Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[C:18]1[C:16]2[CH2:17][CH:13]([CH2:12][N:30]=[N+:31]=[N-:32])[O:14][C:15]=2[CH:21]=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3c(C)cccc3C)O2)cc1
Agent: [Na+]
Product: Cc1cccc(C)c1-c1cccc2c1CC(CN=[N+]=[N-])O2
Yield: 90.9 %

Procedure:
Treatment of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (2.27 g, 5.55 mmol) with sodium azide (1.44 g, 22.23 mmol) generally according to the procedure described for Intermediate 98 gave 1.41 g (91%) of (±)-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.141 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.36 g (93%) of (±)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 254-256° C.; Anal. calcd. for C17H19NOHCl: C, 70.46; H, 6.96; N, 4.83. Found: C, 69.03; H, 7.05; N, 4.66.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:14])[C:3]=1[S:15][C:16]1[C:17]2[N:40]([CH3:41])[CH:39]=[CH:38][C:18]=2[N:19]=[C:20]([N:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)C(=O)OC(C)(C)C)[N:21]=1>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([CH3:14])[C:3]=1[S:15][C:16]1[C:17]2[N:40]([CH3:41])[CH:39]=[CH:38][C:18]=2[N:19]=[C:20]([NH:22][C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)[N:21]=1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1Sc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2ccn(C)c12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccncc2)cc(C)c1Sc1nc(Nc2ccc(C#N)cc2)nc2ccn(C)c12

Procedure:
tert-Butyl 4-(2,6-dimethyl-4-(pyridin-4-yl)phenylthio)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-yl-4-cyanophenylcarbamate is treated with TFA (10 mL) at 25° C. for 2 h. TFA is removed and the obtained residue dissolved in ethyl acetate, and extracted with saturated aqueous NaHCO3 (×2). The organic layer is collected, concentrated, and the purified by chromatography (SiO2, 1:4 hexanes/EtOAc).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:12][CH2:13][CH3:14])([CH2:6][NH:7][C:8](=S)[S:9]C)=[O:5])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C.O>[CH2:1]([O:3][P:4]([CH2:6][N:7]1[C:8]([SH:9])=[N:17][N:16]=[N:15]1)([O:12][CH2:13][CH3:14])=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOP(=O)(CNC(=S)SC)OCC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(Cn1nnnc1S)OCC

Procedure:
To a solution of 2.85 g (11.1 mmol) of methyl 1-diethoxyphosphinylmethyldithiocarbamate in 25 ml of ethanol was added a solution of 0.72 g (11.1 mmol) of sodium azide in 5 ml of water. The reaction mixture was refluxed for 2.5 hours then evaporated to near dryness. Water (20 ml) was added and the aqueous mixture was layered with 40 ml of ethyl acetate and acidified to pH 2.2 by addition of 6N sulfuric acid. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The ethyl acetate solutions were combined, dried (MgSO4) and evaporated to dryness to give 1-diethoxyphosphinylmethyltetrazole-5-thiol.
Reaction SMILES: C[C:2]1[C:3](C)=[C:4]([C:12]#[C:13]CO)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[C:4]1([C:12]#[CH:13])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:2][CH:3]=1
Reactant: Cc1cc2ccccc2c(C#CCO)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#Cc1cccc2ccccc12
Temperature: 120 °C
Yield: 88.8 %

Procedure:
Dimethylhydroxymethyl-1-naphthylacetylene (898 mg, 4.27 mmol) and NaOH (239 mg, KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98% article, 5.98 mmol) were placed in a 30 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 20 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 30 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel to give 577 mg of the desired compound as a yellow solid (yield: 88.8%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[CH3:20][O:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[C:26]([O:28][CH3:29])=[N:27][C:22]([O:21][CH3:20])=[N:23][CH:24]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Product: CCCNC(=O)c1nnc2c(-c3cnc(OC)nc3OC)c(F)ccc2c1N

