Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.C[Si]([N:21]=[C:22]=[O:23])(C)C.Cl>CCCCCC.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:22]([NH2:21])=[O:23])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: Cc1cnc2c(c1)CCCC2C(N)=O
Reaction time: 1 h
Yield: 32.6 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (7.3 g., 0.05 mol.) in hexane (50 ml.) was cooled to 0° C and treated dropwise with 15w/w butyllithium in hexane (26 ml., 0.06 mol.) in a nitrogen atmosphere. The reaction mixture was allowed to stand at 0° C for 1 hour and was then added dropwise over 30 minutes to a solution of trimethylsilylisocyanate (19.5 g., 0.17 mol.) in hexane (50 ml.) keeping the internal temperature at -20° C. The reaction mixture was allowed to stand at -20° C for 1 hour and was then diluted with water (50 ml.) and the pH adjusted to 2.0 with conc. HCl. The hexane layer was separated and discarded and the aqueous solution adjusted to pH 10.0 with sodium carbonate and extracted with chloroform (3 × 25 ml.). The combined extracts were washed with saturated brine, dried and the solvent removed in vacuo. The residue was triturated with n-hexane, filtered and the solid crystallised from ethyl acetate to give the title compound as colourless needles (3.1 g., 35%) m.p. 104° C. identical in all respects to the authentic material (when crystallised from ethyl acetate). Analysis: Found C, 69.1; 7.4; N, 14.7. C11H14N2O requires C, 69.5; H, 7.4; N, 14.7. The hexane soluble material was distilled to give recovered 3-methyl-5,6,7,8-tetrahydroquinoline (4.2 g.) b.p. 120°/15 mm.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)=[CH:3][N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: CCC(COC)n1cc(I)c2c(OC)nccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(COC)n1cc(-c2ccc(C#N)cc2)c2c(OC)nccc21
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridine (200 mg) obtained in Step A-2 of Example 17 in DMF (4 mL)/water (0.40 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (191 mg), tetrakis(triphenylphosphine)palladium(0) (64.2 mg) and potassium carbonate (154 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (40.0 mg).
Reaction SMILES: C[I:2].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[OH:25][C:26]1[C:27]([CH3:41])=[C:28]([CH3:40])[C:29]2[O:33][CH:32]([CH2:34][CH2:35][CH2:36]O)[S:31][C:30]=2[C:38]=1[CH3:39]>CN(C)C=O>[OH:25][C:26]1[C:27]([CH3:41])=[C:28]([CH3:40])[C:29]2[O:33][CH:32]([CH2:34][CH2:35][CH2:36][I:2])[S:31][C:30]=2[C:38]=1[CH3:39]
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Reactant: CI
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCI)O2
Reaction time: 1 h

Procedure:
2 ml of methyl iodide were added to 0.67 g of triphenyl phosphite, and then the temperature of the reaction mixture was raised to reflux temperature, after which the reaction was continued for 1 hour at a bath temperature of 100° C. The temperature of the reaction mixture was reduced to room temperature, and then 0.5 g of 3-(5-hydroxy-4,6,7-trimethyl-1,3,-benzoxathiole-2-yl)propanol (prepared as described in Example 71), 1 ml of methyl iodide and 0.5 ml of dimethylformamide were added to the reaction mixture. The reaction was continued for 3 days at room temperature. At the end of this time, the title compound, having the same properties as the product of (a) above, was obtained by the same treatment and separation procedures as in (a).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CN1C(=O)CCC1>CN(C=O)C>[CH:11]1([C:9]2[CH:10]=[C:6]3[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=4)[CH:3]=[C:2]([N:31]4[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]4)[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C4CC4)cc3n2)cc1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(O)CC3)n3nc(C4CC4)cc3n2)cc1
Temperature: 25 °C

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2J, 100 mg, 0.27 mmol) and 4-hydroxypiperidine (55.0 mg, 0.54 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 15 minutes. After cooling to room temperature, DMF (1 ml) was added. The crude product mixture was filtered by syringe filter and purified by preparatory HPLC (20-40% ACN/water, TFA mode). Lyophilization of the collected fractions gave the titled compound product (30 mg, 26% yield) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.78 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.34 (s, 1H), 6.02 (s, 1H), 5.18 (s, 1H), 4.84 (d, J=4.3 Hz, 1H), 4.12 (d, J=12.6 Hz, 2H), 3.79 (dd, J=4.2, 8.5 Hz, 1H), 3.41-3.36 (m, 1H), 2.11-2.00 (m, 1H), 1.91 (br. s., 2H), 1.65-1.51 (m, 2H), 1.45 (s, 6H), 1.04-0.94 (m, 2H), 0.88-0.75 (m, 2H); ESI-MS: m/z 436.3 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=2[CH3:31])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:33][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=2[CH3:31])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CO)c2)c(C)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Temperature: 25 °C

