Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:28]([O-])([N+]([O-])=O)=[O:29]>>[Cl:1][CH2:2][CH2:3][N:4]([N:28]=[O:29])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(CCCN1CCOCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(CCCN1CCOCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 54.7 %

Procedure:
4.1 g of 1-(2-chloroethyl)-3-(3-morpholinopropyl)-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.4 g of 1-(2-chloroethyl)-1-nitroso-3-(3-morpholinopropyl)-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([C:20](OCC)=[O:21])=[N:17][C:16]=2[CH3:25])=[CH:11][CH:10]=1.C(O)C>C(OCC)(=O)C>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:19][C:18]([C:20]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:21])=[N:17][C:16]=2[CH3:25])=[CH:13][CH:14]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1nc(C)c(-c2ccc(OC)cc2)s1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc(C(=O)N3CCCCC3)nc2C)cc1
Temperature: 92.5 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Piperidine (1.84 g, 21.63 mmol) was added to a stirred solution of ethyl 5-(4-methoxyphenyl)-4-methylthiazole-2-carboxylate (prepared according to the procedure reported in WO 2006/089076, 0.6 g, 2.16 mmol) in a ethanol (10 ml) in a tube at 25° C. under nitrogen atmosphere. The tube was agitated for about 15 minutes under nitrogen and was sealed. The reaction mixture was heated at 90-95° C. for 15 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and was concentrated under reduced pressure. The residue obtained was dissolved in ethyl acetate (50 ml). The mixture was washed with saturated sodium bicarbonate solution (20 ml). The separated organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.50 g, 73.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1>>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)=[O:9]
Reactant: Cc1ccoc1C(=O)O
Reactant: Cc1ccc(CCN)cc1
Product: Cc1ccc(CCNC(=O)c2occc2C)cc1

Procedure:
Prepared in a similar manner as described in example 4 from 3-methylfuran-2-carboxylic acid and 2-p-tolylethanamine. MS (M+H, 244).
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)([CH3:7])[CH3:6])C.[OH-].[Li+].Cl>CO>[OH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:15])=[O:3])[CH2:9]1
Reactant: CCOC(=O)C(C)(C)[C@H]1CCC[C@@H](O)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)[C@@H]1CCC[C@H](O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.00 g of 2-(cis-3-hydroxy-cyclohexyl)-2-methyl-propionic acid ethyl ester are dissolved in 30 ml of methanol. 30 ml of a 1M aqueous lithium hydroxide solution are added and the mixture is stirred for 16 hours at room temperature. The reaction mixture is neutralised with 1M HCl and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>CO.C(OCC)C>[CH2:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(NCc2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1ccc(CNc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.1 %