Procedure:
The title compound was prepared from 4-amino-7-flouro-8-iodo-N-propylcinnoline-3-carboxamide (220 mg, 58.8 mmol) and 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (312 mg, 1.62 mmol) according to Method B to afford a white solid (123 mg, 54%). 1H NMR (300.132 MHz, CDCl3) δ 8.47 (t, J=5.4 Hz, 1H), 8.32 (s, 1H), 7.93 (dd, J=9.1, 5.2 Hz, 1H), 7.53 (dd, J=9.2, 8.4 Hz, 1H), 4.07 (s, 3H), 3.94 (s, 3H), 3.45 (q, J=6.7 Hz, 2H), 1.66 (sextet, J=7.3 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=387 (M+H). HPLC 1.87 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:10]2)(=O)=O.[CH:25]([O:27]CCCC)=[CH2:26].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:25]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:10]2)(=[O:27])[CH3:26]
Reactant: CCCN(CCC)C1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1Cc2ccc(C(C)=O)cc2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-trifluoromethanesulfonyloxy-2-(di-n-propylamino)indan (Example 2) in DMF is treated sequentially with triethylamine, butyl vinyl ether, 1,3-bis(diphenylphosphino)propane, and palladium acetate under nitrogen. The mixture is heated at 80° C. for 0.5 h. (J. Org. Chem. 1990, 55 3654). The reaction mixture is cooled to room temperature and treated with 5% HCl. After stirring for 0.5 h, the mixture is extracted with methylene chloride. The crude product is purified by chromatography to yield the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:36]=[CH:35][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:34])[C:15]([CH2:25][CH2:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:37](Cl)([CH3:40])(=[O:39])=[O:38].N1C=CC=CC=1>CC(C)=O>[CH:28]1([CH2:27][CH2:26][CH2:25][C:15]2([CH3:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]([OH:23])=[C:13]([C:8]3[NH:7][C:6]4[CH:35]=[CH:36][C:3]([NH:2][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:4][C:5]=4[S:10](=[O:12])(=[O:11])[N:9]=3)[C:14]2=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC1(CCCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 88 %

Procedure:
A solution of Example 38B (0.357 g, 0.674 mmol), mesyl chloride (0.209 mL, 2.69 mmol), and pyridine (0.436 mL, 5.39 mmol) in acetone (15 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.339 g, 88%).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1>[OH-].[Na+].CN(C)C=O>[OH:3][N:2]=[C:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][O:14][C:5]2[CH:6]=[CH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:4]=2)=[CH:19][CH:20]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)C(=NO)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of hydroxylamine hydrochloride (0.089 g) in 1N sodium hydroxide solution (1.3 mL) was added to a solution of 4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid (0.291 g) in dimethylformamide and the mixture was heated on a steam bath till all the solids dissolved. The reactants were maintained in solution by intermittent heating over 2 hours, then the mixture was stirred at room temperature overnight. The formed precipitate was filtered off, then the filtrate was diluted with water and adjusted to pH 2 by the addition of dilute hydrochloric acid solution. The resulting solid was recovered by filtration and dried in vacuo to furnish 0.164 g of (Z)-alpha-(hydroxyimino-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid, mp 178°-179° C.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH:17]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH2:9][NH:8][CH2:16]3)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(C3CCOCC3)c(C3CC3)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: c1c2c(cc(C3CC3)c1C1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-cyclopropyl-6-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown solid. MS (m/e): 244.4 ([M+H]+, 100%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:30]=[C:29]3[C:20]([NH:21][C:22]4[C:27]([O:28]3)=[CH:26][CH:25]=[C:24]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:23]=4)=[N:19][C:18]2=[O:40])[CH2:13][CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:30]=[C:29]3[C:20]([NH:21][C:22]4[C:27]([O:28]3)=[CH:26][CH:25]=[C:24]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:23]=4)=[N:19][C:18]2=[O:40])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(n2cc3c(nc2=O)Nc2cc(CCc4cccc(F)c4)ccc2O3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCN1CCC(n2cc3c(nc2=O)Nc2cc(CCc4cccc(F)c4)ccc2O3)CC1
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of [3-(4-{7-[2-(3-fluoro-phenyl)-ethyl]-2-oxo-2,9-dihydro-10-oxa-1,3,9-triaza-anthracen-3-yl}-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester (94 mg, 0.167 mmol, 1 equiv) in dichloromethane (10 mL) at 23° C. was added trifluoroacetic acid (4.0 mL). The reaction was stirred for 30 min then concentrated. The residue was dissolved in water (10 mL) then treated with 1.0 N aqueous hydrochloric acid (2.0 mL). The resulting solution was concentrated, and then the residue was re-dissolved in water (10 mL), treated with hydrochloric acid (2.0 mL) and concentrated. The residue was dissolved in water (10 mL) and then the resulting solution was frozen and then lyophilized to give 88 mg (0.165 mmol, 99%) of the desired product (dihydrochloride salt) as a yellow solid. LCMS (EI): 464.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1.CC([CH:54]1[CH2:60][NH:59][CH2:58][CH2:57][CH2:56][N:55]1C([O-])=O)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:55]3[CH2:56][CH2:57][CH2:58][NH:59][CH2:60][CH2:54]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)c1
Reactant: CC(C)(C)C1CNCCCN1C(=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(CN4CCCNCC4)c3)c2)c1

