Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH3:27][N:28]1[CH2:35][CH2:34][NH:33][CH2:32][C:29]21[CH2:31][CH2:30]2>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:33]3[CH2:32][C:29]4([CH2:31][CH2:30]4)[N:28]([CH3:27])[CH2:35][CH2:34]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: CN1CCNCC12CC2
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)C4(CC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-methyl-4,7-diazaspiro[2.5]octane dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.32 (br. s., 1 H) 0.50-0.78 (m, 3 H) 2.39 (s, 3 H) 2.42 (s, 3 H) 2.86 (br. s., 2 H) 3.31 (br. s., 1 H) 3.41-3.62 (m, 2 H) 3.73 (br. s., 1 H) 7.63-7.68 (m, 1 H) 7.72 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.04 (br. s., 1 H) 8.14 (s, 1 H) 8.38 (d, J=8.08 Hz, 1 H) 8.50 (br. s., 1 H) 12.85 (br. s., 1 H); ESI-MS m/z [M+H]+ 429.3.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C@H:20]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[O:21][CH3:22])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:23]1([C@H:20]([O:21][CH3:22])[C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=2[CH2:9][OH:8])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CO[C@H](c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C)C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CO)C1CCCCC1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of (S)-tert-butyl-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyloxy]-dimethyl-silane (1.13 g, 2.4 mmol) in THF (5 ml) was added a solution of tetrabutylammonium fluoride (4.8 ml, 1 M, 4.8 mmol) at room temperature and stirred for overnight. The reaction mixture was concentrated in vacuo and purified on Biotage column 25+M, eluting with 0-30% ethyl acetate in heptane (10 CV), 30% (2 CV) to yield the title compound (0.6 g, 73%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.8 m (m, 2H) 1.1 (m, 4H) 1.3 (m, 1H) 1.5 (m, 2H) 1.6 (m, 1H) 2.0 (d, J=12.9, 1H) 2.3 (m, 1H) 3.1 (s, 3H) 4.0 (d, J=7.9, 1H) 4.7 (dd, J=13.7 & 7.5 Hz, 2H) 7.3 (d, J=8.3 Hz, 1H) 7.4 (d, J=7.8 Hz, 1H) 7.7 (s, 1H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12](Cl)([Cl:14])=[O:13]>ClCCl>[Cl:14][C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:13]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl anthranilate (6.0 g) in dichloromethane (50 ml) was added dropwise over 15 min to a 0° solution of phosgene (20% in toluene, 100 ml) in dichloromethane (50 ml) under a nitrogen atmosphere. After addition the resulting opaque solution was stirred at room temperature for 5 h before concentrating to dryness to give the title compound as a white solid (8.0 g), m.p. 80°-82°.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][S:7](Cl)(=[O:9])=[O:8])(=[O:4])=[O:3].[NH2:11][C:12]([CH3:16])([CH3:15])[C:13]#[N:14].C(N(CC)CC)C>O1CCCC1>[C:13]([C:12]([NH:11][S:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:9])=[O:8])([CH3:16])[CH3:15])#[N:14]
Reactant: CS(=O)(=O)CCS(=O)(=O)Cl
Reactant: CC(C)(N)C#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C#N)NS(=O)(=O)CCS(C)(=O)=O
Temperature: 25 °C
Yield: 133.2 %

Procedure:
To a stirred solution of 5.00 g (24.2 mmoles) 2-(methylsulfonyl)ethylsulfonyl chloride (Example 32) in 50 ml dry tetrahydrofuran, a solution of 2.11 g (0.025 moles) 2-amino-2-methyl-propionitrile and 2.5 g (0.025 moles) triethylamine in 20 ml dry tetrahydrofuran were added dropwise over 13 minutes. During the course of the addition, the temperature of the mixture rose from 19° C. to 38° C. and a white precipitate formed. After the mixture cooled to room temperature, it was filtered. The solid, inorganic salts, was washed with tetrahydrofuran and ethyl ether. The filtrate and washings were stripped using a rotovap to give 8.2 g of a sticky white solid. Recrystallization of the solid from boiling ethanol gave 3.94 g of the above-identified product, melting point 151°-153° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](O)=O)[CH3:2].[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1)[CH2:9][CH2:10][CH3:11]>C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[NH:19][C:14]2[CH:13]=[C:12]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:17]=[CH:16][C:15]=2[N:18]=1)[CH3:2]
Reactant: CCOCC(=O)O
Reactant: CCCCc1ccc(N)c(N)c1
Solvent: CCOC(C)=O
Product: CCCCc1ccc2nc(COCC)[nH]c2c1

