Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9](=[O:11])[C:8]2[N:12]([CH3:15])[CH:13]=[CH:14][C:7]=2[S:6]1(=[O:17])=[O:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][C:9](=[O:11])[C:8]4[N:12]([CH3:15])[CH:13]=[CH:14][C:7]=4[S:6]3(=[O:17])=[O:16])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Cn1ccc2c1C(=O)CN(CCCBr)S2(=O)=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1ccc2c1C(=O)CN(CCCN1CCN(c3ccc(F)cc3)CC1)S2(=O)=O
Yield: 93.7 %

Procedure:
A suspension of 54 mg (0.17 mmol) of Compound 17, 46 mg (0.25 mmol) of 1-(4-fluorophenyl)piperazine and 57 mg (0.68 mmol) of sodium hydrogencarbonate in 3.4 ml of dioxane was refluxed for 7 hours. Post treatment and purification were conducted as in Example 9, whereby 67 mg of the title compound were obtained (yield: 94%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][C@@H:7]([CH3:17])[CH2:6][CH2:5]2.COC(OC)C1C([CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][C:33]2=[O:39])=CC2CCCNC=2N=1>>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[C:2]([CH2:31][N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][C:33]2=[O:39])=[CH:3][C:4]2[CH2:5][CH2:6][C@H:7]([CH3:17])[NH:8][C:9]=2[N:10]=1
Reactant: COC(OC)c1nc2c(cc1Br)CC[C@H](C)N2
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Product: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CC[C@H](C)N2

Procedure:
From (S)-6-bromo-7-(dimethoxymethyl)-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 264 (enantiomer 1)), synthesized in an analogous manner to intermediate 81, the title compound was obtained as a brown solid. (UPLC-MS 6) tR 0.39; ESI-MS 349.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[NH:6][C:5]2[C:9]3([CH2:26][CH2:25][O:24][CH2:23]3)[N:10]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:17]=3)[C:11](=[O:12])[C:4]=2[C:3]=1[CH3:27].C(N(CC)CC)C.[H][H].CO>CCO.[Pd].C(Cl)Cl>[CH3:27][C:3]1[C:4]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[N:15][N:16]([CH2:18][C:19]([F:22])([F:20])[F:21])[CH:17]=3)[C:9]3([CH2:26][CH2:25][O:24][CH2:23]3)[C:5]=2[NH:6][C:7](=[O:8])[CH:2]=1
Reactant: [H][H]
Reactant: Cc1c2c([nH]c(=O)c1Br)C1(CCOC1)N(c1cnn(CC(F)(F)F)c1)C2=O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(=O)[nH]c2c1C(=O)N(c1cnn(CC(F)(F)F)c1)C21CCOC1
Reaction time: 16 h

Procedure:
As shown in step 24-vi of Scheme 24, to a suspension of Compound 2078 (1.65 g, 3.690 mmol) in EtOH (50 mL) at 23° C. was added triethylamine (1.120 g, 1.543 mL, 11.07 mmol), followed by the addition of Pd/C (430 mg, 0.4041 mmol) (10 wt % dry basis, Degussa type, wet). The reaction vessel was evacuated and the reaction atmosphere replaced with hydrogen gas. After stirring for 16 hours, the reaction mixture was treated with MeOH and DCM (50 mL each) and then filtered through diatomaceous earth, which was subsequently washed with 4:1 DCM:MeOH (100 mL). The combined filtrate was concentrated under reduced pressure to provide 4-methyl-6-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]spiro[1H-pyrrolo[3,4-b]pyridine-7,3′-tetrahydrofuran]-2,5-dione as a white solid (Compound 2079, 2 g, triethylamine impurity), which was used as is in subsequent reactions: ESMS (M+H) 369.30; 1H NMR (DMSO-d6, 300 MHz) δ 8.16 (s, 1H), 7.80 (s, 1H), 6.34 (br s, 1H), 5.17 (q, J=9, 2H), 4.13 (d, J=12, 1H), 3.93 (m, 3H), 2.45 (s, 3H), 2.30 (m, 2H).
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[NH2:12].Cl.[C:14]1([C@H:20]2CCC[C@H:21]2[NH2:25])[CH:19]=[CH:18][CH:17]=CC=1>>[ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[N:12]=[C:21]1[CH2:20][CH2:14][CH2:19][CH2:18][CH2:17][NH:25]1
Reactant: NC1CCCC1c1cccs1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Product: c1csc(C2CCCC2N=C2CCCCCN2)c1