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.034 g, 0.05 mmol), 1,1-dimethylethylhexahydro-1H-1,4-diazepine-1-carboxylate (0.012 g, 0.06 mmol), and acetic acid (0.0036 g, 0.06 mmol) were combined in 1,2-dichloroethane (2 mL), and the mixture stirred for thirty min. Sodium triacetoxyborohydride (0.0148 g, 0.07 mmol) was added and the mixture stirred overnight at room temperature. Solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the protected product. This was treated with 10% TFA in CH2Cl2 for 3 h. The product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed 3× with 2.5 N NaOH, 1× with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a white solid. LC-MS m/z 763.2 (M+H)+, 1.37 min (ret time); mp 116-119° C. Analytical HPLC shows 95.3% purity, (ret time 10.056 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH3:18].[Li][CH2:20]CCC.CI>C1COCC1>[CH3:14][O:13][CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH3:18])=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10]=1[CH3:20]
Reactant: [Li]CCCC
Reactant: CCCOc1ccc(OCOC)cc1OCOC
Solvent: CI
Solvent: C1CCOC1
Product: CCCOc1ccc(OCOC)c(C)c1OCOC
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 4b (165 mg, 0.64 mmol) in anhydrous THF (520 μL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 390 μL, 0.97 mmol) in anhydrous THF (420 μL) at room temperature. After 1 hour, the solution was cooled to −78° C. and methyl iodide (160 μL, 2.58 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1 Hexane:EtOAc) to afford 5b as a yellow oil (166 mg, 95%): 1H NMR (CDCl3, 500 MHz) δ 6.66 (d, J=9.0 Hz, 1H), 6.60 (d, J=9.0 Hz, 1H), 5.02 (s, 2H), 5.00 (s, 2H), 3.80-3.77 (m, 2H), 3.49 (s, 3H), 3.47 (s, 3H), 2.14 (d, J=7.1 Hz, 3H), 1.73-1.69 (m, 2H), 0.94 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 148.5, 148.5, 147.3, 145.6, 126.7, 123.0, 112.8, 110.8, 110.4, 99.2, 57.7, 57.6, 21.2, 10.9, 10.0; IR (film) νmax 2957, 2924, 2853, 1738, 1597, 1487, 1468, 1391, 1335, 1231, 1157, 974, 798 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C14H22O5, 271.1545. found, 271.1558.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12]C(=O)OCC)=[S:11])[CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:3]=1
Reactant: CCOC(=O)NC(=S)Nc1cc(Cl)nc(C)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(Cl)cc(NC(N)=S)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A solution of ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate (275 mg, 1.0 mmol) and 1N sodium hydroxide (3.5 eq) was heated and stirred at 50° C. for 2h. The resulting slurry was cooled to 20-22° C. The solid was collected by vacuum filtration, washed with water, and dried to give 185 mg of 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea (91% yield). 1H NMR (400 MHz, DMSO-d6): δ2.51 (S, 3H), 7.05 (s, 1H), 9.35 (s,1H), 10.07 (s, 1H), 10.91 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 25.25, 104.56, 159.19, 159.33, 167.36, 180.91.
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:41]=[CH:40][C:16]3[N:17]([C:20]4[CH:39]=[CH:38][C:23]([O:24][CH2:25][CH2:26][O:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:37]=5)[C:33]([O:35]C)=[O:34])=[CH:22][CH:21]=4)[CH:18]=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH:4]=1.OC1C=NC=C(C=1)C(OC)=O>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][NH:10][C:11]([C:13]2[CH:41]=[CH:40][C:16]3[N:17]([C:20]4[CH:39]=[CH:38][C:23]([O:24][CH2:25][CH2:26][O:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:37]=5)[C:33]([OH:35])=[O:34])=[CH:22][CH:21]=4)[CH:18]=[N:19][C:15]=3[CH:14]=2)=[O:12])[CH:4]=1
Reactant: COC(=O)c1cncc(OCCOc2ccc(-n3cnc4cc(C(=O)NCc5cccnc5)ccc43)cc2)c1
Agent: COC(=O)c1cncc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cncc(OCCOc2ccc(-n3cnc4cc(C(=O)NCc5cccnc5)ccc43)cc2)c1

Procedure:
An aqueous solution of sodium hydroxide (0.107 mmol, 43 μL, 100 mg/mL) was added to methyl 5-(2-{4-[5-(pyridin-3-ylmethylaminocarbonyl)-1H-benzimidazol-1-yl]phenoxy}ethoxy)nicotinate (prepared according to the procedure described above utilising methyl 5-hydroxynicotinate in place of 3-hydroxypyridine, 37 mg, 0.07 mmol) in methanol and the mixture heated at reflux for 18 h. The mixture was then concentrated in vacuo and purified by preparative HPLC to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 9.15 (t, J=6.0 Hz, 1H), 8.64 (s, 1H), 8.60-8.50 (m, 2H), 8.40-8.39 (m, 2H), 8.38 (d, J=1.6 Hz, 1H), 8.35 (s, 1H), 7.87 (dd, J=8.4, 1.6 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.59 (dd, J=12.4, 8.8 Hz, 3H), 7.35 (dd, J=7.6, 5.2 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 4.51 (d, J=6.0 Hz, 2H), 4.50-4.4 (m, 4H); MS (ES+): m/z 510 [MH+], 511 [MH+2].
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[C:7]([CH3:14])[CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:12])=[C:7]([CH3:14])[CH:6]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)F)cc1C
Product: Cc1cc(OCC(F)F)ccc1C(C)N[S@](=O)C(C)(C)C
Yield: 42 %

