Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH:12]=O)[O:7][CH2:6][CH2:5]2.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][N:26]1[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]1)[O:7][CH2:6][CH2:5]2
Reactant: COc1c(Br)ccc2c1CCOC2C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(Br)ccc2c1CCOC2CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-5-methoxy-3,4-dihydro-1H-isochromene-1-carbaldehyde (230 mg, 0.85 mmol) in 10 mL of DCM was added Boc-piperazine (189 mg, 1.02 mmol) and NaBH(OAc)3 (720 mg, 3.4 mmol), and the mixture was stirred at room temperature overnight. The reaction was diluted with DCM, and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give tert-butyl 4-[(6-bromo-5-methoxy-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[Cl:15])[CH3:2].C(O)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[Cl:15])[CH3:2]
Reactant: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)Nc1ccc(N)cc1Cl
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a cold (ice/water bath) vigorously stirred solution of crude (2-Chloro-4-nitrophenyl)-carbamic acid ethyl ester (5.8 g, 21.8 mmol) in tetrahydrofuran (THF) (100 mL) and acetic acid (12 mL) zinc powder (20 g) was added by small portions maintaining the temperature below 40° C. The mixture was allowed to warm slowly to room temperature and after reaction completion (1 hour) it was filtered via a plug of SiO2 (20 g) with ethyl acetate as an eluent. The obtained solution was evaporated in vacuo and the crude yellow solid residue (4.9 g) was purified by precipitation from tetrahydrofuran (THF)/heptane to give 3.00 g of the title compound as pale yellow solid, yield 56%. LC/MS (m/z) 214, 216 (M+); RT=1.18, (UV, ELSD) 86%, 97%. 1H NMR (DMSO-d6): 1.18 (br. t, 3H), 4.02 (q, 2H), 5.29 (s, 2H, NH2), 6.45 (dd, 1H), 6.61 (d, 1H), 6.98 (br. d, 1H), 8.52 (br. s, NHCO).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][NH:25]1.C(N(CC)CC)C>O1CCCC1>[CH2:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][N:25]1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCc3ccccc3C2)nc1-c1ccc(C)cc1
Yield: 58.8 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 1,2,3,4-tetrahydroisoquinoline (0.108 mL; 0.856 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.072 g (58%) of the titled compound as a colorless oil.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O>[CH:15]1[C:16]2[N:2]=[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]3[CH2:9][O:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccc[n+]1COc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: C1=CC2=Nc3ccccc3OCN2C=C1
Yield: 60.3 %

Procedure:
A mixture of 9.5 g of 2-amino-1-[(o-bromophenoxy)methyl]pyridinium chloride, 8.3 g of potassium carbonate, 0.4 g of copper-bronze in 150 ml of n-propanol and 25 ml of water under N2, is heated under reflux for 12 hours while stirring. The mixture is filtered hot and the deep yellow filtrate is concentrated to dryness. The residue is dissolved in 400 ml of ether, the ether solution is washed, dried and the solvent removed to give about 6.4 g of the crude yellow product. This is recrystallized from cyclohexane to give about 3.6 g of the title product, mp about 125°-127°.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1.[Cl:22][C:23]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:24]=1[C:25](N(OC)C)=[O:26].[NH4+].[Cl-]>C(Cl)Cl.C1COCC1>[Cl:22][C:23]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:24]=1[C:25](=[O:26])[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Cl
Reactant: CSc1nccc(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSc1nccc(CC(=O)c2ccc(Cl)cc2Cl)n1

Procedure:
To the solution of 85 mL of diisopropylamine (Fluka 38300) and 2.5 L of THF at −75° C. under Argon is added 370 mL (0.55 Mol) of butyl lithium (BuLi; 1.6N in hexanes; Fluka 20160) within 1 h. To this is added 71 g (0.5 Mol) of 4-methyl-2-methylsulfanyl-pyrimidine in 250 mL of CH2Cl2 at −75° C. within 30 min. After this, a solution of 118 g (0.5 Mol) of 2,4dichloro-N-methoxy-N-methyl-benzamide in 250 mL of CH2Cl2 at −75° C. within 30 min followed by letting the mixture warn up to rt. After completion, the reaction mixture is poured onto 7 L of NH4Cl satd. and extracted with ethyl acetate. The combined organic layers are washed with brine, dried and evaporated. The crude product is suspended in hexanes. After filtering off and drying 1-(2,4-dichloro-phenyl)-2-(2-methylsulfanyl-pyrimidin-4-yl)-ethanone is obtained as yellow crystals. Title compound: m.p.: 105-107° C.; ES-MS: 313.0/314.9 [M+H]+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.C(N(CC)CC)C>>[O:15]=[C:10]1[C:9]2[NH:16][CH:17]=[CH:18][C:8]=2[C:7]2[CH:6]=[C:5]([S:2](=[O:3])(=[O:4])[NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:14]=[CH:13][C:12]=2[NH:11]1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Agent: Cl
Solvent: CCN(CC)CC
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)NC3CCNCC3)cc2c2cc[nH]c12
Yield: 7.6 %