Procedure:
To a 0° C. solution of methyl 2″-(hydroxymethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (1.500 g, 3.49 mmol) in CH2Cl2 (14 mL) was added CBr4 (2.429 g, 7.33 mmol), and then a solution of triphenyl phosphine (1.830 g, 6.98 mmol) in CH2Cl2 (15 mL). The solution was warmed to room temperature and stirred for twelve hours. The reaction was concentrated, and the residue was purified by flash chromatography on silica gel (0 to 25% EtOAc/hexanes) to afford methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. Rf=0.59 (50% EtOAc/hexanes). LCMS=494.8 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.95 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.40-7.33 (m, 3H), 7.21 (d, J=2.3 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.44-4.39 (m, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].C([O:24][C:25](=[O:55])[C@@H:26]([NH:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:47]2[CH2:52][CH2:51][CH:50]([CH:53]=O)[CH2:49][CH2:48]2)(=[O:46])=[O:45])=[CH:40][CH:39]=1)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][NH:1][CH2:53][CH:50]1[CH2:51][CH2:52][N:47]([S:44]([C:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]([NH:34][C@@H:26]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]([OH:55])=[O:24])=[O:36])=[CH:39][CH:40]=2)(=[O:46])=[O:45])[CH2:48][CH2:49]1
Reactant: O=CC1CCN(S(=O)(=O)c2ccc(NC(=O)N[C@@H](Cc3ccccc3)C(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(NC(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methane-sulfonamide (0.320 g, 1.3 mmol), (2S)-2-{3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-ureido}-3-phenyl-propionic acid benzyl ester (1.3 mmol) and glacial acetic acid (0.074 g, 1.3 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.086 g, 1.3 mmol) was added and the mixture stirred overnight at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1). to give 0.12 g of the product.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:22]([NH:24][C@H:25]([C:30]([OH:32])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1.C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:22]([NH:24][C@H:25]([C:30]([OH:32])=[O:31])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(CCc1ccccc1)C(=O)O)C(=O)O

Procedure:
In the manner described in example 24, one can condense 2-oxo-4-phenylbutyric acid and L-histidinyl-L-leucine in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-histidinyl-L-leucine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:16][CH2:17]C[CH2-].ICC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH2:16][CH3:17])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Reactant: [CH2-]CCC
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cccnc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
2-t-Butoxycarbonylaminopyridine (10 g, 51.5 mmol) was dissolved in tetrahydrofuran (80 mL), and cooled to -78° C. N-butyllithium (80 mL of 1.49M in hexanes, 120 mmol) was added dropwise over a period of 1 h. After stirring for an additional 15 min at -78° C. and then for 2.5 hours at -10° C., the solution was then recooled back down to -78° C. and iodoethane (77.2 mmol, 6.18 mL) was added dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 mL of a saturated ammonium chloride and extracted with ethyl acetate (3×). The organic layers were collected, dried over magnesium sulfate, and concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) to provide the 4.9 g (43%) of the titled product as a light brown solid: mp 101°-102° C.; IR (KBr, cm-1) 3174, 2968, 1725, 1594, 1519, 1442, 1278, 1249, 1156; 1H NMR (300 MHZ, DMSO-d6) δ 8.98 (s, 1 H), 8.17 (m, 1H), 7.61 (m, 1H), 7.15 (m, 1H), 2.52 (q, J=7.5 Hz, 2H), 1.39 (s, 9H), 1.08 (t, J=7.5 Hz, 3H); MS (FD) m/e 222 (M+); UV (EtOH) 270 nm (ε=4398), 223 nm (ε=6745). Anal. Calcd for C12H18N2O2 : C, 64.84; H, 8.16; N, 12.60. Found: C, 64.91; H, 8.34; N, 12.42.
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:20]#[N:21])[C:12](N)=[N:13][C:14]=3[C:15]2=[O:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+]([O-])([O-])=[O:23].[Na+].O>C(O)(=O)C>[CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:20]#[N:21])[C:12]([OH:23])=[N:13][C:14]=3[C:15]2=[O:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)c1ccc2oc3cc(C#N)c(N)nc3c(=O)c2c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1ccc2oc3cc(C#N)c(O)nc3c(=O)c2c1
Temperature: 70 °C

