Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.S(=O)(=O)(O)O>O1CCCC1>[CH2:17]([O:16][C:8]1[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=[C:6]([CH2:4][OH:3])[CH:7]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cc2c(c(OCc3ccccc3)c1)OCCO2
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc2c(c(OCc3ccccc3)c1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.28 g of 5-benzyloxy-1,4-benzodioxane-7-carboxylic acid ethyl ester in 5 ml of tetrahydrofuran is added dropwise at room temperature to a solution of 110 mg of lithium aluminium hydride in 10 ml of tetrahydrofuran and the mixture is stirred at room temperature for a further 30 minutes. Then 0.22 ml of ethyl acetate, 1.5 ml of a mixture (water/tetrahydrofuran=1:1) and finally 2.25 ml of 2N sulfuric acid and added dropwise in succession. The reaction mixture is partitioned between diethyl ether and water. The organic phases are dried over sodium sulfate and concentrated by evaporation. The title compound is obtained from the residue by FC (240 g of silica gel, ethyl acetate/hexane=1:2): Rf (ethyl acetate-hexane=1:2)=0.18.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:5])[C:3]#[N:4].[Li]>CCOCC>[CH3:1][C:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:5])[CH2:3][NH2:4]
Reactant: CC(C)(C#N)c1ccsc1
Agent: [Li]
Solvent: CCOCC
Product: CC(C)(CN)c1ccsc1
Reaction time: 3 h

Procedure:
To a solution of 2-methyl-2-thiophen-3-yl-propionitrile in anhydrous ether (200 mL) was added lithium aluminumhydride (5.7 g, 3 equiv) at 0° C. under nitrogen. Stirring was continued for 0.5 h at 20° C. and 3 h at reflux under nitrogen. After cooling, it was quenched with 10% aqueous Rochelle's salt (Yamada, F. et al. Heterocycles, 1998, 49:451-457) and the solid was removed with filtration and washed with ether. The combined filtrate was washed with water and dried over MgSO4. Evaporation of solvent afforded 2-methyl-2-thiophen-3-yl-propylamine as an oil (4.62 g). 1H-NMR(CDCl3): δ 7.29 (1H, dd), 7.03 (1H, dd), 6.99 (1H, dd), 2.74 (2H, s), 1.29 (6H, s).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](O)=[O:41])=[CH:31]1.ON1C2C=CC=CC=2N=N1.[ClH:53]>C(#N)C.C(O)C.CC(O)C>[ClH:53].[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:40](=[O:41])[CH2:39][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([CH3:29])[CH:31]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCc3cccnc3)ccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCO
Solvent: CC(C)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)C(=O)Cc3cn(C)c4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridine 3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.5 g), 1-methyl-3-indoleacetic acid (0.27 g), and 1-hydroxybenzotriazole (HOBT) (0.24 g) in acetonitrile (10 ml), N-(3-dimethylaminopropyl)-NT-ethylcarbodiimide hydrochloride (WSC) (0.30 g) was added and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:3→0:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (1.1 ml) was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound (0.26 g) as a pale orange white amorphous.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:19]>>[CH2:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:3]3[C:8]([N:9]=[C:10]4[C:15]=2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:22][CH2:21]1)[CH3:19]
Reactant: CCN1CCC(N)CC1
Reactant: COc1ccc2nc3ccccc3c(Cl)c2c1
Product: CCN1CCC(Nc2c3ccccc3nc3ccc(OC)cc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 9-chloro-2-methoxyacridine and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=336). 1H NMR (CD3OD, 400 Hz): 8.2.9-8.27 (d, 1H, J=8.8 Hz), 7.96-7.94 (d, 1H, J=8.8 Hz), 7.92-7.89 (d, 1H, J=9.6 Hz), 7.70-7.66 (m, 1H), 7.53 (m, 1H), 7.46-7.43 (m, 2H), 3.98 (s, 3H), 3.90-3.80 (m, 1H), 3.02-3.8 (bm, 2H), 2.46-2.41 (q, 2H, J=7.2 Hz), 2.05-2.00 (m, 4H), 1.93-1.83 (m, 2H), 1.11-1.08 (t, 3H, J=7.2 Hz).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:27][C:28](=[O:58])[CH2:29][CH:30]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:43]=[C:44]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)[CH:45]=[CH:46][CH:47]=2)=[CH:36][CH:35]=1)[C:31]([NH2:33])=O)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28](=[O:58])[CH2:29][CH:30]([C:31](=[S:10])[NH2:33])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]2[CH:43]=[C:44]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)[CH:45]=[CH:46][CH:47]=2)=[CH:36][CH:35]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CC(C(N)=O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(C(N)=S)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.6 %

