Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>C(Cl)Cl>[C:17]([CH2:18][CH2:19][N:16]1[CH2:15][CH2:14][N:13]=[C:12]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([O:21][CH3:22])=[O:20]
Reactant: C=CC(=O)OC
Reactant: CCCCCCCCCCCC1=NCCN1
Solvent: ClCCl
Product: CCCCCCCCCCCC1=NCCN1CCC(=O)OC
Yield: 72.2 %

Procedure:
2.2 g (9.82 mmoles) of 2-undecyl-2-imidazoline and 1.4 g (16.3 mmoles) of methyl acrylate were dissolved in 50 ml of methylene chloride and the solution was heated to reflux. The reaction was followed by glc. The solution was concentrated and the residue was distilled at 160°-170° C./0.1 mm to give 2.2 g (72.4%) of product.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=4[Cl:33])[N:17]=3)[CH2:11]2)[CH:6]=[CH:5][C:4]=1[C:34](=[O:39])[C:35]([F:38])([F:37])[F:36].O.[OH-].[Na+].Cl>COCCOC>[ClH:32].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=4[Cl:33])[N:17]=3)[CH2:11]2)[CH:6]=[CH:5][C:4]=1[C:34](=[O:39])[C:35]([F:38])([F:37])[F:36]
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Nc1nc(NC2CCCN(c3nc(-c4ccc(Cl)cc4Cl)ccc3C(=O)O)C2)ccc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
220 mg (0.36 mmol) of methyl 2-(3-{[6-amino-5-(trifluoroacetyl)pyridin-2-yl]amino}piperidin-1-yl)-6-(2,4-dichlorophenyl)pyridine-3-carboxylate hydrochloride (Example 8) were dissolved in 10 ml of 1,2-dimethoxyethane, and 4.4 ml of water were added. Then 43 mg (1.1 mmol) of sodium hydroxide were added and the mixture was stirred at RT for 30 min. For workup, 35 ml of 2 N hydrochloric acid were added and the precipitate which formed was filtered off with suction. 180 mg (75% of theory) of the product were obtained in solid form.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][C@H:3]1[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[CH2:25]([O:32][C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:25]([O:32][C:33]([NH:35][CH2:36][C:37]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4][C@H:3]1[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:38])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.1 %

Procedure:
A solution of tert-butyl 3-((1R,2S,5R)-2-amino-5-(tert-butoxycarbonylamino)cyclohexyl)propanoate (90 mg) and 2-(benzyloxycarbonylamino)acetic acid (55 mg) in dichloromethane (2 mL) was treated sequentially with diisopropylethylamine (92 μL), 1-hydroxybenzotriazole hydrate (45 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg). The mixture was stirred at rt for 20 h, then was diluted with dichloromethane, washed sequentially with 1 M aqueous HCl, saturated aqueous NaHCO3 and water, dried over Na2SO4 and concentrated under vacuum to provide tert-butyl 3-((1R,2S,5R)-2-(2-(benzyloxycarbonylamino)acetamido)-5-(tert-butoxycarbonylamino)cyclohexyl)propanoate as a pale yellow gum (125 mg). MS found: (M+H)+=534.5.
Reaction SMILES: [I:1][CH:2]([O:5][C:6](=[O:16])[CH2:7][NH:8]C(OC(C)(C)C)=O)[C:3]#[CH:4].[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[I:1][CH:2]([O:5][C:6](=[O:16])[CH2:7][NH2:8])[C:3]#[CH:4]
Reactant: C#CC(I)OC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CC(I)OC(=O)CN
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
N-t-Butoxycarbonyl glycine iodopropargyl ester (Compound #1) (4.20 g., 12.39 mmole) was dissolved in anhydrous dichloromethane (20 ml.), cooled to 0° C. with an ice-bath, and treated with 10 ml. of trifluoroacetic acid. The reaction mixture was stirred magnetically at 0° C. for 1 hour and then allowed to warm to ambient temperature. The volatile solvents were removed under reduced pressure leaving a clear syrup which crystallized on standing to a white solid (4.20 g., 96% yield) as the desired trifluoroacetate salt product. m.p. 130°-131° C. 1H-NMR (200 MHz, DMSOd6) δ=3.92, s, 2H; 5.00, s; 2H; s; 9.1, broad m. IR (KBr) 1605, 1670, 1765, 2205, 2640 cm-1.
Reaction SMILES: C[Si:2]([CH3:12])([CH3:11])[N:3]([CH2:8][CH:9]=C)[Si:4]([CH3:7])([CH3:6])[CH3:5].[Cl:13]C([SiH3])Cl>C1(C)C(C)=CC=CC=1>[CH3:7][Si:4]([CH3:5])([CH3:6])[N:3]1[CH2:8][CH2:9][CH2:12][Si:2]1([Cl:13])[CH3:11]
Reactant: C=CCN([Si](C)(C)C)[Si](C)(C)C
Reactant: [SiH3]C(Cl)Cl
Solvent: Cc1ccccc1C
Product: C[Si](C)(C)N1CCC[Si]1(C)Cl
Temperature: 65 °C

