Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]([CH3:16])=[CH:6][N:5]2[C:17]=1[C:18]([OH:20])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[NH2:50][C@H:51]([CH2:54][CH2:55][CH2:56][CH3:57])[CH2:52][OH:53]>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[OH:53][CH2:52][C@H:51]([NH:50][C:18]([C:17]1[N:5]2[CH:6]=[C:7]([CH3:16])[CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:4]2=[N:3][C:2]=1[CH3:1])=[O:20])[CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCC[C@@H](N)CO
Reactant: Cc1cc(OCCC(C)C)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCCC(C)C)cc(C)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 mg (0.27 mmol) of 2,6-dimethyl-8-(3-methylbutoxy)imidazo[1,2-a]pyridine-3-carboxylic acid Example 89A, 96 mg (0.30 mmol) of TBTU and 110 mg (1.09 mmol) of 4-methylmorpholine were initially charged in 1.73 ml of DMF. 35 mg (0.30 mmol) of (R)-(−)-2-aminohexanol were then added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water/TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The concentrated fractions were taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted two more times with dichloromethane, the combined organic phases were dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. This gave 91 mg of the target compound (87.5% of theory, purity 98%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH2:10]CCC)[CH3:9])=[O:7])=[C:4]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1.BrC1C=CC(C(O)=O)=C(S(C(C)C)(=O)=O)C=1.CNC>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:4]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1
Reactant: CCCCN(C)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Agent: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)O
Agent: CNC
Product: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)N(C)C

Procedure:
Following the general method as outlined in Intermediate 253, starting from 4-bromo-2-(isopropylsulfonyl)benzoic acid (Intermediate 242) and dimethylamine, the title compound was obtained as a pink solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].S([O-])(O[O-])(=O)=[O:26]>>[CH3:1][C:2]1([CH3:23])[S:6](=[O:26])[C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Product: CC1(C)[C@H](C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S1=O

Procedure:
A penicillin is treated with a peroxymonosulfate at a temperature of from about 0° C. to about 50° C. in an aqueous medium to produce a penicillin sulfoxide.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([OH:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C(C)O)cc(OC)c1Br
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(C(C)=O)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 22 h
Yield: 96.7 %

Procedure:
To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)ethanol (10.8 g, 41.1 mmol) in anhydrous CH2Cl2 (150 mL) was added MnO2 (48 g, 552 mmol). After the mixture was placed under a drying tube and stirred at room temperature for 22 hours, it was filtered through a pad of Celite and silica gel and rinsed with EtOAc. Concentration of the filtrate in vacuo gave 1-(4-bromo-3,5-dimethoxyphenyl)ethanone as a white solid (10.3 g, 97% yield). The product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[N:16][C:15]([C:18]([NH2:20])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[N:16][C:15]([C:18]#[N:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1
Reactant: NC(=O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine-3-carboxamide (1.35 g, 3.69 mmol) and pyridine (1.49 mL, 18.43 mmol) in 1,4-dioxane (30 mL) at 0° C. was added trifluoroacetic anhydride (1.04 mL, 7.37 mmol). The mixture was warmed to room temperature and stirred for 2 days. Aqueous saturated NaHCO3 and ethyl acetate were added. The layers were separated and the aqueous phase was extracted four times with ethyl acetate. The combined organic extracts were washed with brine, dried (NaSO4) and concentrated. Purification by silica gel chromatography (gradient 60% ethyl acetate:hexanes to 100% ethyl acetate) provided the title compound. 1H NMR (acetone-d6) δ 7.75 (1H, d, J=9.6 Hz), 7.68-7.62 (2H, m), 7.37 (2H, dd, J=8.4, 13.9 Hz), 7.13 (1H, t, J=7.6 Hz), 5.08-5.04 (1H, m), 4.06-4.02 (4H, m), 2.20-2.14 (2H, m), 2.00-1.94 (2H, m).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C@@H:29]([F:40])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:43])[CH3:42])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:46])[CH2:22][C:23]([CH3:45])([CH3:44])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C@H:29]([F:40])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:42])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:46])[CH2:22][C:23]([CH3:44])([CH3:45])[O:24]3)=[CH:15][CH:14]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@@H](F)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](F)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
110 μl (630 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 3.5 mg (20 μmol) of (1R,2S)-1-aminoindan-2-ol in 4 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 min. A solution of 77 mg (160 μmol) of 5-(4-fluorophenyl)-6-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 22A) in 4 ml of tetrahydrofuran are then slowly added dropwise, and the mixture is stirred at room temperature for 6.5 h. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1) gives the diasteromerically pure target compounds.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:22])[N:3]=1.[C:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:22])[N:3]=2)=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Reactant: CC(C)(C)c1ccc(N)cc1
Product: Cc1nc(Nc2ccc(C(C)(C)C)cc2)c2ccc(-c3ncccc3C(F)(F)F)cc2n1