Procedure:
The title compound is prepared in 42% yield (1.0 g, clear colorless oil) from 1-(4-(2,2-difluoroethoxy)-2-methylphenyl)ethanone (1.6 g, 7.5 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[CH:9]12[CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][CH:10]2[Si:16]([CH3:19])([CH3:18])Cl>>[F:1][C:2]([F:8])([F:7])[S:3]([O:6][Si:16]([CH:10]1[CH2:11][CH:12]2[CH2:15][CH:9]1[CH2:14][CH2:13]2)([CH3:19])[CH3:18])(=[O:5])=[O:4]
Reactant: C[Si](C)(Cl)C1CC2CCC1C2
Reactant: O=S(=O)(O)C(F)(F)F
Product: C[Si](C)(OS(=O)(=O)C(F)(F)F)C1CC2CCC1C2
Temperature: 60 °C

Procedure:
At room temperature, trifluoromethanesulfonic acid (7.50 g, 49.0 mmol) is added dropwise to 2-norbornyl-dimethylchlorosilane (9.50 g, 49.3 mmol), whose preparation is described in Example 1. The reaction mixture is heated to 60° C. for 10 h. The crude product is distilled under oil pump vacuum. 12.3 g (83%) of colorless, moisture-sensitive liquid having b.p. 100-105° C. (1 mbar) is obtained. Purity 93% (GC).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CCN=C=NCCCN(C)C.[C:17]([CH2:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]([NH:31][C:32]([C:34]2[NH:38][C:37]3[S:39][C:40]([Cl:42])=[CH:41][C:36]=3[CH:35]=2)=[O:33])[C:22]1=[O:43])(O)=[O:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CO.C(Cl)Cl>[Cl:42][C:40]1[S:39][C:37]2[NH:38][C:34]([C:32]([NH:31][CH:23]3[CH2:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH2:20][C:17]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:18])[C:22]3=[O:43])=[O:33])=[CH:35][C:36]=2[CH:41]=1
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)NC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 48 h

Procedure:
Methanesulphonamide (90 mg, 0.94 mmol), 4-(dimethylamino)pyridine (287 mg, 2.35 mmol) and EDCI (225 mg, 1.17 mmol) were added to a suspension of N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 2; 315 mg, 0.78 mmol) in DCM (50 mL) and stirred for 2 days. The reaction was diluted with MeOH:DCM (1:19) (50 mL) and washed with 1M HCl(aq). (50 mL), the organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by applying the material to a 10 g Isolute NH2 column in MeOH:DCM (1:9) (10 mL) and eluted with MeOH:DCM (1:9) (6×10 mL) then MeOH: 2M HCl in Et2O:DCM (5:4:45) (6×10 mL) and the relevant fractions evaporated to give a pink gum which was triturated with refluxing Et2O (25 mL) and after cooling the title product (206 mg, 55%) was collected by filtration as pale pink powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][C:8]#[N:9].Cl.[OH:16][NH2:17]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][C:8](=[N:17][OH:16])[NH2:9]
Reactant: COc1ccc(OCC#N)cc1OC
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(OCC(N)=NO)cc1OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(3,4-dimethoxyphenoxy)acetonitrile (3.8 g) in MeOH—H2O (1:1), hydroxyamine hydrochloride was added and the mixture was stirred at 100° C. for 3 hours. After distilling off the solvent under reduced pressure, the residue was recovered by filtration and washed with water and hexane to give a crude form of the titled compound (4.9 g).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([C:12]([OH:14])=[O:13])[NH:7]2.Br[C:17]1C=C(C)C=C2[C:18]=1C(=O)C=C(C(O)=O)N2>>[CH2:17]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([C:12]([OH:14])=[O:13])[NH:7]2)[CH3:18]
Reactant: O=C(O)c1cc(=O)c2c(I)cccc2[nH]1
Reactant: Cc1cc(Br)c2c(=O)cc(C(=O)O)[nH]c2c1
Product: CCc1cccc2[nH]c(C(=O)O)cc(=O)c12

Procedure:
5-iodo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid; 5-bromo-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid;