Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2([C:11]([CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C1(C)C=CC=CC=1>[C:1]1([S:7][C:8]2([C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[CH2:9][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Reactant: [H][H]
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Temperature: 50 °C
Yield: 89.6 %

Procedure:
460 mg (0.5 mmol) o& tris-triphenylphosphinyl rhodium chloride (=1 mol %, with respect to the reaction components) is added to a 100 ml autoclave. After purging with nitrogen, an air-free solution of 15.7 g (0.05 mol) of 4-chlorophenylethenyl 1-phenylmercapto-cyclopropyl ketone in 40 ml of toluene is added and heated at 50° C. under a hydrogen pressure of 30 bar. The hydrogen pressure is kept between 40 and 50 bar until the absorption of gas is complete. The mixture is subsequently reacted for 1 hour. For working up, the solvent is removed under reduced pressure and the residue which remains is purified on silica gel using dichloromethane as the eluant. 14.2 g (90% of theory) of 4-chlorophenylethyl 1-phenylmercaptocyclopropyl ketone are obtained in the form of an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([C@@H:18]2[CH2:20][C@H:19]2[C:21](=[O:41])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][N:31](C(OCCCC)=O)[CH2:30][CH2:29]3)[CH:23]=2)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([C@@H:18]2[CH2:20][C@H:19]2[C:21](=[O:41])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[CH:23]=2)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCCOC(=O)N1CCN(c2cccc(C(=O)[C@@H]3C[C@H]3c3ccc(OCC(=O)OC(C)(C)C)c(OC)c3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc([C@@H]2C[C@H]2C(=O)c2cccc(N3CCNCC3)c2)ccc1OCC(=O)O

Procedure:
Cyclopropyl adduce 300a was deprotected with TFA/CH2Cl2 in the usual way to provide a pale grey solid. IR(KBr): cm-1 3200-2500(br), 1738, 1680. HR-MS: Calc'd 411.1920, Found 411.1925.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=O)/[CH:27]=[C:28](\O)/[CH2:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:22]=[CH:23][C:24]=1[Cl:25]>C1COCC1.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:26]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:28]([CH2:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[CH:27]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: COc1ccc(NN)cc1
Reactant: O=C(/C=C(\O)COC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(COC3CCCCO3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
4-Methoxyphenylhydrazine hydrochloride (3.88 kg, 21.8 mol) and K2CO3 (3.21 kg, 23.2 mol) were added to a THF/EtOAc solution containing (Z)-1-(3,4-dichlorophenyl)-3-hydroxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-buten-1-one (Example 514) at 0-10° C. The resultant suspension was stirred and allowed to warm to rt overnight (16 h). When HPLC analysis indicated the disappearance of the starting material, the reaction mixture was filtered. The organic reaction filtrate was washed with 1 M aq. citric acid (34.0 L), followed by 10% aq. NaCl (50.0 L) and the resulting product solution was used in the next synthetic step without isolation. HPLC (Method U): Rt=16.22 min. MS (ES+): mass calculated for C22H22Cl2N2O3, 432.10; m/z found, 455.1 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.19 (dd, J=6.8, 2.2 Hz, 2H), 6.96 (dd, J=8.1, 2.1 Hz, 1H), 6.87 (dd, J=2.1, 7 Hz, 2H), 6.58 (s, 1H), 4.86 (d, J=12 Hz, 1H), 4.83-4.81(m, 1H), 4.60 (d, J=12 Hz, 1H), 3.99-3.84 (m, 1H), 3.82 (s, 3H), 3.78-3.74 (m, 1H), 1.91-1.52 (m, 6H). 13C NMR (100 MHz, CDCl3): 159.5, 150.7, 141.8, 133.0, 132.7, 130.9, 130.8, 130.6, 128.1, 127.1, 114.7, 107.7, 98.6, 63.2, 62.6, 60.8, 55.9, 30.9, 25.8, 21.4, 19.7, 14.6.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][CH3:25])[C:16]=2[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][CH3:25])[C:16]=2[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOc1nn(C)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Yield: 82.2 %

