Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-])=O.[OH-:11].[Na+].S.[SH-].[Na+].[S]>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: S
Agent: [Na+]
Agent: [SH-]
Product: Nc1ccc(C=O)cc1

Procedure:
Still another object of this invention is to provide a novel process for producing p-hydroxybenzaldehyde through p-aminobenzaldehyde from p-nitrotoluene. This process comprises reacting p-nitrotoluene with sodium polysulphide prepared by reacting sodium hydroxide with hydrogen sulphide and incorporating the resulting sodium hydrosulphide with sodium hydroxide and then with sulphur, in the presence or absence of an aprotic polar compound in a mixed solvent consisting of an alcohol and an aqueous alkali solution to produce p-aminobenzaldehyde, adding the thus produced p-aminobenzaldehyde to an aqueous solution, preferably a 2-50 wt.% aqueous solution of sulphuric acid at 60°-100° C., preferably 75°-90° C., to produce the sulphate thereof rapidly, diazotizing (after cooling) the thus produced sulphate to obtain a diazonium salt of p-aminobenzaldehyde and then hydrolyzing the thus obtained diazonium salt in water or an aqueous solution of sulphuric acid at 70°-100° C. to obtain p-hydroxybenzaldehyde.
Reaction SMILES: COC1C2N=C(N)SC=2C(N2CCOCC2)=CC=1.ClC(C[C@H]1CC[C@H](OC(=O)C)CC1)=O.[OH:33][C@@H:34]1[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([NH:43][C:44]2[S:45][C:46]3[C:52]([N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)=[CH:51][CH:50]=[C:49]([O:59][CH3:60])[C:47]=3[N:48]=2)=[O:42])[CH2:36][CH2:35]1>>[OH:33][C@H:34]1[CH2:35][CH2:36][C@H:37]([CH2:40][C:41]([NH:43][C:44]2[S:45][C:46]3[C:52]([N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)=[CH:51][CH:50]=[C:49]([O:59][CH3:60])[C:47]=3[N:48]=2)=[O:42])[CH2:38][CH2:39]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@@H](O)CC3)nc12
Agent: CC(=O)O[C@H]1CC[C@H](CC(=O)Cl)CC1
Agent: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C[C@H]3CC[C@H](O)CC3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and (trans)-acetic acid 4-chlorocarbonylmethyl-cyclohexyl ester, the title compound was synthesized in exact the same manner as described for (cis)-2-(4-Hydroxy-cyclohexyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-acetamide and obtained as light yellow crystals (51% yield). MS: m/e=406(M+H+), mp 190-192° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1.C(O[Li])(C)(C)C>[Cu]I.CN1C(=O)N(C)CCC1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(Cl)c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: [Li]OC(C)(C)C
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CN1CCCN(C)C1=O
Product: Clc1cccc(Cl)c1-c1ccccc1
Yield: 17.9 %