Procedure:
To a solution of 0.5 g of 7-isopropyl-2-amino-3-cyano-1-azaxanthone in 80 ml of acetic acid was added gradually 1.0 g of sodium nitrate at 70° C. After one hour period, 3 ml of water was added to the mixture which was heated at 70° C. for a further one hour. The solvent was distilled off under reduced pressure and then, to the residue, water was added. The yellow precipitate was collected by filtration, rinsed with water and recrystallized from ethanol to give 7-isopropyl-2-hydroxy-3-cyano-1-azaxanthone as yellow crystals, m.p. > 300° C.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[C:16]2[C:17](=[O:30])[N:18]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:19][CH2:20][CH2:21][C:15]=2[NH:14][CH:13]=1>ClCCl>[CH3:11][C:12]1[C:16]2[C:17](=[O:30])[N:18]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:19][CH2:20][CH2:21][C:15]=2[NH:14][C:13]=1[CH:3]=[O:4]
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
Dichloromethane (36 ml, 559 mmol) and N,N-dimethylformamide (1.637 ml, 20.9 mmol) were stirred for 5 minutes at −15° C. in an ice-salt bath under an argon atmosphere. The solution was added dropwise with phosphorus oxychloride (1.07 ml, 11.5 mmol) and stirred for 15 minutes while maintaining the temperature at −10° C. 3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-on e 32c (1.26 g, 4.58 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above solution. Upon completion of the addition, the ice-salt bath was removed, and the reaction mixture was stirred for 3 hours at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with iced water, adjusted to about pH 10 with sodium hydroxide solution (10 mol/L) and stirred for 30 minutes, extracted with dichloromethane (30 ml×3). The combined organic extracts were washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (993 mg, yield 71.4%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:26])[CH:12]=[CH:13][N:14]2[CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22].[Br:27]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:27][C:12]1[C:11](=[O:26])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N:14]([CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC(CCC)n1ccc(=O)c2c(-c3ccc(C)cc3C)cccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)n1cc(Br)c(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
5-(2,4-Dimethylphenyl)-1-(1-propylbutyl)quinolin-4(1H)-one, (0.21 g, 0.61 mmol), was dissolved in N,N-dimethylformamide (10 mL). The solution was cooled to 0° C. and N-bromosuccinimide (0.11 g, 0.62 mmol) was added. After 10 minutes, the solution was diluted with water, extracted with ethyl acetate, dried (Na2SO4), and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave 0.136 g (53% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[C:6](=[O:12])[NH:7]2.C1CCC(N=C=NC2CCCCC2)CC1.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][NH:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:13][C:14]([N:42]([CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:16])[C:6](=[O:12])[NH:7]2
Reactant: COC(=O)CNCCNC(=O)OC(C)(C)C
Reactant: Cc1ccnc2[nH]c(=O)c(CC(=O)O)cc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Cc1cc2c(C)ccnc2[nH]c1=O
Reaction time: 0.67 h
Yield: 31.6 %

Procedure:
To a precooled (0° C.) solution of (5-methyl-1,8-naphthyridin-2(1H)-on-3-yl)acetic acid (1.20 g, 5.50 mmol) and DhbtOH (0.987 g, 6.10 mmol) in DMF (25 mL) was added DCC (1.25 g, 6.10 mmol) and the resulting mixture was stirred for 40 min. prior to the addition of methyl N-(2-(tert-butyloxycarbonyl)aminoethyl)glycinate (1.32 g, 6.10 mmol). The mixture was stirred at rt. overnight, evaporated in vacuo, redissolved in ethyl acetate (75 mL) and the DCU filtered off. The organic phase was washed with NaHCO3 (3×25 mL) and with brine (2×25 mL), dried (MgSO4) and evaporated in vacuo. The crude product was purified on silica using MeOH/dichloromethane (95:5 to 90:10 v/v) as the eluent. Fractions containing the product were pooled and evaporated in vacuo. to yield the desired product (752 mg, 33%) (mp 175-77° C.). 1H NMR (DMSO-d6; this compound exists as two rotamers; chemical shifts for the minor rotamer is given in brackets): δ 12.10 (12.08), (s br, 1H), 8.33 (8.33) (d, J=4.8 Hz, 1H), 7.96 (7.90) (s, 1H), 7.09 (d, J=4.8 Hz, 1H), 6.92 (6.70) (m, 1H), 4.07 (4.37) (s, 2H), 3.67 (s, 2H), 3.64 (s, 3H), 3.46 (m, 2H), 3.17 (m, 2H), 2.54 (2.53) (s, 3H), 1.37 (1.35) (s, 9H). 13C NMR (DMSO-d6): δ 170.30 (170.50), 170.04, 162.30, 155.73, 149.47, 149.25, 145.16, 132.92 (133.56), 129.12 (129.28), 119.87, 113.35, 77.97, 52.13, 51.76 (50.12), 47.47 (48.16), 38.98 (38.39), 33.81 (33.99), 28.24, 17.66. FAB+MS (m/z): 433.2087 (M+H+, calc. for C21H28N4O6+H+ 433.2086).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[N:14]=1)=[O:8]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Solvent: C1CCOC1
Product: COc1ccc(CNCc2csc(NC(=O)NCc3ccc(Cl)c(Cl)c3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,4-dichlorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (Intermediate 6) was taken up in tetrahydrofuran and an excess of the 2,4-dimethoxy-benzylamine (20 eq.) was added. The reaction was allowed to stir overnight at room temperature. The volatiles were removed in vacuo. Resulting oil triturated with water to give a gooey solid. Water was decanted off and resulting residue was purified by column chromatography using 0-8% gradient of 7 N ammonia/MeOH and DCM to give 1-(3,4-Dichloro-benzyl)-3-{4-[(2,4-dimethoxy-benzylamino)-methyl]-thiazol-2-yl}-urea.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][O:7][C:8]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>>[CH2:1]1[C@H:5]2[CH2:6][O:7][C:8]3[CH:15]=[CH:14][C:13]([C:16]([Cl:21])=[O:18])=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)C(=O)N1CCC[C@H]1CO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(c1)C(=O)N1CCC[C@H]1CO2