Procedure:
4-(tert-Butyl)-N-{[4-(tert-butyl)phenyl]sulfonyl}-N-[3-(2-methoxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Preparation 18)(278 mg) was dissolved in dioxane, 1M sodium hydroxide solution (4 ml) was added and the reaction was stirred at reflux for 0.5 hours. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and 1M hydrochloric acid. The organic phase was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The product was purified on silica (10 g) eluting with a solvent gradient of pentane:ethyl acetate (1:0 to 6.4) to yield the title compound as a white solid (160 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19](=[O:45])[CH:20]([NH:29][C:30]([C:32]1([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:45])[CH:20]([NH:29][C:30]([C:32]1([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:24][CH:23]=1)[CH3:17]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.2 mL of Trifluoromethanesulfonic anhydride (7.1 mmol) is added slowly dropwise to a solution of 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (2.70 g, 6.4 mmol) and 0.7 mL (8.7 mmol) of pyridine in 20 mL of CH2Cl2 at 0° C., and the solution is stirred at 0° C. for 1 hour. The reaction mixture is then partitioned between water and CH2Cl2. The organic phase is separated and washed with saturated aqueous NaHCO3 solution, dried over MgSO4, filtered, and concentrated to yield 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acid ethyl ester as a tan solid; 1H NMR (250 MHz, CDCl3) δ 7.25 (d, 2H), 7.17 (d, 2H), 4.80 (q, 1H), 4.75 (s, 1H), 4.10 (two quartets, 2H), 3.12 (ABX m, 2H), 2.00-2.20 (m, 2H), 1.60-2.00 (m, 6H), 1.40 (s, 9H), 1.18 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N1C=CC=CC=1>O>[C:19]1([NH:18][C:16](=[O:17])[NH:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:25](=[O:27])[CH3:26])[CH:3]=3)=[CH:14][CH:13]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Oc2ccc(NC(=O)Nc3ccccc3)cc2)ncn1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3ccccc3)cc2)ncn1
Yield: 52 %

Procedure:
N-(4-(6-Aminopyrimidin-4-yloxy)phenyl)-N′-phenylurea (60.0 mg, 0.187 mmol) was heated and stirred in an acetic anhydride (1 ml)-pyridine (1 ml) mixed solvent at 60° C. for 18 hours. After returning the reaction solution to room temperature, it was poured into water and the precipitated crystals were filtered out, washed with water and methanol and blow-dried to obtain the title compound (35.0 mg, 0.096 mmol, 52%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCOCC2)cn1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: Cc1ncc(C(CNC(=O)c2c(F)cccc2Cl)N2CCOCC2)cn1

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:8][CH:7]=1.O.[NH2:24][NH2:25]>CO>[NH:24]([C:3](=[O:2])[CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:8][CH:7]=1)[NH2:25]
Reactant: NN
Reactant: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Solvent: CO
Solvent: O
Product: NNC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of benzyl 4-(2-methoxy-2-oxoethoxy)benzoate (1.0 g, 3.33 mmol) in MeOH (15 mL) was added hydrazine hydrate (1.7 mL). After stirring for 1 h at rt, the reaction mixture was filtered. The cake was washed with MeOH (3×4 mL) and dryed under vacuo at 50° C. overnight gave 936 mg of the title compound (94%) as a white solid in 99.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](ON)=[CH:22][CH:21]=1)([O-:19])=[O:18].O>C(O)(=O)C>[CH2:11]([C:10]1[O:15][C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][C:22]=2[C:9]=1[C:8](=[O:16])[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)CC(=O)c1ccc(O)cc1
Reactant: NOc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 115 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
1-(4-hydroxyphenyl)-1,3-heptandione, 697 g, is dissolved in 2532 g acetic acid. O-(4-Nitrophenyl)hydroxylamine, 488 g, is added in portions at ca 20° C. The formed slurry is diluted with 739 g acetic acid and the mixture heated to 115° C. and stirred for 3 h. The dark solution is cooled and 1635 g water is added keeping the temperature at 70-80° C. The temperature is adjusted to 60° C. and seeding crystals are added. When crystallisation has started, the slurry is cooled to 4° C., filtered and washed with 870 g of 67% aqueous acetic acid followed by 580 g water. Drying at reduced pressure at 70° C. gives 736 g 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran. Yield 69%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])[CH2:2]1.C1(S(O[CH2:32][CH2:33][CH2:34][C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][CH:36]=2)(=O)=O)C=CC=CC=1>CN(C)C=O.C(N(CC)CC)C>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([CH2:34][CH2:33][CH2:32][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[CH2:16][C:15]4[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=4)[C:9]3=[O:21])[CH2:2]2)=[CH:36]1
Reactant: O=S(=O)(OCCCc1c[nH]c2ccccc12)c1ccccc1
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCNC1)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCCc3c[nH]c4ccccc34)C1)C2

