Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:28][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([Cl:27])=[N:25][CH:26]=4)[CH2:15][CH2:14]3)[CH2:12][C:11](=[O:29])[C:10]=2[CH:30]=1)(=[O:4])=[O:3].ClC1C=CC=C(C(OO)=[O:39])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:28][C:13]3([CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([Cl:27])=[N:25][CH:26]=4)[CH2:17][CH2:18]3)[CH2:12][C:11](=[O:29])[C:10]=2[CH:30]=1)(=[O:4])=[O:3].[NH4+:5].[OH-:39]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(Cl)nc3)CC1)O2
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: [NH4+]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The N-oxide of the product of Example 276 was prepared by treating 6-methanesulfonamido-3,4-dihydro-1'-[2-(2-chloro-pyrid-5-yl)ethyl]spiro [(2H)-1-benzopyran-2,4'-piperidine]-4-one (0.170 g, 0.000378 mol) in 120 mL of chloroform with 0.276 g (0.0008 mol) of m-chloroperbenzoic acid at room temperature overnight. Calcium hydroxide (0.12 g, 0.0016 mol) was added, the mixture was stirred one hour at room temperature and was filtered and concentrated in vacuo. Flash chromatography on silica gel using CH2Cl2 :methanol:concentrated NH4OH (90:10:2) gave the title compound, mp 170°-171° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[C:23]=3[CH3:31])[C@H:15]2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:30][C:24]1[C:23]([CH3:31])=[C:22]([C:14]2[C@@H:15]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)[C@@H:16]3[C@@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[N:13]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: Cc1c(C2=NN3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2OCC2CC2)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C2=NN3CC[C@H](O)[C@H]3[C@@H]2OCC2CC2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-((3S,3aR,4S)-4-((tert-butyldimethylsilyl)oxy)-3-(cyclopropylmethoxy)-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (60 mg, 0.13 mmol) in THF (2 mL) at 0° C. was added TBAF (0.26 mL, 0.26 mmol, 1M Solution in THF) and stirred for 1 h at room temperature. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with ethyl acetate. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Crude product was purified by preparative TLC method (50% EtOAc in hexane).
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([CH3:37])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[CH3:36])[CH3:6])C.ClC(C1C(C)=NC(C2C=CC=C(C(F)(F)F)C=2)=CC=1)CCC.ClCC1C(C)=NC(C2C=CC=C(C(F)(F)F)C=2)=CC=1>>[CH3:6][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[CH3:36])([CH3:37])[C:4]([OH:38])=[O:3]
Reactant: CCCC(Oc1ccc(OC(C)(C)C(=O)OCC)c(C)c1)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Agent: CCCC(Cl)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Agent: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CCl
Product: CCCC(Oc1ccc(OC(C)(C)C(=O)O)c(C)c1)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
A] The title compound was prepared in analogy to example 8, via [rac]-2-methyl-2-(2-methyl-4-{1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-phenoxy)-propionic acid ethyl ester, but using instep A] [rac]-3-(1-chloro-butyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine (example 4B]) instead of 3-chloromethyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, as white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]([C:11]([OH:13])=O)=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]2[C:11](=[O:13])[O:16][C:14](=[O:15])[C:4]=2[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1O
Product: CC(=O)Oc1cc2c(cc1C(=O)O)C(=O)OC2=O
Temperature: 25 °C
Yield: 38 %

Procedure:
