Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[C:17]([C:19]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:20]=2[C:21]([O:23]C)=[O:22])[CH:16]=[CH:15][N:14]=1)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[C:17]([C:19]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:20]=2[C:21]([OH:23])=[O:22])[CH:16]=[CH:15][N:14]=1)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(NC(=O)OC)cc2C(=O)OC)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(NC(=O)OC)cc2C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.8 %

Procedure:
To the solution of 24C (0.304 g, 0.667 mmol) in MeOH (6.67 ml) was added 1N NaOH (2.67 ml, 2.67 mmol). The reaction was stirred at rt. After 48 h, the reaction was neutralized with 1N HCl and then it was concentrated to remove the MeOH. The residue was extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over Na2SO4, filtered, and concentrated to afford 24D (0.291 g, 99%) as a yellow solid. MS (ESI) m/z: 442.2 (M+H)+.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:27]([Cl:28])=[CH:26][C:10]3[NH:11][C:12]([O:14][C:15]4[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=4)[C:20]([O:22]C)=[O:21])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O.O>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:27]([Cl:28])=[CH:26][C:10]3[NH:11][C:12]([O:14][C:15]4[CH:16]=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=4)[C:20]([OH:22])=[O:21])=[N:13][C:9]=3[CH:8]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 70 °C

Procedure:
To a solution of methyl 5-[(5-biphenyl-4-yl-6-chloro-1H-benzimidazol-2-yl)oxy]-2-methylbenzoate (11 g, 23.46 mmol) in MeOH/water (1:1) (250 mL) was added NaOH (5 M in water) (23.46 mL, 117 mmol). The mixture was heated at 70° C. for 1 h. The mixture was then cooled, diluted with water and acidified with 2 M aqueous HCl. The precipitated white solid was filtered and dried to afford the title compound as a white powder. LCMS: calculated for C27H19ClN2O3 454.90, observed m/e 455.5 (M+H)+ (Rt 2.27/4 min). 1H NMR (500 MHz, CD3OD): δ 7.98-7.35 (m, 14H), 2.62 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:26])[N:15]4[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]1COCC1>[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:26])[N:15]4[CH2:24][CH2:23][C:22](=[CH2:27])[CH2:21][CH2:20][C:16]4=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Reactant: C1CCOC1
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Product: C=C1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1

Procedure:
A solution of 3-((3-fluorophenyl)ethynyl)-6,7,9,10-tetrahydroazepino[2,1-b]-quinazoline-8,12-dione (0.1 g, 0.29 mmol, 1 equiv) and Tebbe Reagent in THF (5 mL) was stirred at rt for half an hour. Then the reaction mixture was quenched with NaOH aqueous and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 345 (M+H+); 1H NMR (300 MHz, CDCl3) δ 8.26-8.23 (d, J=8.19 Hz, 1H), 7.78 (s, 1H) 7.58-7.55 (dd, J=8.24, 1.52 Hz, 1H), 7.38-7.32 (m, 2H), 7.28-7.26 (m, 1H), 7.13-7.06 (m, 1H), 4.88-4.86 (d, J=7.50 Hz, 2H), 4.42-4.39 (m, 2H), 3.14-3.10 (m, 2H), 2.61-2.51 (m, 4H). mGluR5 PAM EC50: +++++. Fold shift at 10 μM: ++.
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:20]([O-])([OH:22])=[O:21].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH:1]1([S:7][C:8]2[CH:13]=[C:12]([N+:20]([O-:22])=[O:21])[CH:11]=[CH:10][C:9]=2[NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: CCS(=O)(=O)Nc1ccccc1SC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1SC1CCCCC1
Temperature: 0 °C
Yield: 63.8 %

