Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:22])[S:12][C:13]=2[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>>[CH3:37][O:36][C:32]1[CH:31]=[C:27]([CH:26]=[C:25]([O:24][CH3:23])[C:33]=1[O:34][CH3:35])[C:28]([NH:22][C:11]1[S:12][C:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)=[O:29]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(-c2nc(N)sc2CCc2ccccc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3cc(OC)c(OC)c(OC)c3)sc2CCc2ccccc2)cc1
Yield: 67.2 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-phenylethyl-thiazol-2-ylamine prepared in Example 57 and 3,4,5-trimethoxy-benzoyl chloride prepared in the step 1 of Example 37 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product as a foam, which was recrystallized with petroleum ether and ethyl acetate at a ratio of 2:1 (V:V) to obtain a product as a white solid in a yield of 67.2%, mp: 78-79 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.03 (2H, t, J=7.60 Hz, CH2), 3.19 (2H, t, J=7.60 Hz, CH2), 3.80 (6H, s, 2×OCH3), 3.81 (3H, s, OCH3), 3.91 (3H, s, OCH3), 6.78 (2H, d, J=8.40 Hz, ArH), 7.02 (2H, s, ArH), 7.15˜7.32 (7H, m, ArH), 11.54 (1H, br, CONH); EI-MS m/e (%): 504.2 (M+, 24), 413.2 (53), 195.1 (100); HREI-MS Calcd. for C28H28N2O5S: 504.1719. found: 504.1716.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Br[C:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][C:15]([NH:21]C=O)=[N:14][C:13]=2[N:12]([C@@H:24]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[C@@H:26]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:25]2)[CH:11]=1>C(#N)C.CN(C=O)C>[Cl:1][C:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][C:15]([NH2:21])=[N:14][C:13]=2[N:12]([C@@H:24]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[C@@H:26]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:25]2)[CH:11]=1
Reactant: COc1nc(NC=O)nc2c1c(Br)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1nc(N)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reaction time: 8 h

Procedure:
Using N-chlorosuccinimide, the substance was prepared and worked up in analogy with compound (19). The halogenation reaction time was 8 hours. Acetonitrile/DMF (4:1) was used as the solvent. Colorless solid (70%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Br:17][C:18]1[N:26]=[CH:25][C:24]2[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]3[N:35]=[CH:36][CH:37]=[C:38](Cl)[C:21]=3[C:20]=2[CH:19]=1.BrC1N=CC2N(COCC[Si](C)(C)C)C3N=C(Cl)C=CC=3C=2C=1>O1CCCC1.O.C(OCC)(=O)C>[Br:17][C:18]1[N:26]=[CH:25][C:24]2[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:22]3[N:35]=[CH:36][CH:37]=[C:38]([O:1][C@@H:2]4[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]4)[C:21]=3[C:20]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: C[Si](C)(C)CCOCn1c2cnc(Br)cc2c2c(Cl)ccnc21
Agent: C[Si](C)(C)CCOCn1c2cnc(Br)cc2c2ccc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2ccnc3c2c2cc(Br)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a solution of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (64 mg, 0.32 mmol) in tetrahydrofuran (1.2 mL) was added sodium hydride as 60% dispersion in mineral oil (13 mg, 0.32 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before a mixture of 6-bromo-4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole with 6-bromo-2-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (4:1, 60 mg, 0.1 mmol) was added in one portion, and the reaction mixture was stirred at this temperature for 10 minutes before being warmed to 40° C. for 2 hours. The cooled reaction mixture was then diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 0-65% ethyl acetate in heptane) to afford the title compound as a colorless oil, which was used in the next step without any further purification (60 mg, 70%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[N:31]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[C:32]=[O:33]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:32]([NH:31][CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=NCCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCc1ccccc1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 31.5 mg (0.21 mmol) of (2-isocyanatoethyl)benzene. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 32 mg (61.8% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].O(C)[Na].CN([CH:12]=[C:13]1[C:19](=O)[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)[CH2:15][CH2:14]1)C>CO>[CH3:3][C:2]1[N:4]=[CH:12][C:13]2[CH2:14][CH2:15][N:16]([C:25](=[O:35])[C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]=2[N:5]=1
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc2C1=O
Reactant: CC(=N)N
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Reaction time: 0.08 h
Yield: 99.7 %