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-5,6-dimethoxy-1-oxo-1,3-dihydro-isoindole and 3-(3-benzenesulphonyloxy-propyl)-indole in dimethylformamide and triethylamine analogously to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C@@H:15]([NH2:27])[CH:16]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:17][C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1>C(Cl)Cl.Cl>[CH3:12][O:13][C:14](=[O:28])[C@@H:15]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:16]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:22][C:23]([F:25])([F:26])[F:24]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H](N)C(CC(F)(F)F)CC(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
A solution of 4-chlorobenzenesulfonyl chloride (2.66 g, 12.2 mmol, 97% pure) in CH2Cl2 (7 mL) was added to a solution of (2S)-2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)pentanoic acid methyl ester (2.173 g, 8.14 mmol) and pyridine (1.97 mL, 24.4 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at 25° C. for 4 hours, then cooled to 0° C. IN HCl (15 mL) was added followed by dichloromethane (10 mL) and the phases were separated. The organic phase was washed with 1N HCl (15 mL) and brine, dried over Na2SO4, and concentrated to afford 4.1 g of crude mixture as a yellow solid. The solids were recrystallized from heptane (14 mL) to afford 3.035 g of the title product (84% yield). Mass Spectrum (+ESI): 442 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[S:11][C:12]([CH2:15]Cl)=[CH:13][N:14]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:9][C:10]1[S:11][C:12]([CH2:15][NH:1][C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][N:14]=1
Reactant: Cc1cccnc1N
Reactant: ClCc1cnc(Cl)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cccnc1NCc1cnc(Cl)s1
Temperature: 180 °C
Yield: 83.4 %

Procedure:
A mixture of 2-amino-3-methylpyridine (2.16 g, 20 mmol) and 2-chloro-5-(chloromethyl)thiazole (1.68 g, 10 mmol) in N-methylpyrrolidinone (10 mL) was heated at 180° C. in a microwave reactor for 10 min. The cooled reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluted with 10% ethyl acetate in hexanes to provide the title compound as an oil (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([N:17]1[CH2:21][CH2:20][C:19](=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH2:10]([N:17]1[CH2:21][CH2:20][CH:19]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)nc(NC2CCN(Cc3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
A mixture of 2-amino-4,6-dimethylpyridine (2.0 g), 1-benzylpyrrolidin-3-one (2.9 g), acetic acid (2.9 mL), and chloroform (34 mL) was ice-cooled, followed by addition of sodium triacetoxyborohydride (4.9 g), and the mixture was stirred for 18 h while heating slowly to room temperature. To the reaction mixture was added 1 M aqueous sodium hydroxide to make it basic, and then the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=65:35) to obtain 1-benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g). (2) 1-Benzyl-3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (1.3 g) was dissolved in methanol (13 mL), followed by addition of 20% Pd(OH)2/C (0.26 g), and the mixture was stirred at room temperature for 20 h under hydrogen atmosphere. The catalyst was removed by Celite filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol=19:1) to obtain 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.10 g). (3) A mixture solution of 3-(4,6-dimethylpyridin-2-ylamino)pyrrolidine (0.73 g), 4-trifluoromethoxyphenylacetic acid (0.12 g), EDC.HCl (0.12 g), HOBt.H2O (0.12 g), and chloroform (1.0 mL) was stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with chloroform and washed with 1 M aqueous sodium hydroxide and brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=19:1) and then crystallized with hexane and diethyl ether to obtain the title compound (0.14 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23].Br[CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23]
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Reactant: CC(C)(C)C(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(=O)C(C)(C)C)CC3)c2n1
Temperature: 70 °C
Reaction time: 76 h
Yield: 32 %

