Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)[CH:6]=C[C:4](S(OCCCC#C)(=O)=O)=[CH:3][CH:2]=1.[F:17][C:18]([F:30])([F:29])[CH2:19][CH2:20][S:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:30][C:18]([F:17])([F:29])[CH2:19][CH2:20][S:21]([CH:24]([CH2:4][CH2:3][CH2:2][C:1]#[CH:6])[C:25]([O:27][CH3:28])=[O:26])(=[O:22])=[O:23]
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of 2.0 g of 4-pentynyl p-toluenesulfonate and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 30 ml of dimethyl sulfoxide, 1.2 g of potassium carbonate was added at room temperature. The mixture was stirred at 60° C. for 4 hours and at 90° C. for 1 hour, and then allowed to stand near room temperature. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.90 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-6-heptynoate (hereinafter referred to as the present compound (11)).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH2:34][O:35][CH3:36])[CH:28]=1>>[CH3:36][O:35][CH2:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][N:29]1[C:27]1[CH:28]=[C:23]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH:24]=[N:25][CH:26]=1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: COC[C@@H]1CCCN1c1cncc(Br)c1
Product: COC[C@@H]1CCCN1c1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [C], 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to 3-bromo-5-((S)-2-methoxymethyl-pyrrolidin-1-yl)-pyridine (intermediate A-6) to give the title compound as a yellow oil. MS: 352.3 (M+H+).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[CH:18]=[C:17]([O:19][CH:20]([F:22])[F:21])[N:16]([CH3:23])[N:15]=2)=[C:9]([F:24])[CH:8]=1.C(=O)([O-])O.[Na+]>ClC(Cl)(Cl)Cl>[Cl:4][C:18]1[C:14]([C:10]2[CH:11]=[C:12]([CH3:13])[C:7]([Cl:6])=[CH:8][C:9]=2[F:24])=[N:15][N:16]([CH3:23])[C:17]=1[O:19][CH:20]([F:22])[F:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Reaction time: 16 h

Procedure:
22 g (0.16 mol) of sulfuryl chloride were added dropwise to a solution of 43 g (0.15 mol) of 3-(4-chloro-2-fluoro-5-methylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 250 ml of tetrachloromethane. After the reaction solution had subsequently been stirred for 16 hours, 200 ml of saturated aqueous sodium hydrogen carbonate solution were added dropwise. The organic phase was thereupon separated off, washed using saturated sodium chloride solution, dried over magnesium sulfate, then filtered and subsequently concentrated. Yield: 46 g.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:22]1[CH2:23][CH2:24][N:19]([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:20][CH2:21]1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CC(C)(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1
Yield: 52 %

Procedure:
Prepared in analogy to example 1 (b) from 2-tert-butoxy-5-methanesulfonyl-benzoic acid (Example A12) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 52%). MS (m/e): 449.3 (M+H+, 50%), 466.4 (M+NH4+, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:20].O1CCOCC1>>[ClH:20].[ClH:20].[CH3:19][N:17]([CH2:16][CH2:15][O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:18]
Reactant: CN(C)CCOC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CCOC1CCNCC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-ol, sodium hydride and DMF was stirred for 5 minutes at room temperature, then 2-chloro-N,N-dimethylethylamine was added to the resultant and further stirred for 30 minutes at room temperature to give 2-[(1-tert-butoxycarbonylpiperidine-4-yl)oxy]-N,N-dimethylethylamine. A mixture of the obtained 2-[(1-tert-butoxycarbonylpiperidine-4-yl)oxy]-N,N-dimethylethylamine and 4M HCl-dioxane solution was stirred for 7 hours at room temperature to give N,N-dimethyl-2-(piperidine-4-yloxy)ethylamine dihydrochloride.
Reaction SMILES: N([O-])=[O:2].[Na+].Cl.[CH3:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:8]>O>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([CH:6]=[O:2])=[O:8])=[CH:10][CH:11]=1
Reactant: O=N[O-]
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=CC(=O)c1ccc(O)cc1