Procedure:
Copper(I) iodide (19 mg, 0.1 mmol), iodobenzene (204 mg, 1.0 mmol), 1,10-phenanthroline (18 mg, 0.1 mmol), 1,3-dichlorobenzene (220 mg, 1.5 mmol), tBuOLi (160 mg, 2.0 mmol), and DMPU (0.5 mL), 125° C., 12 hours. After column chromatography (hexanes) 40 mg (18%) of a colorless oil was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:16].[CH3:17][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([OH:9])[CH3:17])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(C(=O)c2ccccc2)ccc1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cc(C(C)(O)c2ccccc2)ccc1Br
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-bromo-3-methylphenyl)-phenylmethanone (200 mg, 0.727 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:14]=2[CH3:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:38][C:39]([F:48])([F:47])[CH2:40][CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].O>ClCCl>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][S:43]([CH2:42][CH2:41][CH2:40][C:39]([F:48])([F:47])[F:38])(=[O:45])=[O:44])=[CH:20][CH:21]=2)[C:14]([CH3:15])=[C:10]([C:8](=[O:9])[NH:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: O=S(=O)(Cl)CCCC(F)(F)F
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-1H-imidazole-4-carboxylic piperidin-1-ylamide, from Ex 2, Step 1 (0.49 g, 1.20 mmol) was dissolved in dichloromethane (20 ml), cooled to 0° C. and triethylamine (0.67 ml, 4.8 mmol) added followed by 4,4,4-trifluorobutane-1-sulfonyl chloride (prepared as described in WO00/010968) (0.38 g, 1.80 mmol). The reaction mixture was stirred at room temperature for 3 hrs. TLC showed remaining starting material and another portion of triethylamine and 4,4,4-trifluorobutane-1-sulfonyl chloride was added and the reaction mixture stirred overnight. Water was added, the product extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. Flash chromatography (hexane:EtOAc 1:3-EtOAc) followed by recrystallization (hexane:EtOAc) afforded 0.45 g (61%) of the title compound as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[C:8]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:7]=2.[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C>[N:31]1([CH:37]2[CH2:42][CH2:41][N:40]([CH2:2][C:3]3[C:4]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)=[N:5][C:6]4[C:11]([C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[C:8]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:7]=4)[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(S(C)(=O)=O)ccc12
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(S(C)(=O)=O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A suspension of methyl 3-(bromomethyl)-7-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.713 g, 1.42 mmol) and 1,4′-bipiperidine (0.311 g, 1.846 mmol) in acetonitrile (25 mL) was stirred at room temperature for 3 h. The solvent was removed under reduced pressure. The residue was diluted with saturated aqueous NaHCO3, and the mixture was extracted with methylene chloride (three time). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-10% MeOH with 0.1% NH3/CH2Cl2) to give methyl 3-(1,4′-bipiperidin-1′-ylmethyl)-7-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.730 g, 87% yield). MS (m/z) 590.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[C:17]([S:18]([CH3:20])=[O:19])=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12].Cl.CN(C)CCCN=C=NCC.Cl.C(N(CC)CC)C.[C-]#N.[K+]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CC(C)(O)C#N.C(#N)C>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:16]([S:21]([CH3:24])(=[O:22])=[O:23])=[C:17]([S:18]([CH3:20])=[O:19])[C:9]=1[CH3:8]
Reactant: Cn1nccc1O
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1S(C)=O
Agent: CC(C)(O)C#N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1S(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
90 mg (0.91 mmol) of 5-hydroxy-1-methylpyrazole and a spatula tip of 4-(dimethylamino)pyridine were added to 230 mg (0.83 mmol) of 2-methyl-3-methylsulfinyl-4-methylsulfonylbenzoic acid in 20 ml of CH2Cl2. 191 mg (0.99 mmol) of 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the mixture was stirred at RT for 90 min. 3 ml of 1M HCl were then added, and the organic phase was freed from the solvent. 168 mg (1.66 mmol) of triethylamine, 10 drops of acetone cyanohydrin and a spatula tip of potassium cyanide were added to the residue in 15 ml of acetonitrile. The reaction mixture was stirred at RT for 16 h and then freed from the solvent. 15 ml of CH2Cl2 were added to the residue, and 2 ml of 1M HCl were then added. After phase separation, the organic phase was freed from the solvent. The residue was stirred with 25 ml of a mixture of aqueous saturated sodium bicarbonate solution and diethyl ether at RT for 10 min. The phases were separated, and the aqueous phase was acidified with dilute HCl and then extracted three times with CH2Cl2. The combined organic phases were freed from the solvent. This gave 171 mg of clean product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C)C=O.O>[CH2:15]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH:14]=[CH2:13]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-nitrophenol (13.9 g, 100 mmol) in N,N-dimethylformamide (300 mL) was added with sodium hydride (4.2 g, 100 mmol 60%) followed by allyl bromide (13.3 g, 110 mmol) and the reaction was allowed to stir at room temperature for 2 hours The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 1-(allyloxy)-2-nitrobenzene. The oil was re-dissolved in mesitylene (500 mL) and heated at reflux for 3 d. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, dichloromethane:hexanes 0.5:9.5) provided 6.8 g, (50%) of 2-allyl-6-nitrophenol as a yellow oil. To a solution of 2-allyl-6-nitrophenol (6.6 g, 36.84 mmol) in dichloromethane (300 mL) was added 3-chloroperoxybenzoic acid (77%, 16.5 g, 73.67 mmol) The reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was washed with a 1:1 solution of 10% sodium sulfite:saturated sodium bicarbonate (2×300 mL). The solvent was removed in vacuo to give crude yellow oil. The oil was diluted with methanol (300 mL) and added to a solution of potassium carbonate (15.0 g, 108.5 mmol) the solution was allowed to stir at room temperature 2 h. The solvent was removed in vacuo. The residue was washed with water (1000 mL) and ethyl acetate (500 mL). The aqueous layer was acidified with 1 N aqueous hydrogen chloride and washed with ethyl acetate (500 mL). The combined organics were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate) and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, dichloromethane:hexanes 4:10) provided 3.18 g (44%) of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol as yellow solid. mp 63-65° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:18][CH2:19][OH:20])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2.[N+:21]([C:24]1[CH:34]=[CH:33][C:27]([C:28]([N:30]=[C:31]=[S:32])=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1COCC1>[Br:17][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[O:9][C:10]1[CH:11]=[N:12][C:13]([Cl:16])=[CH:14][C:15]=1[C:2]2([NH:1][C:31]([NH:30][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:34][CH:33]=1)=[S:32])[CH2:18][CH2:19][OH:20]
Reactant: NC1(CCO)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(NC(=S)NC1(CCO)c2cc(Br)ccc2Oc2cnc(Cl)cc21)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.7 %