Procedure:
By the procedure described in U.S. Pat. No. 2,520,516 (1950) 2-(2-thienyl)cyclopentylamine hydrochloride, M.P. 168°-172° C., was prepared and substituted for cis-2-phenylcyclopentylamine hydrochloride in Example 1 to give the desired product, M.P. 144°-151° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:3]=[C:4]([CH2:5][O:6][CH2:7][C:8]3([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[CH:27]=[C:28]([C:30]([N:31]([CH3:32])[CH3:33])=[O:34])[CH:29]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN(C)C(=O)c1cc(Br)cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(COCC2(c3ccccc3)CCNCC2)cc(-c2ccc(C#N)cc2)c1
Temperature: 120 °C

Procedure:
tert-Butyl 4-((3-bromo-5-(dimethylcarbamoyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (41.2 mg, 0.08 mmol), 4-cyanophenylboronic acid (34.3 mg, 0.23 mmol), and tetrakis(triphenylphosphine) palladium(0) (12.1 mg, 0.01 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. After flushing with nitrogen, 0.28 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 29 mg (66%). 1H-NMR (CD3OD, 500 MHz) δ 7.81-7.84 (m, 2H), 7.76 (s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.49 (s, 1H), 7.42-7.44 (m, 2H), 7.32-7.35 (m, 2H), 7.17-7.22 (m, 2H), 4.51 (s, 2H), 3.52 (s, 2H), 3.15 (s, 3H), 2.99 (s, 3H), 2.88-2.95 (m, 2H), 2.67-2.72 (m, 2H), 2.24-2.27 (m, 2H), 1.91-1.97 (m, 2H). 13C-NMR (CD3OD, 126 MHz) δ 172.2, 144.9, 144.2, 140.9, 139.9, 137.3, 132.9, 128.4, 128.1, 127.4, 127.2, 126.2, 125.7, 124.7, 118.7, 111.5, 79.9, 72.2, 42.1, 41.8, 39.1, 34.7, 32.7. Mass spec.: 454.31 (MH)+. Accurate mass spec.: m/z 454.2496 [MH]+, Δ=0.3 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[CH2:9])=[CH:4][C:3]=1[CH3:11].[ClH:12]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:12])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: Cl
Reactant: C=C(C)c1ccc(C)c(C)c1
Product: Cc1ccc(C(C)(C)Cl)cc1C

Procedure:
1,2-dimethyl-4-isopropenylbenzene is reacted with hydrogen chloride to give 1,2-dimethyl-4-(α-chloroisopropyl)benzene and finally
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]=[O:13])[CH2:8][CH2:7]1)=O.Cl.[NH2:20][OH:21].C([O-])(=O)C.[NH4+].C(O)C>O>[CH:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[N:20][OH:21])[C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[CH2:7][CH2:8]1)=[O:13]
Reactant: NO
Reactant: O=CN1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=CN1CCC(C(=NO)c2ccc(Cl)cc2Cl)CC1
Yield: 14.1 %