4-Hydroxy-benzene-1,2,5-tricarboxylic acid (4.1 g, 18.1 mmol), prepared according to J. Am. Chem. Soc. (1949) 71, 11, was treated with acetic anhydride (50 mL) and heated at reflux for 5 hours. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The orange-pink residue was washed with diethyl ether (3×30 mL) and dried under reduced pressure at room temperature overnight to provide the title compound (1.71 g, 38%).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[C:8]=2[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].[CH3:20][NH2:21]>C(O)C>[CH3:20][NH:21][C:15](=[O:17])[CH2:14][C:9]1[C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CN
Reactant: CCOC(=O)Cc1cccc2c(C(C)C)nccc12
Solvent: CCO
Product: CNC(=O)Cc1cccc2c(C(C)C)nccc12

Procedure:
Ethyl 1-isopropylisoquinoline-5-acetate (0.4 g) was dissolved in 20 ml of ethanol, and 5 ml of a 40% aqueous solution of monomethylamine was added. The mixture was stirred under heat for 12 hours. After the reaction, the solvent was distilled off. The residue was extracted with benzene, washed in water, and dried. The solvent was distilled off under reduced pressure. Recrystallization from benzenecyclohexane afforded 0.15 g of 1-isopropylisoquinoline-5-acetic acid methylamide as colorless needles having a melting point of 153.2° to 153.7° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([C:25]4[N:26]=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[C:30]([O:35]C)[CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.B(Br)(Br)Br.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:37][C:22]1[C:23]([C:25]2[N:26]=[CH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[C:30]([OH:35])[CH:29]=3)=[CH:24][C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)=[CH:20][N:21]=1
Reactant: COc1ccc2cc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)ncc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2ccc(O)cc2cn1
Temperature: 0 °C

Procedure:
Into the DCM (5 ml) solution of 4-{4-[6-amino-5-(7-methoxyisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (101 mg, 0.171 mmol), cooled in an ice/water bath, was added 1.00 M of boron tribromide in DCM (2.0 ml) over 5 min. The mixture was stirred at 0° C. and warmed to rt overnight. After that time, the mixture was basified with saturated Na2CO3 until pH 10 and extracted with EtOAc (3×30 ml). The extracts were washed with brine (2×20 ml), dried over MgSO4, filtered and concentrated in vacuo, giving the title compound as a light-yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.90-2.02 (m, 2H), 2.09-2.18 (m, 2H), 2.74-2.82 (m, 2H), 3.18-3.24 (m, 2H), 4.26-4.36 (m, 1H), 7.27 (d, J=2.4 Hz, 1H), 7.36 (dd, J=2.4 & 9.2 Hz, 1H), 7.84-7.87 (m, 2H), 8.06 (d, J=0.8 Hz, 1H), 8.07 (d, J=3.2 Hz, 1H), 8.10 (s, 1H), 8.17 (d, J=2.4 Hz, 1H), 9.08 (s, 1H). MS(ES+): m/z=387.14 (100) [MH+]. HPLC: tR=0.66 & 1.85 min (ZQ3, polar—5 min; peak splitting).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]1(=[O:25])[N:17]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:16](=[O:24])[CH:15]=[CH:14]1.ON1C2C=CC=CC=2N=N1.[NH:36]1[CH2:41][CH2:40][CH:39]([CH2:42][C:43]2[N:44]([CH2:57][CH2:58][CH3:59])[N:45]=[C:46]3[C:55]=2[C:54]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[N:48]=[C:47]3[NH2:56])[CH2:38][CH2:37]1>CN(C=O)C.O>[NH2:56][C:47]1[C:46]2=[N:45][N:44]([CH2:57][CH2:58][CH3:59])[C:43]([CH2:42][CH:39]3[CH2:40][CH2:41][N:36]([C:21](=[O:23])[CH2:20][CH2:19][CH2:18][N:17]4[C:13](=[O:25])[CH:14]=[CH:15][C:16]4=[O:24])[CH2:37][CH2:38]3)=[C:55]2[C:54]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[N:48]=1
Reactant: O=C(O)CCCN1C(=O)C=CC1=O
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC1CCN(C(=O)CCCN2C(=O)C=CC2=O)CC1
Reaction time: 1 h
