Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(O)(=O)C.[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34][CH2:33][C:32]2=[O:41])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:34][CH2:33][C:32]4=[O:41])[CH2:27][CH2:26]3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN3CCC(N4C(=O)CCc5ccccc54)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.203 g) and acetic acid (0.063 ml) were added to a 1,2-dichloroethane solution (5 ml) of 1-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.170 g), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.235 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→90:10). The purified product was condensed to dryness to give the title compound (0.205 g) as pale yellow amorphous.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:23])=[O:22])=[CH:24][CH:25]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(-c1ccc(C(N)=O)cc1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1ccc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzamide (83.4 mg) in acetonitrile (10 mL) were added sodium iodide (74.3 mg) and chloro(trimethyl)silane (0.251 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and the obtained solid was washed with ethyl acetate to give the title compound (75.0 mg).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:19])=[O:18]
Reactant: OCCCCC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCC1CC1
Reaction time: 2 h

Procedure:
To a stirred 0° C. solution of 683 mg (6.0 mmol) of 4-cyclopropylbutanol and 1.25 mL (9.0 mmol) of triethylamine in 10 mL of CH2Cl2 was added 697 μL (9.0 mmol) of methanesulfonyl chloride dropwise under Ar. The cold bath was allowed to expire over a 2 h period at which time the reaction mixture was diluted with CH2Cl2, washed with cold 1M HCl, water, sat. NaHCO3, brine, dried over MgSO4 and the solvents removed to give the title compound as a yellow oil:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH3:9])=[C:4]([CH2:10][CH2:11][CH2:12][CH3:13])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[CH2:10]([C:4]1[C:5]([CH3:9])=[C:6]([Cl:16])[N:7]=[C:2]([NH2:1])[N:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1nc(N)nc(O)c1C
Product: CCCCc1nc(N)nc(Cl)c1C

Procedure:
By reacting 2-amino-6-butyl-5-methylpyrimidine-4-ol (0.82 g, 4.52 mmol) and phosphorous oxychloride (10 ml), there was obtained the object compound (720 mg).
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:12][C:9]([C:13]([O:15]C)=[O:14])([CH2:10][CH2:11]1)[CH2:8][CH2:7][CH2:6]2)=[O:4].[OH-].[Li+]>O1CCCC1.O>[C:9]12([C:13]([OH:15])=[O:14])[CH2:12][C:5]([C:3]([OH:4])=[O:2])([CH2:11][CH2:10]1)[CH2:6][CH2:7][CH2:8]2
Reactant: COC(=O)C12CCCC(C(=O)OC)(CC1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C12CCCC(C(=O)O)(CC1)C2
Temperature: 70 °C

Procedure:
A solution of bicyclo[3.2.1]octane-1,5-dicarboxylic acid dimethyl ester (crude 3.01 g from step 2) in tetrahydrofuran (100 mL) was treated with 1 M of lithium hydroxide in water (75 mL) and warmed at 70° C. for 6 hours. The reaction was concentrated under reduced pressure and the resulting residue was partitioned between water and ethyl acetate. The aqueous layer was collected and washed again with ethyl acetate. The aqueous layer was acidified with 1N HCl to pH 2, and then extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated to afford 725 mg of white solid, which was used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[F:7][C:8]([F:31])([CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14]>COCCOC>[C:13]([C:12]([C:11]([C:10]([C:9]([C:8]([CH2:25][CH2:26][S:27]([NH:6][CH2:5][CH2:4][CH2:3][Cl:2])(=[O:29])=[O:28])([F:7])[F:31])([F:24])[F:23])([F:22])[F:21])([F:20])[F:19])([F:18])[F:17])([F:16])([F:15])[F:14]
Reactant: O=S(=O)(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCCCCl
Agent: Cl
Solvent: COCCOC
Product: O=S(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)NCCCCl

Procedure:
3-chloropropylamine hydrochloride (6.0 g), diaza(1,3)bicyclo[5.4.0]-undecane (DBU, 4.1 g) and 1,2-dimethoxyethane (21.5 g) solvent were placed in the round bottom flask equipped with mechanical stirring under nitrogen. Solution of 2-(perfluorohexyl)ethanesulfonyl chloride CF3(CF2)5(CH2)2SO2Cl (10.1 g), in 1,2-dimethoxyethane (10 g) solvent was added dropwise during 30 minutes at 20-25° C. while stirring at 250 rpm. Then additional DBU (2.6 g) was added. Reaction mixture was stirred for 2 h after the DBU addition was completed. The reaction was monitored by GC to ensure the complete conversion of 2-(perfluorohexyl)ethanesulfonyl chloride. The final reaction mixture was filtered from solids through 2 mm layer of CELITE 545. The solids were washed with 1,2-dimethoxyethane and combined filtrate was evaporated in vacuum to obtain 11.3 g of crude CF3(CF2)5(CH2)2SO2NH(CH2)3Cl as yellow solid. 9.5 g of the crude product was additionally dissolved in hot toluene (7 g) and washed with 14 mL of 2.5 wt % HCl aqueous solution, followed with 12 mL water wash. Toluene solution was evaporated in vacuum to obtain 8.35 g of CF3(CF2)5(CH2)2SO2NH(CH2)3Cl (GC purity 93%, yield 88%).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]1([F:37])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([NH:35]N)[C:28]=2[O:27]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:37][C:26]1([F:25])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([N:35]3[C:17]([C:12]4[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:6]5[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:24])[F:1])[CH:5]=5)[N:11]=4)=[CH:18][CH:19]=[N:20]3)[C:28]=2[O:27]1
Reactant: NNc1cccc2c1OC(F)(F)O2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cccc2c1OC(F)(F)O2