Procedure:
This compound is prepared according to synthesis 25, from 326 mg (1 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 236 mg (1 mmol) of 4-amino-1-tert-butoxycarbonyl piperidine hydrochloride and 700 μL (5 mmol) of triethylamine. After purification by chromatography on silica (eluent chloroform/methanol/ammonia 65/25/4) then trituration in methanol, 16 mg (4%) of 4-oxo-8-(piperidin-4-ylsulfamoyl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [C:1]12([SH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18].C(OCC)C>CS(C)=O>[C:1]12([S:11][C:19]3[CH:20]=[CH:21][CH:22]=[C:15]([Br:14])[C:16]=3[C:17]#[N:18])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: SC12CC3CC(CC(C3)C1)C2
Reactant: N#Cc1c(F)cccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#Cc1c(Br)cccc1SC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-Adamantanethiol (278 mg) was dissolved in dimethyl sulfoxide (10 mL). Sodium hydride (60% in mineral oil, 42 mg) was added, and the solution was stirred at room temperature for 20 minutes. 2-Bromo-6-fluorobenzonitrile (300 mg) was added and the solution was heated to 130° C. for 1 hour. The solution was cooled, added to diethyl ether, washed with 1 M aqueous HCl three times, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the title compound.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:18][C:17]([CH:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)=[N:16][CH:15]=3)=[O:13])=[CH:6][C:5]=12.C(N(CC)CC)C.[CH3:31][CH:32]([CH3:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>CN(C)C=O.O>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C:14]3[S:18][C:17]([CH:19]4[CH2:23][CH2:22][N:21]([S:34]([CH2:33][CH:32]([CH3:38])[CH3:31])(=[O:36])=[O:35])[CH2:20]4)=[N:16][CH:15]=3)=[O:13])=[CH:6][C:5]=12
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: O=C(NCc1ccn2ccnc2c1)c1cnc(C2CCNC2)s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)CS(=O)(=O)N1CCC(c2ncc(C(=O)NCc3ccn4ccnc4c3)s2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(imidazo[1,2-a]pyridin-7-ylmethyl)-2-(pyrrolidin-3-yl)thiazole-5-carboxamide, 2.7-trifluoroacetic acid (150 mg, 0.236 mmol) was dissolved in N,N-dimethylformamide (0.7 mL). Triethylamine (0.3 mL, 2.152 mmol) was added, followed by 2-methylpropane-1-sulfonyl chloride (74.0 mg, 0.472 mmol) and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered, and concentrated and purified by normal phase chromatography to give the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 9.24 (t, J=5.9 Hz, 1H), 8.49 (d, J=7.0 Hz, 1H), 8.35 (s, 1H), 7.89 (s, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.41 (s, 1H), 6.83 (dd, J=7.0, 1.7 Hz, 1H), 4.48 (d, J=5.9 Hz, 2H), 3.91 (p, J=7.2 Hz, 1H), 3.74 (dd, J=9.8, 7.3 Hz, 1H), 3.51-3.35 (m, 3H), 2.99 (d, J=6.6 Hz, 2H), 2.46-2.33 (m, 1H), 2.24-2.03 (m, 2H), 1.03 (d, J=6.7 Hz, 6H); MS (ESI(+)) m/e 448 (M+H)+.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](Cl)=[S:19])=[CH:13][CH:12]=1.C(OCC)C>O>[O:17]([C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)[C:18]([S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:19]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: S=C(Oc1ccccc1)SCc1ccccc1
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
Benzyl mercaptan (1.24 g, 10 mmol) was added to an aqueous (20 mL) solution of NaOH (0.8 g, 20 mmol) at room temperature and stirred for 15 minutes. Phenyl thionochloroformate (2.07 g, 12 mmol) was next added dropwise to this solution at the same temperature and stirred for a further 2 hours. Diethyl ether (20 mL) and water (50 mL) was added and the organic layer separated. The aqueous layer was extracted with diethyl ether (3×20 mL). The combined organic fractions were dried with Na2SO4, filtered, the solvent removed and the crude product chromatographed (using silica gel, 2% ethyl acetate in petroleum spirits) to afford the title compound (1.95 g, 75%) as a yellow oil. 1H-nmr (CDCl3) δ 4.43 (2H), 7.10-7.50 (10H). 13C-nmr (CDCl3) δ 41.7, 122.1, 126.7, 127.8, 128.8, 129.3, 129.6, 135.1, 154.0, 213.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([NH:12][CH2:13][C@H:14]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:15]([OH:17])=[O:16])=[O:11])=[CH:8][CH:7]=1.Cl.CC[N:33]([CH:37](C)C)C(C)C.C[N:41](C=O)C>>[NH:1]([CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][CH2:13][C@H:14]([NH:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])[C:15]([OH:17])=[O:16])=[O:11])=[CH:28][CH:29]=1)[C:37]([NH2:33])=[NH:41]
Reactant: NCCOCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Product: N=C(N)NCCOCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)cc1