Procedure:
Using procedures analogous to those already described, (4-tert-Butyl-phenyl)-[2-methyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amine is prepared by condensing 4-chloro-2-methyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline with 4-tert-butylaniline. Mass spec. 436.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:34]([F:37])([F:36])[F:35])=[C:30]([CH:33]=1)[CH:31]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:31][C:30]2[CH:33]=[C:26]([F:25])[CH:27]=[CH:28][C:29]=2[C:34]([F:36])([F:35])[F:37])[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cc(F)ccc1C(F)(F)F
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Fc1ccc(C(F)(F)F)c(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 5-fluoro-2-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ESI) m/z 506.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][NH2:40]>>[O:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][NH:40][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([C:21]2[CH:20]=[CH:19][C:18]3[N:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:32])=[O:6])[CH:9]=4)[CH:15]=[N:16][C:17]=3[CH:22]=2)=[CH:24][CH:25]=1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)O)cc4)ccc32)c1
Reactant: NCc1ccco1
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)NCC5CCCO5)cc4)ccc32)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 7 starting from 4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)-phenyl]-1H-benzimidazol-5-yl}benzoic acid and 2-furanmethanamine, tetrahydro- (Aldrich, Cat. No. 131911). LCMS (M+H)+: m/z=538.3.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[C:10]([CH:14]1CC2O[CH:15]1C=C2)(OC)=[O:11].Cl.C(Cl)Cl>O>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:10](=[O:11])[CH:14]=[CH2:15])[CH3:2]
Reactant: CCCCC(CC)CN
Reactant: COC(=O)C1CC2C=CC1O2
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)NCC(CC)CCCC
Temperature: 140 °C
Reaction time: 15 h

Procedure:
7.2 parts 30% methanolic Na-methylate solution are added to 64.5 parts 2-ethylhexylamine. 77 parts 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene are added drop-wise at 30° to 35° C. during cooling. The reaction medium is then stirred for 15 hours and neutralised with 4 parts concentrated hydrochloric acid. 100 parts methylene chloride and 50 parts water are added, the organic phase separated off, and the aqueous phase extracted twice with 25 ml methylene chloride in each instance. The combined organic phases are reduced in a rotary evaporator at a bath temperature of 90° C. and a vacuum of 20 Torr. The residue is heated under a high vacuum to 110° to 120° C. (bath temperature 140° C.). On conclusion of the furane separation, the sedimentation temperature increases and the product distills over. 66.6 parts N(2-ethylhexyl)acrylamide with a boiling point of 123° C. at 0.4 Torr are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=[C:8]([CH:22]([CH3:24])[CH3:23])[C:9]=1[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([CH3:3])[CH3:2].[CH:31]([C:34]1[CH:35]=[C:36]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:37]=[C:38]([CH:52]([CH3:54])[CH3:53])[C:39]=1[N:40]1[CH:44]=[CH:43][N:42]=[C:41]1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47](I)[CH:46]=1)([CH3:33])[CH3:32].N1C=CC=CC=1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.O.[Cu]I.CC#N>[O:21]([C:49]1[CH:50]=[C:45]([C:41]2[N:40]([C:39]3[C:38]([CH:52]([CH3:54])[CH3:53])=[CH:37][C:36]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)=[CH:35][C:34]=3[CH:31]([CH3:33])[CH3:32])[CH:44]=[CH:43][N:42]=2)[CH:46]=[CH:47][CH:48]=1)[C:17]1[CH:16]=[C:15]([C:11]2[N:10]([C:9]3[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][C:6]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:7][C:8]=3[CH:22]([CH3:24])[CH3:23])[CH:14]=[CH:13][N:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1-n1ccnc1-c1cccc(O)c1
Reactant: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1-n1ccnc1-c1cccc(I)c1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1-n1ccnc1-c1cccc(Oc2cccc(-c3nccn3-c3c(C(C)C)cc(-c4ccccc4)cc3C(C)C)c2)c1
Temperature: 100 °C
Reaction time: 96 h
Yield: 70 %