Procedure:
To a stirred mixture of 5-amino-6-chloro-2-ethyl-N-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridine-8-carboxamide (Example 4, Step 4, 150 mg, 0.446 mmol) and 1-bromo-3,3-dimethylbutan-2-one (72 μL, 0.670 mmol) in N,N-dimethylformamide (4.4 mL) were added sodium iodide (67 mg, 0.670 mmol) and triethylamine (0.156 mL, 1.12 mmol). The reaction mixture was stirred at 70° C. for 76 h. After removal of solvent, the residue was dissolved in ethyl acetate (100 mL), and washed with aqueous sodium bicarbonate (5 mL) and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Flash column chromatography (NH-silica gel) of the residue eluting with hexane/ethyl acetate (9:1 to 1:1) afforded a pale brown solid, which was recrystallized from ethyl acetate to afford 62 mg (32%) of the title compound as off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]4[C:27]([C:28](=[O:44])[C:29]5[C:34]([F:35])=[CH:33][CH:32]=[C:31]([NH:36][S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])[C:30]=5[F:43])=[CH:26][NH:25][C:22]4=[N:23][CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:43][C:30]1[C:29]([C:28]([C:27]2[C:21]3[C:22](=[N:23][CH:24]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:18]=4)[CH:20]=3)[NH:25][CH:26]=2)=[O:44])=[C:34]([F:35])[CH:33]=[CH:32][C:31]=1[NH:36][S:37]([CH2:40][CH2:41][CH3:42])(=[O:38])=[O:39]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cc23)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C5CCNCC5)c4)cc23)c1F
Yield: 16.1 %

Procedure:
In a reaction flask, 4-(4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (P-1001, 42.0 mg, 0.067 mmol) is dissolved in 9.0 mL of dichloromethane and 1.0 mL of trifluoroacetic acid and the reaction is stirred at room temperature for 2 hours. Aqueous saturated sodium bicarbonate is added and the mixture is extracted with ethyl acetate. The aqueous layer is frozen and lyophilized and the residue is suspended in tetrahydrofuran and sonicated. The mixture is filtered twice and the filtrate is concentrated under vacuum. The resulting material is purified by reverse phase HPLC, eluting with acetonitrile/water with 0.1% formic acid, 5-47.5% acetonitrile over 40 minutes. Appropriate fractions are combined and dried by lyophilization to provide the desired compound as a white solid (P-1002, 5.7 mg). MS (ESI) [M+H+]+=529.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-6-(3-(piperazin-1-yl)propoxy)-2-p-tolyl-1H-inden-1-one (30 mg, 1.2 eq, 0.063 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (11 mL, 1.5 eq) and methylsulfonyl chloride (4.0 mL, 1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (17 mg, 74% for 2 steps).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=2[CH2:21][O:22][CH3:23])[CH:7]=1.[CH3:30][O:31][C:32]1[C:37](B(O)O)=[CH:36][CH:35]=[C:34]([O:41][CH3:42])[N:33]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.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>[C:26]([C:4]1[C:5]([O:24][CH3:25])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=2[CH2:21][O:22][CH3:23])[CH:7]=[C:2]([C:37]2[C:32]([O:31][CH3:30])=[N:33][C:34]([O:41][CH3:42])=[CH:35][CH:36]=2)[CH:3]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: COc1ccc(B(O)O)c(OC)n1
Reactant: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(Br)cc(C(C)(C)C)c1OC
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: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(OC)nc2OC)cc(C(C)(C)C)c1OC
Yield: 79.2 %

Procedure:
step 1—A sealed tube containing 315 (117 mg, 0.243 mmol), 2,6-dimethoxy-pyridin-3-yl boronic acid (53 mg, 0.290 mmol, CASRN 221006-70-8), Pd(PPh3)4 (28 mg, 0.024 mmol), Na2CO3 (76 mg, 0.717 mmol) in a mixture of MeOH (3 mL) and DCM (1 mL) was irradiated in a microwave reactor at 115° C. for 30 minutes. The reaction mixture was concentrated, diluted with EtOAc, washed with brine and dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20% to 30% EtOAc) to afford 104 mg (79%) of N-(4-{(E)-2-[3-tert-butyl-5-(2,6-dimethoxy-pyridin-3-yl)-2-methoxy-phenyl]-vinyl}-3-methoxymethyl-phenyl) methanesulfonamide (322) as a colorless oil.