Procedure:
A mixture of 105 g of 4-(2,4-dichlorobenzoyl)-1-formylpiperidine, 70 g of hydroxylamine hydrochloride, 135.0 g of ammonium acetate, 1.05 l of ethanol and 350 ml of water was stirred and heated at 130° for 40 hrs. The reaction mixture was evaporated and 2 l of water was added to the residue. The water was decanted from the oil and oil was washed two times with 500 ml water and then dissolved in about 400 ml dichloromethane. The insoluble material was collected. The dichloromethane extract was washed twice with 600 ml of water and the organic extract was evaporated. Trituration with diisopropyl ether and crystallization from acetone/ether gave 15.6 g (14.2%) of product, mp, 149°-150°.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:12][NH:13][C:14]([C:16]2[N:17]=[C:18]([C:35]#[N:36])[C:19]3[C:20](=[O:34])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[C:25]=2[OH:26])=[O:15])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:27]([N:21]1[C:20](=[O:34])[C:19]2[C:18]([C:35]#[N:36])=[N:17][C:16]([C:14]([NH:13][CH2:12][C:8]3([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11]3)=[O:15])=[C:25]([OH:26])[C:24]=2[CH:23]=[CH:22]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3c(=O)n(Cc4ccccc4)ccc3c2O)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCC2)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
1-{[(7-Benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-methyl}-cyclobutanecarboxylic acid tert-butyl ester (32 mg, 0.066 mmol) was dissolved in 2 mL of CH2Cl2. Trifluoroacetic acid (0.4 mL) was added, and the mixture was stirred at r.t. for 2 h. The mixture was concentrated in vacuo, and the residue was dissolved in saturated NaHCO3. The aqueous solution was washed with ether, and then acidified to pH about 1 with 4 M HCl to give a white suspension. The solid was isolated by filtration and dried under vacuum to give 22 mg of the title compound as an off-white solid. MS: (+) m/z 433.35 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[C:13]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:14]([C:19]([N:21]2[CH2:24][C:23]([CH2:26][CH2:27][OH:28])([OH:25])[CH2:22]2)=[O:20])[CH:15]=[CH:16][C:17]=1[F:18].C(N(CC)CC)C>ClCCl>[F:11][C:12]1[C:13]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:14]([C:19]([N:21]2[CH2:24][C:23]([CH2:26][CH:27]=[O:28])([OH:25])[CH2:22]2)=[O:20])[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(CCO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
A solution of oxalyl chloride (13 μL, 0.15 mmol) in dichloromethane (1 mL) was cooled to −78° C., and DMSO (22 μL, 0.31 mmol) was then added. To this mixture was added 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxyethyl)azetidin-3-ol (67.8 mg, 0.14 mmol) as a suspension in dichloromethane (1 mL). After stirring at −78° C. for 10 min, triethylamine (78 μL, 0.56 mmol) was added and the mixture was allowed to warm to rt. The solution was diluted with dichloromethane, and washed with 0.5 N HCl. The aqueous phase wash then extracted with dichloromethane. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to provide [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]acetaldehyde as a white solid (22.1 mg, 0.045 mmol, 32% yield). 1H NMR (400 MHz, CDCl3): δ 9.82 (s, 1H), 8.46 (s, 1H), 7.39 (m, 1H), 7.33 (m, 1H), 7.11 (m, 1H), 6.81 (m, 1H), 6.61 (m, 1H), 4.32-3.96 (br m, 4H), 3.41 (t, 2H), 3.07 (s, 1H); MS (EI) for C18H14F3IN2O3: 491 (MH+).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[N:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:18]([CH3:29])=[C:17]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:16]=1>C(O)C.O1CCCC1.O.NN>[NH2:3][CH2:12][CH2:13][CH2:14][C:15]1[N:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:18]([CH3:29])=[C:17]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:16]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)cc(CCCN2C(=O)c3ccccc3C2=O)n1CCc1ccc(F)cc1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)OCc2ccccc2)cc(CCCN)n1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1.364 g portion of benzyl 5-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was dissolved in a mixed solvent of 10 ml ethanol and 10 ml tetrahydrofuran, and 0.139 ml of hydrazine monohydrate was added, followed by stirring at room temperature for 24 hours. Then, 0.252 ml of hydrazine monohydrate was added, followed by stirring at 50° C. for 5 hours. Further, 0.252 ml of hydrazine monohydrate was added, followed by stirring at 50° C. for 20 hours. The reaction liquid was cooled to room temperature and then filtered through celite. The filtrate was concentrated under a reduced pressure, chloroform was added to the residue, and the resulting precipitate was removed by celite-filtration. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex (registered trademark), ethyl acetate) to obtain 850 mg of benzyl 5-(3-aminopropyl)-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate as a colorless oil.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:12])O1.Cl.[Na+].[Cl-].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:38]1([C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)CC)C>C1COCC1>[CH2:47]([O:46][C:44]([N:38]1[CH2:43][CH2:42][N:41]([C:4](=[O:12])[C@H:5]([OH:6])[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:40][CH2:39]1)=[O:45])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: COC(=O)C[C@H]1OC(C)(C)OC1=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 21.1 %