Procedure:
To a stirred solution of 0.233 g of acetamidine hydrochloride in 36 ml of methyl alcohol under argon is added 0.133 g of NaOCH3. After 5 minutes, 0.600 g of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one is added and stirring continued for 18 hours. The volatiles are evaporated to a residue which is dissolved in ethyl acetate and passed through a pad of silica gel. The filtrate is evaporated in vacuo to give 590 mg of the desired product as tan crystals, m.p. 211°-212° C. HR FABMS: Exact mass (M+H):361.1295.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH3:14])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.BrC1SC(C)=NC=1.O1C2(CCC(=O)CC2)OCC1.[NH:33]1[CH2:36][CH:35]([NH:37][C:38](=[O:55])[CH2:39][NH:40][C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[C:48]([C:51]([F:54])([F:53])[F:52])[CH:49]=3)[N:44]=[CH:43][N:42]=2)[CH2:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[OH:1][C:2]1([C:9]2[S:13][C:12]([CH3:14])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:33]2[CH2:34][CH:35]([NH:37][C:38](=[O:55])[CH2:39][NH:40][C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[C:48]([C:51]([F:52])([F:54])[F:53])[CH:49]=4)[N:44]=[CH:43][N:42]=3)[CH2:36]2)[CH2:4][CH2:3]1
Reactant: Cc1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ncc(Br)s1
Agent: O=C1CCC2(CC1)OCCO2
Product: Cc1ncc(C2(O)CCC(N3CC(NC(=O)CNc4ncnc5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
Reaction of 4-hydroxy-4-(2-methylthiazol-5-yl)cyclohexanone (prepared by the reaction of 5-bromo-2-methylthiazole with 1,4-dioxaspiro[4.5]decan-8-one using the sequence described in Example 24 Step A-B) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH:12]([CH3:14])[CH3:13].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Sc1cc2cc[nH]c2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)Sc1cc2c(cc1Cl)NCC2
Yield: 71.1 %

Procedure:
6-Chloro-5-isopropylthioindole (D65) (0.49 g, 2.16 mmol) was treated with sodium cyanoborohydride as in the method of Description 10 to give the title compound (0.35 g, 71%) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C1=COCCC1
Reactant: CCOC(=O)CCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCOC1CCCCO1

Procedure:
66 g. (0.412 mol) of ethyl 6-hydroxyhexanoate [prepared as described by S. R. Sandler and W. Karo, in `Organic Functional Group Preparation` , Academic Press, New York, and London, vol. 1, page 262. (cf. G. B. Hatch and H. Adkins, J. Am. Chem. Soc., 59 1694 (1937))] were dissolved in 400 ml. of methylene chloride, and the mixture was reacted with 45 g. of dihydropyran and 1 g. of p-toluenesulphonic acid at 25°C. for 20 minutes. The reaction mixture was washed with an aqueous sodium bicarbonate solution, dried and concentrated. The residue was distilled in vacuo to obtain 77 g. of the title compound having the following physical characteristics:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)[C@H:3]([OH:6])[CH2:4]Cl.[OH-].[K+].O>C(O)C>[F:15][C:10]1[CH:9]=[C:8]([CH2:7][C@H:2]([NH2:1])[C@H:3]2[CH2:4][O:6]2)[CH:13]=[C:12]([F:14])[CH:11]=1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reaction time: 0.5 h

Procedure:
(1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylamine (EXAMPLE 17, 33mg, 0.14 mmol) and absolute ethanol (1.5 mL) are mixed. Potassium hydroxide (9.8 mg, 0.175 mmol) in absolute ethanol (0.5 mL) is added to this mixture and the resulting mixture is stirred at 20-25 deg for 30 min. At this time ESMS indicates formation of the product (MH+=200.1). Water (2 mL) is added and mixture is concentrated under reduced pressure to half the volume and then diluted with ethyl acetate (15 mL). The organic phase is separated and the aqueous phase is extracted with ethyl acetate (2×10 mL). The organic phases are combined, washed with saline and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to give the title compound, MH+=200.1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(C)=O.CCN(C(C)C)C(C)C.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Cl>O>[N:1]([CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1ccccc1Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1ccccc1Cl

Procedure:
Sodium azide (3.36 g, 51.1 mmol, Eq: 1.05) was charged in the reactor followed by DMSO (35.2 g, 32.0 ml) and Hunig's base (642 mg, 868 μl, 4.87 mmol, Eq: 0.1). The suspension was stirred for 10 Min. at 25° C. Then 1-chloro-2-(chloromethyl)benzene (8 g, 6.29 ml, 48.7 mmol, Eq: 1.00) was added dropwise over 60 min. (Tr=25° C.) and stirred at 25° C. until reaction completion (<2 h). The resulting white suspension was treated with water (1.6 g, 1.6 ml) and stirred for 45 Min. at R.T. The suspension was filtered and the filter cake was washed with DMSO (17.6 g, 16.0 ml) to give a colorless solution of 1-(azidomethyl)-2-chloro-benzene solution.
Reaction SMILES: CCO[C:4]([CH:6]1[C:12](=[O:13])[CH2:11][CH:10]([C:14](OCC)=O)[C:8](=[O:9])[CH2:7]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[OH:9][C@H:8]1[CH2:7][C:6](=[CH2:4])[C@H:12]([OH:13])[CH2:11][C:10]1=[CH2:14]
Reactant: CCOC(=O)C1CC(=O)C(C(=O)OCC)CC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@H](O)C(=C)C[C@H]1O

