Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.Cl[C:9]1[N:14]=[C:13]([F:15])[C:12]2[O:16][C:17]3[C:22]([C@@:23]4([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[C:25]([NH2:32])=[N:24]4)[C:11]=2[CH:10]=1)=[CH:21][C:20]([C:33]1[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:19][CH:18]=3.[O:40]1[CH2:45][CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41]1.C(O)(C(F)(F)F)=O>>[O:40]1[CH2:45][CH2:44][CH:43]=[C:42]([C:9]2[N:14]=[C:13]([F:15])[C:12]3[O:16][C:17]4[C:22]([C@@:23]5([C:31]6[C:26](=[N:27][CH:28]=[CH:29][CH:30]=6)[C:25]([NH2:32])=[N:24]5)[C:11]=3[CH:10]=2)=[CH:21][C:20]([C:33]2[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:19][CH:18]=4)[CH2:41]1
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Reactant: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(C2=CCCOC2)nc3F)c2cccnc21

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 5 above, but using (S)-3-Chloro-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,5′-pyrrolo[3,4-b]pyridin]-7′-amine 2,2,2-trifluoroacetate and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in step 4. MS m/z=496.0 [M+H]+. Calculated for: C28H0F2N5O2.C2HF3O2: 609.50 (TFA salt)
Reaction SMILES: C([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:24]3[CH2:25][C:20]4([C:27](=[O:29])N)[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)=[O:15])[CH2:10]1)=[O:7])(C)(C)C.[OH-:30].[Na+]>C1COCC1.CO>[CH2:17]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:24]3[CH2:25][C:20]4([C:27]([OH:30])=[O:29])[CH2:21][CH:22]([CH2:26][C@@H:18]2[CH2:19]4)[CH2:23]3)=[O:15])[CH2:10]1)=[O:7])[CH:18]([CH3:26])[CH3:19]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OC2C3CC4CC2CC(C(N)=O)(C4)C3)C1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)COC(=O)NC1CCN(C(=O)OC2C3CC4C[C@@H]2CC(C(=O)O)(C4)C3)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (3R) (1-(methoxycarbonyl)-4-adamantyl) 3-(isobutoxycarbonylamino)pyrrolidine-1-carboxylate (130 mg, 0.28 mmol) in THF (5 mL) and MeOH (10 mL) was added 5% aq NaOH (5 mL). The mixture was stirred at rt for 3 d. The mixture was concentrated under reduced pressure, diluted with water (15 mL) and washed with ether (80 mL). The aqueous layer was diluted with 10% aq citric acid (30 mL) and extracted with EtOAc (3×40 mL). The combined organic extracts were dried over MgSO4 and concentrated to leave (3R)-4-(3-(isobutoxycarbonylamino)pyrrolidine-1-carbonyloxy)adamantane-1-carboxylic acid (178 mg) as an oil.
Reaction SMILES: ClC(OC(Cl)=O)C.[CH2:8]([N:15]1[C:22](=[O:23])[CH:21]2[CH:17]([CH2:18][N:19](CC3C=CC=CC=3)[CH2:20]2)[C:16]1=[O:31])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([N:15]1[C:16](=[O:31])[CH:17]2[CH:21]([CH2:20][NH:19][CH2:18]2)[C:22]1=[O:23])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1Cc1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C1C2CNCC2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
1-Chloroethylchloroformate (3.24 mL) was added dropwise to a solution of compound 1 (5.22 g) in dichloromethane (75 mL) at 0° C. The solution was then heated to reflux for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was then dissolved in methanol (75 mL) and heated to reflux for another 3 hours. The mixture was cooled to 0° C. and ether (200 mL) was added. Filtration afforded the title compound 2 as a white solid (3.38 g, 90%). LCMS: Rf: 0.380 min, M+H+: 231.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=O.C([Li])CCC.[CH3:15][C:16]1[C:24]([CH3:25])=[C:23]([CH3:26])[C:22](C)=[CH:21][C:17]=1[C:18](Cl)=O>O1CCCC1>[CH3:26][C:23]1[C:24]([CH3:25])=[C:16]([CH3:15])[C:17]([CH3:18])=[CH:21][C:22]=1[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1cc(C(=O)Cl)c(C)c(C)c1C
Reactant: CCOC(=O)CC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(C)c(C)c(C)c1C
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
A 5 L, 3-necked flask is equipped with an overhead stirrer, addition funnel, thermowell and argon inlet. The flask is purged with argon then charged with ethyl hydrogen malonate (139.8 g, 1.06 mol) and tetrahydrofuran (2.3 L). The flask is cooled to -65° C. in a dry-ice/acetone bath. The n-butyllithium (892 mL, 2.23 mol) is transferred to the addition funnel then added dropwise to the stirred solution over a 2 hour period. After complete addition the reaction is warmed to -5° C. and stirred for 15 minutes. The resulting thick slurry is cooled to -65° C. The addition funnel is rinsed with tetrahydrofuran (20 mL) and the 2,3,4,5-tetramethylbenzoyl chloride (152.6 g, 0.776 mol) in tetrahydrofuran (250 mL) is transferred to the addition funnel under argon then added dropwise to the reaction over a 1.5 hour period. After complete addition the mixture is stirred at -65° C. for 1.5 hours. The reaction is allowed to warm to -20° C. then quenched over a water-ice mixture (3 L total volume). The solution is acidified to pH 2 by the slow addition of concentrated HCl. The product is extracted with ether (3×1 L), washed with saturated NaCO3 (2×1.5 L) and brine (1×1.5 L), dried over MgSO4, then concentrated in vacuo to a tan oil. An additional reaction is carried to produce a total of 185.1 g of crude product. Attempts to purify this material by vacuum distillation result in the apparent partial decomposition of the product. The remaining material is divided into two portions with each being chromatographed over 2 kg of silica eluted with methylene chloride. The TLC pure fractions are combined, concentrated in vacuo at 40° C. to constant weight, 108.5 g (42% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([SH:18])[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[CH2:26]([S:18][C:4]1[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1nc(S)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: BrCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1nc(SCc2ccccc2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
To a solution of 5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine-7-thiol (50 mg, 0.18 mmol) and triethylamine (63 μl, 0.45 mmol) in DMSO (1 ml) was added benzyl bromide (43 μl, 0.36 mmol). The reaction mixture was stirred under N2 at 25° C. for 3 hours. The mixture was poured onto water and extracted with EtOAc. The organic extracts were dried over Na2SO4 and the solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a light yellow solid (40 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1>[Zn]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[C:5]([NH2:14])=[CH:4][CH:3]=1
Reactant: COCCCNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Zn]
Product: COCCCNc1nc(Cl)ccc1N