Procedure:
Methyl 2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (17.1 g, 90.9 mmol) was stirred in a 1:1 mixture of THF: 1 M HCl (200 mL) for 1 h at room temperature. After addition of NaCl to nearly saturate the aqueous layer, the mixture was extracted with EtOAc, and the extracts were dried over Na2SO4 and concentrated. To the resulting oil dissolved in dry DMF (500 mL) was added HOBt (13.5 g, 100 mmol) and EDCI (19.2 g, 100 mmol). After stirring for 5 min, benzyl piperazine-1-carboxylate (19.3 mL, 100 mmol) and triethylamine (13.9 mL, 100 mmol) were added to the reaction mixture, which was left stirring at room temperature overnight. Purification via silica gel chromatography using 0-10% MeOH/CH2Cl2 provided a colorless oil 4-((R)-2-hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylic acid benzyl ester (6.71 g, 21%). LC/MS: m/z 351.5 (M+H)+ at 2.67 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:6](=[O:28])[N:5]([CH3:29])[C:4]=2[N:3]=1.[Cl:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Si:21]([O:20][CH2:19][CH2:18][CH2:17][N:7]1[C:8](=[O:16])[C:9]2[N:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]([O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=3)=[N:3][C:4]=2[N:5]([CH3:29])[C:6]1=[O:28])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)CCn1c(Br)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Oc2cccc(Cl)c2)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Temperature: 90 °C
Yield: 99.8 %

Procedure:
Step 1 8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 1.03 mmol, intermediate 82), 3-chlorophenol (0.14 g, 1.08 mmol), potassium carbonate (0.29 g, 2.06 mmol) were combined in DMF (5 mL) and heated at 90° C. for 15 h. The reaction was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1 N LiCl (2×75 mL), dried with magnesium sulfate, filtered and evaporated under reduced pressure to give 1-(3-((tert-butyldimethylsilyl)oxy)propyl-8-(3-chlorophenoxy)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.55 g, 100% yield) as a yellow oil. LCMS retention time=6.238 min and 85% purity, LCMS MH+=535.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[CH:28]1.N1CCCCC1>CO>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:28]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]-1,4-diazepane-1-carboxylate (0.142 g, 0.392 mmol) in methanol (2 mL) was added with 1H-indole-3-carboxaldehyde (0.0569 g, 0.392 mmol) and piperidine (0.00334 g, 0.0392 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/methanol). The resulting solid crude product was washed with a mixed solvent of hexane and ethyl acetate to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)-1,4-diazepane-1-carboxylate (0.141 g, 73%).
Reaction SMILES: [CH2:1]1[O:19][C:18]2[CH:17]=[CH:16][C:5]([NH:6][C:7]3[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:4][C:3]=2[O:2]1>CO>[NH2:13][C:12]1[C:7]([NH:6][C:5]2[CH:16]=[CH:17][C:18]3[O:19][CH2:1][O:2][C:3]=3[CH:4]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccc2c(c1)OCO2
Solvent: CO
Product: Nc1cccnc1Nc1ccc2c(c1)OCO2