Procedure:
adding sodium nitrite and hydrochloric acid to a solution of 4-hydroxyacetophenone in water to form 4-hydroxyphenylglyoxal;
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[CH3:33][N:34]([CH3:40])[C:35](=[O:39])[C:36](O)=[O:37].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:32][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:36](=[O:37])[C:35]([N:34]([CH3:40])[CH3:33])=[O:39])=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: CN(C)C(=O)C(=O)O
Reactant: Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(=O)Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.9 %

Procedure:
1-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.23 mmol) was dissolved in DMF (2 mL) and treated with N,N-dimethyloxamic acid (27 mg, 0.23 mmol), Hunig's base (0.14 mL, 0.8 mmol) and TBTU (81 mg, 0.25 mmol). The reaction mixture was stirred at rt for 18 h. Solvent was removed in vacuum and water was added. A solid precipitated out and it was collected by filtration, dissolved in DMF and purified using reverse phase prep HPLC to afford the title compound as a pale yellow solid (11 mg). 1HNMR (500 MHz, DMSO-D6) δ 8.47 (s, 1H), 8.16 (s, 1H), 7.70-7.50 (m, 5H), 5.76 (m, 1H), 4.10-3.10 (m, 6H), 3.16 (s, 6H). LCMS: m/e 535 (M+H)+, ret time 1.33 min (method 1).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>CN(C=O)C.ClCCl>[CH3:1][N:2]([CH3:16])[C:3]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: CN(C)c1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)c1c(F)c(F)c(F)c(F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a suspension of 4.22 g (17.8 mmol) of 2-(dimethylamino)-3,4,5,6-tetrafluorobenzoic acid and 85 ml of dichloromethane, added 1.7 ml (19.5 mmol) of oxalyl chloride. After the bubbling subsided, five drops of DMF were added and the solution was stirred at room temperature for 21 hours. The solution was evaporated to 4.8 g of an oil which was used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)[CH:10]=[C:9]1[C:27]1[C:28]2[S:41][C:40]([CH2:42][OH:43])=[CH:39][C:29]=2[N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)[CH:10]=[C:9]1[C:27]1[C:28]2[S:41][C:40]([CH2:42][O:43][S:52]([CH3:51])(=[O:54])=[O:53])=[CH:39][C:29]=2[N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[N:31]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(COS(C)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-indole-1-carboxylic acid tert-butyl ester [1.21 g, 1.98 mmol, Intermediate (78)] in dichloromethane (25 mL) at 0° C. was added triethylamine (0.29 mL, 2.28 mmol) and methane sulfonyl chloride (0.34 mL, 4.40 mmol). The mixture was stirred at 0° C. for 30 minutes then at room temperature for 4 hours. It was diluted with dichloromethane then washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (dichloromethane/methanol, 90/10 as eluant) to produce 2-(1-tert-butoxycarbonyl-5-methanesulfonyloxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-indole-1-carboxylic acid tert-butyl ester [0.85 g, 62%, Intermediate (79)] as a yellow foam. LC/MS: 689.3 (M+H), RT=2.58 minutes.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:13]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:18][C@H:15]1[CH2:16][CH2:17][N:13]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methanesulfonyl chloride (15 mL, 0.19 mol) is added to a cooled (0° C.) solution of toluene (300 mL) containing (S)-1-benzylpyrrolidin-3-ol (24.5 g, 0.14 mol) and triethylamine (80 mL, 0.57 mol). The resulting mixture is stirred at 0° C. for 15 min, and allowed to warm to room temperature with stirring for 2 h. The mixture is quenched with a 5% aqueous solution of sodium bicarbonate (250 mL). The organic layer is washed with a 5% aqueous solution of sodium bicarbonate (2×250 mL), washed with water (1×250 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give N (35.1 g, 99%) as an orange oil. 1H NMR (300 MHz, CDCl3): δ2.07 (m, 1H), 2.30 (m, 1H), 2.49 (m, 1H), 2.75-2.90 (m, 3H), 2.98 (s, 3H), 3.61 (d, J=13.0 Hz, 1H), 3.68 (d, J=13.0 Hz, 1H), 5.18 (m, 1H), 7.15-7.30 (m, 5H). LCMS m/z calcd for C12H17NO3S 255 ([M+]); found 256 ([M+H]+, 100%), 160 (40%).
Reaction SMILES: C(N1C2CCC(=N[OH:18])CC=2C(C2C=CC(Cl)=CC=2)=N1)C1C=CC=CC=1.[CH2:26]([N:33]1[C:42]2[CH2:41][CH2:40]N[CH2:38][CH2:37][C:36]=2[C:35]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C1COCC1>[CH2:26]([N:33]1[C:42]2[CH2:41][CH2:40][C:38](=[O:18])[CH2:37][C:36]=2[C:35]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ON=C1CCc2c(c(-c3ccc(Cl)cc3)nn2Cc2ccccc2)C1
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCc2c(c(-c3ccc(Cl)cc3)nn2Cc2ccccc2)C1