Procedure:
N-trimethylsilyl-2-chloro-2-methyl-1-aza-2-silacyclopentane (cyclic APMCS, which may be referred to as c-APMCS) was prepared as follows. To a 300 mL nitrogen purged bottle equipped with stir bar was added 20.1 g (0.1 mol) of N,N-bis(trimethylsilyl) allyl amine, 11.5 g (0.1 mol) of dichloromethylsilane, and 0.81 mL of 2.4 wt % Karsted's Catalyst in xylene. The solution was stirred for 72 hrs, then heated at 65° C. for 2 hrs, and heated at 100° C. for a further 3 days. The product was distilled at 85-90° C. at 25 mm Hg. GC/MS confirmed structure. Proton NMR was also used to determine structure.
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][CH2:12][N:13]=[C:14]=[O:15]>C1COCC1>[CH2:1]([O:8][NH:9][C:14]([NH:13][CH2:12][CH2:11][Cl:10])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: O=C(NCCCl)NOCc1ccccc1
Yield: 97 %

Procedure:
To a stirred solution of benzyloxyamine (36.63 g, 0.297 mol) in THF (250 ml) was added a solution of 2-chloroethyl isocyanate (25.4 ml, 1.0 equiv.) in THF (50 ml) over 20 minutes. The resulting cloudy solution was refluxed for 10 minutes, cooled and evaporated. Trituration of the residue with ether-hexane gave N-benzyloxy-N'-(2-chloroethyl)urea as a white solid (65.82 g, 97% yield), mp 67°-68° C. after recrystallization from hexane-ether. To a stirred solution of this urea (65.8 g, 0.287 mol) in the THF (500 ml) at room temperature was added sodium hydride (11.8 g of 60% dispersion in oil, 1.02 equiv.) in portions over 30 minutes. The cloudy solution was refluxed for 10 minutes, cooled and evaporated. To the resulting semi-solid was added 2% aqueous citric acid (60 ml) and hexane (250 ml). After vigorous agitation, the resulting solid was collected by filtration and washed with water and hexane, to give 1-benzyloxy-2-imidazolidinone as a tan solid (52.66 g, 93% yield), mp 64°-65° C. after recrystallization from water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:30]([O:32]CC)=[O:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:35][CH3:36])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:30]([OH:32])=[O:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:35][CH3:36])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(CCOc2ccccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(Cl)c(CCCC3(C(=O)O)CCN(CCOc4ccccn4)CC3)c2c1
Temperature: 70 °C
Reaction time: 21 h
Yield: 101.4 %