Procedure:
A warm solution of dry, recrystallized diethyl 1,4-cyclohexanedione-2,5-dicarboxylate (30.75 g, 120 mmol) in 350 ml anhydrous tetrahydrofuran (THF) was added to a refluxing solution of 1.0 M LAH in THF (600 mL) over a 2 hour period. After an additional 1.5 hours at reflux and subsequent cooling, a saturated solution of aqueous Rochelles's salt (app. 73 mL) was added dropwise to the reaction mixture. The tartrate complex was filtered, washed with THF and the filtrate was concentrated to a paste. The paste was recrystallized from hot ethyl acetate; yield 4.39 g (31.3 mmol, 26.1%). A second recrystallization yielded 3.81 g (27.2 mmol, 22.6%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccn1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Agent: Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccccn1
Reaction time: 15.5 h
Yield: 57 %

Procedure:
A solution of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (166 mg, 0.621 mmol), 2-(bromomethyl)pyridine hyrdobromide (189 mg, 0.745 mmol), DIPEA (265 μL, 1.52 mmol) and KI (10 mg, 0.060 mmol) in CH3CN (6 mL) was warmed to 50° C. and stirred for 15.5 h according to General Procedure A. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (94:5:1) afforded COMPOUND 73 (127 mg, 57%) as an orange solid. 1H NMR (CDCl3) δ 1.75-1.85 (m, 3H), 1.93-2.02 (m, 1H), 2.09-2.21 (m, 2H), 2.42 (s, 6H), 3.80 (bs, 2H), 6.81-6.85 (m, 2H), 6.96 (dd, 2H, J=7.7, 3.9 Hz), 7.23-7.30 (m, 3H), 8.18 (d, 1H, J=4.8 Hz), 8.40 (d, 2H, J=4.4 Hz); ES-MS m/z 359 (M+H).
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH3:8])(=O)=O.CC(C)([O-])C.[K+].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][C:40]4[N:45]=[CH:44][C:43](O)=[CH:42][CH:41]=4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[N:24]1.Cl>O.CS(C)=O>[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][C:40]4[CH:41]=[CH:42][C:43]([O:5][CH2:6][C@H:7]([O:9][CH:10]5[CH2:15][CH2:14][CH2:13][CH2:12][O:11]5)[CH3:8])=[CH:44][N:45]=4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[N:24]1
Reactant: C[C@@H](COS(C)(=O)=O)OC1CCCCO1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OC1CCCCO1
Temperature: 100 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
(2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate (214 mg, 0.90 mmol) and potassium tert-butoxide (200 mg, 1.8 mmol) were added to a dimethyl sulfoxide solution (5 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (300 mg, 0.90 mmol) obtained in Example 6-3), and the reaction solution was stirred for 24 hours at 100° C. The reaction solution was cooled to room temperature, then water and aqueous 1 N hydrochloric acid solution (0.9 ml, 0.9 mmol) were added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1) to obtain N-(1-methyl-1H-pyrazol-3-yl)-6-[(5-{[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]oxy}pyridin-2-yl)oxy]quinazoline-4-amine (322 mg, yield: 75%) as a pale brown solid.
Reaction SMILES: [N+:1]([CH2:3][C:4](OC)=[O:5])#[C-:2].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>>[N+:1]([CH2:3][C:4]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:5])#[C-:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: C1COCCN1
Product: [C-]#[N+]CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
Prepared in accordance with Method B with methyl isocyanoacetate (2.51 g, 25.30 mmol) and morpholine (3.30 mL, 38.05 mmol). The reaction mixture was stirred 24 h at RT and then concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10% aqueous citric acid (2×25 mL), dried over MgSO4, filtered and evaporated. 2-Isocyano-1-morpholinoethanone SLA 07118 was obtained as a brown oil (2.28 g, 58% yield).
Reaction SMILES: C([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:9]=1[C:10]([C:16]([OH:19])([CH3:18])[CH3:17])=[N:11]2)CCC>Br.C(O)(=O)C>[F:24][C:22]1[CH:21]=[CH:20][C:9]2[C:10]([C:16]([OH:19])([CH3:18])[CH3:17])=[N:11][C:12]3[CH:13]=[CH:14][NH:15][C:6](=[O:5])[C:7]=3[C:8]=2[CH:23]=1
Reactant: CCCCOc1nccc2nc(C(C)(C)O)c3ccc(F)cc3c12
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(O)c1nc2cc[nH]c(=O)c2c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A suspension of 2-(1-butoxy-9-fluorobenzo[c]-1,6-naphthyridin-6-yl)propan-2-ol (30 mg, 0.091 mmol) in HBr/acetic acid (33% wt) (1.0 ml) was stirred for 22 hr at room temperature. The resulting solution was concentrated to a crude oil that solidified on standing. Acetonitrile (5 ml) was added, and then concentrated to dryness in an attempt to drive off all acetic acid. The resulting solids were triturated with EtOAc (1 mL). Collection of the solids by vacuum filtration affords 9-fluoro-6-(1-hydroxy-1-methylethyl)benzo[c]-1,6-naphthyridin-1(2H)-one (HBr salt). 1H NMR (500 MHz, DMSO-D6) δ 11.90 (br d, 1H), 9.80 (dd, 1H), 9.40 (dd, 1H), 7.61-7.57 (overlapping m, 2H), 6.77 (d, 1H), 6.46 (br peak, HBr/H2O, possibly OH peak), 1.71 (s, 6H). LRMS (ESI) calc'd for (C15H13FN2O2) [M+H]+, 273.1; found 273.0.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.CN([CH:28]=[O:29])C>C1COCC1>[C:1]([N:5]1[CH:28]([OH:29])[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([Cl:13])[CH:9]=2)[C:6]1=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)N1C(=O)c2ccc(Cl)cc2C1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of N-tert-butyl4-chlorobenzamide (1.06 g, 5.00 mmol) in anhydrous THF (20 mL) was cooled to −78° C. under nitrogen. To the stirred solution was added dropwise tert-butyllithium solution in pentane (1.7M, 7.3 mL, 12.5 mmol), such that the internal temperature remained below −70° C. The resulting suspension gradually turned from pale to bright yellow. The mixture was stirred for an additional 1 hour at −78° C. DMF (1.5 mL, 19.5 mmol) was added dropwise to the slurry below −70° C. resulting in formation of a clear light yellow solution. The solution was allowed to warm to −20° C. (became colorless) before it was quenched with sat. aq. NH4Cl (10 mL) and allowed to warm to RT. The biphasic mixture was diluted with ethyl acetate (20 mL), and the layers were seperated. The organic layer was washed with water (20 mL), brine (20 mL), and dried over anhydrous MgSO4. The organic solvent was removal under reduced pressure to afford 2-tert-butyl-5-chloro-3-hydroxyisoindolin-1-one (1.18 g, 98% yield) as a colorless solid.
Reaction SMILES: [NH:1]([C:20]([O:22]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:27]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:28][CH2:29]C(ON1C(=O)CCC1=O)=O>>[NH:27]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:28][CH2:29][C:20]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:22]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)CCNC(=O)OC(C)(C)C
Yield: 70.7 %