Procedure:
To the product from step 1 (148 mg, 0.387 mmol) in methanol (3 mL) was added 1M HCl in diethyl ether (6 mL) and the resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo to obtain the title product as a solid (128 mg, 93%); MS; m/z 283 (M+H): LCMS (UV) 97%: Elemental analysis Calc C, 60.85; H, 6.81; N, 7.88; Found C, 57.26; H, 7.21; N, 7.24. 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.73 (m, 1H), 1.87-2.12 (m, 3H), 3.17-3.21 (m, 2H), 3.84-3.87 (m, 2H), 4.19-4.23 (dd, 1H J1=3.6 Hz, J2=10.8 Hz), 4.11-4.16 (m, 1H), 4.44 (s, 2H), 7.0 (d, 2H J=8.8 Hz), 7.29-7.38 (m, 5H); 7.48-7.49 (m, 2H) 9.1 (s, 1H), 9.8 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([O:18][C@H:19]3[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31]([OH:33])=[O:32])[CH2:20]3)[N:6]=[C:7]3[C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:3]=1.[ClH:34].[CH3:35][CH2:36]O>>[ClH:34].[Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([O:18][C@H:19]3[CH2:23][NH:22][C@H:21]([C:31]([O:33][CH2:35][CH3:36])=[O:32])[CH2:20]3)[N:6]=[C:7]3[C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:3]=1
Reactant: COc1cc2c3c(nc(O[C@@H]4C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C4)c2cc1Br)CCCC3
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H]1C[C@@H](Oc2nc3c(c4cc(OC)c(Br)cc24)CCCC3)CN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the product from Step 1, (4R)-4-[(8-bromo-9-methoxy-1,2,3,4-tetrahydrophenanthridin-6-yl)oxy]-1-(tert-butoxycarbonyl)-L-proline (500 mg, 0.96 mmol) in EtOH (80 mL) was bubbled HCl (g) for 30 min. The mixture was then stirred for 2 days at r.t. and then the solvent was removed in vacuo to yield the title compound. LRMS (M+H)+=448.9.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][NH:20][C@H:21]1[CH2:40][N:25]2[C:26]3[C:31]([C:32]([CH2:33][C:34]([O:36]CCC)=[O:35])=[C:24]2[CH2:23][CH2:22]1)=[CH:30][CH:29]=[CH:28][CH:27]=3>>[CH3:19][N:20]([C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])[CH:11]=1)[C@H:21]1[CH2:40][N:25]2[C:26]3[C:31]([C:32]([CH2:33][C:34]([OH:36])=[O:35])=[C:24]2[CH2:23][CH2:22]1)=[CH:30][CH:29]=[CH:28][CH:27]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: CN(C(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 3-(piperidin-1-ylsulfonyl)benzoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 510.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[K+].I[CH3:14].O>CN(C=O)C>[CH3:14][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To room temperature solution of 5-chloroindole (4.97 g) in dry DMF (40 mL) was added potassium hydroxide pellets (2.76 g) and stirred 1 h until most of the solid dissolved. The resulting mixture was cooled to 0° C. in an ice bath and iodomethane (2.45 mL) was added dropwise and later stirred overnight at room temperature under argon. The reaction mixture was poured into water and extracted twice with ETOAc. The combined ETOAc portions were combined, washed with water, dried over magnesium sulfate, concentrated, and flash chromatographed with 10% ETOAc/Hexane to give 1-methyl-5-chloroindole as a pink liquid (5.43 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[CH2:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[C:25]([C:34]#[N:35])=[CH:24]1)[CH3:22].[CH2:36]([Sn:40](I)([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH3:39]>C1COCC1>[CH2:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[C:25]([C:34]#[N:35])=[C:24]1[Sn:40]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:36][CH2:37][CH2:38][CH3:39])[CH3:22]
Reactant: CCn1cc(C#N)c2ccc(OC)cc21
Reactant: CCCC[Sn](I)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C#N)c2ccc(OC)cc2n1CC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
A solution of THF (60 mL) and diisopropylamine (5.5 mL, 39 mmol) is cooled to −78° C. n-Butyllithium (14.5 mL, 2.5M in hexanes, 36.2 mmol) is added dropwise over 5 minutes. The LDA mixture is stirred at −78° C. for 10 minutes, and then at 0° C. for 20 minutes. The solution is re-cooled to −78° C. 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (5.0 g, 25 mmol), prepared as in example 1A, is taken up in THF (30 mL) and added dropwise to the LDA mixture over 15 minutes. The reaction is stirred at −78° C. for 10 minutes, and at 0° C. for 30 minutes. Once again, the reaction mixture is cooled to −78° C. Tributyltin iodide (10 mL, 35 mmol) is added dropwise. This is stirred at −78° C. for 15 minutes, and then at 0° C. for 30 minutes. The reaction mixture is absorbed onto silica gel and concentrated. Purification by chromatography (CH2Cl2) yields 1-ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (12.05 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH3:16])=[CH:10][CH:9]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[N:28][OH:29])[CH2:15][CH3:16])=[CH:10][CH:9]=1
Reactant: CCC(=O)c1ccc(Oc2cc(F)cc(C3(OC)CCOC3C)c2)cc1
Reactant: NO
Agent: Cl
Product: CCC(=NO)c1ccc(Oc2cc(F)cc(C3(OC)CCOC3C)c2)cc1
Yield: 83 %

Procedure:
Using an analogous procedure to that described in Example 66, 4'{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenoxy}propiophenone was reacted with hydroxylamine hydrochloride to give 4'-{5-fluoro-3-{(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenoxy}propiophenone oxime in 83% yield, m.p. 94°-96° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])CCC.[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36])([CH3:31])([CH3:30])[CH3:29].C(O)(=O)C>C(O)C>[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH:36][C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O
Yield: 98.3 %