Procedure:
In 20 ml of acetic acid was dissolved 1.5 g of N-[2-(cyclohexylthio)phenyl]ethanesulfonamide, 0.33 g of 61% nitric acid was added dropwise on heating at 80°-85° C., and then the mixture was stirred on heating for 1 hour. The reaction solution was poured into ice water, neutralized with a saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The dichloromethane layer was washed, in turn, with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude crystals were purified by silica gel column chromatography (eluent: n-hexane:dichloromethane:ethyl acetate=20:10:1) and recrystallized from carbon tetrachloride-n-hexane to give 1.1 g of N-(2-cyclohexylthio-4-nitrophenyl)ethanesulfonamide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:54]1[CH:59]=[C:58](B(O)O)[CH:57]=[N:56][CH:55]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)=[C:15]([C:58]4[CH:59]=[N:54][CH:55]=[N:56][CH:57]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1cncnc1
Reactant: O=C1C(Br)=C(c2ccc(Cl)cc2)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cncnc2)=C(c2ccc(Cl)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 71 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-chlorophenyl)-1H-inden-1-one obtained in Step 6 of Example 28 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (acetone/hexanes=2:3) to obtain the title compound (71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].CCCC(O[C@@]1(C(COC(C)=O)=O)[C@@]2(C)C[C@H](O)[C@]3(F)[C@]4(C)C(=CC(C=C4)=O)[C@@H](F)C[C@H]3[C@@H]2CC1)=O.[N+:48]([O-])([OH:50])=[O:49]>S(=O)(=O)(O)O>[N+:48]([C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6])([O-:50])=[O:49]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: CCCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 77.4 %

