Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[C:15]([C:17]1([NH:26][C:27](=[O:35])[CH:28]([NH2:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]1)#[N:16]>>[C:15]([C:17]1([NH:26][C:27](=[O:35])[CH:28]([NH:34][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]1)#[N:16]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC(C)(C)C)CC1
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC(C)(C)C)NC2=NS(=O)(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared starting from 3-chloro-benzo[d]isothiazole 1,1-dioxide and 2-amino-4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt according to the procedure from Example 10, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to acetonitrile. MS, m/z 460=M+1.
Reaction SMILES: [CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]5=[C:15](I)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH3:37][Zn+]>C1COCC1>[CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]5=[C:15]([CH3:37])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Zn+]
Reactant: COC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)CC1CCn2c1c(C)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Methyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.923 g, 1.54 mmol) was mostly dissolved in anhydrous THF (15.4 mL) to give a turbid suspension which was degassed with N2 for about 15 min. Bis(tri-t-butylphosphine)Pd(0) (0.071 g, 0.139 mmol) and 2.0 M methylzinc chloride in THF (2.318 mL, 4.64 mmol) were added at 25° C. The reaction mixture was sealed and heated at 70° C. to give a dark suspension. After 2 h at 70° C., the reaction mixture was cooled to 25° C., quenched with NaHCO3 (4 mL), stirred for 5 min, and filtered through a celite pad. The filtrate was diluted with MTBE, washed with H2O (twice), brine, and dried over MgSO4. The solvent was evaporated in vacuo to give a solid. The solid was dissolved in DCM/hexanes (1:1) and purified by silica gel column chromatography to give the titled compound (0.582 g) as a white solid. LCMS m/z=486.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 1.58-1.66 (m, 2H), 1.67-1.79 (m, 2H), 1.80-1.91 (m, 2H), 2.05-2.14 (m, 2H), 2.23 (s, 3H), 2.26-2.36 (m, 1H), 2.51 (dd, J=−15.92, 10.11 Hz, 1H), 2.82-2.90 (m, 1H), 2.94 (dd, J=15.79, 4.67 Hz, 1H), 3.32-3.43 (m, 1H), 3.73 (s, 3H), 3.75-3.80 (m, 1H), 3.92-4.01 (m, 1H), 4.02-4.10 (m, 1H), 5.09 (s, 2H), 6.86 (dd, J=8.72, 2.40 Hz, 1H), 7.04 (d, J=2.27 Hz, 1H), 7.10 (d, J=8.84 Hz, 1H), 7.47 (d, J=8.08 Hz, 1H), 7.61 (d, J=8.08 Hz, 1H), 7.71 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][S:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27]CC2C=CC([N+]([O-])=O)=CC=2)=[O:26])[CH2:9][N:8]1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)(=[O:3])[NH2:2].P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[C:1]([CH2:4][S:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([OH:27])=[O:26])[CH2:9][NH:8]1)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSCC(N)=O)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CSCC(N)=O)C3)[C@H](C)[C@H]12
Yield: 66.9 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(carbamoylmethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin -4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.42 g), 20% palladium hydroxide on carbon (0.4 g), 0.05M phosphate buffer (pH 6.3, 20 ml), and tetrahydrofuran (20 ml) was stirred at ambient temperature for 4 hours under atmospheric pressure of hydrogen. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to remove the organic solvent. The resulting residue was washed twice with ethyl acetate (20 ml) and the aqueous layer was concentrated under reduced pressure to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (20 ml) eluting in turn with water (100 ml) and 5% aqueous acetone (100 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(carbamoylmethyl)thiomethylpyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.16 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][C:14]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:15][C:16]=3[CH3:17])[C:9](=[O:26])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:27]1([C@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>COCCO.O>[CH3:17][C:16]1[CH:15]=[C:14]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[NH:13][C:12]=1[CH:11]=[C:10]1[C:3]2[C:2]([NH:35][CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:34])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]1=[O:26]
Reactant: C[C@@H](N)c1ccccc1
Reactant: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Solvent: O
Solvent: COCCO
Product: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(NC(C)c3ccccc3)c21
Temperature: 115 °C
Yield: 83.1 %

