Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH:13]2[CH3:16])=[CH:9][CH:8]=1.C(=O)=O.CC(C)=O.[N:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>O1CCCC1>[CH3:16][C:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([N:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH:15]=2)[CH2:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CC1CCc2ccc(Br)cc21
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC1=CCc2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Yield: 46.5 %

Procedure:
n-Butyllithium (8.6 mL, 13.76 mmol) was added to a three-neck flask under argon atmosphere. Upon cooling by a dry ice-acetone bath, 8 mL of tetrahydrofuran, 6-bromo-1-methyl-indan 38d (1.32 g, 6.26 mmol) were added successively under stirring. The reaction mixture was reacted in the dry ice-acetone bath for 2 hours followed by dropwise addition of a solution of di-tert-butyl azodicarboxylate (1.87 g, 8.14 mmol) in 10 mL of tetrahydrofuran. The mixture was stirred for another 30 minutes and the ice-acetone bath was removed. The mixture was warmed up to room temperature and stirred for 20 hours. The reaction was quenched by addition of 20 mL of saturated ammonium chloride. The mixture was extracted with ethyl acetate (25 mL×3). The combined organic extracts were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(3-methyl-inden-5-yl)hydrazine-1,2-dicarboxylate 38e (1.05 g, yield 46.7%) as a yellow oil.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:9])[CH2:6][C:7]#[CH:8].[N:11]#[C:12][NH2:13]>>[ClH:1].[CH2:6]([C:5]1[N:9]=[C:12]([NH2:13])[NH:11][CH:4]=1)[C:7]#[CH:8]
Reactant: C#CCC(N)C(=O)OC
Reactant: N#CN
Agent: Cl
Product: C#CCc1c[nH]c(N)n1
Yield: 59 %

Procedure:
2-Amino-pent-4-ynoic acid methyl ester hydrochloride (2.91 g, 17.8 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (1.65 g, 59%) as a yellow oil (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.30 (s, 1H), δ 5.02 (d, 2H), δ 2.26 (t, 1H) ppm; 13C NMR (75 MHz, CD3OD) δ 150.1, 127.2, 109.6, 83.6, 69.8, 15.9 ppm; HRMS (ESI) calcd for C6H7N3 (M+) 122.0712, found 122.0713.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=O)[O:9]C2C=CC=CC=2)[CH:2]=1.FC(F)(F)C(O)=O.[C:24]1([C:30](=[C:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C(OCC)C>CS(C)=O.C(Cl)Cl>[C:24]1([C:30]([C:31]2[CH:47]=[CH:46][CH:45]=[C:33]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:43])([F:44])[F:42])=[CH:37][N:36]=3)[CH:32]=2)=[C:48]2[CH2:53][CH2:52][N:51]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:9])[CH2:50][CH2:49]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C(=C3CCNCC3)c3ccccc3)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Nc1cccnc1)N1CCC(=C(c2ccccc2)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of phenyl pyridin-3-ylcarbamate (27.1 mg, 0.127 mmol) in DMSO (3 mL) was added 2-(3-(phenyl(piperidin-4-ylidene)methyl)phenoxy)-5-(trifluoromethyl)pyridine trifluoroacetate (52 mg, 0.13 mmol), followed by triethylamine (0.018 mL, 0.127 mmol). The reaction was stirred at 60° C. for 3 h and then cooled to RT. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and saturated aqueous NH4Cl, dried and concentrated. Purification by silica gel column chromatography (0-5% MeOH/CH2Cl) gave an oil. Diethyether was added followed by CH2Cl2 and the title compound crashed out as a solid (9.2 mg, 13% yield). MS (APCI 10V) AP+ 531.23; 1H NMR (400 MHz, CDCl3) δ ppm 2.43 (t, 2H) 2.50 (t, 2H) 3.51-3.58 (m, 4H) 6.75 (s, 1H) 6.90-6.92 (m, 1H) 6.94-7.04 (m, 2H) 7.12 (dd, 2H) 7.17-7.23 (m, 3H) 7.26-7.37 (m, 3H) 7.86 (dd, 1H) 7.97 (dd, 1H) 8.23 (br. s., 1H) 8.42 (s, 2H).
Reaction SMILES: [H-].[Na+].C(S)CC.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[N:20]2[C:15]([C:16]([S:23]C(=O)N(C)C)=[CH:17][CH:18]=[CH:19]2)=[CH:14][CH:13]=1)=[O:11])[CH3:8].Cl[O-].[Na+]>O1CCCC1>[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[N:20]2[C:15]([C:16]([SH:23])=[CH:17][CH:18]=[CH:19]2)=[CH:14][CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1ccc2c(SC(=O)N(C)C)cccn2c1=O
Agent: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(S)cccn2c1=O
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a suspension of 0.395 g of 60% sodium hydride (mineral oil dispersion) in 20 ml of anhydrous tetrahydrofuran is added 0.82 ml of n-propyl mercaptan under ice-cooling. After stirring for 30 minutes, the resultant mixture is mixed with 2.634 g of 3-ethoxycarbonyl-9-dimethylcarbamoylthio-4H-quinolizin-4-one in 40 ml of tetrahydrofuran, and stirred at room temperature for another 15 hours. The reaction mixture is mixed with 8 ml of aqueous sodium hypochlorite and extracted with methylene chloride. The organic layer is washed with water, dried over sodium sulfate and concentrated to give a residue, which is chromatographed on a column of 30 g of silica gel eluting with methylene chloride-methanol (9:1 v/v) to give crude product, which is recrystallized from ethyl acetate to give 1.153 g (Yield: 56.3%) of 3-ethoxycarbonyl-9-mercapto-4H-quinolizin-4-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCc1ccccc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCCc1ccccc1
Temperature: 120 °C
Reaction time: 40 h

