Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([O:10]C)[C:3]=1[CH:12](SCCC(O)=O)[CH2:13]C(C)C.CC1C=C[C@@H](C(C)C)CC=1.[N+](CC)([O-])=O.[C].[S].CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C>C1CCCCC1.[N+](C)([O-])=O>[CH:7]1[CH:2]=[C:3]2[CH:12]=[CH:13][O:10][C:4]2=[CH:5][CH:6]=1
Reactant: COc1cc(O)c(C(CC(C)C)SCCC(=O)O)c(OC)c1
Agent: CC1=CC[C@H](C(C)C)C=C1
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Agent: [C]
Solvent: CC[N+](=O)[O-]
Solvent: C[N+](=O)[O-]
Solvent: C1CCCCC1
Product: c1ccc2occc2c1
Temperature: 55 °C
Yield: 53 %

Procedure:
Under the condition of 25° C. and 1 atmospheric pressure, 5.2 mg of 3-[1-(2-hydroxy-4,6-dimethoxyphenyl)-3-methylbutylthio] propanoic acid and 7.2 mg of α-phellandrene were added to the solvent system consisting of of 5 mL of cyclohexane, 4 mL of nitroethane and 1 mL of nitromethane contained in a pyrex glass container and dissolved. Further, 264 mg of lithium perchloride (acceleration of carbon-sulfur cleavage reaction along with the photo electron transportation of a sulfur atom progressed by light irradiation to methylene blue and acceleration of inner molecular ring forming reaction) and 2.3 mg of methylene blue were added and dissolved completely. Lithium perchloride and methylene blue were completely dissolved in the lower layer (nitroalkane layer). By heating this solution to 55° C., homogenized completely and under the argon gas flow halogen lamp (visible ray lamp, wave length from 400 nm to 700 nm) was irradiated for 4 hours. After irradiation, by cooling the reaction solution to 25° C., phase separation occurred again (separated solution system). In the lower layer, methylene blue, lithium perchloride, disulfide generated along with the progress of the reaction and un-reacted starting materials were refined. And, in the cyclohexane layer, the reacted product is refined. Yield is 53%.
Reaction SMILES: FC(F)(F)C(O)=O.CC(OC([N:15]([C:23]1[NH:24][CH:25]=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([O:39][C:40]3[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[C:42]([Cl:48])[CH:41]=3)[C:33]=2[F:49])=[O:29])[N:27]=1)C(OC(C)(C)C)=O)=O)(C)C>ClCCl>[NH2:15][C:23]1[NH:24][CH:25]=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([O:39][C:40]3[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[C:42]([Cl:48])[CH:41]=3)[C:33]=2[F:49])=[O:29])[N:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c[nH]c(N)n3)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
EDC (0.035 g, 0.183 mmol) and HOBT (0.025 g, 0.183 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.048 g, 0.153 mmol) and 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-imidazole-4-carboxylic acid (0.050 g, 0.153 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. Saturated aqueous sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give crude bis(1,1-dimethylethyl)(4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate as an oil. Trifluoroacetic acid (0.3 mL, 3.89 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (0.066 g, 0.106 mmol) in dichloromethane (2 mL). The mixture was stirred at RT overnight, concentrated and purified by reverse phase HPLC (acetonitrile:water with 0.1% formic acid) to give the title compound (0.017 g, 27%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09-8.18 (m, 2H), 7.81 (s, 1H), 7.51 (s, 1H), 7.44-7.50 (m, 2H), 7.30 (t, 1H), 7.10 (s, 1H), 5.45 (br. s., 2H), 4.44 (d, 2H). MS m/z 420 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].[NH:18]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([N:18]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:19]1)=[O:12])=[O:7]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of the carboxylic acid (2.7 g, 11 mmol) from step A and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (2.0 g, 11 mmol) in DMF (30 mL) cooled in an ice bath was added BOP (5 g, 11 mmol) followed by triethylamine (3 mL, 22 mmol). The mixture was allowed to warm to temperature and stirred overnight. Ethyl acetate (150 mL) was added. The resulting solution was washed with NaHCO3 and brine each three times, dried over MgSO4 and concentrated. Chromatography on silica gel eluting with EtOAc provided 4.4 g (96%) of the desired product. MS (M-Boc+H)+ 316.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([NH:21][C:22](=[O:24])[CH3:23])[N:10]([CH2:25][CH2:26]O)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([NH:21][C:22](=[O:24])[CH3:23])[N:10]([CH2:25][CH2:26][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