Procedure:
A mixture of 4-chloro-5-[3-methyl-5-(morpholine-4-carbonyl)-1H-pyrrol-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (37 mg, 0.1 mmol) and (R)-(+)-1-phenylethylamine (121 mg, 1 mmol) in 2-methoxyethanol (0.5 mL) was heated at 110-120° C. for 1.5 hours. The reaction was diluted with water and filtered. The precipitate was washed with water, little ethanol, ethyl acetate, hexane and dried to give 38.1 mg (81%) of the title compound as a yellow solid. MS 459 [M++1].
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]1=[NH:15].[CH2:16]1[CH:23]2[C:19]3([C:25](O)=[O:26])[CH2:20][CH:21]([CH2:24][CH:17]1[CH2:18]3)[CH2:22]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8]/[C:7]/1=[N:15]\[C:25]([C:19]12[CH2:20][CH:21]3[CH2:24][CH:17]([CH2:16][CH:23]1[CH2:22]3)[CH2:18]2)=[O:26]
Reactant: COCCn1c2c(sc1=N)CCCC2
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCn1c2c(s/c1=N\C(=O)C13CC4CC(CC1C4)C3)CCCC2

Procedure:
A mixture of the product of Example 68A (293 mg, 1.00 mmol), hexahydro-2,5-methano-pentalene-3a-carboxylic acid (199 mg, 1.20 mmol), HATU (570 mg, 1.50 mmol) and triethylamine (836 mL, 6.00 mmol) in 15 mL of DMF was processed according to the method of Example 3B to afford the title compound: 1H NMR (500 MHz, DMSO-d6) δ 1.53-1.62 (m, 4H) 1.67-1.82 (m, 8H) 2.07-2.12 (m, 2H) 2.23-2.27 (m, 2H) 2.45-2.49 (m, 3H) 2.54-2.59 (m, 2H) 3.23 (s, 3H) 3.63 (t, J=5.3 Hz, 2H) 4.16 (t, J=5.5 Hz, 2H); MS (DCI/NH3) m/z 361 (M+H)+.
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:6]=1[C:7]#[N:8].O>CS(C)=O>[I:13][C:10]1[CH:11]=[CH:12][C:5]([S:2][CH3:1])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C[S-]
Reactant: N#Cc1cc(I)ccc1F
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc(I)cc1C#N
Yield: 93.4 %

Procedure:
Sodium thiomethoxide (0.142 g) was added to a solution of 2-fluoro-5-iodobenzonitrile (0.5 g) in DMSO (1 mL) and the mixture stirred. An exotherm was noted. After stirring for 90 min, water was added and the solid that precipitated was collected, washed with water and dried at 50° C. under vacuum to leave the subtitle compound as an off-white solid (0.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[OH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:33]1[NH:34][C:35]([CH3:36])=[C:31]([CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([OH:23])[CH2:29][CH2:28]2)[C:32]=1[CH3:39])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCC(O)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCC(O)CC1
Temperature: 25 °C

Procedure:
A mixture of 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (150 mg, 0.42 mmol), 4-(4-hydroxy-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (99 mg, 1 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for days. The reaction was concentrated and the residue was purified on a silica gel column to give the titled compound as a pale greenish-brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH3:17]OC(OC)(C)C.Cl>CO.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:16])[CH2:9][C:10]([CH3:14])([CH3:15])[C:11]([O:13][CH3:17])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)c1ccc(Br)cc1)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(C)(C)CC(=O)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 22 h

Procedure:
To a solution of 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid (8.33 g, 29.2 mmol) and 2,2-dimethoxypropane (3.95 g, 37.9 mmol) in methanol (100 mL) was added 1 M HCl in dioxane (2.0 mL). The reaction mixture was stirred at 50° C. for 22 h. The mixture was concentrated under reduced pressure. Toluene (2×60 mL) was added and the mixture concentrated again (2×) to afford methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate as an off-white, semi-solid (8.60 g, 99%). This material was used in the next step without further purification. LC-MS: ret. time 3.23 min; m/z 298.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 6H), 3.28 (s, 2H), 3.67 (s, 3H), 7.58 (d, 2H), 7.78 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]>>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([CH2:16][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[CH:18]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)c1cccc(CBr)c1
Product: CCCc1c(OCc2cccc(C(=O)OC)c2)ccc(C(C)=O)c1O