Procedure:
The crude nitro compound from Step A (11.5 g.) was hydrogenated in 175 ml. of methanol using 0.5 g. of 5% palladium on carbon as catalyst, the theoretical amount of hydrogen being consumed in 16 hours. The catalyst was removed on a filter. The filtrate was concentrated in vacuo and the dark residue was extracted with 75 ml. of 2.5 N hydrochloric acid and 75 ml. of water. The crude solution was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].I.CS[C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[NH:21]>C(O)C.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[NH:21])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15]
Reactant: CSC(=N)c1cccs1
Reactant: Cc1cc2cc(N)ccc2n1CCN(C)C
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2cc(NC(=N)c3cccs3)ccc2n1CCN(C)C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
A solution of compound 24 (0.275 g, 1.266 mmol) in dry ethanol (5 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.72 g, 2.532 mmol) at room temperature and stirred for overnight (16 h). The reaction was diluted with sat. NaHCO3 solution (25 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 25 (0.32 g, 78%) as a foam. 1H NMR (DMSO-d6) δ 2.22 (s, 6H), 2.39 (s, 3H), 2.46-2.51 (m, 2H, merged with DMSO peak), 4.14 (t, 2H, J=6.9 Hz), 6.09 (s, 1H), 6.20 (brs, 2H), 6.61 (dd, 1H, J=1.2, 8.4 Hz), 6.87 (s, 1H), 7.09 (t, 1H, J=4.2 Hz), 7.27 (d, 1H, J=8.7 Hz), 7.57 (d, 1H, J=5.1 Hz), 7.70 (d, 1H, J=3.3 Hz); ESI-MS (m/z, %) 327 (MH+, 100); ESI-HRMS calculated for C18H23N4S (MH+), calculated: 327.1637; observed: 327.1653; HPLC purity: 98% by area.
Reaction SMILES: [CH:1]1([C:4](=[O:18])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])=[O:7])[CH2:3][CH2:2]1.[CH:19](OCC)(OCC)[O:20][CH2:21][CH3:22]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:18])[C:5](=[CH:19][O:20][CH2:21][CH3:22])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1cc(SC)ccc1C(=O)CC(=O)C1CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(SC)cc1OC)C(=O)C1CC1
Yield: 99.4 %

Procedure:
A mixture of 3-cyclopropyl-1-(2-methoxy-4-methylsulphenylphenyl)-propan-1,3-dione (25.4 g) and triethyl orthoformate (39 g) in acetic anhydride was stirred and heated at reflux for 3 hours. After cooling the mixture was evaporated to dryness and the residue was dissolved in toluene and re-evaporated to dryness to give 3-cyclopropyl-2-ethoxymethylene-1-(2-methoxy-4-methylsulphenylphenyl)-propan-1,3-dione (30.6 g) as a red gum which was not further purified.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30])([O-:22])=[O:21]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([NH:19][S:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N+:20]([O-:22])=[O:21])(=[O:30])=[O:31])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)c2cccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(OCc2ccccc2)c2cccnc12
Yield: 88.9 %

Procedure:
In a similar fashion using route 18 general procedure 26, 5-benzyloxy-quinolin-8-ylamine 565 (336 mg, 1.34 mmol), 2-nitrobenzenesulfonyl chloride (357 mg, 1.61 mmol), and pyridine (3 ml) gave the title compound (519 mg, 89%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1>C(N(CC)CC)C.C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(I)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(C#C[Si](C)(C)C)s1
Yield: 92.6 %

Procedure:
Under a dry nitrogen atmosphere 3.0 grams (0.031 mole) of trimethylsilylacetylene was added to a stirred mixture of 5.5 grams (0.025 mole) of 2-iodo-5-methylthiophene in 50 ml of triethylamine. To this mixture was added approximately 0.05 gram of dichlorobis(triphenylphosphine)palladium (II) and approximately 0.05 gram of copper (I) iodide. The resultant mixture was stirred at room temperature for approximately 18 hours. The triethylamine was removed from the mixture by evaporation under reduced pressure leaving a residue. This residue was dissolved in diethyl ether and the resultant solution was washed in succession with an aqueous, 10% ammonium chloride solution, water, and an aqueous, saturated sodium chloride solution. The washed organic solution was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with n-hexane, to yield 4.5 grams of 1-trimethylsilyl-2-(5-methylthien-2-yl)ethyne as an oil.