Procedure:
20.8 g of ethoxyacetic acid are added to 23 g of crude 4-butyl-1,2-phenylene-diamine and the mixture is heated at 130° for 90 minutes. It is allowed to cool and is taken up in ethyl acetate, washed with sodium bicarbonate solution and then three times with water, dried over sodium sulphate and filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is chromatographed on 600 g of silica gel using chloroform as the solvent. After a small initial fraction, 2-ethoxymethyl-5-butyl-benzimidazole is obtained in the main fraction.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[N:32]=[CH:31][N:30]([CH3:33])[C:29]=2[CH:34]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:33][N:30]1[C:29]2[CH:34]=[C:25]([NH:24]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=[CH:27][C:28]=2[N:32]=[CH:31]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: Cn1cnc2ccc(N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1cnc2ccc(N/C(=C3\C(=O)Nc4ccccc43)c3ccccc3)cc21

Procedure:
Prepared from 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-2-indolinone and 2 equivalents of 6-amino-1-methyl-benzimidazole, melting point 163-165° C., in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[CH2:21][C:22]1[N:27]2[CH:28]=[N:29][CH:30]=[C:26]2[CH:25]=[CH:24][CH:23]=1.[H-].[Na+].[OH:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1.S(=O)(=O)(O)O>O1CCCC1>[OH:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[CH:21][C:22]2[N:27]3[CH:28]=[N:29][CH:30]=[C:26]3[CH:25]=[CH:24][CH:23]=2)=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1cccc2cncn12
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc(C=Cc2cccc3cncn23)cc1
Temperature: 25 °C

Procedure:
Imidazo[1,5-a]pyridine-5-methyltriphenylphosphonium chloride (4.29 g), which is prepared from equimolar quantities of triphenylphosphine and 5-chloromethylimidazo[1,5-a]pyridine, is added to slurry of sodium hydride (0.5 g, 50% mineral oil dispersion) in 100 ml of dry tetrahydrofuran at 0° under nitrogen. After 1 hour at 0° a solution of p-hydroxybenzaldehyde (0.61 g) in 15 ml of dry tetrahydrofuran is added. The reaction is allowed to warm to room temperature, is then refluxed for 1 hour, cooled and acidified with dilute sulfuric acid. The aqueous layer is washed with ethyl acetate, adjusted to pH=7 with 50% sodium hydroxide and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to yield 5-[2-(p-hydroxyphenyl)-ethen-1-yl]-imidazo[1,5-a]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]/[N:19]=[CH:4]/[C:3]2[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[CH:14][CH:13]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=Cc1c(F)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1cccc(Cl)c1/C=N/Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 31.4 %