Procedure:
A solution of the above carboxylic acid derivative (2.38 g; 9.64 mmol) in thionyl chloride (10 ml) was heated under reflux for 1.5 h. The excess thionyl chloride was evaporated under reduced pressure to giving (S)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzoxazepine-5-one-7-carboxylic acid chloride (2.56 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:20]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28]([CH3:33])[C:29](=[O:32])[CH2:30]Cl.O>CN(C)C=O>[CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:20]=1)[C:3]([O:5][CH2:30][C:29](=[O:32])[N:28]([CH3:33])[CH3:27])=[O:4]
Reactant: Cc1ccc2c(n1)Oc1ccc(C(C)C(=O)O)cc1C2
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(n1)Oc1ccc(C(C)C(=O)OCC(=O)N(C)C)cc1C2
Temperature: 75 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
Under a nitrogen atmosphere, 5.4 g of α,2-dimethyl-5H-[1]-benzopyrano [2,3-b]pyridine-7-acetic acid is dissolved in 22 ml of dimethylformamide, whereafter 1.9 g of potassium carbonate and 2.7 g of N,N-dimethyl-2-chloroacetamide are added, and the mixture is stirred at 75° C. for 2 hours. Under cooling with ice, 50 ml of water is added to the resulting reaction mixture. The precipitated crystals are collected by filtration and washed with water, and then recrystallized from isopropyl alcohol to obtain 6.4 g of N,N-dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano[2,3-b]-pyridine-7acetate as white crystals having a melting point of 150° to 151° C.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CS(O[CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)(=O)=O>CS(C)=O.[Cl-].[Na+].O>[C:1](=[S:3])([O:4][CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)[CH3:2]
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: CC([O-])=S
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=S)OC1CCC2(CC1)OCCO2
Temperature: 40 °C
Yield: 64.8 %

Procedure:
Potassium thioacetate (21.39 g, 187 mmol) was added to a stirred mixture of 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (29.5 g, 125 mmol) in DMSO (31.2 ml) and the mixture was heated at 40° C. for 24 h. The mixture was cooled, brine was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried, and evaporated. The residue was purified by column chromatography on silica gel using a Biotage 65i cartridge, eluting with EtOAc/isohexane to give 1,4-dioxaspiro[4.5]dec-8-yl ethanethioate (17.5 g, 81 mmol, 64.8% yield) as a red oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][N:12]=1
Reactant: [H][H]
Reactant: COc1cc(OCc2ccccc2)ccn1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(O)ccn1
Yield: 99.9 %

Procedure:
A solution of 4-(benzyloxy)-2-methoxypyridine produced in Example (16a) (4.65 g, 21.6 mmol) and 10% palladium carbon (2.30 g, 2.16 mmol) in ethanol (100 mL) was stirred in a hydrogen atmosphere at room temperature for 30 minutes. The insoluble matter was separated by filtration and then the filtrate was concentrated to obtain the title compound (2.70 g, 99%) as a colorless oil.