Procedure:
Amine 15-5 (40 mg, 0.095 mmol), PCA.HCl (15 mg, 0.10 mmol), and DIPEA (35 mL, 0.20 mmol) were combined in 1 mL DMF and heated at 50° for 16 h. Concentration, and flash chromatography (silica, 20:1:1 EtOH/NH4OH/H2O) provided 15-6 as a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2n[nH]c4ncccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2n[nH]c3ncccc23)Oc2c(CN3CCNCC3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0292 g, 0.0633 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (aminopropyl silica was used, chloroform/methanol) to obtain (Z)-2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0132 g, 58%).
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li+].CC([N-]C(C)C)C.[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1C=O)([O-:14])=[O:13].C1C[O:26][CH2:25]C1>>[OH:26][CH:25]([C:21]1[CH:20]=[CH:19][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:22]=1)[CH2:1][C:2]#[N:3]
Reactant: C1CCOC1
Reactant: CC#N
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: N#CCC(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of CH3CN (0.7 ml, 16 mmol) in THF (10 ml) was added LDA (8 ml, 2M in THF, 16 mmol) at −78° C. and the mixture was stirred at this temperature for 10 min. A chilled (−78° C.) solution of nitrobenzaldehye (10) (2.0 g, 13 mmol) in THF (15 ml) was added slowly. The resulting mixture was stirred at −78° C. for 15 mins. The reaction was quenched by the addition of sat. NH4Cl aq (10 ml) and the mixture allowed to warm to room temperature. The organic layer was collected and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (30 to 65% EtOAc-hexanes gradient) gave 3-hydroxy-3-(3-nitrophenyl)propanenitrile (11) as colorless oil, Yield (1.9 g, 77%); 1H NMR (400 MHz, CDCl3) δ 8.30 (t, J=3.2 Hz, 1H), 8.21-8.24 (m, 1H), 7.76-7.80 (m, 1H), 7.71 (t, J=8.0 Hz, 1H), 5.20 (t, J=2.4 Hz, 1H), 2.22 (d, J=6.0 Hz, 2H), 1.24 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.I[CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14]>>[CH3:14][O:13][Si:12]([O:17][CH3:18])([O:15][CH3:16])[CH2:11][CH2:10][CH2:9][S:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CO[Si](CCCI)(OC)OC
Reactant: Sc1ncccn1
Product: CO[Si](CCCSc1ncccn1)(OC)OC
Yield: 74 %

Procedure:
2-(3-(trimethoxysilyl)propylthio)pyrimidine was synthesized from 2-mercaptopyrimidine and iodopropyltrimethoxysilane in the similar method as described above. 1H NMR (CD3Cl): δ(ppm) 8.62 (2H, m, Pyr.-H), 7.11 (1H, m, Pyr.-H), 3.57 (9H, s, —CH3), 3.25 (2H, m, —CH2—), 1.88 (2H, m, —CH2—), 0.83 (2H, t, JH-H=8.25, —CH2—). Yield: 74%.
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=O.[C:12]([O-:15])([O-])=[O:13].[K+].[K+].[CH3:18]O>>[NH:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:12]([O:15][CH3:18])=[O:13]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: O=C([O-])[O-]
Reactant: CO
Agent: [K+]
Product: COC(=O)c1ccc[nH]1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a stirred solution of 2-(trichloroacetyl)pyrrole (10.00 g, 47.1 mmol) in MeOH (20 mL) was added K2CO3 (8.44 g, 61.2 mmol). The resulting mixture was stirred under reflux for 3 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give 2 as a dark brown solid (5.50 g, 93%). 1H NMR (CDCl3) δ 9.49 (bs, 1H), 6.92-6.96 (m, 2H), 6.26 (m, 1H), and 3.86 (s, 3H); 13C NMR (CDCl3) δ 162.05, 123.33, 122.79, 115.56, 110.66, and 51.72.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:15][C:16]([OH:18])=[O:17])[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture of 3-trifluoromethoxy-benzaldehyde (3 g, 15.78 mmol), malonic acid (2.13 g, 20.51 mmol), piperidine (0.134 g, 1.58 mmol) and pyridine (10 ml) was kept at reflux temperature until carbon dioxide formation ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 60 g ice and 30 ml 6N HCl. The precipitate was isolated, washed with water and dried yielding 2.21 g (60%) 3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]3[CH3:26])=[O:14])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1CCCCN1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1CCCCN1C(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reaction time: 3 h
Yield: 19.4 %