Procedure:
Lawesson's reagent (81 mg, 0.2 mmol) was added to a solution of compound 51.1 (50 mg, 0.1 mmol) in THF (2 mL). The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched with water (5 mL). The reaction mixture was extracted with dichloromethane (3 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The product was purified via flash chromatography (50% ethyl acetate in hexanes) to yield compound 51.2 (40 mg) as a clear film. MS ESI (pos.) m/e: 516 (M+H). 1H NMR (400 MHz) (CDCl3) δ 7.72 (4H, s); 7.67 (1H, s); 7.51-7.48 (3H, m); 7.31-7.28 (2H, m); 7.0-6.97 (2H, m); 5.14 (2H, s); 4.25-4.22 (1H, m); 3.51-3.46 (1H, m); 2.78-2.72 (1H, m); 1.38 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1COCC1>[C:12]([NH:16][C:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cnc(Cl)nc1Cl
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 24.85 g (117.5 mmol) of 2,4-dichloro-pyrimidine-5-carbonyl chloride in 125 ml of THF is cooled to −15° C. It is slowly mixed with a solution of 13.2 ml (124.5 mmol) of tert-buylamine and 17.4 ml (125.7 mmol) of triethylamine in 50 ml of THF, so that the temperature of the reaction mixture remains less than −10° C. It is stirred for another 2 hours at −10° C., then the cooling bath is removed, and the reaction mixture is heated to room temperature while being stirred. After 1 hour, the precipitate that is formed is filtered off, and the filtrate is completely concentrated by evaporation. The residue that is obtained is purified by chromatography (hexane/ethyl acetate 4:1). 14.01 g (56.6 mmol, corresponding to 50% of theory) of the product is obtained.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:5](=[O:26])[O:4]1>O1CCOCC1>[ClH:1].[CH3:2][CH:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5](=[O:26])[O:4]1
Reactant: CC1OC(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC1OC(=O)N(C2CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4M Hydrogen chloride in 1,4-dioxane (20 ml) was added to a solution of the product from step (i) (1.4 g) in 1,4-dioxane (20 ml) and the mixture stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue triturated with ether. Yield 1.0 g.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CN(C)C=O.C(N(CC)C(C)C)(C)C.[CH:45]1([S:48](Cl)(=[O:50])=[O:49])[CH2:47][CH2:46]1>>[CH:45]1([S:48]([N:22]2[CH2:21][CH2:20][C:18]3[N:19]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:9][CH:10]=4)[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]=3[CH2:23]2)(=[O:50])=[O:49])[CH2:47][CH2:46]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(S(=O)(=O)C2CC2)CC3)cc1
Reaction time: 2 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea hydrochloride (0.1000 g, 0.2310 mmol) in dry N,N-Dimethylformamide (1.60 mL, 20.7 mmol) was added N,N-Diisopropylethylamine (0.161 mL, 0.924 mmol) followed by Cyclopropanesulfonyl chloride (0.0354 mL, 0.347 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.19 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.31 (q, J=15.1, 2H), 3.89 (dd, J=12.2, 9.2, 2H), 3.75-3.52 (m, 5H), 3.44 (d, J=5.0, 2H), 3.19-3.05 (m, 2H), 2.99 (d, J=3.7, 2H), 2.75-2.66 (m, 1H), 1.24 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H), 0.93 (dt, J=13.8, 5.5, 4H). LC/MS-m/z+501.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=CC(C([O:27][CH2:28][C@H:29]2[O:33][C@@H:32]([N:34]3[CH:41]=[C:40]([CH3:42])[C:38](=[O:39])[NH:37][C:35]3=[O:36])[C@H:31]([O:43][CH2:44][CH2:45][O:46][CH3:47])[C@@H:30]2[CH3:48])(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)(Cl)Cl>[CH3:48][C@@H:30]1[C@@H:29]([CH2:28][OH:27])[O:33][C@@H:32]([N:34]2[CH:41]=[C:40]([CH3:42])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[C@@H:31]1[O:43][CH2:44][CH2:45][O:46][CH3:47]
Reactant: COCCO[C@@H]1[C@H](C)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COCCO[C@@H]1[C@H](C)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