Yield: 37 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.266 g, 1.39 mmol) was added to a mixture of 4-maleimidobutyric acid (0.254 g, 1.39 mmol) and 1-hydroxybenzotriazole (0.187 g, 1.39 mmol) in DMF (13 mL). The mixture was stirred for 1 hour, then 1-(piperidin-4-ylmethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.450 g, 1.39 mmol) was added. The mixture was stirred for 1 hour, then water (60 mL) was added, and the mixture was stirred an additional hour. The aqueous layer was extracted with ethyl acetate (2×75 mL) and dichloromethane (2×75 mL). The organic layers were combined, washed with water (2×100 mL) and brine, and then concentrated under reduced pressure. The resulting residue was purified by HPFC on silica gel (gradient elution with 2-20% CMA in chloroform) to provide 0.251 g of 1-(4-{4-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]piperidin-1-yl}-4-oxobutyl)-1H-pyrrole-2,5-dione as a yellow foam. Anal. Calcd for C27H32N6O3.0.75H2O: C, 64.36; H, 6.68; N, 16.53. Found: C, 64.59; H, 6.73; N, 16.74.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:28]=[CH:27][CH:26]=[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C1CCN(Cc2cccc(N)c2)CC1
Product: CCOC(=O)C1CCN(Cc2cccc(Nc3nc(Cl)ncc3F)c2)CC1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and ethyl 1-(3-aminobenzyl)piperidine-4-carboxylate were reacted to provide 2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]methyl]phenyl]-5-fluoro-4-pyrimidineamine. LCMS: purity: 97%; MS (m/e): 394 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](OC=C)(=O)[CH3:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][CH:24]=[CH2:25])=[CH:10][CH:9]=2)[CH:16]=1
Reactant: OCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=COCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a solution of (4-(5-bromo-2-chlorobenzyl)phenyl)methanol (intermediate AK) (1.5 g, 4.81 mmol), [IrCl(cod)]2 (31 mg, 0.046 mmol) and sodium carbonate (0.29 g, 2.73 mmol) in toluene (6 mL) was added vinyl acetate (0.84 mL, 9.10 mmol) under argon. The reaction mixture was heated to 100° C. and stirred for 4 h. The solution was allowed to cool to room temperature, and then diluted with 50 mL of ethyl acetate. The mixture was washed with water (20 mL) and then with brine (20 mL), and dried over sodium sulfate. The residue was concentrated and purified by column chromatography (eluent EA:PE:Et3N=1:30:0.01) to provide 1.09 g of white solid. 1H NMR (CDCl3, 400 MHz): δ 7.36˜7.28 (m, 5H), 7.22 (d, 2H), 6.61 (dd, J=14.4 and 6.8 Hz, 1H), 4.78 (s, 2H), 4.37˜4.33 (dd, J=14.4 and 2.4 Hz, 1H), 4.14˜4.12 (dd, J=6.8 and 2.4 Hz, 1H), 4.09 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:16][C@H:15]([CH2:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[ClH:34]>C(O)C>[OH2:20].[ClH:34].[ClH:34].[NH2:26][CH2:25][CH2:24][CH2:23][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][N:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:16]1
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3c(N)nc4ccccc4c3n21
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)N1Cc2nc3c(N)nc4ccccc4c3n2[C@@H](CCCN)C1
Product: O
Temperature: 75 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-[(11S)-6-amino-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (5.41 g, 11.4 mmol) was dissolved in 25 mL of ethanol and 25 mL of a 1.8 M solution of HCl in ethanol was added. The reaction mixture was heated to 75° C. After 1 hour, the reaction mixture was cooled and filtered to give a white solid. The resulting solid was stirred in refluxing ethanol for 30 minutes. The suspension was cooled and filtered to give a white solid. The solid was washed with a small portion of cold ethanol and then dried by suction to give (11S)-11-(3-aminopropyl)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine dihydrochloride hydrate (2.98 g) as an off-white powder (Anal. calcd for C17H22N6O2S2.2.0 HCl.1.0H2O: C, 43.87; H, 5.63; N, 18.06. Found: C, 43.83; H, 5.53; N, 17.99). The free base could be prepared by dissolving the material in dilute NH4OH solution and extraction into CHCl3.