Procedure:
Into 100 ml of 96% sulfuric acid was placed 3,4-difluorobenzoic acid (11.95 g, 0.0756 mol). The solution was stirred at room temperature until the DFBA was dissolved, and then cooled to 0° C. Nitric acid (7.9 g of 90% fuming) was added dropwise to the cooled mixture. After addition, the solution was warmed to room temperature and stirred until completion of the reaction. After pouring on to 500 g of ice water, the solids were filtered and washed with water. After drying, 11.88 g of 2-nitro-4,5-difluorobenzoic acid was isolated. The material was identified by GCMS and 19F NMR analysis. An additional 2.41 g of product was obtained by extraction of the acid washes and removal of the solvent.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([Cl:15])[C:9]=2[NH:8][CH:7]=1)=[O:5])C.O[Li].O>C1COCC1.O>[Cl:15][C:14]1[C:9]2[NH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c[nH]c2c(Cl)ncnc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 7-chloro-4,6-diazaindole 5 (4.0 g, 18 mmol) in THF (90 mL) was added a solution of LiOH.H2O (2.5 g, 59 mmol) in H2O (60 mL). The reaction mixture was stirred at 100° C. for 1 d, concentrated and recrystallized from H2O (20 mL). The crystals were collected by filtration, washed with H2O and dried under high vacuum. The off-white solid was shown to be the lithium salt of the diazaindole carboxylic acid 6 (quantitative), which was used without further purification. 1H NMR: (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.14 (s, 1H); LC/MS: (ES+) m/z (M+H)+=198; HPLC Rt=0.47 min., column G.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH:24]([CH2:28][O:29][CH3:30])[O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[N:48]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]([CH2:46][C:47]#[N:48])[C:25](=[O:27])[CH:24]([CH2:28][O:29][CH3:30])[O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(CC#N)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A solution of tert-butyl(1-(4-(3-(methoxymethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (60 mg, 0.116 mmol) in DMF (2 ml) was added potassium carbonate (48 mg) and 2-bromoacetonitrile (41.9 mg, 0.349 mmol). The reaction mixture was stirred at room temperature for 16 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give crude product which was purified by column (biotage, 25 g) eluted with ethyl acetate and cyclohexane to afford product (35 mg). 1H NMR (500 MHz, CDCl3): 7.20-7.33 (m, 10H), 5.10 (t, 1H), 4.97 (s, 1H), 4.82 (dd, 2H), 4.03 (dd, 2H), 3.36 (s, 3H), 2.44-2.50 (m, 4H), 2.06 (m, 1H), 1.80 (m, 1H), 1.24-1.36 (br, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(NC3C=CC(OC4C=CN=C(NCCCCN(C)C)N=4)=CC=3C)=O)=[CH:10][C:9]=2[C:40]([F:43])([F:42])[F:41])[CH:5]=[CH:6][CH:7]=1.[Br:44]C1C=C(B(O)O)C=CC=1>CCCCCC.CCOC(C)=O>[Br:44][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[C:40]([F:43])([F:42])[F:41])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Oc2ccnc(NCCCCN(C)C)n2)ccc1NC(=O)Nc1ccc(-c2cccc(Cl)c2)c(C(F)(F)F)c1
Reactant: OB(O)c1cccc(Br)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cccc(Br)c2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Ex. 3 (Step 3.1) for 1-(3′-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butylamino)-pyrimidin-4-yloxy]-2-methyl-phenyl}-urea but using 3-bromophenylboronic acid (Aldrich). The title compound: MS: 315.9 [M-1]−; HPLC DtRet=4.9; Rf=0.16 (Hexane/EtOAc, 4:1).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:39]([NH2:45])[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1>>[O:44]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:39][NH:45][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])=[CH:38][CH:37]=1
Reactant: NCc1ccco1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: O=C(NCc1ccco1)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 86.9 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 53 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 610 [M+H]+.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[Cl:14][CH2:15][C:16](=[O:37])[C@@H:17]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(O)(C)C>[Cl:14][CH2:15][C@@H:16]([OH:37])[C@@H:17]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N[C@@H](CSc1ccccc1)C(=O)CCl)OCc1ccccc1
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)O
Product: O=C(N[C@@H](CSc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
To a suspension of 2.15 g aluminium isopropoxide in 35 ml of isopropanol were added 3.64 g of benzyl [3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate and the mixture was stirred at 50° C./ 400 mbar for 4 hours. The mixture was cooled to 0° C., the pH was adjusted to 1 by adding hydrochloric acid and the isopropanol was evaporated. The residue was partitioned between water and dichloromethane and the organic layer was evaporated. The residue was chromatographed on silica to give 2.9 g (80%) of pure benzyl (1R, 2S)-[3-chloro-2-hydroxy -1-(phenylthiomethyl)-propyl]-carbamate. IR (KBr): 3360 br (NH, OH), 1690 s (C=O), 1540 s (amide II).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]#[C:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:28])[C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=4)=[CH:13][O:14]3)=[CH:9][CH:8]=2)[CH2:2]1.FC(F)(F)C(O)=O.[CH3:36][O:37][CH2:38][CH2:39][C:40](O)=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.O.C(#N)C>[CH3:36][O:37][CH2:38][CH2:39][C:40]([N:1]1[CH2:4][CH:3]([C:5]#[C:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:28])[C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=4)=[CH:13][O:14]3)=[CH:9][CH:8]=2)[CH2:2]1)=[O:41]
Reactant: CS(=O)(=O)Nc1ccc(-c2coc3cc(C#CC4CNC4)ccc3c2=O)cc1
Reactant: COCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COCCC(=O)N1CC(C#Cc2ccc3c(=O)c(-c4ccc(NS(C)(=O)=O)cc4)coc3c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(4-(7-(azetidin-3-ylethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide.trifluoroacetic acid salt (80 mgs, 0.16 mmol), 3-methoxypropanoic acid (0.03 mL, 0.24 mmol), HATU (91 mgs, 0.24 mmol), in N,N-dimethylformamide (1 mL) was added diisopropylethylamine (0.1 mL, 0.41 mmol) and the mixture stirred at room temperature for 16 hours. The reaction mixture was diluted with water and acetonitrile, and the resulting solid was filtered and washed with acetonitrile and ether and dried to give N-(4-(7-((1-(3-methoxypropanoyl)azetidin-3-yl)ethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)[CH3:3].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[C:21](=[N:27]O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[CH:6][CH:7]=3)=[N:27][C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Reactant: CN(C)Cc1ccc(CN)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccc(CN(C)C)cc2)[nH]c1-c1ccc(Cl)cc1
Yield: 39.7 %