Procedure:
A mixture of 3-(1-(3,5-diisopropyl-[1,1′-biphenyl]-4-yl)-1H-imidazol-2-yl)phenol (3.12 g, 7.87 mmol), 1-(3,5-diisopropyl-[1,1′-biphenyl]-4-yl)-2-(3-iodophenyl)-1H-imidazole (3.98 g, 7.87 mmol), copper(I) iodide (0.15 g, 0.787 mmol), picolinic acid (2.91 g, 23.61 mmol) and potassium phosphate (8.35 g, 39.3 mmol) in DMSO (45 mL) was heated at 100° C. under a nitrogen atmosphere. The reaction progress was monitored by HPLC (C18, 95% MeCN in water, 1.0 mL per min.). HPLC after 4 days indicated about 70% desired product. The reaction was worked up until no increase of desired product. 5% aqueous sodium carbonate was added to the reaction mixture until pH around 10. The resulting solid was isolated by filtration and washed with water (3×). This crude mixture was purified by aluminum column chromatography (eluants: DCM/MeOH: 99/1 to 9/5), followed by silica gel column chromatography (eluant: Hexane/acetone: 7/3) to afford a light yellow solid (3.6 g, 59% yield).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17]CC)=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCCC(C(Cl)=O)C1)(=O)C1C=CC=CC=1.[CH2:37]([NH2:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[CH2:37]([NH:45][C:15]([CH:11]1[CH2:12][CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10]1)=[O:17])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Reactant: CCCCCCCCN
Agent: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Product: CCCCCCCCNC(=O)C1CCCN(C(=O)c2ccccc2)C1

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with 1-benzoyl-3-piperidinecarbonyl chloride (219.0 mg; 0.87 mmol) and commercially available octylamine (144 μl; 0.87 mmol). The crude product was purified by chromatography on silica, eluting with 100% ethyl acetate, giving N-(n-octyl) 1-benzoyl-3-piperidinecarboxamide (207.5 mg) as a colorless waxy oil. MS m/z (positive ion) 345 (MH+; 100), 216 (30).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([SH:11])[N:4]=1.[OH-].[K+].[N+]([N:17]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([CH3:25])=[N:18]1)([O-])=O>O.C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:11][C:21]2[NH:17][N:18]=[C:19]([CH3:25])[C:20]=2[N+:22]([O-:24])=[O:23])[N:6]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: Cc1nn([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)nc(Sc2[nH]nc(C)c2[N+](=O)[O-])n1
Reaction time: 0.75 h
Yield: 78.5 %

Procedure:
4,6-Dimethoxy-2-mercaptopyrimidine (4.65 g) was dissolved in water containing potassium hydroxide (1.7 g in 75 mls of water). 1,4-Dinitro-3-methylpyrazole (4.65 g) dissolved in the minimum of ethanol was then added dropwise. After the exothermic reaction had subsided, the mixture was stirred for 45 minutes. The precipitated solid was filtered off, washed with fresh water, and dried to give 6.3 g of the desired product, mp 175°-6° C.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([NH:20][S:21]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:5]1[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])([CH3:19])[CH3:18]
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2[nH]1
Product: Cc1ccc(C(c2ccc(C)cc2)c2c(S(=O)(=O)NC(C)C)[nH]c3ccccc23)cc1
Yield: 74.6 %