Reaction SMILES: C(O)(C)C.[CH2:5]([NH2:15])[C:6]1[CH:14]=[CH:13][C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C(N(CC)CC)C>[CH2:10]1[O:11][C:12]2[CH:13]=[CH:14][C:6]([CH2:5][NH:15][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)=[CH:7][C:8]=2[O:9]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: N#Cc1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#Cc1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 89 %

Procedure:
15 ml of isopropyl alcohol, 75 mg of triethylamine and 125 mg of piperonylamine were added to 140 mg of 4-chloro-6-cyanoquinazoline. The obtained mixture was heated under reflux for 5 hours and filtered to recover a precipitate. This precipitate was introduced to a silica gel column, followed by eluting with ethyl acetate to give 200 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CCNCC
Product: CCN(CC)C(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and N-ethyl-ethanamine.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1ccc(Br)cc1
Product: N#Cc1ccc(-c2cc([N+](=O)[O-])ccc2F)cc1

Procedure:
4-Bromobenzonitrile and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane were coupled using the procedure described in Example 7 part c) to afford 2′-fluoro-5′-nitrobiphenyl-4-carbonitrile as a brown solid: δH(400 MHz, CDCl3) 7.37 (1H, dd, J 9 and 9), 7.70 (2H, dd, J 8 and 1), 7.80 (1H, dd, J 8 and 1), 8.29-8.33 (1H, m), 8.37-8.40 (1H, m).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:15][C:16]([N:18]([CH2:26][CH:27]=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH:13]=[CH2:14].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]([CH2:26][CH:27]([OH:28])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)N(CC=O)Cc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOC(=O)N(Cc1ccccc1)CC(O)C#C[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (trimethylsilyl)acetylene (23.75 ml) in tetrahydrofuran (250 ml) was added a 1.6M solution of butyllithium in hexane (105 ml) below -60° C. After stirring for one hour, a solution of 2-(N-allyloxycarbonyl-N-benzylamino)acetaldehyde (32.86 g) in tetrahydrofuran (30 ml) was added to the mixture below -60° C. The solution was stirred at the same condition for one hour and an aqueous saturated ammonium chloride (100 ml) was added to the reaction mixture below -60° C. After stirring at the ambient temperature for one hour, ethyl acetate (300 ml) was poured into the mixture. The solution was washed with brine (150 ml×2), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (300 g) and eluted with a mixture of hexane and ethyl acetate (9:1, V/V) to give 1-(N-allyloxycarbonyl-N-benzylamino)-4-trimethylsilyl-3-butyn-2-ol (19.77 g) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][C:12]([NH2:14])=[O:13])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[Cl:8].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:8][C:7]1[N:6]=[C:5]([CH3:9])[N:4]=[C:3]2[C:2]=1[N:1]=[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15])[N:10]2[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: Cc1nc(Cl)c(N)c(NCC(N)=O)n1
Reactant: O=Cc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CC(N)=O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
Heat a mixture of 2-[(5-amino-6-chloro-2-methyl-pyrimidin-4-yl)amino]acetamide (2.2 g, 0.01 mol), 2-chlorobenzaldehyde (2.86 g, 0.02 mol), p-toluene sulfonic acid (0.2 g) and molecular sieves (1.0 g) in toluene (50 mL) to reflux for 16 h. Cool and remove the sieves by filtration through diatomaceous earth. Concentrate the filtrate under reduced pressure to afford a residue. Dissolve the residue in dry dichloromethane (50 mL) and add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.3 g, 0.01 mol) at 0° C. Allow to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane, wash with 1 N aqueous sodium hydroxide solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with dichloromethane:methanol (98:2) to provide the title compound (0.3 g). ES/MS m/z 336 (M+1).