Procedure:
4-(Dimethylaminomethyl)phenylmethylamine (11.7 g) and ethyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate (15.1 g) were dissolved in pyridine (220 ml) and the solution was refluxed under heating for 12 hr. The solvent was concentrated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give the objective ethyl 5-(4-chlorophenyl)-2-[4-(dimethylaminomethyl)phenyl]imidazole-4-carboxylate (9.0 g), melting point 175-176° C.
Reaction SMILES: Cl.[C:2]1([C:8]2([NH2:11])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:21]([O:25][C:26]([N:28]([CH3:58])[C:29]([C:31]1[C:32]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)=[N:33][N:34]2[C:39]([F:40])=[CH:38][C:37]([C:41]3[CH:42]=[C:43]([CH:47]=[CH:48][C:49]=3[CH3:50])[C:44](O)=[O:45])=[CH:36][C:35]=12)=[O:30])=[O:27])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:40][C:39]1[N:34]2[N:33]=[C:32]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)[C:31]([C:29]([N:28]([CH3:58])[C:26](=[O:27])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:30])=[C:35]2[CH:36]=[C:37]([C:41]2[CH:42]=[C:43]([C:44](=[O:45])[NH:11][C:8]3([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:10][CH2:9]3)[CH:47]=[CH:48][C:49]=2[CH3:50])[CH:38]=1
Reactant: NC1(c2ccccc2)CC1
Reactant: Cc1ccc(C(=O)O)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2(c3ccccc3)CC2)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
To a solution containing 1-phenylcyclopropanamine hydrochloride (0.010 g, 0.061 mmol), diisopropylethylamine (0.086 mL, 0.49 mmol), 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.032 g, 0.061 mmol) and DMF (0.41 mL) was added HATU (0.047 g, 0.12 mmol) in one portion. The solution was maintained at room temperature for 1 h and concentrated. The resultant residue was purified on silica gel (30-100% ethyl acetate/hexanes, 45 min. gradient) to afford tert-butyl 7-fluoro-2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a residue. LCMS retention time: 2.938 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 637 (MH+).
Reaction SMILES: [CH3:1][N:2]([S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][N:16]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)COCc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3ncc(COCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A mixture of ethyl [(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methoxy]acetate (0.08 g), 1N aqueous sodium hydroxide solution (0.30 mL), tetrahydrofuran (4 mL) and methanol (4 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.04 g, yield 45%) as pale-yellow crystals. melting point 197-198° C.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6](=[NH:28])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1.Br[CH2:30][C:31](=O)[CH2:32][CH3:33]>>[CH2:32]([C:31]1[NH:5][C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([CH3:24])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[CH:26][CH:27]=3)=[N:11][CH:12]=2)=[N:28][CH:30]=1)[CH3:33]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(=N)N)cn2)cc1
Reactant: CCC(=O)CBr
Solvent: CC(=O)O
Product: CCc1cnc(-c2ccc(-c3ccc(OCC(C)(C)C(=O)OC)cc3)nc2)[nH]1
Yield: 101.3 %

Procedure:
By using methyl 3-(4-{5-[amino (imino)methyl]pyridin-2-yl) phenoxy)-2,2-dimethylpropanoate acetate (400 mg), and 1-bromobutan-2-one (234 mg), the procedure was carried out in the same manner as in Example 35(2) to obtain methyl 3-[4-[5-[5-ethyl-1H-imidazol-2-yl)-2-pyridyl]phenoxy]-2,2-dimethylpropanoate (397 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([O:23]CC)=[O:22])[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:30].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([OH:23])=[O:22])[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:30]
Reactant: CCCCC(C(=O)OCC)N1CCC(CNC(=O)c2cc(Cl)c(N)nc2OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(C(=O)O)N1CCC(CNC(=O)c2cc(Cl)c(N)nc2OC)CC1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of ethyl 2-[4-({[(6-amino-5-chloro-2-methoxypyridin-3-yl)carbonyl]amino}methyl)piperidin-1-yl]hexanoate (4.3 g, 9.75 mmol) in methanol (50 ml) was added 2N aqueous sodium hydroxide (9.8 ml, 19.5 mmol) and the mixture was refluxed for 12 h. After cooled to room temperature, concentrated in vacuo. The resultant solid was treated with 2N aqueous hydrochloric acid (19.5 ml) to afford white solid, which was collected by filtration, washed with water (50 ml) gave 3.8 g (94%) of the title compound as white powder.