Procedure:
Using 5.60 g of Boc-Asn-Leu-OEt and 5.60 g of Boc-β-Ala-OSu, the same procedure as in Reference Example 35 was repeated to obtain 4.71 g (yield: 70.6%) of the above objective compound having a melting point of 148°-153° C.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(Cl)C2C=CC=CC=2)C=CC=CC=1.[Li].C(O)(=O)C.CI>C1COCC1.O>[C:1]1([C:7]([CH2:9][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: ClP(c1ccccc1)c1ccccc1
Agent: [Li]
Solvent: O
Solvent: CC(=O)O
Solvent: CI
Product: O=C(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dehydroxylation of Benzoin. Diphenylphosphinouschloride (5.0 g, 22.6 mmol) was added dropwise to a suspension of lithium shot (158 mg, 22.6 mmol) in THF (10 ml) at room temperature. After about 2 hours all the lithium had dissolved and a solution of benzoin (2.4 g, 11.3 mmol) in THF (25 ml) was added dropwise. The clear yellow reaction mixture was stirred overnight at room temperature and turned a bright orange color. Acetic acid (678 mg, 11.2 mmol) was then added, followed by methyliodide (1.6 g, 11.3 mmol). After stirring for an additional 30 minutes, the reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo giving a yellow oil. MPLC purification on silica gel (eluting solvent, ethyl acetate) gave desoxybenzoin (1.7 g, 76 wt % yield) as a white crystalline solid.