Procedure:
A reaction mixture of 2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (2.8 g, 7.87 mmol) and 4-nitrobenzoyl isothiocyanate (1.639 g, 7.87 mmol) in THF (100 mL) was stirred at RT for 1 hour. The reaction mixture was then concentrated under reduced pressure to afford N-(7-bromo-3-chloro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-ylcarbamothioyl)-4-nitrobenzamide (5 g, 8.87 mmol).
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1)=O.[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>C1(C)C=CC=CC=1>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:4]2[CH:5]=[CH:6][CH:7]=[C:3]2[CH:1]=[CH:22][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]([CH3:16])[CH:10]=1)#[N:13]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C#N)ccc1-n1cccc1C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cccn1-c1ccc(C#N)cc1C
Temperature: 100 °C
Yield: 98.9 %

Procedure:
The mixture of 4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile (15 g, 71.4 mmol) and (carbethoxymethylene)-triphenylphosphorane (27.5 g, 78.6 mmol) in toluene was heated to 100° C. overnight. Then it was cooled to room temperature, concentrated and purified by silica gel column chromatography (PE:EA=5:1) to afford ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)acrylate as a yellow oil (19.8 g, 98%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:7]2.[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[S:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=3[S:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(CC(C)C)ccc23)c1

Procedure:
The product from Example 12d (100 mg, 45.3 mmol) was reacted with the product from Example 4c (105 mg, 45.3 mmol) for 18 h following the procedure from Example 1g giving the title compound after purification of the crude product by HPLC with TFA as the trifluoroacetic acid salt (90 mg, 47%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.97 (d, J=6.62 Hz, 6H), 2.13-2.30 (m, 1H), 2.33 (s, 3H), 2.89 (d, J=6.99 Hz, 2H), 6.29 (d, J=6.99 Hz, 1H), 6.73 (d, J=8.46 Hz, 2H), 7.00 (d, J=8.09 Hz, 1H), 7.13-7.34 (m, 4H), 7.81 (d, J=8.46 Hz, 1H), 8.43 (d, J=6.99 Hz, 1H), 9.03 (d, J=8.46 Hz, 1H), 10.99 (br. s., 1H), 14.36 (br. s., 1H); MS (ESI+) m/z 416 (M+H)+; (ESI−) m/z 414 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].S(C1C=CC(C)=CC=1)(O[CH3:37])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH3:37])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:30])[F:31])#[N:2]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(S(N)(=O)=O)cc3)C2=S)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CNS(=O)(=O)c1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 50 °C
Yield: 30.3 %