Procedure:
A mixture of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid (125 mg, 0.45 mmol) and oxalyl chloride (2 ml) in dichloromethane (6.0 ml) was stirred at 25 deg C. for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated to dryness. To the resulting crude dichloromethane (6.0 ml) and DMAP (64 mg, 0.52 mmol) was added followed by addition of 2-methylpiperidine (43 mg, 0.43 mmol). The resulting mixture was stirred at 25 deg C. for 14 h. After completion of the reaction (monitored by LCMS), solvent was removed in vacuo and purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 30 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(2-methylpiperidin-1-yl)ethanone as trifluoroacetic acid salt.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])(O)=O.[Na+].[CH3:19][C:20](N(C)C)=O.C(I)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:19][CH3:20])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(=O)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCI
Solvent: ClCCl
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a dry 100 mL 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet were added 3.00 g of 2-fluoro-4-nitrobenzoic acid, 3.00 g of NaHCO3, and 20 mL of anhydrous dimethylacetamide. The suspension was treated with 3.50 mL of ethyl iodide and stirred at RT under N2 for 18 h. The reaction mixture was filtered to remove solids and the filtrate concentrated in vacuo to give an orange residue which was dissolved in 100 mL of CH2Cl2. The solution was washed with saturated aqueous NaHCO3 (3×50 mL), water (1×60 mL), and dried over anhydrous Na2SO4. Removal of drying agent by filtration and passage through a silica gel plug (3×5 cm) gave a light yellow solution which was concentrated in vacuo to afford 3.10 g (90%) of ethyl 2-fluoro-4-nitrobenzoate as a light yellow crystalline solid, m.p. 70-73° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]2[CH:11]=[N:12][NH:13][C:7]=2[CH:6]=1.[I:19]I.[OH-].[K+]>CN(C=O)C>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]2[C:11]([I:19])=[N:12][NH:13][C:7]=2[CH:6]=1
Reactant: Fc1ccc(Oc2cc3[nH]ncc3cn2)c(F)c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2cc3[nH]nc(I)c3cn2)c(F)c1
Reaction time: 5 h
Yield: 72.9 %

Procedure:
To a room temperature solution of 6-(2,4-difluorophenoxy)-1H-pyrazolo[4,3-c]pyridine (0.10 g) in DMF was added 0.11 g of iodine and 0.049 g of potassium hydroxide. After 5 hours, additional 10% of iodine was added and a reaction mixture was stirred for an additional one hour. The mixture was quenched with 1 M sodium bisulfite (50 mL) solution and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over MgSO4, and concentrated to give 0.11 g of 6-(2,4-difluorophenoxy)-3-iodo-1H-pyrazolo[4,3-c]pyridine (71% yield). Mass Spec. M+H=374.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:12][C@:11]1([F:27])[CH2:25]I)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O-])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Na+].C1OCCOCCOCCOCCOCCOC1.O>CS(C)=O>[C:1]([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:12][C@@:11]1([F:27])[CH2:25][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CI)[C@H]1OC(=O)c1ccccc1
Reactant: O=C([O-])c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@](F)(CC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
Chiral (2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,4-difluor-O-2-(iodomethyl)-4-methyl-tetrahydrofuran-3-yl benzoate (0.56 g, 1.15 mmol), sodium benzoate (0.825 g, 5.73 mmol) and 18-crown-6 (0.03 g, 0.115 mmol) were suspended in DMSO (20 mL), the solution was heated to 100° C. and stirred under nitrogen atmosphere for 18 h, then cooled to r.t., water (30 mL) was added into it, the mixture was extracted by EA (30 mL×3), the organic layer was washed with H2O, brine and H2O, removed solvent by reduced pressure, the residue was purified by silica gel column chromatography (PE:EA=1:2) to afford the title compound as a colorless oil (0.34 g, 61%).