) solvent such as ethanol. If a solvent is used, it is preferred that the mole ratio of solvent:pentadienoate ester be approximately 1:1. The percentage of catalyst in the reaction mass may vary from 0.125% up to about 2.0% with a percentage of catalyst of about 0.25% being preferred. When using a Lindlar catalyst, the hydrogenation reaction produces a mixture of ethyl-2 -methyl-cis-3-pentenoate and ethyl-2-methyl-4-pentenoate in the ratio of from about 6:4 up to about 7:3. As a result, the desired ethyl-2-methyl-4-pentenoate for use in the instant invention may, if desired, be enriched with respect to the ethyl-2-methyl-4-pentenoate by means of fractional distillation or the mixture resulting may be used as such for its organoleptic properties as a tobacco flavor adjuvant or enhancer. Where the catalyst used is palladium-on-carbon rather than a Lindlar catalyst (palladium-on-calcium carbonate), a mixture of ethyl-2-methyl-cis-3-pentenoate, ethyl-2-methyl-4-pentenoate and ethyl-2-methyl-pentanoate is formed which may be used as such for its organoleptic properties as a tobacco flavor adjuvant or enhancer or which may be separated as by means of fractional distillation. In any event, at the end of the hydrogenation reaction, the reaction mass is filtered in order to separate catalyst from liquid phase desired product, and the filtrate is distilled using a fractional distillation column operated under vacuum.
Reaction SMILES: [I-].I[C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[OH:15])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8]>>[NH2:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]1[CH:4]=[CH:3][C:14]([OH:15])=[CH:13][CH:12]=1
Reactant: N[C@@H](Cc1ccc(O)c(I)c1)C(=O)O
Agent: [I-]
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Electrolysis was carried out using the same cell, anode, membrane and procedure as in Example 15, except that the pH of the anolyte and catholyte was 7.0. At 85% iodide conversion, the yield of 3-iodo-L-tyrosine was 58% based on initial iodide.