Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]1[O:29][C:28](=[O:30])[NH:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:26][CH:25]([CH3:24])[O:29][C:28]4=[O:30])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1CNC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)OC4=O)nc3)CC2)c(C)c1
Yield: 29.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (93 mg) described in Preparation Example 73 and 5-methyloxazolidin-2-one (30 mg), the title compound (29 mg) was obtained.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH:23]=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27]CC)=O)=[CH:18][CH:17]=1)#[N:15]>CCCCCC>[CH2:33]([O:32][C:30]([C:24]1[CH:23]=[N:22][C:19]2[C:18]([C:25]=1[OH:27])=[CH:17][C:16]([C:14]#[N:15])=[CH:21][CH:20]=2)=[O:31])[CH3:34]
Reactant: CCOC(=O)C(=CNc1ccc(C#N)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc2ccc(C#N)cc2c1O
Yield: 94.8 %

Procedure:
To 100 mL vigorously refluxing diphenyl ether (Aldrich) was added in open air, in portions over the course of one hour, 10.5 g (36.5 mmol) diethyl 2-(4-cyanophenylamino)methylenemalonate. The solution was refluxed for one additional hour. After allowing the solution to cool to below 100° C., it was poured into 200 mL hexane. The resulting precipitate was filtered and washed well with hexane to yield 8.39 g (34.6 mmol, 94%) of the title compound as a light brown solid: MH+: 243, mp>265° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CS(O)(=O)=O>>[CH2:7]([O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N#CCC(=O)O
Reactant: CCCCCCCCCCO
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCOC(=O)CC#N

Procedure:
Cyanoacetic acid (20.85 g, 0.245 mol) was added to decanol (47 mL, 0.25 mol) and methane sulfonic acid (0.5 mL, 7.8 mmol), followed by heating under reduced pressure while removing the water by-product through the use of a dean stark trap. The reaction was cooled upon completion, providing the title compound in quantitative yield.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[N:13]1[C:17]([CH3:18])=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=[N:14]1)([O-])=O.C[O-].[Na+]>CO>[CH3:18][C:17]1[C:16]([N+:19]([O-:21])=[O:20])=[CH:15][NH:14][N:13]=1
Reactant: Cc1c([N+](=O)[O-])cnn1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
2-(2,4-Dinitrophenyl)-3-methyl-4-nitropyrazole (16.0 g, 0.055 mole) was dissolved in methanol (250 ml). Sodium methoxide (11.0 g, 0.22 mole) was added dropwise as a suspension in methanol. The colour of the reaction mixture changed from yellow to a dark red. The reaction mixture was then stirred at room temperature for 3 h. The methanol was removed in vacuo to give a dark red oil, which was neutralized by pouring onto ice/HCl. The resulting brown precipitate of dinitroanisole was filtered off and discarded. The aqueous filtrate was neutralized with 10% sodium carbonate solution and extracted with ethyl acetate (3×200 ml), dried and evaporated to dryness to give a yellow solid. Crystallisation from ether/methanol gave pale yellow needles of 3-methyl-4-nitropyrazole (6.0 g, 86%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3([CH2:21][CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18][CH2:17]3)[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)n1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)n1ncc2c1-c1ccccc1OC21CCNCC1
Yield: 101.8 %