Procedure:
A mixture of 0.12 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yloxy)-ethyl]piperidine-4-carboxylate in 5 cm3 of dioxane, 5 cm3 of methanol and 1 cm3 of aqueous 5N sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 21 hours. After cooling to about 20° C., the reaction mass was concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 60° C. The residue was taken up in 5 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and then purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200μ; diameter 1.5 cm; mass 20 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume). The fractions containing the product were combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The foam was taken up in 2 cm3 of methanol, filtered, washed with 1 cm3 of methanol and 2 cm3 of diethyl ether and then oven-dried under reduced pressure (10 kPa) at about 50° C. 0.115 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yloxy)ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid melting at about 70° C. and becoming sticky.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:5])=[O:4].[H-].[Na+].[CH3:28]I>CN(C=O)C>[F:25][C:2]([F:24])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH3:28])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:4])=[O:5]
Reactant: CCCN(CCC)C1Cc2cc(O)c(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc(OC)c(OS(=O)(=O)C(F)(F)F)cc2C1

Procedure:
A solution of 5-trifluoromethansulfonyloxy-6-hydroxy-2-(di-n-propylamino)indan (Example 7) in DMF is added to a suspension of sodium hydride in DMF under nitrogen. The mixture is alkylated with methyl iodide to yield the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:31]=[C:32]([C:36]2([OH:44])[CH2:42][CH:41]3[NH:43][CH:38]([CH2:39][CH2:40]3)[CH2:37]2)[CH:33]=[CH:34][CH:35]=1>CS(C)=O>[CH3:26][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14][CH:13]([CH2:12][N:43]4[CH:41]5[CH2:40][CH2:39][CH:38]4[CH2:37][C:36]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:45])[F:46])[CH:31]=4)([OH:44])[CH2:42]5)[O:27][C:17]3=2)[N:22]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CC2CCC(C1)N2
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1C2CCC1CC(O)(c1cccc(C(F)(F)F)c1)C2)O3
Temperature: 100 °C
Yield: 34.4 %

Procedure:
(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.70 g, 1.8 mmole) and 3-(3-trifluoromethyl-phenyl)-8-azabicyclo[3.2.1]octan-3-ol (0.59 g, 2.4 mmole) were combined in 3 mL of DMSO and heated at 100° C. under nitrogen for 4 hours. After cooling to room temperature, the mixture was partitioned between 400 mL of ethyl acetate and 400 mL of saturated sodium bicarbonate solution. The organic phase was removed, washed with 400 mL of water, dried over magnesium sulfate, filtered and concentrated in vacuum to 1.29 g of a crude oil. The residue was column chromatographed on silica gel using 10% methanol in ethyl acetate as eluant to give 0.30 g of a yellow oil. Crystallization from ethanol/ether with the addition of 0.073 g of fumaric acid gave 0 040 g of the (S)-enantiomer of the title compound as a light yellow solid, m.p. 146-150° C.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]1=O>>[CH3:2][C:1]1[S:3][C:11]2[CH2:10][CH2:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=2[N:4]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C1CCCC(Br)C1=O
Product: CCOC(=O)C1CCc2sc(C)nc2C1

Procedure:
The compound is prepared by action of thioacetamide on 2-bromo-5-ethoxycarbonyl cyclohexanone (II), as described in Example 1. B.P.0.4 =116°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH2:11][C:9]2=[O:20])=[CH:6][CH:7]=1
Reactant: Clc1ccc(C=C2CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1CCC1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of 1-chloro-4-(cyclopropylidenemethyl)benzene (5 g, 30 mmol) in CH2Cl2 (80 ml) was added in 5 separate portions m-chloroperbenzoic acid (5.3 g, 30 mmol) at 0° C. After stirring at 0° C. for 3 h, the reaction mixture was washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4 and concentrated. To the crude product in CH2Cl2 (40 ml) was added 10% HBF4 (11.6 ml 48% HBF4 and 46 ml H2O). After stirring at rt for 17 h, the mixture was extracted with CH2Cl2, washed with saturated NaHCO3 aq. solution and brine. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent i-hexane, KMnO4 stain) to give 2-(4-chlorophenyl)cyclobutanone (3.470 g, 64%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:43]=[C:23]4[C:24]([C:28]5[CH:33]=[C:32]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:31]=[CH:30][C:29]=5[O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:42][CH:40]([F:41])[CH2:39][O:38][C:29]1[CH:30]=[CH:31][C:32]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:33][C:28]=1[C:24]1[C:23]2[N:22]([N:21]=[C:20]([NH:19][C:17]3[CH:16]=[CH:15][C:12]4[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=4[CH:18]=3)[N:43]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(S(C)(=O)=O)ccc5OCC(F)F)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(OCC(F)F)c(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c1