Procedure:
1-(2,4-dihydroxy-3-propylphenyl)ethanone was allowed to react with methyl 3-bromomethylbenzoate according to the procedure of Example 69 and the product was purified by recrystallization from methylene chloride-ether to give 3-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]benzoic acid methyl ester, the title compound, mp 141°-143°, in 89% yield. Analysis Calculated for C20H22O5 : C, 70.16; H, 6.48. Found: C, 69.99; H, 6.41.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)(C(OC(C)(C)C)=O)[C:9]([O:11][C:12](C)(C)C)=[O:10])=[CH:3][CH:2]=1.Cl.C(OCC)(=O)C>FC(F)(F)C(O)=O>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([CH2:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccncc1)(Cc1ccncc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
The crude crystals (17.1 g) of di-tert-butyl 2,2-bis[(4-pyridyl)methyl]malonate synthesized by the above process were dissolved in trifluoroacetic acid (90 ml), and the solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resultant concentrated residue was heated for 20 minutes in a bath controlled at 200° C. and then dissolved in methanol (170 ml). A 4N hydrogen chloride in ethyl acetate (100 ml; 400 mmol) was added to the solution, and the mixture was stirred for 2 hours and then concentrated under reduced pressure. The resultant concentrated residue was made basic by addition of aqueous 2.5N sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 6.0 g (yield: 51%) of methyl 2,2-bis[(4-pyridyl)methyl]acetate as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: O=C(CC1CCNCC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CC1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1
Reaction time: 4 h
Yield: 35 %

Procedure:
A mixture of 2.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.57 parts of 1-(4-fluorophenyl)-2-(4-piperidinyl)ethanone hydrochloride, 2.65 parts of sodium carbonate and 22.5 parts of N,N-dimethylformamide is stirred for 4 hours at 70°-80° C. The reaction mixture is poured onto water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from 2-propanol, yielding 1.4 parts (35%) of 1-[3-[4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperidinyl]propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 208° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N+:12]([O-])[C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[OH:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=3)[N:11]=[N:12][C:13]=2[CH:19]=1
Reactant: O=C(O)c1ccc(-c2nc3ccc(O)cc3[n+]([O-])n2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2nnc3cc(O)ccc3n2)cc1
Reaction time: 0.5 h

Procedure:
3-(4-Carboxyphenyl)-7-hydroxybenzo[e][1,2,4]triazine 1-oxide (Compound VII-1, 350 mg, 1.23 mmol) was dissolved in 70% ethanol in water (20 ml) at reflux. 5.0 equivalents of Na2S2O4 were added. The reaction turned dark brown. After 30 minutes, the solution was concentrated to remove ethanol and the solid was filtered and washed with water and dried (12 mg). 1H NMR (DMSO-d6 400 MHz): δ 8.67 (d, 2H), 8.16 (d, 2H), 8.09 (d, 1H), 7.77 (d, 1H), 7.67 (s, 1H). MS (ESI): m/z 268.43 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:6]=1[O:20][CH3:21].[CH2:23]([O:30][C:31](=[O:47])[N:32]([CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1Br)[CH2:33][CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([C:37]2[CH:38]=[CH:39][C:40]([C:42]([F:43])([F:44])[F:45])=[CH:41][C:36]=2[CH2:35][N:32]([C:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:47])[CH2:33][CH3:34])[CH:8]=[CH:7][C:6]=1[O:20][CH3:21]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)OCc1ccccc1
Reactant: COC(=O)Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1ccc(OC)c(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester and (2-bromo-5-trifluoromethyl-benzyl)-ethyl-carbamic acid benzyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18].CN(C=O)C>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:9]=1)=[O:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Temperature: 80 °C
Yield: 84.8 %

Procedure:
A flask charged with 1H-imidazole-4-carboxylic acid methyl ester (0.29 g, 2.3 mmol), K2CO3 (0.60 g, 4.3 mmol), SEM-Cl (0.45 mL, 2.5 mmol) and DMF (5 mL) was heated for 12 h at 80° C. The reaction was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4 and concentrated. The residue was purified by elution from a 20-g SPE cartridge (silica) with 5% MeOH/DCM to give 0.50 g (85%) of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid methyl ester. This compound was stirred overnight at RT in MeOH (3.0 mL) and 1N NaOH (1.9 mL) and then concentrated to give 0.43 g (70%) of the title compound as a white solid. Mass spectrum (ESI), m/z): Calcd. for C10H18N2O3Si, 243.1 (M+H), found 243.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]1[CH2:27][CH2:26][C:10]2([CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11]2)[CH:9]=[CH:8]1)=[O:5])[CH3:2].[H][H]>C(O)C>[CH2:15]1[C:10]2([CH2:26][CH2:27][CH:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:9]2)[CH2:11][CH2:12][NH:13][CH2:14]1
Reactant: [H][H]
Reactant: CCOC(=O)C=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Solvent: CCO
Product: CCOC(=O)CC1CCC2(CCNCC2)CC1