Procedure:
Benzyl 1-isopropylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.1 g, 2.6 mmol) was stirred in methanol (14.4 mL) with Pd/C (140.3 mg, 0.1318 mmol) under a balloon of hydrogen for 16 h. The reaction was filtered through a syringe filter and the solvent evaporated to give 1-isopropylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (750 mg, 100%). ESI-MS m/z calc. 283.2, found 284.3 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C([Li])(CC)C.CN([CH:27]=[O:28])C>C1COCC1>[CH:27]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:28]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(F)(F)F
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(C=O)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a solution of tert-butyl 2-(trifluoromethyl)phenylcarbamate (1.0 g, 3.83 mmol) and N,N,N′N′-tetramethylethylenediamine (1.27 mL, 8.43 mmol) in 20 mL of anhydrous THF at −78° C. was added sec-butyllithium (8.43 mL of a 1.0 M solution in hexanes, 8.43 mmol) dropwise over 15 min. The reaction was stirred at −78° C. for 1 h and then there was added DMF (0.33 mL, 4.21 mmol). The reaction was stirred at −78° C. for 1 h and then was quenched with sat'd aq NH4Cl (10 mL) and allowed to warm to ambient temperature. The reaction mixture was diluted with water and extracted with EtOAc. The organics were washed with 1N HCl and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 6:1 hexane/EtOAc) to afford 0.4 g (36%) of the title compound. 1H NMR (CDCl3): δ 10.06 (s, 1H), 8.07 (d, 1H, J=7.7 Hz), 7.83 (d, 1H, J=7.8 Hz), 7.43 (t, 1H, J=7.8 Hz), 6.83 (broad s, 1H), 1.47 (s, 9H). LRMS (ESI): 290.15 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH3:10])[CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:11][C:12]1[C:13]2[C:14]3[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16](S)[C:15]=3[CH:22]=[CH:23][CH:24]=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:37].Cl.Cl>C(O)C>[ClH:37].[ClH:37].[Br:11][C:12]1[C:13]2[C:14]3[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:9][CH2:8][CH:7]([CH3:10])[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:15]=3[CH:22]=[CH:23][CH:24]=2
Reactant: CC(CN)Cn1ccnc1
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: CC(CNC1=Nc2ccc(Br)c3cccc1c23)Cn1ccnc1

Procedure:
The free base of the title compound was prepared by the procedure of Example 55, employing 2.8 grams of 3-(1H-imidazol-1-yl)-2-methylpropanamine, 5.3 grams of 6-bromobenz(cd)indol-2-thiol, 6.45 grams of mercuric acetate, and 500 ml of ethanol. The crude free base was purified by the chromatographic procedure of Example 46, 5.5 grams of product being obtained. This was converted to the dihydrochloride salt by treatment with excess 2.3N ethanolic hydrogenchloride, followed by precipitation with acetone. The yield was 1.2 grams and the mp 180° C. with decomposition.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[C:1]([CH:9]=[CH:10][C:11]([Cl:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C=CC(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C=CC(=O)c1ccccc1

Procedure:
3-Benzoylacrylic acid (3 g.) was refluxed for 2 hours with 100 ml. of methylene chloride and 10 ml. thionyl chloride. Concentration to dryness gave 3-benzoylacrylyl chloride. Methanol (15 ml.) was added and the resulting solution stirred for 0.5 hour. Ether (35 ml.) was added. The resulting organic mixture was washed in sequence with 15 ml. of water, 15 ml. of 1N sodium hydroxide and twice with 15 ml. of water, concentrated to an oil, the oil triturated with 25 ml. of hot hexane, decanted from insolubles and the hexane concentrated to yield methyl 3-benzoylacrylate (1.9 g., oil, m/e 190).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[OH:7].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][O:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1ccccn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccccn1