Procedure:
{8-[2-(2,2-Difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine was prepared from 7-{8-[2-(2,2-difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.340 g, 0.555 mmol) and trifluoroacetic acid (1 mL) in a manner analogous to Example 312 to give product (0.262 g, 92%). MP=122-125° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.48 (s, 1H), 8.80 (d, 1H), 8.20 (s, 1H), 8.00 (d, 1H), 7.65 (d, 1H), 7.50 (m, 2H), 7.32 (s, 1H), 7.10 (t, 1H), 6.98 (d, 1H), 6.28 (br m, 1H), 4.54 (m, 2H), 3.23 (s, 3H), 2.67-2.77 (br m, 9H). MS=514 (MH)+.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[N:21]=[C:20]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[NH:19][N:18]=2)[CH:12]=[C:13]([Cl:15])[CH:14]=1.C(=O)(O)[O-].[Na+].C(OC(=O)C)(=O)C>C(#N)C>[Cl:15][C:13]1[CH:12]=[C:11]([NH:16][C:17]2[N:21]=[C:20]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:3](=[O:5])[CH3:2])[CH2:25][CH2:24]3)[NH:19][N:18]=2)[CH:10]=[C:9]([Cl:8])[CH:14]=1
Reactant: Clc1cc(Cl)cc(Nc2n[nH]c(NC3CCNCC3)n2)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(Nc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a stirred suspension of N3-(3,5-dichlorophenyl)-N5-(piperidin-4-yl)-1H-1,2,4-triazole-3,5-diamine 2,2,2-trifluoroacetate (50 mg, 0.113 mmol) in acetonitrile (5 mL), was added saturated sodium bicarbonate solution (5 mL) and acetic anhydride (14 mg, 0.136 mmol). The reaction mixture was stirred overnight at rt. The solution was extracted with EtOAc (3×10 mL) and dried with sodium sulfate. Removal of solvent gave the crude product, which was purified by flash chromatography to give 35 mg (84%) desired product as a white solid. MS +m/z: 369.0 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3]/[CH:4]=[CH:5]/[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:19]=[CH:20][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[NH:8][CH:7]=1>[Pd].CO>[CH3:39][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][C:16]2[CH:17]=[C:18]([N:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]3)[CH:19]=[CH:20][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[NH:8][CH:7]=1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1Oc1cccc2[nH]cc(/C=C/CN(C)C)c12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1Oc1cccc2[nH]cc(CCCN(C)C)c12

Procedure:
A mixture of EXAMPLE 339E (715 mg) and 5% palladium on carbon (143 mg) in methanol (20 mL) was hydrogenated at 30 psi for 16 hours at ambient temperature. The reaction mixture was filtered, concentrated and the crude product was chromatographed on silica gel with 7N-methanolic ammonia in methylene chloride.
Reaction SMILES: [Cl-].[Li+].[C:3]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:4]=1.[CH3:22][C:23]1[C:24](OS(C(F)(F)F)(=O)=O)=[C:25]([CH2:44]/[CH:45]=[C:46](\[CH3:53])/[CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:26]([O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[C:27]2[C:31]=1[CH2:30][O:29][C:28]2=[O:32].C([Sn](CCCC)(CCCC)CCCC)=C.[F-].[K+]>CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C(OCC)(=O)C.O>[CH3:22][C:23]1[C:24]([CH:3]=[CH2:4])=[C:25]([CH2:44]/[CH:45]=[C:46](\[CH3:53])/[CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])[C:26]([O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[C:27]2[C:31]=1[CH2:30][O:29][C:28]2=[O:32]
Reactant: COC(=O)CC/C(C)=C/Cc1c(OS(=O)(=O)C(F)(F)F)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=Cc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 55 °C