Procedure:
To a solution of 2-chloro-6-fluorobenzaldehyde (1.0 g, 6.32 mmol) in ethanol was added (4-bromophenyl)hydrazine (1.7 g, 7.59 mmol) and aq. solution of NaHCO3 (0.637 g, 4.59 mmol). The reaction mixture was stirred at RT for 5-6 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified by column chromatography on silica gel, eluting with 4.6% EA: pet. ether to afford 0.650 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 6.98 (d, J=7.8 Hz, 2H), 7.23-7.40 (m, 5H), 8.07 (s, 1H), 10.87 (br s, 1H). MS (m/z): 329.17 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:21])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:8][CH2:7]1.[CH3:22][S:23]([C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29])(=[O:25])=[O:24]>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[O:12][CH:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH:4]([OH:21])[CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Reactant: NCCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: CS(=O)(=O)c1ccccc1C(=O)NCCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
Prepared as described in Example 1 from 4-amino-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.26 g) and 2-(methylsulphonyl)benzoic acid (0.156 g). The title compound was obtained as a white solid (0.170 g).
Reaction SMILES: Br[CH:2]([CH2:13][C:14]([Cl:17])([F:16])[F:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:17][C:14]([F:15])([F:16])[CH:13]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCCCCCCCC(Br)CC(F)(F)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: OCCCCCCCCCC=CC(F)(F)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The stirred intermediate 10-bromo-12-chloro-12,12-difluorododecanol, 31.9 grams (0.095 mole), was cooled, and 15.9 grams (0.11 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred for 16 hours. After this time the reaction mixture was warmed to 70° C. where it was stirred for one hour. The reaction mixture was cooled, and then it was taken up in 200 mL of methylene chloride. The solution was washed in turn with one 150 mL portion of aqueous 1N hydrochloric acid, one 100 mL portion of water, one 100 mL portion of an aqueous solution saturated with sodium bicarbonate, one 100 mL portion of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under high vacuum yielding 14.3 grams of 12-chloro-12,12-difluoro-10-dodecenol, b.p. 130°-131° C./1.1-1.2 mm.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.C(Br)C#C>O.CN(C)C=O>[CH2:12]([O:13][CH2:9][C:4]1[O:3][CH:7]=[CH:6][CH:5]=1)[C:11]#[CH:10]
Reactant: OCc1ccco1
Reactant: C1CCOC1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOCc1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a mixture of sodium hydride (7.7 g, 190 mmol, 60% in oil) and tetrahydrofuran (100 mL) was added dropwise furfuryl alcohol (15 mL, 170 mmol) at 0° C. The reaction mixture was warmed to room temperature, N,N-dimethylformamide (30 mL) was added at that temperature, and the mixture was stirred at that temperature for 30 minutes. The reaction mixture was returned to 0° C., propargyl bromide (23 g, 190 mmol) was added at that temperature, and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:30) to give the title compound (7.6 g, 32% yield).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][O:10][CH2:11][C:12](N)=[S:13].[O-2].[Ca+2]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].CN(C=O)C>[CH3:9][O:10][CH2:11][C:12]1[S:13][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1ccccc1I
Reactant: COCC(N)=S
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COCc1nc2ccccc2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A mixture of 2-iodoaniline (5 g, 22.8 mmol), 2-methoxy-thioacetamide (2.4 g, 22.8 mmol), calcium oxide (1.28 g, 22.8 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (104 mg, 0.114 mmol), diphenylphosphinoferrocine (253 mg, 0.456 mmol) and DMF (23 mL) was stirred at 60° C. for 2 h under nitrogen. The resulting mixture was purified by column chromatography (10 to 20% ethyl acetate:hexanes) to afford 2.5 g (61%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.01-7.9 (m, 1H), 7.98-7.89 (m, 1H), 7.50-7.45 (m, 1H), 7.41-7.38 (m, 1H), 4.86 (s, 2H), 3.54 (s, 3H).
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH:14]3[C:12]([C:16]([O:18]C)=[O:17])([CH2:13]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Cl>C1COCC1.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH:14]3[C:12]([C:16]([OH:18])=[O:17])([CH2:13]3)[C:11]2=[O:20])=[CH:8][CH:9]=1
Reactant: COC(=O)C12CC1CN(c1ccc(F)cc1)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C12CC1CN(c1ccc(F)cc1)C2=O
Reaction time: 1 h
Yield: 88.6 %

Procedure:
LiOH (0.2 g, 8.4 mmol) was added into a suspension of methyl 3-(4-fluorophenyl)-2-oxo-3-aza-bicyclo[3.1.0]hexane-1-carboxylate (1.2 g, 4.8 mmol) in THF (20 mL) and water (1 mL). The reaction was stirred for 1 hour. The reaction mixture was poured into water and the solution brought to pH 4 with 1M HCl. The mixture was extracted with EtOAc, washed with brine, dry with Na2SO4, filtered and concentrated to afford the title compound (1 g, 79% yield) as a light brown solid. LRMS (APCI pos) m/e 235.9 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[F:15][C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[C:11]([C:16]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:12]=1
Reactant: CCOC(=O)C1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(c2cc(O)cc(F)c2)CCOCC1
Reaction time: 3.25 h
Yield: 99.9 %