Procedure:
A solution of pyridin-2-ol (1 g), tert-butyl bromoacetate (2.33 mL) and cesium carbonate (6.85 g) in DMF (20 mL) was stirred at 60° C. overnight. The reaction mixture was poured into water, and the mixture was partitioned twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.18 g).
Reaction SMILES: I.[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13](=[NH:24])[NH:14][CH2:15][C:16](=O)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:6]2[N:5]=[N:4]1>Cl>[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13]3[NH:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:24]=3)=[C:6]2[N:5]=[N:4]1
Reactant: Cn1nnc2c(C(=N)NCC(=O)c3ccccc3)ncn2c1=O
Agent: Cl
Agent: I
Product: Cn1nnc2c(-c3nc(-c4ccccc4)c[nH]3)ncn2c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of crude 3-methyl-4-oxo-N-(2-oxo-2-phenylethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboximidamide hydroiodide (250 mg) in 3N HCl (17 mL) was heated at 80° C. overnight. After being cooled to room temperature, the mixture was left at 4° C. for 1 hour and the precipitate was filtered and washed successively with cold water, ethyl acetate and diethyl ether to give a 97:3 mixture of hydrochloride and hydroiodide salt (elemental analysis) of the title compound.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15](Cl)=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:22][C:23](=[O:25])[NH2:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:23](=[O:25])[NH:24][C:15]([CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOC(N)=O
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: CCCCOC(=O)NC(=O)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p.=180-183° C., MS: m/e=325.4 (M+H+) was prepared in accordance with the general method of example 6 from 9H-xanthene-9-carbonyl chloride and carbamic acid butyl ester.
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH3:31][C:32]1([CH3:66])[C:56]2[C:36]([CH:37]=[C:38]3[CH:55]=[C:54]4[C:41]([C:42]5[C:47]([C:48]6[C:53]4=[CH:52][CH:51]=[CH:50][CH:49]=6)=[CH:46][CH:45]=[CH:44][CH:43]=5)=[CH:40][C:39]3=2)=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.CO.C1(C)C=CC=CC=1>[CH3:66][C:32]1([CH3:31])[C:56]2[C:36]([CH:37]=[C:38]3[C:39]=2[CH:40]=[C:41]2[C:54]([C:53]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[C:47]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=42)=[CH:55]3)=[CH:35][C:34]([C:2]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[CH:18][CH:17]=3)=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]3)=[CH:33]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: Brc1c2ccccc2c(-c2ccc(-c3cccs3)c3ccccc23)c2ccccc12
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(C)C=C(c2c3ccccc3c(-c3ccc(-c4cccs4)c4ccccc34)c3ccccc23)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 62.7 %

Procedure:
A mixture of 6.5 g (14 mmol) of 2-(4-(10-bromoanthracen-9-yl)naphthalene-1-yl)thiophene, 7.53 g (16 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.16 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium, 11 ml of 2M Na2CO3, 30 ml of EtOH and 65 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 4 h. After finishing the reaction, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction. To give 6.4 g (yield 63%) of yellow product which was recrystallized from toluene. MS (m/z, FAB+): 728.1; 1H NMR (CDCl3, 400 MHz): chemical shift (ppm) 9.13 (s, 1H), 8.64˜8.56 (m, 3H), 8.31˜8.05 (m, 5H), 7.95˜7.83 (m, 9H), 7.68˜7.61 (m, 2H), 7.55 (d, J=8.00 Hz, 1H), 7.49˜7.40 (m, 6H), 7.18 (d, J=6.20 Hz, 1H), 7.02 (t, J=6.20 Hz, 1H), 6.55 (d, J=8.00 Hz, 1H), 1.81 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[F:20])[CH2:7][C@@H:6]1[CH3:21])=[O:4].[Cl:22][C:23]1[CH:32]=[CH:31][C:26]2[NH:27][C:28](=[O:30])[O:29][C:25]=2[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:22][C:23]1[CH:32]=[CH:31][C:26]2[N:27]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=4[F:20])[CH2:7][C@@H:6]3[CH3:21])=[O:4])[C:28](=[O:30])[O:29][C:25]=2[CH:24]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)[C@@H](C)C2)c(F)cc1Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(Cl)ccc43)[C@@H](C)C2)c(F)cc1Cl