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro-[3.4]octan-5-yl)benzenesulfonamide (Compound 81, 97 mg, 0.20 mmol), methyl tosylate (37 mg, 0.20 mmol), and Cs2CO3 (65 mg, 0.20 mmol) in acetonitrile (1 mL) was heated at 50° C. for 20 h in a sealed tube. After being cooled room temperature, the reaction mixture was diluted with water and extracted with EtOAc (3×). The organic layer was dried over magnesium sulfate and concentrated to give a residue that was purified by column chromatography on silica gel (hexanes:DCM:acetone=5:9:1) to afford 30 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]-octan-5-yl)-N-methylbenzenesulfonamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.37 (s, 1H), 8.10 (dd, 2H), 7.58-7.49 (m, 2H), 4.52 (d, 1H), 2.80 (m, 3H), 2.78-2.69 (m, 2H), 2.63-2.47 (m, 2H), 2.29 (m, 1H), 1.74 (m, 1H). LCMS [M+1+Na]+ 518.0.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:9]2([CH2:11][CH2:10]2)[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:6]1)=[O:4].[OH-].[Na+].Cl>CCCCCC.C(OCC)(=O)C>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[C:9]2([CH2:11][CH2:10]2)[C:8]1=[O:12]
Reactant: COC(=O)C1CN(Cc2ccc(OC)cc2OC)C(=O)C12CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CN2CC(C(=O)O)C3(CC3)C2=O)c(OC)c1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of 5-(2,4-dimethoxybenzyl)-4-oxo-5-azaspiro[2.4]heptane-7-carboxylic acid methyl ester (2.02 g) in tetrahydrofuran/methanol (1/1, 12 ml) was added a 1M aqueous solution of sodium hydroxide (12 ml) at room temperature, and the mixture was stirred for 1 hour. To this reaction solution was added a 2M aqueous solution of hydrochloric acid (6 ml), and the mixture was stirred, and then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, the solution was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. To the resulting solid was added diisopropyl ether (8 ml), and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (1.59 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=3[F:21])[N:9]=[CH:10][C:3]=12.C(=O)([O-])N.[CH:26]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])[CH3:27].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH:26]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([O:38][C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=4[F:21])[N:9]=[CH:10][C:3]=23)[CH2:36][CH2:37]1)=[O:31])([CH3:28])[CH3:27]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Agent: CC(C)(C)[O-]
Agent: NC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 12 °C
Yield: 74.4 %

Procedure:
Toluene (1.6 L) was transferred to a 4 L jacketed reaction vessel fitted with a mechanical stirrer, nitrogen inlet and a temperature probe. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) (97.0 g, 0.297 mol) was added with stirring into the reaction vessel under nitrogen, and a slurry was obtained. The carbamate, 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (5) (66.57 g, 0.356 mol), was added at room temperature. The reactor was cooled to 12° C. and sodium tert-butoxide (37.09 g, 0.386 mol) was added with stirring. The internal temperature gradually increased to 34° C. due to an exotherm. Then the internal temperature was brought down to 23-25° C. The reaction mixture became a thick slurry and was stirred at room temperature for 2.5 h. The precipitate from the reaction mixture was filtered, washed with toluene (250 mL) followed by water (3×500 mL), and vacuum dried overnight at room temperature. The dried solid product was slurried in EtOH (500 mL) at room temperature, filtered, and washed with water (2.5 L) until the filtrate was neutral. The washed solid product was dissolved in refluxing EtOH (1.3 L), and the resulting clear solution was gradually cooled to room temperature. The product (6) crystallized out and was isolated by filtration and dried overnight in a vacuum oven at 40° C., 20 torr to provide 105.5 g of product (6) (74%). HPLC analysis, >99% (purity, by peak area). 1H NMR (Bruker 400 MHz, CDCl3) δ 8.62 (s, 1H, Ar—H), 8.32 (s, 1H, Ar—H), 7.93 (m, 3H, Ar—H), 5.62 (m, 1H, —O—CH—), 4.95 (m, 1H, CH3—CH—CH3), 3.91 (m, 2H, —CH2—), 3.37 (m, 2H, —CH2—), 3.12 (s, 3H, —SO2CH3), 2.09 (m, 2H, —CH2—), 1.87 (m, 2H, —CH2—), 1.27 (d, 6H, J=8 Hz, CH3—CH—CH3); mass spec. (electrospray) m/z 478 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28]([OH:30])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[C@@H:41]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@H:40]([NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:56]([O:55][C:54]([NH:53][C@H:40]1[C@H:41]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C@@H:42]([CH3:44])[CH2:43][N:38]([C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[NH:31][C:28]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:39]1)=[O:60])([CH3:57])([CH3:58])[CH3:59]
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (0.005 g, 0.01 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.0064 g, 0.015 mmol), and HATU (0.012 g, 0.031 mmol) in DMF (0.2 mL) and DIPEA (0.0064 mL, 0.037 mmol) was stirred at room temperature for 2 h. The mixture was quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, then purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.05% TFA, at a flow rate of 30 mL/min.) to afford the sub-title compound (0.0032 g, 30%). LCMS calc. for C44H60N7O7Si [M+H]+: m/z=826.4. found: 826.4.