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=461.3 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:5]([CH:8]([CH3:10])[CH3:9])([CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6]#[N:7])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Reactant: CNCCc1ccccc1
Product: COc1ccc(C(C#N)(CCCN(C)CCc2ccccc2)C(C)C)cc1OC

Procedure:
Reaction of 1f with N-methyl-2-phenylethanamine produced 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile which was further reacted in a manner analogous to the procedure reported in Liang, C. D. et al., Tetrahedron Lett., (1986) 27, 1971-1974.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 150 °C
Reaction time: 72 h
Yield: 21.2 %

Procedure:
2-Amino-4-chloropyridine (2.00 g) was dissolved in N-methylpyrrolidone (31.8 ml) under a nitrogen atmosphere, and 4-nitrophenol (6.51 g) and N,N-diisopropylethylamine (15.9 ml) were added, followed by stirring at 150° C. for 3 days. The reaction mixture was allowed to cool down to room temperature, and partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide (32 ml). The organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:5). Fractions containing the target compound were concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as a brown solid (764 mg, 21.2%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C:29]([OH:28])([CH3:34])[CH3:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(C)(O)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC(C)(O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 88%), MS (ISP) m/z=417.5 [(M+H)+], mp 241° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2-hydroxy-2-methyl-propionic acid.
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:10]1[C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:19])([CH3:9])([CH3:8])[CH3:7].[C:20](O)([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:6]([C:10]1[C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=1[OH:19])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1c(O)ccc2c1CCO2
Reactant: CC(C)(C)O
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1O)CCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5.6 %

Procedure:
Methanesulfonic acid (10 ml) was added dropwise, under ice cooling, to a solution consisting of 4-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran [J. Org. Chem., 53, 4135 (1988); 2.84 g, 15 mmol], tert-butyl alcohol (10 g, 120 mmol) and chloroform (20 ml). After stirring at 0° C. for 15 min, the mixture was poured into ice water. The mixture was neutralized with an aqueous solution of 1N sodium hydroxide and subjected to extraction with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (n-hexane) to afford 4,6-di-tert-butyl-5-hydroxy-2,3-dihydrobenzofuran [210 mg (yield, 6%)].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])C)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[OH-:19].[NH4+]>>[C:7]([O:15][C:13](=[O:19])[NH:12][C:5]1[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]([Cl:1])=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17])([CH3:8])([CH3:2])[CH3:6]
Reactant: [OH-]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1[N+](=O)[O-]

Procedure:
Reaction of N-(4-chloro-2-nitro-5-trifluoromethyl-phenyl)-acetamide [CAS 157554-77-3] (4.02 g, 14.2 mmol) with Boc-anhydride (3.26 g, 14.9 mmol) according to the general procedure A (method c) and subsequent reaction with ammonium hydroxide (25%; 4.38 ml, 28.4 mmol) gave after aqueous work up and purification by column chromatography on silica gel (hexane/ethyl acetate 4:1) compound A12.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C@H:7]([NH:10]C(=O)OC(C)(C)C)[CH2:8][OH:9])=[CH:3][CH:2]=1.Cl>CO>[NH2:10][C@@H:7]([C:4]1[CH:5]=[CH:6][C:1]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:2][CH:3]=1)[CH2:8][OH:9]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: N[C@H](CO)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 41.3 %