Procedure:
To a suspension of 10 g (46.66 mmol.) of cis-1-tert-butoxycarbonyl-3,5-dimethyl piperazine and 12.90 g (93.3 mmol.) of potassium carbonate in N,N-dimethylformamide (50 ml) was added, at room temperature, 11.15 g (56 mmol.) of 1-bromo-3-phenylpropane. The mixture was stirred for 40 hours at 120° C., which was then cooled to room temperature. To the reaction system was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (ethyl acetate/hexane 20-30%) to give the object compound as a yellow oily product. The yield was 12.21 g (79%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[I:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:30][CH2:31][O:32][C:33]([CH3:35])=[O:34]>C1C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[CH2:20]([O:19][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([I:27])=[C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:2][CH2:1][CH2:3][CH:30]=[CH:31][O:32][CH:33]2[CH2:35][CH2:18][CH2:9][CH2:10][O:34]2)[CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccccc2c1I
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N(CCCC=COC1CCCCO1)c1cc(OCc2ccccc2)c2ccccc2c1I
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A solution of 80 (53 mg, 112 μmol) in benzene (5 mL) was added to a mixture of 50% aqueous NaOH (0.5 g) and benzyltributylammonium chloride (70 mg, 224 μmol, 2 equiv). The mixture was stirred vigorously for 15 min and 100 (147 mg, 556 μmol, 5 equiv) was added. The mixture was stirred vigorously for 12 h at 25° C. Ice-cold H2O (50 mL), and EtOAc (10 mL) were added. The aqueous layer was extracted with EtOAc (10 mL), the combined organic layers were dried (Na2SO4) and the solvent was removed under vacuum. Chromatography (SiO2, 2×20 cm, 10-25% EtOAc-hexane gradient elution) afforded 108 (58 mg, 72 mg theoretical, 80%) as an oil: 1H NMR (CDCl3, 400 MHz) δ 8.31 and 8.27 (two d, J=8.3, 8.8 Hz, 1H), 8.21 (d, J=8.2 Hz, 1H), 7.61-7.49 (m, 4H), 7.42-7.33 (m, 3H), 6.82-6.69 (m, 1H), 6.21 (m, 0.5H), 6.13 (d, 0.5H), 5.32-5.17 (m, 2H), 5.01 (dt, J=12.2, 7.5 Hz, 0.5H), 4.86 and 4.82 (two m, 1H), 4.41 (m, 0.5H), 3.81 (m, 2H), 3.51 (m, 1H), 3.36-3.21 (m, 1H), 2.12 and 1.92 (two m, 2H), 1.83-1.49 (m, 8H), 1.29 (s, 9H); IR (film) νmax 2940, 1699, 1591, 1407, 1366, 1338, 1158, 1099, 1037 cm−1.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Na].C(O)C.[CH3:9][N:10]1[C:18]2[N:17]=[CH:16][N:15]([CH2:19][C:20](=[N:22]O)[NH2:21])[C:14]=2[C:13](=[O:24])[NH:12][C:11]1=[O:25]>C(OCC)(=O)C>[CH3:9][N:10]1[C:18]2[N:17]=[CH:16][N:15]([CH2:19][C:20]3[N:22]=[C:2]([CH3:1])[O:3][N:21]=3)[C:14]=2[C:13](=[O:24])[NH:12][C:11]1=[O:25]
Reactant: CC[O-]
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(N)=NO
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(Cn2cnc3c2c(=O)[nH]c(=O)n3C)no1
Reaction time: 4 h