Procedure:
A mixture of 1-cyano-7-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (45 mg, 0.12 mmol) (prepared according to U.S. Pat. No. 7,629,357) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (50 mg, 0.29 mmol) in ethanol was microwaved at 140° C. for 1 h. Reaction mixture was quenched with acetic acid (3 equivalents) and concentrated. Residue was purified by silica gel chromatography, eluting with 5-50% EtOAc/hexanes to provide the title compound 55 mg (0.118 mmol) in 98% yield. 1H NMR (200 MHz) CDCl3, δ in ppm: 13.92 (s, 1H), 8.29 (d, J=8.4 Hz, 1H), 7.42 (m, 2H), 4.56 (br s, 1H), 3.55 (d, J=6.2 Hz, 2H), 2.04 (br m, 2H), 1.83 (br m, 2H), 1.56-1.24 (m, 21H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH2:12]([N:18]=[C:19]=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([NH:18][C:19]([N:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[S:8]1)=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCN=C=O
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Product: CCCCCCNC(=O)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example I, compound 6x (91% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and n-hexyl isocyanate as a white solid. IR(CHCl3) 3298, 1713, 1539 cm−1; 1H-NMR (CDCl3) δ0.89 (t, J=6.8 Hz, 3H), 1.28-1.43 (m, 6H), 1.60-1.68 (m, 2H), 3.40-3.46 (m, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.58 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 8.77 (s, 1H); ESIMS m/e 313 and 315 (M++1, 35Cl and 37Cl).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH3:17][O:18][NH2:19].[OH-].[Na+]>O1CCOCC1.O>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([NH:19][O:18][CH3:17])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCNc1nc(NCCC)nc(NOC)n1
Temperature: 60 °C
Yield: 90.2 %

Procedure:
A mixture of 6-chloro-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (XXXIV) (2.30 g, 10.01 mmol), O-methyl-hydroxylamine hydrochloride (1.67 g, 20.02 mmol) and NaOH (0.72 g, 18.00 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was heated at 60° C. for 3 h. After this time, NaOH (0.72 g, 18.00 mmol) was added and the reaction mixture was heated for another 3 h. The volatiles were removed under reduced pressure. Saturated NaHCO3 solution (100 mL) was added to the residue, the mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield 2.17 g (90%) of N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine (XLI). ESI-MS (m/z): 241 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[OH:37]>CCOCC>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[O:37][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: COC(c1cc(C)no1)c1ccccc1CCl
Reactant: Oc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(c1cc(C)no1)c1ccccc1COc1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To 0.25 g (1 mmol) of 5-(2-chloromethyl-α-methoxybenzyl)-3-methylisoxazole, 2 ml of N,N-dimethylformamide, 0.28 g (2 mmol) of potassium carbonate and 0.33 g (2 mmol) of 2,5-dichlorophenol were added and stirred at 80° C. for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and recrystallized from ether/n-hexane to give 5-[2-(2,5-dichlorophenoxymethyl)-α-methoxybenzyl]-3-methylisoxazole (0.28 g, 74.0%) as colorless crystals. mp. 78.5-79.5° C.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH2:10])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH2:8][CH:21]3[CH:22]([CH2:10][C:9]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17](=[O:23])[CH2:18][CH2:19][CH2:20]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C(=C)c1ccccc1)c1ccccc1
Reactant: O=C1C=CCCC1
Solvent: Cc1ccccc1
Product: O=C1CCCC2CC(c3ccccc3)=C(c3ccccc3)CC12

Procedure:
A mixture of 2,3-diphenyl-1,3-butadiene (2.772 g, 13.44 mmol) and cyclohex-2-enone (1 eq.) was refluxed in toluene (26 mL) for 48 h. The reaction mixture was then concentrated and purified on SiO2 (20% ethyl acetate/hexane) to yield 6,7-diphenyl-3,4,4a,5,8,8a-hexahydro-2H-naphthalen-1-one.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>ClCCl>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:29])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NCc1nccnc1Cl
Reactant: CN1CCC(C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC(C(=O)NCc2nccnc2Cl)CC1
Yield: 83 %