Procedure:
To a solution of (S)-tert-butyl 1-(biphenyl-4-yl)-2-hydroxyethylcarbamate (608 mg, 1.940 mmol) in MeOH (3 mL) was added HCl (4M in dioxane, 8 mL) at room temperature. The mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was dissolved in DCM (10 mL)/water (1.0 mL) and stirred with NaHCO3 for 1 hour. The mixture was filtered off and rinsed with DCM. The filtrate was dried over sodium sulfate, filtered off and concentrated under reduced pressure providing (S)-2-amino-2-(biphenyl-4-yl)ethanol (171 mg) as a white solid. LCMS m/z 214.2 (M+H)+, Rt 0.58 min.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>ClCCl>[CH3:56][S:57]([O:39][C@H:36]1[CH2:37][CH2:38][C@@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)(=[O:59])=[O:58]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](OS(C)(=O)=O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (250 mg) and triethylamine (240 μL) are dissolved in dichloromethane (2 mL), treated with methanesulfonyl chloride (40 μL) and stirred for 12 hours at room temperature. The mixture is partitioned between ethylacetate and water. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is used directly in the next step. LC (method 5): tR=1.19 min; Mass spectrum (ESI+): m/z=794 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Cl)[CH:35]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:40][C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCc4cccnc4)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (3.9 g) obtained in Example 2 was suspended in dimethyl sulfoxide (230 ml), and to the suspension was added potassium carbonate (4.0 g), and the mixture was stirred at room temperature for 30 minutes. 3-picolylchloride hydrochloride (1.9 g) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (500 ml), and the precipitated crystals were recovered by filtration to obtain the title compound (2.9 g, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([NH2:10])=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>O1CCCC1>[CH2:1]([O:3][C:4]1[C:9]([NH:10][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncncc1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOc1ncncc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of 4-ethoxypyrimidine-5-amine (1.00 g, 7.19 mmol) and pyridine (1.74 ml, 21.6 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.49 ml, 10.8 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (1.73 g, 76.5%) as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH2:19].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A mixture of 1-fluoro-2,4-dinitrobenzene (1) (15 g, 0.81 mmol), glycine methyl ester hydrochloride (11.5 g, 0.92 mmol), K2CO3 (22.3 g, 0.162 mmol) and methanol (300 mL) was heated at 60° C. for 30 minutes. After cooling in an ice bath, the resulting yellow precipitate was collected by filtration, washed with water and methanol and dried in vacuo. Yield 10.5 g (51%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: NCCCO
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Product: OCCCNc1nc2nc(SCc3ccccc3)nc(Cl)c2s1

Procedure:
Prepared by the method of Example 231, using the product of Example 219 and 3-aminopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1COCC1>Cl.O1CCOCC1>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC1CCN(c2ccc(Cl)cn2)CC1
Reaction time: 20 h
Yield: 302 %

Procedure:
A solution of tert-butyl (1-(5-chloropyridin-2-yl)piperidin-4-yl)carbamate (1.15 g, 3.70 mmol) in HCl in Dioxane (4M, 5 mL) and THF (5 mL) was stirred at rt for 6.5 h. 4M HCl in Dioxane (2 mL) was added and the reaction mixture stirred for another 20 h. The reaction mixture was filtered, the residue was washed with EtOAc and dried to give the title compound (1.06 g, 100%) as a solid. 1H NMR (500 MHz, CD3OD): 8.10 (s, 1H), 8.06 (d, 1H), 7.52 (d, 1H), 4.36 (d, 2H), 3.62-3.54 (m, 1H), 3.42 (dt, 2H), 2.18 (d, 2H), 1.82 (dq, 2H); 13C NMR (CD3OD): 151.4, 144.4, 134.6, 120.0, 114.7, 45.2, 29.1; Mass Spectrum: M+H 212.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24]>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: COc1ccccc1Br
Product: COc1ccccc1N1N(C2CCCCCCC2)C(=O)C1(C)C

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 73 and 1-bromo-2-methoxybenzene was used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([O:8][C:9](=[O:31])[C@H:10]([C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)[CH2:11][C:12]#[C:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=O)[CH3:7])=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][NH2:48])=[CH:43][CH:42]=1>C1COCC1>[CH2:1]([O:3][C:4]([CH:6]([O:8][C:9](=[O:31])[C@H:10]([C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)[CH2:11][C:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:47]([C:44]2[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=2)[N:48]=1)[CH3:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)OC(=O)[C@@H](CC#CC(=O)c1ccc(Cl)c(Cl)c1)c1cccc(C)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)OC(=O)[C@@H](Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-6-(3,4-dichloro-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid 1-ethoxycarbonyl-ethyl ester from Example 502 (15.5 g, 0.0336 mol) in THF (150 mL) was added Cs2CO3 (8.8 g, 0.027 mol) followed by 4-methoxyphenyl hydrazine HCl (6.5 g, 0.037 mol). The resulting slurry was stirred at rt overnight and then slowly quenched with 1 N HCl until pH 2-3. The mixture was transferred to a separatory funnel and extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to an oil. The crude oil was purified by pad filtration on silica gel using EtOAc/hexanes to obtain the pyrazole as mixture of two regioisomers in 4:1 ratio (18.6 g, 95%). Chiral HPLC (Method S): Rt (R,S)=5.6 min; (S,S)=6.3 min. 1H NMR (400 MHz, CDCl3): 7.31-7.07 (m, 8H), 6.91-6.86 (m, 3H), 6.23 (s, 1H), 5.13 (dd, J=10.4, 7.0 Hz, 1H), 4.16 (m, 1H), 4.07 (dd, J=14.4, 7.2 Hz, 2H), 3.82 (s, 3H), 3.51 (dd, J=14.9, 9.6 1H), 3.04 (dd, J=14.9, 6.3 Hz, 1H), 2.37 (s, 3H), 1.42 (d, J=7.0 Hz, 3H), 1.12 (t, J=7.3 Hz, 3H).