Procedure:
A mixture of a sodium ethylate solution prepared from 6.76 g of metallic sodium and 290 ml of anhydrous ethanol, 35 g of 2-(3-methyl-xanthine-7-yl)-acetamidoxime and 43.0 g of ethyl acetate is heated to boiling under stirring for 4 hours. The hot reaction mixture is filtered, the filtrate is evaporated in vacuo and the residue is dissolved in 200 ml of water. The pH of the solution is adjusted to 7 by adding 10% hydrochloric acid, the precipitate is filtered by suction and crystallized twice from water. Thus, 18.0 g of 3,7-dihydro-3-methyl-7-([5-methyl-1,2,4-oxadiazole-3-yl]-methyl)-1H-purine-2,6-dione are obtained, m.p.: 262°-264° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([O:22]C1C=CC=CC=1)=O.[CH2:29]([NH2:32])[CH2:30][NH2:31]>>[NH2:31][CH2:30][CH2:29][NH:32][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:22]
Reactant: NCCN
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NCCN)c(=O)n(C)c1=O

Procedure:
Example 42 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and ethane-1,2-diamine. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.0 Hz, 1 H) 7.62 (d, J=8.0 Hz, 1 H) 7.01 (t, J=8.0 Hz, 1 H) 3.63 (t, J=4.0 Hz, 2 H) 3.27 (s, 3 H) 3.15 (t, J=4.0 Hz, 2 H) 3.11 (s, 3 H). [M+H] calc'd for C15H17FIN5O3, 462; found, 462.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[O:19][CH3:20].[CH3:22][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])(=[O:25])=[O:24]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[O:19][CH3:20])[C:29](=[O:30])[C:28]1[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=[C:26]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:27]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COC(=O)CNc1cnccc1-c1ccc(F)cc1OC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester (example 176, intermediate a) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.CO>[ClH:38].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccc(F)cc1
Yield: 90 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 90% of theory, C28H29FN6O3 (516.6); Rf value: 0.29 (silica gel; dichloromethane/methanol=5:1); EKA mass spectrum: (M+H)+=517; (M+H+Na)++=270.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[CH:10]=[O:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=2[CH:10]=[O:11])=[CH:15][CH:14]=1
Reactant: CC1(C)CCC(Br)=C(C=O)C1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A suspension of 2-bromo-5,5-dimethylcyclohex-1-enecarbaldehyde (250 mg, 1.15 mmol), 4-chlorophenyl boronic acid (270 mg, 1.727 mmol) and Pd(Ph3P)4 (66.5 mg, 0.058 mmol) in dioxane (2.5 mL) was stirred at room temperature in a 5 mL microwave vial under an atmosphere of nitrogen. A solution of potassium carbonate (318 mg, 2.3 mmol) in water (0.3 mL) was added and the solution became clear. The vial was capped and heated to 100° C. for 12 minutes in a microwave. The reaction was cooled to room temperature, diluted with CH2Cl2, filtered through a plug of Celite, and concentrated. The crude residue was purified by flash chromatography on silica gel (0-25% EtOAc/heptanes) to afford 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde as a clear colorless oil (220 mg, 77% yield).
Reaction SMILES: [NH3:1].[OH-].[NH4+].[C:4]([O:7]C1C=CC(C=C)=CC=1)(=[O:6])C.[C:16](=[O:18])=[O:17]>O>[C:4](=[O:6])([O-:17])[O-:7].[NH4+:1].[NH4+:1].[NH3:1].[C:16](=[O:18])=[O:17]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: N
Agent: O=C=O
Agent: [NH4+]
Solvent: O
Product: O=C([O-])[O-]

Procedure:
In carrying out the process of this invention, ammonia gas or ammonium hydroxide is added to the solution of 4-acetoxystyrene polymer and heating is conducted at a temperature of about 50° C. to about 150° C. for a time sufficient to hydrolyze the acetoxy groups to phenol groups. Wet carbon dioxide gas is then introduced into the reaction solution as a sparge below the solution surface. During the introduction of carbon dioxide gas, the temperature is held at about 110° C. to about 180° C. The carbon dioxide reacts with the ammonia to form ammonium carbonate which under the influence of heat decomposes to ammonia, carbon dioxide and water, which then can be distilled or sparged out with nitrogen from the reaction solution.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.Br[CH2:31][C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[CH2:31][N:19]1[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20]1(=[O:27])=[O:28]
Reactant: BrCc1nc2ccccc2s1
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Product: Cc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1Cc1nc3ccccc3s1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 2-bromomethyl-benzothiazole. MS: ESI (negative): 502 (M-H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[NH2:17][C:18]1[N:22]([CH:23]([CH3:25])[CH3:24])[N:21]=[CH:20][CH:19]=1>CN(C=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:23]([N:22]1[C:18]([NH:17][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:19][CH:20]=[N:21]1)([CH3:25])[CH3:24]
Reactant: CC(C)n1nccc1N
Reactant: O=C(O)c1ccccc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nccc1Nc1ccccc1C(=O)O
Yield: 97.3 %