Procedure:
Compound 7 was prepared according to the procedure described in Example 2 using 2-chloro-1-[(S)-4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (6), 6-chloro-3H-benzooxazol-2-one and K2CO3 in DMF: HPLC retention time, 2.87 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A, 0.1% formic acid/5% acetonitrile/94.9% water, B, 0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 468.3, found, 468.4.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:6][C:5]([CH3:27])=[CH:4][N:3]=1.C([N:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1)(OC(C)(C)C)=O.[H-].[Na+]>CN(C=O)C>[CH3:27][C:5]1[CH:6]=[C:7]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:2]([O:41][CH:38]2[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]2)=[N:3][CH:4]=1
Reactant: Cc1cnc(F)c(-c2nccc3cc(S(=O)(=O)Nc4nccs4)ccc23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc(OC2CCNCC2)c(-c2nccc3cc(S(=O)(=O)Nc4nccs4)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial charged with 1-(2-fluoro-5-methylpyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Example 377) (50 mg, 0.125 mmol) was added 1-boc-4-hydroxypiperidine (27.6 mg, 0.137 mmol) and DMF (499 μl) and the resulting solution cooled in an ice water bath prior to the addition of NaH (60% in mineral oil) (12.48 mg, 0.312 mmol). The mixture was stirred overnight at room temperature (ice melt) affording conversion to desired product as the primary species. To the light brown solution was added IPA (0.5 ml) and AcOH (50 μl). The resulting mixture was dried under reduced pressure affording a yellow oil to which DCM (1 ml) and TFA (0.3 ml) was added. The resulting mixture was stirred at room temperature for 2 hrs affording no Boc cleavage according to LC-MS. Another 0.7 ml of TFA was added and stirring was continued at room temperature for 2 hr affording complete Boc cleavage. The mixture dried under reduced pressure, dissolved in DMSO (1 ml) and purified with RP-HPLC (Gilson) ramping ACN in H2O (5-95%, 0.1% TFA modifier) affording separation of impurities. The product containing eluents were dried under reduced pressure and free-based with a 5 g SCX-2 column washing with MeOH, then 2M NH3 in MeOH. The basic wash was dried under reduced pressure affording a light yellow film which was lyophilized from MeOH/H2O to provide 1-(5-methyl-2-(piperidin-4-yloxy)pyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as an off-white powder (25 mg, 0.052 mmol, 41.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J=5.67 Hz, 1H), 8.43 (d, J=1.66 Hz, 1H), 8.16 (dd, J=0.78, 2.45 Hz, 1H), 8.04 (d, J=5.38 Hz, 1H), 7.88 (dd, J=1.71, 8.85 Hz, 1H), 7.66-7.74 (m, 2H), 7.02 (d, J=4.01 Hz, 1H), 6.59 (d, J=4.11 Hz, 1H), 5.27 (td, J=3.47, 6.94 Hz, 1H), 2.91 (br. s., 2H), 2.61-2.79 (m, 2H), 2.30 (s, 3H), 1.86-2.01 (m, 2H), 1.56 (br. s., 2H). m/z (ESI) 482.1 (M+H)+
Reaction SMILES: [NH:1]([C:8]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([CH3:19])=[CH:16][C:17]=1[Cl:18])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>O1CCOCC1>[NH:1]([C:8]1[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:12]([C:10](=[O:11])[CH:9]=1)=[C:17]([Cl:18])[CH:16]=[C:15]([CH3:19])[N:14]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c(C(=O)C=C(Nc2ccccc2)Nc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(Cl)c2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2n1
Temperature: 80 °C
Yield: 14.4 %

Procedure:
A mixture of 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (100 mg, 0.25 mmol) and t-BuOK (42 mg, 0.38 mmol) in anhydrous dioxane (4 mL) was heated to 80° C. for 4 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The solution was washed with water and brine, dried over MgSO4, and concentrated in vcaco. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex gave 2-anilino-5-chloro-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (13 mg, 14%): LCMS RT: 2.47 min, MH+: 362 and 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (68 mg, 75%): LCMS RT: 2.24 min, MH+: 362.3. Alternatively, the cyclization could be achieved by using other bases such as NaH and other aprotic solvents such as THF and DMF.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][O:12][CH3:13])([CH3:7])[CH2:3][C:4](=O)[CH3:5].[CH3:15][NH:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>[Pt]=O>[CH3:1][C:2]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][O:12][CH3:13])([CH3:7])[CH2:3][CH:4]([N:16]([CH3:17])[CH3:15])[CH3:5]
Reactant: CNC
Reactant: COCCC(=O)NC(C)(C)CC(C)=O
Agent: O=[Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COCCC(=O)NC(C)(C)CC(C)N(C)C
Reaction time: 12 h