Procedure:
A mixture of lithium chloride (4.8 g), tris (dibenzylideneacetone)-dipalladium (0) chloroform adduct (0.65 g), triphenylarsine (1.6 g) and methyl (E) 6-(1,3-dihydro-7-methyl -3-oxo-4-p- toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate (24.2 g) in N-methylpyrrolidinone (220 ml) was heated to 55° C. Vinyltributyltin (15 g) was added. After 3 hours the mixture was added to water (500 ml), potassium fluoride (16 g) and ethyl acetate. The organic solution was dried, filtered through celite and evaporated to afford methyl (E) 6-(1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-vinylisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Yield: 62 %

Procedure:
A mixture of 7.4 g. (24.5 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine and 2.0 g. of 10% palladium-on-carbon in 150 ml. of ethanol and 75 ml. of ethyl acetate is stirred under one atmosphere of hydrogen for 2.5 hours. The reaction is filtered through diatomaceous earth and evaporated. Crystallization of the residue from ether-pentane gave 4.6 g. (62%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(NC(C)C)(C)C.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33].CN(C=O)C>CC1OCCC1.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.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(COC1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: CC1CCCO1
Product: CC(C)(C)C#Cc1ccc2c(c1)[C@@]1(COCC(N)=N1)c1cc(Br)cnc1O2
Temperature: 90 °C
Yield: 25.6 %

Procedure:
A vial was charged with (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine, diisopropylamine (0.785 mL, 5.51 mmol), Pd(PPh3)4 (0.127 g, 0.110 mmol), copper(I) iodide (0.021 g, 0.110 mmol), and 3,3-dimethyl-1-butyne (0.203 mL, 1.652 mmol). DMF (3 mL) were added, the vial was sealed under argon and heated to 90° C. for 60 minutes. The reaction mixture was diluted with 2-MeTHF then washed with water. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-3-bromo-7-(3,3-dimethylbut-1-ynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.120 g, 0.281 mmol, 25.6% yield) as a white solid. Step 2: A vial was charged with (S)-3-bromo-7-(3,3-dimethylbut-1-ynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.060 g, 0.141 mmol), 2-fluoropyridin-4-ylboronic acid (0.050 g, 0.352 mmol), potassium phosphate (0.299 g, 1.407 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.98 mg, 7.04 μmol) Dioxane (2 mL) and water (0.5 mL) were added, the vial was sealed under argon and heated to 80° C. for 1 hour. The reaction mixture was then diluted with 2-MeTHF, dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (95:5 EtOAc/MeOH)/DCM] gave (S)-7-(3,3-dimethylbut-1-ynyl)-3-(2-fluoropyridin-4-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.029 g, 0.066 mmol, 46.6% yield) as a yellow solid. [M+H]+=443.0
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C1COCC1>CCOCC.[Zn]>[F:15][C:9]([F:16])([C:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=C1CCCCC1
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C1(O)CCCCC1
Yield: 69.3 %

Procedure:
A stirred suspension of zinc (0.981 g, 15.01 mmol) in a solution of cyclohexanone (0.491 g, 5.0 mmol) and ethyl 2-bromo-2,2-difluoroacetate (2.031 g, 10.01 mmol) in an. THF (5 mL) was sonicated for 4-5 h and then heated to reflux for 1-2 h. The reaction mixture was cooled and diluted with ether and washed with 1 N HCl, satd. NaHCO3, water, brine and dried (MgSO4). Evaporation of solvents afforded an oil which was purified by silica gel FCC (5-10% EtOAc in DCM) to afford ethyl 2,2-difluoro-2-(1-hydroxycyclohexyl)acetate as a clear oil (770 mg, ˜70%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 4.37 (q, J=7.2 Hz, 2H), 2.10-2.01 (m, J=3.4 Hz, 1H), 1.82-1.69 (m, 3H), 1.68-1.54 (m, 6H), 1.38 (t, J=7.2 Hz, 3H), 1.20 (br. s, 1H).