Procedure:
A mixture of ethyl 4-[3-(benzyloxy)-5-fluorophenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (2.70 g, 7.5 mmol) and 10% palladium on activated carbon (0.27 g) in ethanol (100 ml) was stirred under a hydrogen atmosphere for 3.25 hr. Catalyst was removed by filtration and evaporation of the filtrate gave the titled compound as a colorless liquid (2.01 g, quantitative yield).
Reaction SMILES: N#N.[Cl:3][C:4]1[N:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]([N+:15]([O-])=O)=[C:6](Cl)[N:5]=1.[O-2].[Mg+2]>[Pd].O1CCOCC1>[NH2:15][C:7]1[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:9][C:4]([Cl:3])=[N:5][CH:6]=1
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Agent: [Mg+2]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(Cl)ncc1N

Procedure:
10% Palladium on carbon (0.2 eq) was added to a N2-flushed mixture of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1 eq) and magnesium oxide (2 eq) in 1,4-dioxane (0.15 M). The reaction was purged with H2 under atmospheric pressure at rt. After 16 h additional portions of 10% Pd/C (0.3 eq) and MgO (5 eq) were added and the reaction continued to purge with H2 under atmospheric pressure for 6 h at rt. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel and washed with CH2Cl2. The filtrate was transferred to a separatory funnel, washed twice with H2O and once with brine, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was dissolved in CH2Cl2, loaded onto a SiO2 column, and purified by flash chromatography (10-20-30% EtOAc in hexanes) to give ethyl 5-amino-2-chloropyrimidine-4-carboxylate. LC/MS (m/z): 202.0 (MH+).
Reaction SMILES: C([O:8][C@@H:9]1[CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[C@H:11]([CH2:24][O:25]CC2C=CC=CC=2)[C@H:10]1[O:33][C@H:34]1[O:87][C@H:86]([CH2:88][O:89]CC2C=CC=CC=2)[C@@H:53]([O:54][C@@H:55]2[O:84][C@H:83]([CH3:85])[C@@H:74]([O:75]CC3C=CC=CC=3)[C@H:65]([O:66]CC3C=CC=CC=3)[C@H:56]2[O:57]CC2C=CC=CC=2)[C@H:44]([O:45]CC2C=CC=CC=2)[C@H:35]1[O:36]CC1C=CC=CC=1)C1C=CC=CC=1>CO.Cl.[OH-].[Pd+2].[OH-].[C]>[C@@H:55]1([O:54][C@@H:53]2[C@@H:86]([CH2:88][OH:89])[O:87][C@H:34]([O:33][C@H:10]3[C@H:9]([OH:8])[CH2:13][NH:12][C@@H:11]3[CH2:24][OH:25])[C@H:35]([OH:36])[C@H:44]2[OH:45])[O:84][C@H:83]([CH3:85])[C@@H:74]([OH:75])[C@H:65]([OH:66])[C@H:56]1[OH:57]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@@H]3[C@@H](COCc4ccccc4)N(C(=O)OCc4ccccc4)C[C@H]3OCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)CN[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 35.2 %

Procedure:
The compound (13.3 g, 10.3 mmol) synthesized in Example 2 (2 g) was dissolved in 1% hydrochloric acid methanol solution (250 mL) and 20% palladium hydroxide-carbon (4 g) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 2 hours. After the catalyst was removed by celite filtration, 28% ammonia water (5 mL) was added thereto and the mixture was stirred for 10 minutes. After the solvent was distilled off under reduced pressure and the residue was passed through ion exchange resin (Dowex 50w×8) column with water (200 mL), 1% ammonia water (200 mL) was flowed through. The ammonia water containing the desired compound was concentrated under reduced pressure and was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (1.6 g, 35%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]/[CH:9]=[N:10]/O)[C:5]([I:12])=[CH:4][CH:3]=1.[OH-].[Na+]>O>[Cl:1][C:2]1[N:7]2[N:10]=[CH:9][N:8]=[C:6]2[C:5]([I:12])=[CH:4][CH:3]=1
Reactant: O/N=C/Nc1nc(Cl)ccc1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(I)c2ncnn12
Yield: 100.2 %