Procedure:
To a solution of 2-aminomethyl-3-chloropyrazine hydrochloride (content 70%; 7.85 mmol, 1.7 g) in N,N-diisopropylethylamine (39.3 mmol, 6.84 ml) and dichloromethane (30 ml) at 0° C. was added carefully 1-methylpiperidine-4-carbonyl chloride hydrochloride (9.42 mmol, 2.2 g). Then the cooling bath was removed. After two hours saturated aqueous sodium hydrogencarbonate solution (40 mL) was added and extracted five times with dichloromethane (30 mL). The organic extracts were combined, dried and concentrated and co-evaporated twice with toluene to give N-((3-chloropyrazin-2-yl)methyl)-1-methylpiperidine-4-carboxamide (1.75 g)
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1)=O)(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCC[C@@H](C(=O)O)C1
Yield: 86 %

Procedure:
A mixture of (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid in a 1:1 solution of TFA: CH2Cl2 (6 mL) was stirred at rt for 3 h. The mixture was concentrated under reduced pressure. The residue was triturated in ethyl ether (50 mL) and the resulting solid was collected by filtration to afford (1R,3R)-3-aminocyclohexanecarboxylic acid trifluoroacetate (253 mg, 86%) as a white solid that did not require further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[N-:13]=[N+]=[N-].[Na+].CS(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:13][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a mixture of 6-Methoxy-1-indanone (15 g, 92.6 mmol), sodium azide (26.7 g, 277.8 mmol), in CHCl3 was added methane sulfonic acid (60 g, 926 mmol) via addition funnel at 0° C. Reaction mixture was warm to room temperature. Stirring was continued for 3 hr, then poured into cold water. The organics were extracted with methylene chloride and washed with water, sat. NaCl and dried over Na2SO4. Organic solution was concentrated in vacuo and the residue was purified with silica gel eluting with 20% EtOAc/Hexane to give the title compound as a yellow solid (10.5 g, 63%). MS (ES) m/z 178.1.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:23]1([CH3:34])[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31](O)=[O:32])[CH:24]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:31](=[O:32])[CH2:30][O:29][C:25]3[CH:24]=[C:23]([CH3:34])[CH:28]=[CH:27][CH:26]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Cc1cccc(OCC(=O)O)c1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Product: Cc1cccc(OCC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)c1
Yield: 45 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 3-tolyloxyacetic acid in a yield of 45%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)ccn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a stirring solution of (4-bromopyridin-2-yl)methanol (1.50 g, 8.0 mmol) in DCM (4 mL) was added tert-butylchlorodimethylsilane (1.20 g, 8.0 mmol) following by TEA (1.60 g, 12.0 mmol). The reaction mixture was stirred at room temperature for 12 h then washed with brine and EA. The combined organic layers were dried over MgSO4, filtered, and concentrated to yield an amber liquid. The crude product was purified by chromatography (EA/Hexanes) to produce 1.67 g (70%) of 4-bromo-2-((tert-butyldimethylsilyloxy)methyl)pyridine INT-70 as a light yellow liquid. LCMS-ESI (m/z) calculated for C12H20BrNOSi: 302.3; found 303.0 [M+H]+, tR=4.87 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=5.3, 1H), 7.68 (dd, J=1.9, 0.7, 1H), 7.35-7.24 (m, 1H), 4.80 (s, 2H), 0.99-0.86 (m, 9H), 0.16-0.06 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH:28]([CH3:30])[CH3:29])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2].[Se](=O)=[O:32]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH:28]([CH3:29])[CH3:30])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cc2cccc(OC(C)C)c2)c2cc(OC)c(OC)cc12
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(OC)cc12
Yield: 65.8 %

Procedure:
The above 1-(3-isopropoxybenzyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester (2.20 g, 5.38 mmol) was dissolved into 100 ml of ethyl acetate. Then selenium dioxide (1.08 g, 9.73 mmol) was added and the mixture was refluxed for 30 minutes. The reaction mixture was filtered through a thin layer of silica gel. The filtrate was concentrated and then purified through a flash column chromatography using hexane and ethyl acetate (2.5/1 ratio) to give 1-(3-isopropoxybenzoyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester as a solid (1.50 g, 66%).