Procedure:
To 2-iodobenzoic acid (54 g, 0.218 mol) in DMF (570 ml) is added K2CO3 (33.4 g, 0.242 mol), then 5-amino-1-isopropylpyrazole (27.3 g, 0.218 mol) and finally copper (II) acetate monohydrate (0.9 g, 4.5 mmol). The reaction mixture is refluxed overnight and then the DMF is evaporated. The residue is poured into ice/water and then the mixture is acidified with acetic acid and concentrated HCl to a pH of about 4. A precipitate forms which is collected by filtration, washed with water and dried in a vacuum oven at 40° C. to afford 52 g (97.2%) of N-(1-isopropylpyrazol-5-yl)anthranilic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[CH:11]=[C:10]3[NH:15][C:16]([C:18]4[C:19](=[O:38])[NH:20][CH:21]=[CH:22][C:23]=4[NH:24][CH:25]([CH3:37])[CH2:26][C:27]4[C:32]([F:33])=[C:31]([F:34])[CH:30]=[C:29]([F:35])[C:28]=4[F:36])=[N:17][C:9]3=[C:8]([CH3:39])[C:7]=2[C:6]1=O>[Zn].C(O)(=O)C>[CH3:41][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:6][C:7]2[C:8]([CH3:39])=[C:9]3[N:17]=[C:16]([C:18]4[C:19](=[O:38])[NH:20][CH:21]=[CH:22][C:23]=4[NH:24][CH:25]([CH3:37])[CH2:26][C:27]4[C:28]([F:36])=[C:29]([F:35])[CH:30]=[C:31]([F:34])[C:32]=4[F:33])[NH:15][C:10]3=[CH:11][C:12]=2[C:13]1=[O:14]
Reactant: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c2c(cc3[nH]c(-c4c(NC(C)Cc5c(F)c(F)cc(F)c5F)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2
Yield: 12.3 %

Procedure:
A mixture of 6-(2-(dimethylamino)ethyl)-4-methyl-2-(2-oxo-4-(1-(2,3,5,6-tetrafluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.25 g, 0.44 mmol), zinc dust (0.29 g, 4.38 mmol), and 7.5 mL of acetic acid was heated at reflux for 13-14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 30 mg of the designed compound as yellowish solid. NMR (500 MHz, DMSO-d6) δ 12.93 (s, 1H, NH), 11.28 (d, J=8.5 Hz, 1H, NH), 11.27 (s, 1H, NH), 7.78-7.74 (m, 1H, ArH), 7.59 (s, 1H, ArH), 7.37 (d, 0.1=7.5 Hz, 1H, ArH), 6.20 (d, J=7.5 Hz, 1H, ArH), 4.46 (s, 2H, CH2), 4.30-4.27 (m, 1H, CH), 3.60-3.57 (m, 2H, CH2), 3.08-3.06 (m, 2H, CH2), 2.48 (m, 2H, CH2), 2.19 (s, 6H, 2×CH3), 1.83 (s, 3H, CH3), 1.36 (d, J=6.5 Hz, 3H, CH3); Mass (ESI, positive) m/z 557.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[CH2:12][CH3:13].C(N(CC)C(C)C)(C)C.[NH2:27][C@@H:28]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]([F:51])([F:50])[F:49])[CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:27][C@@H:28]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]([F:51])([F:49])[F:50])[CH2:29][N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])=[O:16])[S:10][C:11]=1[CH2:12][CH3:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (200 mg, 0.74 mmol), N,N-diisopropylethylamine (0.64 ml, 3.69 mmol) and 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (284 mg, 0.74 mmol)[prepared according to Preparation 6] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (414 mg, 0.886 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (316 mg, 0.526 mmol, 71% yield) as a white foam: LCMS (ES) m/e 601, 603 (M, M+2)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CB(O)O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A solution of 2-chloro-3-nitropyridine (20 g, 0.126 mol), methylboronic acid (8.3 g, 0.139 mol), tetrakis(triphenylphosphine)palladium (0) (14.58 g, 0.013 mol) and potassium carbonate (52.3 g, 0.378 mol) in anhydrous 1,4-dioxane (100 ml) was refluxed for 2 days. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 14 g of the titled compound as brown oil.