Procedure:
1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-one oxime. A solution of 3.87 g of the compound from step G in 80 mL of THF with 5 mL of 1 M HCl was heated at reflux for 16 h. The volatiles were removed in vacuo and water was added (300 mL). The mixture was adjusted to pH 9 by the addition of 1 M NaOH and then was extracted with CH2Cl2. The combined extracts were washed with brine and the solvent was removed in vacuo to provide 1-benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-one. This product (3.13 g) was treated with hydroxylamine hydrochloride (3.0 g) in 20 mL of pyridine. The reaction mixture was stirred at RT for 14 h then was diluted with water (300 mL), and stirred an additional hour. The mixture was filtered on paper and the solids were washed with EtOAc and dried in vacuo to afford 2.48 g of the desired compound. 1H NMR (500 MHz, acetone-d6): 10.24 (s, 1H), 7.30-7.26 (m, 2H), 7.06-7.02 (m, 2H), 6.91-9.87 (m, 2H), 6.85-6.81 (m, 1H), 6.77-6.73 (m, 2H), 4.87 (s, 2H), 3.21 (s, 2H), 2.31 (t, J=6.6 Hz, 2H), 2.09 (t, J=6.6 Hz, 2H).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[C:5]1=[O:24].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35]>C1(C)C=CC=CC=1>[CH2:15]([C:12]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:11]2[C:6](=[CH:7][C:8]([F:23])=[CH:9][CH:10]=2)[C:5]([OH:24])=[C:4]([C:3]2[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:35])(=[O:36])[N:37]=2)[C:13]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2cc(F)ccc21
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2cc(F)ccc21
Yield: 70 %

Procedure:
A suspension of the compound of Example 18G (39 mg, 0.10 mmol) and 2-aminobenzenesulfonamide (17 mg, 0.10 mmol) in toluene (1 mL) was warmed at reflux for 2 h. The solution was cooled and concentrated in vacuo to afford a yellow foam which was purified by flash chromatography eluting with ethyl acetate in hexane to afford the title compound (33 mg, 0.07 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([N:1]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]2=[O:16])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 25 °C