Procedure:
(E)-N-(6-chloro-3-iodopyridin-2-yl)-N′-hydroxyformimidamide (6.0 g, 0.02 mol) is treated with polyphosphoric acid (40 g) at 80° C. for 4 h with stirring. The reaction mixture is diluted with cold water (100 mL), and then neutralized with 10 N aq. sodium hydroxide solution to pH 8. The aqueous solution is extracted with dichloromethane (100 mL×3). The combined organic extracts are washed with saturated aq. sodium bicarbonate solution (50 mL), brine (30 mL×3), dried over sodium sulfate, filtered, and filtrate concentrated to afford 5-Chloro-8-iodo-[1,2,4]triazolo[1,5-a]pyridine (5.6 g, 94%) as an off-white solid. LCMS Purity: 95% by UV 254 nm detection; LCMS-ESI (m/z): calcd for C6H3ClIN3, 278.9; [M+H]+ found, 279.9. 1H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:16][CH3:17])[C:10]([NH:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[O:18]1[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:16][CH3:17])[C:10]([N:11]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[CH2:24][CH:21]3[CH2:22][CH2:23][O:18][CH2:19][CH2:20]3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CCOCC1
Reactant: CCc1nn2c(Br)cccc2c1NCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nn2c(Br)cccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethylamine (106 mg) in tetrahydrofuran (3 mL) was added tetrahydropyran-4-carbaldehyde (123 mg) at room temperature, and then sodium triacetoxyborohydride (229 mg) was gradually added. After stirring the reaction mixture for 1 hour, saturated aqueous sodium bicarbonate was added thereto. The obtained mixture was extracted with ethyl acetate, and organic extract was washed with brine and then dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (10 g) and the title compound (120 mg) was obtained as a yellow oil from the ethyl acetate:n-hexane (1:6) fraction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]3)=[O:14])[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][O:22][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:17][CH2:16]3)=[O:14])[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCC(CO)CC3)nc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCC(COS(C)(=O)=O)CC3)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 34 %

Procedure:
4-Hydroxymethyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide (300 mg, 0.43 mmol) and N-ethyldiisopropylamine (95 μl, 0.56 mmol) were dissolved in CH2Cl2 (10 ml), methanesulfonyl chloride (36 μl, 0.47 mmol) was added and the mixture stirred at ambient temperature for 3 days. Purification as described in the general procedure E afforded the product as a white solid (34%).MS: m/e=466 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[C:12](C(OCC)=O)([C:18]([O:20]CC)=[O:19])[C:8]2[S:9][CH:10]=[CH:11][C:7]1=2)=[O:5])C.[OH-].[K+].OO.Cl>O1CCOCC1>[S:9]1[CH:10]=[CH:11][C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:14]3[C:13](=[C:12]([C:18]([OH:20])=[O:19])[C:8]1=2)[CH:17]=[CH:16][S:15]3
Reactant: CCOC(=O)C1(C(=O)OCC)c2ccsc2C(C(=O)OCC)(C(=O)OCC)c2ccsc21
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1c2ccsc2c(C(=O)O)c2ccsc12
Temperature: 50 °C
Yield: 86 %

Procedure:
Benzo[1,2-b;4,5-b′]dithiophene-4,4,8,8-tetracarboxylic acid tetraethyl ester (20g) was suspended in dioxane (600g) and KOH (75g) under inert atmosphere and heated to 40° C. Hydrogenperoxide (8.6 g; w=35%) was added and the suspension heated at 50° C. for 3 hours. The reaction mixture was acidified with 2M HCl (730 g) and the yellow precipitate filtered off, washed with water and dried in vacuum to yield benzo[1,2-b;4,5-b′]dithiophene-4,8-dicarboxylic acid (10,1 g) in 86% yield.