Procedure:
6-Chloro-N-(3-methoxypropyl)-3-nitropyridin-2-amine (2.84 mmol, 0.698 g) was added to an oven dried 50 mL round-bottomed flask equipped for stirring under nitrogen. Methanol (15 mL) and acetic acid (1.5 mL, glacial) were then added. Zinc (15.29 mmol, 1.0 g, 20-30 mesh) was then added and the resultant mixture was allowed to stir at room temperature for 16 hr. Analysis of the reaction by LC/MS indicated a complete conversion to product at this time. This resultant mixture was then filtered over Celite®, concentrated in-vacuo, and transferred to a 250 mL seperatory funnel with ethyl acetate (2×30 mL) and water (2×20 mL). The layers were separated and the organic layer was washed once with saturated aqueous sodium chloride (40 mL). The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo affording 6-chloro-N2-(3-methoxypropyl)pyridine-2,3-diamine (35A) as a brown oil which was used directly in the next step without further purification. ESI-MS: mix 216.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C@@H:10]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[O:27][C:23]=4[CH:22]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[CH:31](=O)[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:31]([N:14]([C@@H:10]([CH2:11][CH2:12][CH3:13])[CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C@H:15]1[CH2:16][CH2:17][C@H:18]([C:21]2[CH:30]=[CH:29][C:24]3[NH:25][C:26](=[O:28])[O:27][C:23]=3[CH:22]=2)[CH2:19][CH2:20]1)[CH3:32]
Reactant: CCC[C@@H](CSc1ccc(F)cc1)N[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC[C@@H](CSc1ccc(F)cc1)N(CC)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 0.25 h

Procedure:
To (a) (S)-6-{trans-4-[1-(4-fluorophenylsulfanyl)pentan-2-ylamino]cyclohexyl}-3H-benzoxazol-2-one (292 mg, 0.687 mmol) in THF (10 mL) was added acetaldehyde (30 mg, 0.68 mmol) and 4 Å molecular sieves. After stirring for 0.25 hours, sodium triacetoxyborohydride (204 mg, 0.962 mmol) was added. The reaction mixture was stirred for 0.75 hours then concentrated under reduced pressure. The crude residue was taken up in methanol (10 mL), and solid NaOH was added until the pH was >8. The solution was concentrated under reduced pressure. Purification by flash chromatography (silica, 1:1 Hexanes:EtOAc) gave (b) (S)-6-{trans-4-[ethyl(1-(4-fluorophenylsulfanyl)-pentan-2-yl)amino]cyclohexyl}-3H-benzoxazol-2-one (210 mg, 67%), as a clear oil: IR (KBr): 3219, 2926, 1764, 1589 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.34 (m, 2H), 7.05-6.92 (m, 5H), 3.02 (m, 3H), 2.79 (m, 1H), 2.64 (m, 6H), 2.38 (m, 1H), 1.93-1.78 (m, 4H), 1.47-1.29 (m, 4H), 0.93 (t, J=5 Hz, 3H), 0.89 (t, J=6 Hz, 3H); API-MS (m/z): 457 [M+H]+; calcd for C26H33FN2O2S, 457.2325; found, 457.2324; HPLC: method C, 6.55 minutes (>99%), method D, 12.37 minutes (>99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27]N4C5C=CC=CC=5N=N4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:45]1[C:53]2[CH:52]=[CH:51][CH:50]=[C:49](O)[C:48]=2[CH:47]=[CH:46]1.CN(C)C=O>C(#N)C>[CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:49]4[CH:50]=[CH:51][CH:52]=[C:53]5[C:48]=4[CH:47]=[CH:46][NH:45]5)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]2)[CH2:4][O:3]1
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(On2nnc3ccccc32)cc1=O
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2cccc3[nH]ccc23)cc1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84.6 %