Procedure:
Substantially the same procedure as in Example 266 was repeated using 4,4'-dimethylbenzhydrol (0.96 g, 4.50 mmol) and N-isopropylindole-2-sulfonamide (1.00 g, 4.46 mmol) to give 1.44 g (yield: 75%) of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH:18]([CH3:19])[CH2:17][C:16](=O)[CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH:18]([CH3:19])[CH2:17][CH:16]([NH2:27])[CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: [BH3-]C#N
Reactant: CC1CC(=O)CN1S(=O)(=O)c1cccc2cnccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1CC(N)CN1S(=O)(=O)c1cccc2cnccc12
Temperature: 20 °C
Reaction time: 24 h

Procedure:
To 30 ml of methanol were added 1.45 g of the thus obtained 1-(5-isoquinolinesulfonyl)-5-methyl-3-pyrrolidone, 0.39 g of ammonium acetate and 0.32 g of sodium cyanoborohydride, followed by stirring at 20° C. for 24 hours. The methanol was removed under reduced pressure, and 100 ml of chloroform was added to the resultant product. Then, the mixture was washed twice with 50 ml each of water, washed once with 50 ml of a 50% aqueous sodium hydrogencarbonate solution, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C200, 50 g; solvent: chloroform) to obtain 0.96 g of 1-(5-isoquinolinesulfonyl)-3-amino-5-methylpyrrolidine [Compound (77)]. Compound (77) was analyzed to give the following data.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:31]([O:33][CH3:34])=[O:32]>ClCCl>[CH3:34][O:33][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:32]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Yield: 87.4 %

Procedure:
Using the method for the preparation of the side chain acid in Example 3, 4.62 g (20 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 8.4 ml (60 mmol) of triethylamine, 8.0 ml (63 mmol) of chlorotrimethylsilane, 200 ml of dichloromethane, and 2.5 ml (30 mmol) of methyl chloroformate gives 5.04 g of 6-[4-(methoxycarbonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: CO.[CH3:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([O:19]CC)=[O:18])=[CH:11]2.[Li+].[OH-]>C1COCC1>[CH3:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([OH:19])=[O:18])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(OCCSC)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSCCOc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 70 °C
Yield: 41.4 %

Procedure:
A methanol solution of ethyl 5-{[2-(methylthio)ethyl]oxy}-1H-indole-2-carboxylate (0.099 g, 0.356 mmol) was treated with 1 N LiOH (4 mL). The reaction mixture turned cloudy and THF was added until the cloudiness disappeared. The reaction was heated to 70° C. until TLC showed consumption of the starting material. The reaction mixture was partitioned between EtOAc and water and the basic layer was separated. The basic layer was acidified with conc. HCl and extracted with EtOAc, the layers were separated and the EtOAc was evaporated to afford the title compound (0.037 g, 41%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 10.74 (br. s., 1H), 7.44 (d, 1H), 7.17 (d, 1H), 7.11 (s, 1H), 6.96 (dd, 1H), 4.19 (t, 2 H), 2.88 (t, 2H), 2.20 (s, 3H). LCMS: m/z=251.9 (M−1).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10](=[C:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])[C:11]([F:14])([F:13])[F:12]>>[Cl:20][CH:15]([C:10]1([C:11]([F:12])([F:13])[F:14])[O:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[O:8]1)[C:16]([F:19])([F:18])[F:17]
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Reactant: Oc1cccnc1O
Product: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2cccnc2O1

Procedure:
11 g of 2,3-dihydroxypyridine were reacted with 23.5 g of 2,3-dichloro-1,1,1,4,4,4-hexafluorobut-2-ene as described in Example 2. After distillation under high vacuum, the product was obtained in an amount of 15.5 g (=50% of theory) in the form of colourless crystals. The NMR spectra showed the following characteristic absorptions: 19F NMR: -68.5 and -81.6 ppm. 1H NMR: 4.81 ppm.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:19])[C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1ccnc(Nc2ccc(I)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccnc(N(C)c2ccc(I)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and 2-chloro-4-methoxypyrimidine (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125° C. for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg). (2) Under an argon atmosphere, N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg) was added to a suspension of sodium hydride (11 mg) in anhydrous DMF (5 ml), and the resulting mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.0096 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 23 hours. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=3/1) to obtain N-(4-iodophenyl)-4-methoxy-N-methylpyrimidin-2-amine (46 mg).