To a suspension of N-(3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (269 mg, 0.74 mmol) in CH2Cl2 (9 mL) and triethylamine (155 μl, 1.11 mmol) was added methanesulphonyl chloride (65 μl, 0.81 mmol and the reaction stirred at room temperature for 16 h. The reaction mixture was poured onto ice/water and the organic layer was dried over MgSO4, filtered and evaporated. The crude product was dissolved in THF (10 ml) and morpholine (320 μl, 3.7 mmol) was added. The reaction was heated to 55° C. for 24 h before evaporating the solvent in vacuo. The crude was partitioned between CH2Cl2 and dilute aqueous NaHCO3 and the organic layer was dried over MgSO4, filtered and evaporated. Purification using chromatography (silica gel, gradient 0 to 10% methanol/CH2Cl2) gave N-(3-(4-fluorophenyl)-1-(2-morpholinoethyl)-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide as a white solid (141 mg) which was used as such in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][OH:30])=[N:4][CH:5]=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:11]([Cl:24])[CH:10]=1>CN(C)C=O.[Cu]I>[Cl:24][C:11]1[CH:10]=[C:9]([NH:8][C:7]2[C:2]3[NH:1][C:26]([CH2:27][CH2:28][CH2:29][OH:30])=[CH:25][C:3]=3[N:4]=[CH:5][N:6]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1
Reactant: Nc1c(C#CCCCO)ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: OCCCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
A mixture of 5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}amino)pyrimidin-4-yl]pent-4-yn-1-ol (140 mg) and copper(I) iodide (19 mg) in N,N-dimethylformamide (2.0 mL) was stirred at 80° C. for 5 hrs. After concentration under reduced pressure, and the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate→methanol:ethyl acetate=15:85) to give the title compound (95.2 mg) as pale-brown powder crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:55])[N:26]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:27]([CH2:30][C@@H:31]([O:33][C:34](=[O:48])[C@@H:35]([NH:37]C(OCC3C=CC=CC=3)=O)[CH3:36])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.CO>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:55])[N:26]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[N:27]([CH2:30][C@@H:31]([O:33][C:34](=[O:48])[C@@H:35]([NH2:37])[CH3:36])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)OC(=O)[C@H](C)N)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)—((S)-1-(4-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl-carbamoyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazol-1-yl)propan-2-yl)2-(benzyloxycarbonylamino)propanoate (74.7 mg, 0.1 mmol) in EtOAc (15 mL)/MeOH (10 mL) was added catalytic amount of Pd/C (10%, ˜55% w/w water content, 20 mg) under N2 atmosphere. The suspension was degassed in vacuo and purged with H2. The reaction mixture was stirred at rt for 20 min under H2 balloon. Then the mixture was filtered and the solid was washed with MeOH (5 mL×3). The filtrate was used for the next step immediately.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[BH4-].[Na+].O.[F:15][C:16]([F:21])([F:20])[C:17](O)=O>>[F:15][C:16]([F:21])([F:20])[CH2:17][N:5]([CH2:17][C:16]([F:21])([F:20])[F:15])[C:4]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(N(CC(F)(F)F)CC(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
3-Methyl-4-nitroaniline 3.9 g (25 mmol) was dissolved in 100 mL of trifluoroacetic acid with stirring under N2 at 60° C. Next, sodium borohydride pellets (14 g, 15 eq.) were added portionwise. Ten minutes after the addition of the pellets, the reaction was heated to 90° C. After 12 h at 90° C., the reaction was cooled, added slowly to water, and then filtered. The resulting solid filtrate was washed first with water and then with hexanes and was then dried. This procedure resulted in 6.6 g (82% yield) of a light yellow powder. Data for compound 101: 1H-NMR (CDCl3, 500 MHz) 8.10 (d, 1H, J=9.3 Hz), 6.78 (dd, 1H, J=9.3 and 2.9 Hz), 6.72 (d, 1H, J=2.9 Hz), 4.13 (q, 4H, J=8.4 Hz), 2.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:22][CH2:23][CH3:24])=[C:13]([NH:16][C:17](=[O:21])[CH:18]=[CH:19][CH3:20])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:25]#[N:26].[CH3:31][NH:32][CH3:33]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:22][CH2:23][CH3:24])=[C:13]([NH:16][C:17](=[O:21])[CH2:18][CH:19]([N:32]([CH3:33])[CH3:31])[CH3:20])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:25]#[N:26]
Reactant: CNC
Reactant: CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cc1OCC
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)CC(C)N(C)C

Procedure:
To a stirred solution of N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxy-6-quinolinyl]-2-butenamide (0.212 g, 0.50 mmol) in 25 ml of 2.0 M dimethylamine in tetrahydrofuran was added 0.02 ml of 40% aqueous Triton B. After 66 h at 25° C. the solution was concentrated, and the residue was partitioned between methylene chloride and water. The residue from the organic layer was dissolved in ether, and the solution was passed onto a pad of hydrous magnesium silicate. The pad was washed with ether and ethyl acetate to give the product as an amber foam after evaporation (0.23 g). Mass spectrum (electrospray, m/e) 469.9 (M+H)+, 235.5 (M+2H)+2.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.[CH2:14]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[CH2:15][CH3:16]>>[CH3:12][C:9]1[C:8]2=[C:13]3[C:4](=[CH:5][CH:6]=[C:7]2[S:11][CH:10]=1)[NH:2][C:20]1[CH2:21][CH2:22][N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][C:19]3=1
Reactant: Cc1csc2ccc(NN)cc12
Reactant: CCCN1CCC(=O)CC1
Agent: Cl
Product: CCCN1CCc2[nH]c3ccc4scc(C)c4c3c2C1

Procedure:
The compound is formed analogously to that described in Example 5, from 2.15 g of 5-hydrazino-3-methylbenzothiophene hydrochloride and 1.9 g of 1-propyl-4-piperidone. Melting point: 169° C.
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])=[C:11]([Br:24])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C1COCC1.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])=[C:11]([Br:24])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCN(CCC)C(=O)COc1c(Br)ccc(C(=O)OCC)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C(=O)COc1c(Br)ccc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.24 g (2.70 mmol) of ethyl 2,4-dibromo-3-(N,N-di-n-propylaminocarbonylmethoxy)benzoate were dissolved in 10 ml of THF and 10 ml of H2O, and 0.117 g of NaOH was added. After stirring at RT for 12 h the mixture was admixed with 6 N HCl and extracted with CH2Cl2. Drying of the organic phase over Na2SO4 gave 2,4-dibromo-3-(N,N-di-n-propylaminocarbonylmethoxy)benzoic acid as a viscous colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][C:5]=2[N:4]=1.[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[N:16]([CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][C:5]=2[N:4]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CCc2nc(CCl)[nH]c(=O)c2C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCc2nc(CN=[N+]=[N-])[nH]c(=O)c2C1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 98.5 %

Procedure:
To a solution of 2-(chloromethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one (150 mg, 0.66 mmol, reagent preparation 17) in DMF (3 mL) was added sodium azide (215 mg, 3.3 mmol). The resulting mixture was stirred at rt for 35 min. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with aqueous lithium chloride (10%), dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 2-(azidomethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one (151 mg, 0.65 mmol, 98% yield) as a waxy yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.70 (br s, 1H), 4.41 (s, 2H), 2.66 (t, 2H), 2.33 (s, 2H), 1.58 (t, 3H), 1.00 (s, 6H); MS (EI) for C11H15N5O: 234 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[C:4]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[N:19]=[CH:18]3)[N:3]=1.[Li+].[Cl-].Br[C:28]1[S:29][C:30]2[C:36]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)=[C:35]([C@H:44]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:34]([CH3:55])=[CH:33][C:31]=2[N:32]=1>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.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:51]([O:50][C@@H:44]([C:35]1[C:34]([CH3:55])=[CH:33][C:31]2[N:32]=[C:28]([C:2]3[C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=[C:4]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[N:20]([CH3:24])[N:19]=[CH:18]5)[N:3]=3)[S:29][C:30]=2[C:36]=1[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:45]([O:47][CH2:48][CH3:49])=[O:46])([CH3:52])([CH3:53])[CH3:54]
Reactant: Cn1ncc2cc(-c3ccc(NC(=O)C(F)(F)F)c(Br)n3)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(-c4ccc5c(cnn5C)c4)ccc3NC(=O)C(F)(F)F)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