Procedure:
A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Example 109, Step 1, 0.25 g, 0.47 mmol) in acetonitrile (10 mL, 0.048M) was treated with cesium carbonate (0.31 g, 0.95 mmol) and 1H-indol-4-ol (75.4 mg, 0.56 mmol). The resulting reaction mixture was stirred at 25° C. for 3.5 h. At this time, the reaction was treated with N,N-dimethylformamide (1.0 mL) and the reaction was heated at 80° C. overnight. The reaction mixture was then concentrated in vacuo and partitioned between water (75 mL) and ethyl acetate (75 mL). The emulsified bilayer was filtered through filter paper and rinsed with water and ethyl acetate. The layers were separated, and the organics were washed with a saturated aqueous sodium chloride solution (50 mL). The combined aqueous layers were acidified with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 24 g, 1-10% methanol/methylene chloride) afforded 2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (207.1 mg, 81%) as a viscous brown/black oil as a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].CS(O[CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:6]=1[CH:7]=[O:8]
Reactant: COCCCCOS(C)(=O)=O
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCCCn1c(-c2ccccc2)nc(Cl)c1C=O
Temperature: 90 °C
Reaction time: 7 h
Yield: 99.1 %

Procedure:
To a solution of 4-chloro-2-phenyl-1H-imidazole-5-carbaldehyde (500 mg) and 4-methoxybutyl methanesulfonate (660 mg) in N,N-dimethylacetamide (10 ml) was added cesium carbonate (2.4 g), and the mixture was stirred at 90° C. for 7 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (702 mg).
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[F:20])C1C=CC=CC=1.CO>[C].[Pd].C(OCC)(=O)C>[F:20][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:18][CH3:19])[C:9]=1[OH:8])[C:13]([OH:15])=[O:14]
Reactant: COc1cc(C(=O)O)cc(F)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)cc(F)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4-benzyloxy-3-fluoro-5-methoxybenzoic acid were added 20 ml of methanol, 20 ml of ethyl acetate and 50 mg of 10% palladium-carbon and the mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. Then, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain 4.5 g of 3-fluoro-4-hydroxy-5-methoxybenzoic acid represented by the formula:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.N1C=CC=CC1=O.[CH3:59][C:60]([OH:64])([C:62]#[CH:63])[CH3:61]>>[OH:64][C:60]([CH3:61])([CH3:59])[C:62]#[C:63][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1
Reactant: NC(=O)c1nc2n(c1COc1ccccn1)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: O=c1cccc[nH]1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(COc3ccccn3)n1CCO2
Yield: 5 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((pyridin-2-yloxy)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with 2-pyridone) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as an off-white solid (5 mg, 5%).
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)(=O)=O.CS(Cl)(=O)=O.[F:22][C:23]([F:36])([F:35])[S:24]([O:27]S(C(F)(F)F)(=O)=O)(=[O:26])=[O:25]>>[F:22][C:23]([F:36])([F:35])[S:24]([O:27][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CS(=O)(=O)Cl
Product: O=C(O)/C=C/c1ccc(OS(=O)(=O)C(F)(F)F)cc1

Procedure:
13.4 g of (E)-3-(4-(trifluoromethylsulfonyloxy)phenyl)acrylic acid was synthesized as described for (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid using trifluoromethansulfonic acid anhydride methanesulfonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=1[CH2:20][CH2:21][C:22](OCC)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=1[CH2:20][CH2:21][CH2:22][OH:23])[C:18]#[N:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1CCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 g (3.04 mmol) of ethyl 3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]propionate was dissolved in 15 ml of tetrahydrofuran (dehydrated). 1.5 ml (2.3 mmol) of 2 M Lithium borohydride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. The solvent was evaporated. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH2:13])[CH2:7]2.[CH3:14][O:15]C1C=C2C(=CC=1OC)C(=O)CC2>>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:15][CH3:14])[CH2:9][CH:8]([NH2:13])[CH2:7]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: COc1ccc2c(c1)CC(N)C2
Agent: Cl
Product: COc1cc2c(cc1OC)CC(N)C2