Procedure:
9.6 g (26.0 mmol) of the protected spiro compound from Step B were dissolved in 400 ml ethanol, and the solution was filled into a hydrogenation vessel followed by 2 g Pd(II) hydroxide on charcoal. The reaction was carried out at 40° C. and 1 atm hydrogen, and it was complete after about 40 hours. The catalyst was removed by filtration through silica gel, and the filtrate was concentrated under reduced pressure. The remaining oil was treated with dry ether, filtered, and the filtrate was acidified with ethereal hydrochloric acid. The hydrochloride of the title compound was collected by filtration, washed two times with ether, dissolved in water, and the solution was made alkaline with 2 N aqueous sodium hydroxide solution. After extraction with dichloromethane the organic layer was dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1SC=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23]1C=CC(C=O)=[CH:24]1>>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:22]=[CH:21][S:23][CH:24]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C(=C/c1cccs1)NC(=O)OCc1ccccc1
Reactant: O=Cc1ccsc1
Product: COC(=O)/C(=C/c1ccsc1)NC(=O)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99a) was used except that 3-thiophenecarboxaldehyde (762 mg) was used as the aldehyde component to afforded the desired product (549 mg). 1H NMR (300 MHz, CDCl3) δ 3.795 (s, 3H), 5.19 (s, 2H), 5.99 (br., 1H), 7.07 (m, 1H), 7.34(m, 7H), 7.49(d, 1H, J=5 Hz), 7.77(s, 1H). LC/MS: 2.32 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[CH:20]1([C:26](=O)[CH2:27][C:28]#[N:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:26]2[C:27]([C:28]#[N:29])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=3)[N:1]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Reactant: N#CCC(=O)C1CCCCC1
Product: N#Cc1c(C2CCCCC2)nc2ccc(C(F)(F)F)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-trifluoromethyl-phenyl)-phenyl-methanone and 3-cyclohexyl-3-oxo-propionitrile (prepared as described in example 110 step A). Off-white solid. MS (ESI): 381.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([O:24]CC)=[O:23])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([OH:24])=[O:23])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 3-(2′,4′-dichlorobiphenyl-4-ylsulfonamido)benzoate (0.4 g) was dissolved in a mixture of THF (5 mL) and methanol (5 mL). 1 M NaOH (10 mL) was added and the mixture stirred for 3 hours at room temperature followed by 1 hour at 50° C., by which stage a clear solution had formed. Concentrated HCl was added and the precipitate collected as a white solid. The solid was dissolved in ethyl acetate and dried with Na2SO4. Evaporation gave the title compound as a white solid, recrystallised from ethyl acetate/petrol. 13C NMR (250 MHz, DMSO-d6): δ 122.4, 124.1, 125.0, 126.3, 126.5, 127.7, 129.6, 130.4, 131.9, 132.2, 132.5, 133.8, 137.1, 137.9, 138.9, 142.0 and 166.8. MS, m/z: Calcd, 420.99. Found, 421.22 (M).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.[C:10](=O)(O)[O-].[Na+].COS(OC)(=O)=O>CC(=O)CC>[OH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc(O)cs1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: COC(=O)c1cc(O)cs1

Procedure:
50.0 g (0.347 mol) of 4-hydroxy-2-thiophenecarboxylic acid and 58.3 g (0.694 mol) of sodium bicarbonate are heated at the boiling point in 900 ml of absolute 2-butanone under nitrogen, and 43.7 g (0.347 mol) of dimethylsulfate are added dropwise in the course of 20 minutes. The mixture is heated under reflux for a further 2.5 hours. It is then evaporated in vacuo and the residue is partitioned between saturated sodium bicarbonate solution and ether. The aqueous phase is extracted five more times with 80 ml of ether each time. The combined organic phases are dried over sodium sulfate/active charcoal, filtered and evaporated.