In a 10 mL reaction vial, N-(2-bromo-6-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)-2,2,2-trifluoroacetamide (24 mg, 0.06 mmol) was dissolved in dioxane (3 mL) at room temperature. The solution was bubbled with argon for 5 min. Then Sn2(n-Bu)6 (0.057 mL, 0.108 mmol), LiCl (30 mg, 0.7 mmol), Pd(PPh3)2Cl2 (6.3 mg, 0.009 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) were added sequentially. The resulting reaction mixture was sealed and heated to 90° C. in oil bath. To this mixture, a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (44 mg, 0.09 mmol) in dioxane (1.5 mmol) was added slowly through syringe pump over 1.5 h. The resulting reaction mixture was stirred at 100° C. in oil bath for 16 h. The reaction was then diluted with EtOAc (20 mL) and filtered to remove solid. The filtrate was concentrated and purified on silica gel column with 0-20% EtOAc/Hex to afford product. LCMS-ESI+: calc'd for: C37H33ClF3N5O4S: 736.2, 737.2, 738.2 (M+H+); found: 736.1, 737.1, 738.1 (M+H+).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:21]([OH:35])[CH2:22][NH:23][C@H:24]([CH3:34])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]=[CH:15]2)C1C=CC=CC=1.O1CCCC1>[Pd].O>[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:21]([OH:35])[CH2:22][NH:23][C@H:24]([CH3:34])[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]=[CH:15]2
Reactant: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A mixture of 3.5 g of 8-benzyloxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride, 240 mg of 10% palladium-charcoal, 100 ml of tetrahydrofuran and 10 ml of water is shaken at room temperature at an atmospheric pressure under a hydrogen atmosphere for 2 hours. Insoluble materials are collected by filtration and washed with an aqueous 10% ethanol solution. The filtrate and washings are combined, and the combined solution is concentrated under reduced pressure to remove solvent. The residue is crystallized with a mixture of ethanol, water and isopropyl ether, and crystalline precipitates are collected by filtration. 2.38 g of 8-hydroxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride are obtained as colorless crystals. Yield: 83%
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([F:32])=[C:9]([F:31])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])[CH:14]=[C:13]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]2=[O:30].[N+:33]([O-])([O-:35])=[O:34].[K+]>>[Cl:6][C:7]1[C:8]([F:32])=[C:9]([F:31])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[CH:22]=[C:21]([N+:33]([O-:35])=[O:34])[C:20]([F:23])=[CH:19][C:18]=1[F:24])[CH:14]=[C:13]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]2=[O:30]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To 15 ml of sulfuric acid was added 2.5 g of ethyl 8-chloro-6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate. With ice cooling, 950 mg of potassium nitrate was added in portions and the solution was stirred overnight at room temperature. The reaction solution was poured into ice water and stirred overnight at room temperature. The precipitate was collected by filtration and washed with water, ethanol and diethyl ether to give 2.4 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH3:28]O>>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[C:7]([CH2:11][O:12][CH3:28])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc([N+](=O)[O-])cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2-n-butyl-4-chloro-5-hydroxymethyl-1-(4-nitrobenzyl)imidazole (10.5 g, 32.4 mmol, 1 eq), conc. sulfuric acid (26 mL) and methanol (300 mL) were mixed and refluxed overnight. The solvent was removed in vacuo and the residue taken up in water (about 300 mL). The pH was adjusted to 5 with 1N NaOH and then this aqueous portion extracted with ethyl acetate (3× 250 mL). The organic layers were collected, dried (MgSO4) and the solvent removed in vacuo to yield 11.57 g of an amber oil. NMR (200 MHz, CDCl3) δ8.22 (d, 2H, J=8 Hz); 7.15 (d, 2H, J=8 Hz); 5.26 (s, 2H); 4.25 (s, 2H); 3.23 (s, 3H); 2.52 (t, 2H, J=7 Hz); 1.64 (t of t, 2H, J=7,7 Hz); 1.28 (t of q, 2H, J=7,7 Hz); 0.81 (t, 3H, J=7 Hz). Anal. Calcd. for C16H20ClN3O3.(H2O)0.5 : C, 55.41; H, 6.10; Cl, 10.22. Found: C, 55.21; H, 6.22; Cl, 9.92.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: OC1CCOCC1
Product: Fc1cc(Br)ccc1OC1CCOCC1

Procedure:
The title compound was prepared from 4-bromo-2-fluorophenol and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (EI): 274 and 276 M+.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[CH3:36][O:37][CH2:38][CH:39]1[CH2:43][CH2:42][CH2:41][NH:40]1.O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:40]5[CH2:41][CH2:42][CH2:43][CH:39]5[CH2:38][O:37][CH3:36])[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:26][CH2:25]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: COCC1CCCN1
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: COCC1CCCN1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)c1ccccc1OC

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-(methoxymethyl)pyrrolidin-1-yl)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and 2-(methoxymethyl)pyrrolidine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.