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:6])[CH2:4][OH:5].Cl[C:8]1[CH:16]=[N:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>CS(C)=O>[CH2:4]([O:5][C:8]1[CH:16]=[N:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])[CH:3]([CH3:6])[CH3:2]
Reactant: O=C(O)c1ccncc1Cl
Reactant: CC(C)CO
Agent: [Na]
Solvent: CS(C)=O
Product: CC(C)COc1cnccc1C(=O)O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Sodium metal (7.3 g, 0.32 mol) was added in small portions to 2-methyl-1-propanol (145 mL, 0.63 mol) at 80° C. over 30 min period, and the reaction mixture was stirred for an additional 3 h at 80° C. Subsequently, a solution of commercially available 3-chloroisonicotinic acid (10 g, 63 mmol) in 5 mL of DMSO was added to the reaction mixture at 80° C. The resulting slurry was heated to 120° C. for an additional 16 h, then cooled down to room temperature, concentrated down to half volume under the reduced pressure, and filtered. The filtrate was concentrated down to half volume under the reduced pressure, and filtered again. The combined solids were mixed with 10 mL of MeOH and 1 mL of water and acidified with concentrated HCl at 0° C. to pH=7. The resulting precipitate was filtered out and dried under vacuum, resulting in 10 g (81%) of 3-isobutoxyisonicotinic acid. 1H-NMR (400 MHz, d6-DMSO): δ 8.47 (s, 1H), 8.23 (d, 1H), 7.46 (d, 1H), 3.91 (d, 2H), 2.04 (m, 1H), 0.94 (d, 6H). MS (EI) for C10H13NO3: 196 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][OH:30])[C:5]([CH2:21][O:22]C2CCCCO2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.C(N(C(C)C)C(C)C)C.[CH3:40][Si:41]([CH2:44][CH2:45][O:46][CH2:47]Cl)([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][O:30][CH2:47][O:46][CH2:45][CH2:44][Si:41]([CH3:43])([CH3:42])[CH3:40])[C:5]([CH2:21][OH:22])=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CO)c(COCOCC[Si](C)(C)C)cc(C)c32)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (200 mg, 0.466 mmol) and iPr2EtN (0.16 mL, 0.93 mmol) in CH2Cl2 (2 mL) was added SEMCl (0.124 mL, 0.69 mmol), and then the mixture was stirred at 40° C. for 1 hr. The reaction mixture was concentrated (during the concentration, the THP group was partially removed) and then purified by SiO2 column chromatography (heptane/EtOAc=1/0 to 1/3) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.81 (d, J=3.79 Hz, 1H), 7.58 (d, J=8.30 Hz, 2H), 7.32 (d, J=8.30 Hz, 2H), 7.08 (s, 1H), 6.99 (d, J=3.79 Hz, 1H), 4.79 (d, J=5.81 Hz, 2H), 4.68 (s, 2H), 4.67 (s, 2H), 3.54-3.63 (m, 2H), 3.05 (t, J=5.80 Hz, 1H), 2.54 (s, 3H), 2.35 (s, 3H), 0.82-0.96 (m, 2H), 0.01 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:25][C:26]([Cl:33])([Cl:32])[C:27]([N:29]=[C:30]=[O:31])=[O:28]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:30]([NH:29][C:27](=[O:28])[C:26]([Cl:33])([Cl:32])[Cl:25])=[O:31])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)S[C@H]1C[C@@H](COC(=O)NC(=O)C(Cl)(Cl)Cl)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (100 mg) was dissolved in 3 ml of dry ethyl acetate. To the solution was added 0.05 ml of trichloroacetyl isocyanate under ice-cooling in a nitrogen stream, followed by stirring at the same temperature for 1 hour. The mixture was diluted with ethyl acetate, washed successively with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-trichloroacetylaminocarbonyloxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])[CH:6]=[CH:5]2
Reactant: COc1ccccc1CN
Reactant: Clc1ccc2cc(Br)ccc2n1
Product: COc1ccccc1CNc1ccc2cc(Br)ccc2n1

Procedure:
6-Bromo-2 chloroquinoline (727 mg, 3.0 mmol) and 2-methoxybenzylamine (823 mg, 6.0 mmol were stirred in a sealed tube at 120° C. for 16 h. The reaction mixture was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->70:30 gradient). (6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as a light yellow solid (868 mg, 84%), MS: m/e=343.1 (M+H+).