Procedure:
This compound was prepared in the same manner as [5-(methyloxy)-2,3-dihydro-1H-inden-2-yl]amine hydrochloride from 5,6-bis(methyloxy)-2,3-dihydro-1H-inden-1-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH2:35].O1CCCC1>>[CH3:9][N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([NH:35][CH3:34])=[O:24])[CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)O)c2)c1)C(=O)OC(C)(C)C
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2)c1
Yield: 64 %

Procedure:
Using 3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoic acid (150 mg) and 2 mol/L methylamine-tetrahydrofuran solution (5 mL), a procedure as in Reference Example 284 was performed to give the title compound as a colorless oil (yield 99 mg, 64%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]2[C:10]=1[N:11]=[C:12]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[N:13]2[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>C(O)C>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([N:13]2[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])=[N:11][C:10]3[C:14]2=[N:15][C:16]([CH3:18])=[N:17][C:9]=3[N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:24][CH:23]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3F)n(-c3ccc(Cl)cc3)c2n1
Reactant: CN1CCNCC1
Solvent: CCO
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3F)n(-c3ccc(Cl)cc3)c2n1

Procedure:
A solution of 1-methylpiperazine (200 μl) in ethanol (0.8 ml) was added to 6-chloro-9-(4-chlorophenyl)-8-(2-fluorophenyl)-2-methyl-9H-purine I-(11A-1)c (24 mg, 0.06 mmol) and placed on a 60° C. shaker apparatus for 30 minutes. The reaction was loaded directly onto a TLC preparative plate for purification using 10% methanol/ethyl acetate as the solvent to obtain the desired title compound 11A-1: +ESI MS (M+1) 465. A solution of the material in methylene chloride/methanol was treated with excess 1 N HCl in diethyl ether, stirred, evaporated to dryness, and then triturated in diethyl ether to afford the hydrochloride salt of compound 11A-1 (35 mg, quantitative): +ESI MS (M+1) 437.2; 1H NMR (400 MHz, CD3OD) δ 7.70–7.25 (br m, 7H), 7.09 (t, J=9.1 Hz, 1H), 5.80 (br s, 2H), 3.74 (br s, 4H), 3.36 (br s, 2H), 2.99 (s, 3H), 2.64 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[Cl:13][C:6]1[C:2]([CH3:1])=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:4][C:5]=1[CH3:7]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
To a solution of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (0.100 g, 0.598 mmol) in DMF (2 ml) was added N-chlorosuccinimide (0.120 g, 0.897 mmol). The reaction mixture was stirred at RT for 4 h. The solvent was evaporated and purification by column chromatography (hexanes/EtOAc) afforded ethyl 4-chloro-3,5-dimethyl-1H-pyrrole-2-carboxylate (0.035 g, 29%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.68 (br. s., 1H) 4.22 (q, 2H) 2.19 (s, 3H) 2.15 (s, 3H) 1.28 (t, 3H). MS: m/z 202.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[C:28]1([NH:34][C:35]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:34][C:35](=[O:36])[C:37]2[CH:38]=[CH:39][C:40]([C:41]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:27])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:43][CH:44]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccccc2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCCC2)cc1
Product: O=C(Nc1ccccc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 215 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-piperidinylbenzamide and 4-phenylaminocarbonylbenzaldehyde. [M+H]+ calcd for C32H29N5O2: 516.24; found: 516.07.
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].C[CH2:8][CH:9]([C:14](OCC)=[O:15])[C:10](OC)=[O:11]>CO>[CH3:4][C:3]1[N:6]=[C:10]([OH:11])[C:9]([CH3:8])=[C:14]([OH:15])[N:5]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)C(CC)C(=O)OC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Cc1nc(O)c(C)c(O)n1
Temperature: 23 °C
Yield: 88.8 %

Procedure:
According to the procedure of D. J. Brown et al., J. Chem. Soc. 1964, 3204, a solution of 9.2 g (400 mmol) of sodium metal dissolved in 200 mL of methanol was treated first with 19.8 g. (210 mmol) of acetamidine hydrochloride and then with 34.4 mL (34.8 g, 200 mmol) of diethyl methyl malonate. The reaction mixture was heated to reflux for 4 hours, cooled to 23° C., and filtered. The filtrate was concentrated in vacuo. The residue from the filtrate and the isolated solids were combined and dissolved in water (300 mL). The aqueous solution was acidified with aqueous 3N HCl (133 mL). The fine white solid which precipitated from this solution was isolated by filtration and dried in vacuo to give 24.9 g (89%) of pure product, m.p. 300° C.