Trifluoroacetic acid (1.5 mL) was added dropwise to a stirred solution of 3′-deoxy-5′-O-(4-methoxytrityl)-3′-methyl-2′-O-(2-methoxyethyl)-5-methyluridine (370 mg, 0.63 mmol) in 50 mL of chloroform at 0° C. The mixture was stirred at rt for 30 min, concentrated, and then dissolved in ethyl acetate. The solution was washed with dilute sodium bicarbonate and brine. The organic phase was dried (Na2SO4) and concentrated. The resulting residue was purified by flash chromatography on a silica gel column. Elution with 1:1, 1:3 and then 0:1 hexanes-EtOAc provided 170 mg of the title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].CCN(C(C)C)C(C)C>C(Cl)Cl.[Cl-].[Na+].O.CC(=O)OCC.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[F:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Nc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1F)c1ccc(Br)s1
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of 5-bromo-thiophene-2-carboxylic acid (5) (207 mg, 1 mmol), oxalyl chloride (420 μl) and catalytic amount of DMF in 5 ml DCM was stirred at r.t for 2 h before evaporation to dryness. The resulting solid residue was dissolved in 5 ml DCM and to which were added 2-fluoroaniline (193 μl, 2 eq) and DIEA (522 μl). The reaction mixture was stirred at r.t for overnight before worked up with EA/aq. HO/brine. The org. phase was concentrated and then purified on a flash silica gel column to give 267 mg (5-bromo(2-thienyl))-N-(2-fluorophenyl)carboxamide (9) as off-white solid. (yield: 89%, purity>95%).
Reaction SMILES: O1CCOCC1.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C(N(CC)CC)C>[C:32]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: C=C(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(OCCCCCCO)cc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To 500 ml of dry dioxane in a reaction flask are added 9.0 g of 4-(6-hydroxyhexyloxy)-4'-nitrostilbene and 5 g triethylamine. The solution is heated to 50° C., and 3.7 g of methacryloyl chloride is added dropwise. The reaction is stirred at 45°-50° C. for about 6 hours and an additional 3.7 g of methacryloyl chloride is added. The reaction mixture is stirred for about 10 hours at 50° C., the dioxane is removed and the resultant residue is slurried with water in a blender. The solid is filtered, washed with water, and dried. The crude product is recrystallized from ethanol, mp 90°-95° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[BH4-].[Na+].[C:17](O)(=O)[CH3:18]>C1COCC1>[CH2:17]([N:6]1[CH2:5][CH2:4][CH:3]2[C:8](=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][CH:2]2[Br:1])[CH2:7]1)[CH3:18]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCC2C(=C([N+](=O)[O-])C=CC2Br)C1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 5-bromo-8-nitroisoquinoline (1 g, 3.95 mmol) in 20 mL THF was cooled to 0° C. and treated sequentially with sodium borohydride (0.75 g, 19.83 mmol) followed by the slow addition of acetic acid (20 mL). The reaction mixture was allowed to warm to room temperature, and an additional 2 equiv. of sodium borohydride was added. After quenching with water and treatment with sodium hydroxide solution to make basic, the reaction mixture was extracted with ethyl acetate. The organic residue was chromatographed on silica gel (25% ethyl acetate in hexane) to give the N-ethyl-5-bromo-8-nitrotetrahydroisoquinoline (0.8 g, 70% yield).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[CH2:18][C:17]2[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1[CH:35]=[CH:34][N:33]=[N:32][CH:31]=1>>[CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:9]1[CH2:10][CH2:11][C:12]2[C:17](=[C:16]([C:30]3[CH:35]=[CH:34][N:33]=[N:32][CH:31]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Reactant: Brc1ccnnc1
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2CCc3cccc(-c4ccnnc4)c3C2)cc1
Yield: 45 %

Procedure:
The title compound was synthesized as described for Intermediate example I-48 in 45% yield starting from [(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydronaphthalen-1-yl]boronic acid and 4-bromopyridazine (1 equiv): 1H NMR (400 MHz, CDCl3) δ ppm 9.24 (dd, 1 H), 9.17 (dd, 1 H), 7.31-7.36 (m, 5 H), 7.25-7.30 (m, 4 H), 7.15-7.24 (m, 4 H), 7.00 (dd, 1 H), 3.59-3.70 (m, 4 H), 2.92-3.08 (m, 2 H), 2.69-2.89 (m, 2 H), 2.51-2.62 (m, 1 H), 2.13-2.25 (m, 1 H), 1.71-1.86 (m, 1 H); MS (ESI) m/z 406[M+H+].