Procedure:
To a mixture of 201 parts (1 mole) of N-(1,1-dimethyl-3-oxobutyl)-3-methoxypropionamide and 91 parts (2 moles) of dimethylamine are added 0.5 part of platinum oxide and 3 parts of p-toluenesulfonic acid. The liquid mixture is poured into a hydrogenation bottle, flushed with hydrogen and pressurized with hydrogen on a Parr hydrogenation apparatus at 69 psi. and hydrogenated for about 12 hours, with hydrogen pressure being replenished to 70 psi. when it has dropped to 27 psi. The mixture is then stripped on a rotary evaporator and the residue, a yellow liquid, is dissolved in 16% aqueous hydrochloric acid and extracted with four 100-ml. portions of chloroform. The aqueous solution is then made alkaline by the addition of a solution of 30 parts of sodium hydroxide in 75 parts of water, the alkaline solution is again extracted with four 100-ml. portions of chloroform and the chloroform extracts are stripped and distilled. The desired product, N-(1,1-dimethyl-3-dimethylaminobutyl)-3-methoxypropionamide, is obtained boiling at 87°-95° C./0.5 mm. It contains 12.1% nitrogen, as compared with 12.2% theoretical.
Reaction SMILES: [CH2:1](O)[CH3:2].[N+:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)([O-:6])=[O:5]>O.FC(F)C(F)(F)C(F)(F)S(O)(=O)=O.C1(C)C=CC=CC=1>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:1][CH3:2])=[O:12])=[CH:14][CH:15]=1)([O-:6])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)C(F)(F)C(F)(F)C(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 94.4 %

Procedure:
700 g of toluene, 235 g of ethanol (5.2 mol), 350 g of 4-nitrobenzoic acid and 10 g of hexafluoropropanesulfonic acid hydrate are weighed into a 2-1 four-necked flask equipped as described in Example 1. The procedure described in Example 1 is then repeated. Using the work-up described in Example 1 gives 386 g of ethyl 4-nitrobenzoate and, after drying, 382 g of dry ethyl 4-nitrobenzoate, which corresponds to a yield of 94.4% of theory, in a purity of 99.2% by HPLC of solidification point 56° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])[CH:2]=[CH2:3].[H-].[Na+].Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[C:22]([O:18][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:4]=1[CH2:1][CH:2]=[CH2:3])([CH3:29])[CH3:28])[CH3:27]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: C=CCc1cc(OCc2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1cc(OCc2ccccc2)ccc1OC(C)(C)C(=O)OCC
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
2-Allyl-4-benzyloxy-phenol (WO 9728137 A1 19970807, Adams et al.) (6.04 g, 25.1 mmol) in dry DMF (75 mL) was cooled in an ice bath and treated with NaH (1.78 g, 44.5 mmol, 60% oil dispersion). After 30 min, the red reaction mixture was treated over 5 min with ethyl bromoisobutyrate (7.4 mL, 50 mmol). The cold bath was removed after 5 min. The reaction was stirred 20 min and placed in an oil bath (T=85° C.). After 18 h, the mixture was cooled and partitioned between brine (75 mL) and ether (200 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to a brown oil (12 g). The crude product was purified by flash chromatography using hexanes:ethyl acetate (100:0 to 5:1) to give the desired product (8.47 g, 95%).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH-].[Na+].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33].Cl>C(Cl)Cl.[Cl-].C([N+](C)(C)C)C>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc3ccccc3)c3ccccc32)cc1
Yield: 116.1 %

Procedure:
Boc-D-Trp-OBzl (2.0 g) and ethyltrimethylammonium chloride (16.2 mg) were dissolved in methylene chloride (30 ml), and powdered sodium hydroxide (507 mg) was added. To this mixture was added a solution of Tos-Cl (1.45 g) in methylene chloride (5 ml) at room temperature. The reaction mixture was stirred for three and half an hour. After addition of 1N-hydrochloric acid (7.5 ml), the organic layer was separated, washed with sodium chloride solution, dried over magnesium sulfate, and evaporated to give Boc-D-Trp(Tos)-OBzl as an oil (3.23 g).