Procedure:
41.1 g (0.3 mol) of p-aminobenzoic acid and 300 M of acetic acid were put into a 250 M flask to dissolve the p-aminobenzoic acid in the acetic acid, and then 29.4 g (0.3 mol) of maleic anhydride was slowly added thereto at 10° C. to obtain a yellow precipitate. This precipitate was recrystallized with a solution of DMF (dimethylformamide) and ethanol (50:50, w/w) to form an intermediate. The intermediate was treated at 85° C. for 15 minutes using sodium acetate and acetic anhydride, was cooled to room temperature, and was then precipitated in an ice water bath to obtain a precipitate. The obtained precipitate was recrystallized with a solution of ethyl acetate and n-hexane (50:50, w/w) to obtain N-(p-carboxyphenyl)maleimide.
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[C:12]([F:14])[C:11]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:6][C@H:5]([O:7][C:8]2[CH:13]=[C:12]([F:14])[C:11]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:10]([F:36])[CH:9]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 72.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (98 mg, 0.158 mmol) prepared in Example 135a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (54 mg, 73%) as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[CH2:23]([NH2:25])[CH3:24]>CO.C(Cl)Cl>[CH2:23]([NH:25][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:24]
Reactant: CCN
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCNCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with ethylamine hydrochloride (23.9 mg, 0.30 mmol) as described in General Procedure X to afford Iad (53.0 mg, 60.4%) as an ivory colored solid, tlc Rf=0.1 (10% MeOH/CH2Cl2−0.2% Et3N), m/z obs=326 (M+1).
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([CH2:58][OH:59])=[CH:54][CH:53]=2)=[CH:48][CH:47]=1>>[OH:59][CH2:58][C:55]1[CH:56]=[CH:57][C:52]([C:49]2[CH:48]=[CH:47][C:46]([NH:45][C:11]([C:13]3[CH:14]=[C:15]([S:19]([C:22]4[CH:23]=[C:24]5[C:29](=[C:30]([CH3:32])[CH:31]=4)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]5[NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=4)(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:51][CH:50]=2)=[CH:53][CH:54]=1
Reactant: Nc1ccc(-c2ccc(CO)cc2)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CO)cc6)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using (4′-amino-[1,1′-biphenyl]-4-yl)methanol in place of 8-aminooctanol. ES/MS calcd. for C38H33N4O6S+ 673.2. Found m/z=673.2 (M+H)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[CH2:45][CH3:46]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:47])[CH2:45][CH3:46]
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: CCC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.310 g, 0.94 mmol) and triethylamine (0.13 mL, 0.94 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise propionyl chloride (0.08 mL, 0.94 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to an oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.168 g colorless crystals. Mp 169° C. Mass spectrum, m+ =385. Anal (C23H33N5O6) theory C, 58.09; H, 6.99; N, 14.73; found C, 57.79; H, 6.93; N, 14.46.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][OH:29]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH2:27][CH2:28][OH:29])[CH:12]=2)=[O:10])=[CH:18][CH:19]=1
Reactant: OCCBr
Reactant: COc1ccc(COC(=O)c2ccc(=O)[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccc(=O)n(CCO)c2)cc1
Yield: 79.6 %

Procedure:
To a solution of 6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester (4.41 g, 17 mmol) and K2CO3 (2.58 g, 18.7 mmol) in DMF (100 mL) at room temperature, was added 2-bromoethanol (2.02 g, 16.2 mmol). The reaction mixture was stirred at 80° C. for 30 h, whereupon the DMF was evaporated under vacuum. The crude product was column chromatographed (silica gel, 2→5% MeOH in CH2Cl2), to give 3.91 g of 1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=2)=[CH:4][CH:3]=1.[F-].[K+].[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])[CH2:26][OH:27].O>O1CCOCC1>[CH2:30]([O:29][C:25]([CH2:26][O:27][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=2)=[CH:4][CH:3]=1)=[O:28])[CH2:31][CH2:32][CH3:33]
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(F)c([N+](=O)[O-])c2)c1=O
Reactant: CCCCOC(=O)CO
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCOC(=O)COc1ccc(-c2ncc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 84 %

Procedure:
Then, 1.10 g of 3-(4-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-13) was dissolved in 4.0 ml of 1,4-dioxane, to which 0.812 g of potassium fluoride and 0.925 g of butyl glycolate, and the mixture was heated under reflux for 1.5 hours. After completion of the reaction, the reaction mixture was left cooling to room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 1.25 g (yield, 83%) of 3-[4-(butoxycarbonylmethoxy)-5-nitrophenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (the present compound depicted below).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:16][C:17]1[C:18]([O:25][CH3:26])=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[F:24][C:23]1[CH:22]=[C:21]2[C:19](=[C:18]([O:25][CH3:26])[C:17]=1[F:16])[N:20]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1c(N)ccc(F)c1F
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc2c(OC)c(F)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
2.84 g (0.013 mole) of diethyl ethoxymethylenemalonate were added to 1.74 g (0.011 mole) of 3,4-difluoro-2-methoxyaniline (VIII) (prepared as described in Preparation 13). The mixture was then stirred at 140°-150° C. for 3 hours, after which 20 ml of diphenyl ether were added, and the mixture was stirred at 240°-250° C. for 1 hour. At the end of this time, the mixture was allowed to cool to room temperature, and then hexane was added to precipitate crystals, which were collected by filtration. 1.60 g of ethyl 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3-carboxylate (IX) were obtained as colorless crystals.