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH3:5])=[N+]=[N-].O1CCCC1.CP(C)C>>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(Cl)c3)c(=O)n12
Agent: CP(C)C
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3cccc(Cl)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(3-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.29 mmol) in tetrahydrofuran (3 mL, 40 mmol) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.35 mL, 0.35 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give the crude product (0.090 g), which was used directly in next step. LCMS calculated for C15H15ClN3OS (M+H)+: m/z=320.1. Found: 320.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([N+:14]([O-:16])=[O:15])=[C:5]2[OH:13]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2cc(Cl)ccc2[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Cl)cc2c(O)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A suspension of 6-chloro-4-hydroxycarbostyril (1.82g; 0.0093 mole) in glacial acetic acid (10 ml) was shaken with concentrated nitric acid (2.5 ml; d, 1.42) and the mixture heated on a water bath at 100° C until a clear solution resulted. Cooling of the orange solution gave a bright yellow solid which was filtered, washed well with acetic acid and then ethanol. Drying in vacuo over P2O5NaOH gave analytically pure 6-chloro-4-hydroxy-3-nitrocarbostyril; decomposes 200° C. (Found: C, 45.31; H, 2.31 N, 11.93; Cl, 14.78; C9H5N2CIO4 requires; C, 44.93; H, 2.09; N, 11.64 Cl, 14.74%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13]OS(C)(=O)=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:19]([CH2:13][CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:12]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CC(c2ccc(Br)cc2)=NO1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 75 °C
Yield: 112.7 %

Procedure:
Methanesulfonic acid 3-(4-bromo-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl ester (55 g, 164.2 mmol) was added to dimethyl formamide (200 ml) followed by addition of sodium azide (21.4 g, 328.4 mmol). The mixture was heated to 75° C. for six hours and then added to aqueous sodium chloride (300 ml) followed by extraction with gethyl acetate (3×300 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to yield the desired product (52 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:36]([NH:35][C:27]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:37])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from the previous step (94 mg, 0.3 mmol) in THF (3 mL) was added phenyl 3-methoxy-5-(trifluoromethyl)phenylcarbamate from Example 115A (140 mg, 0.45 mmol), diisopropylethylamine (80 uL, 0.45 mmol), and 4-dimethylaminopyridine (4 mg, 0.03 mmol). The solution was stirred at 50° C. overnight, allowed to cool to room temperature, and diluted with EtOAc. The solid was then filtered to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-methoxy-5-(trifluoromethyl)phenyl)urea (89 mg, 0.17 mmol, 56%). 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.48 (s, 1H), 7.44 (t, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 7.29-7.24 (m, 2H), 6.85 (s, 1H), 3.99 (s, 6H), 3.81 (s, 3H); LC-MS (ESI) m/z 531 (M+H)+.
Reaction SMILES: [OH-].[NH4+:2].[OH:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[N:5]1>O1CCCC1>[N:4]1([O-:3])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[N:5]1.[NH4+:2]
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: [O-]n1nnc2ccccc21
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Ammonium hydroxide (4.15 ml, 75 mmol) was added slowly to a solution of 1-hydroxybenzotriazole (10 g, 74 mmol) in tetrahydrofuran (100 ml) at 0° C. (ice-bath) and stirred for 2 hrs. Filtration and washing with tetrahydrofuran gave ammonium 1H-1,2,3-benzotriazol-1-olate (10.57 g) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]2C2CCCCO2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[NH:13]2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)Oc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-[(1-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (313 mg) in dry MeOH (3.13 mL) was added TFA (0.313 mL) and the mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo to give a yellow residue which was triturated with Et2O and filtered to give the title compound as an off-white solid (218 mg).