Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([C:15]1([CH2:25][CH:26]([CH3:28])[CH3:27])[C:19]2[CH2:20][NH:21][CH2:22][CH2:23][C:18]=2[C:17](=[O:24])[O:16]1)[CH:12]([CH3:14])[CH3:13]>ClCCl>[CH2:1]([NH:8][C:9]([N:21]1[CH2:22][CH2:23][C:18]2[C:17](=[O:24])[O:16][C:15]([CH2:25][CH:26]([CH3:28])[CH3:27])([CH2:11][CH:12]([CH3:14])[CH3:13])[C:19]=2[CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)CC1(CC(C)C)OC(=O)C2=C1CNCC2
Solvent: ClCCl
Product: CC(C)CC1(CC(C)C)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Benzyl isocyanate (0.04 g, 0.3 mmol) was added to a solution of 3,3-diisobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (0.075 g, 0.30 mmol prepared in a manner analogous to compound 2) in dichloromethane (10 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.042 g, 36%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.75-0.93 (m, 12H), 1.39-1.60 (m, 4H), 1.77-1.92 (m, 2H), 2.28-2.45 (m, 2H), 3.36-3.55 (m, 2H), 4.03-4.18 (m, 2H), 4.34-4.48 (m, 2H), 4.85-5.03 (m, 1H), 7.17-7.39 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.ClC1C(=O)N(C)C=C([N+]([O-])=O)C=1>>[NH2:10][C:4]1[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cn1cc(Cl)cc([N+](=O)[O-])c1=O
Agent: Cn1cc([N+](=O)[O-])cc(Cl)c1=O
Product: Cn1cc(Cl)cc(N)c1=O

Procedure:
The title compound was prepared in analogy to the procedure for Step E5, but 5-chloro-1-methyl-3-nitro-1H-pyridin-2-one (Step L5) was used instead of 3-chloro-1-methyl-5-nitro-1H-pyridin-2-one to afford the title compound as a gray solid. ESI-MS: tR=0.54 min, [M+H]+ 159/161 (LC-MS 1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:27]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:36])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3sccc32)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCc3sccc3C2c2ccc(C(F)(F)F)cc2)cc1
Yield: 101.3 %

Procedure:
4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.35 mmol) was dissolved in dichloromethane (0.5 mL) and triethylamine (0.5 mL) was added. To this solution p-anisoyl chloride (60 mg, 0.35 mmol) dissolved in dichloromethane (0.5 ml) was added in one portion. The mixture was filtered and evaporated to afford 148 mg (100%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:14]=1)[O:5][CH2:6][C:7]([O:9]CC)=[O:8]>[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:14]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)COc1cc(F)cc(C2(OC)CCOCC2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Product: COC1(c2cc(F)cc(OCC(=O)O)c2)CCOCC1
Yield: 91.5 %

Procedure:
A solution of ethyl 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyacetate (Step 1) (0.3 g, 1 mmol) in ethanolic LiOH (1M, 1.5 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with 5% citric acid (10 mL) and extracted with ether (2×15 mL). The ether extracts were combined and washed with water (2×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 0.26 g (95%) of 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyacetic acid as a colorless viscous liquid: 1H NMR (CDCl3/300 MHz) δ 6.78 (d, 2H, J=10.5 Hz), 6.50 (d, 1H, J=10.5 Hz), 4.68 (s, 2H), 3.82 (m, 4H), 2.99 (s, 3H), 1.92 (m, 4H); FABMS m/z=284 (M+H). HRMS calcd for C14H17FO5 283.0982, found 283.0993.
Reaction SMILES: [CH2:1](Br)[CH3:2].[Mg].[CH2:5]([N:12]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC.C1C=CC=CC=1>[CH2:5]([N:12]1[CH2:13][CH2:14][C:15]([CH2:1][CH3:2])([O:16][CH2:17][CH2:18][OH:19])[CH2:20][CH2:21]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCBr
Reactant: c1ccc(CN2CCC3(CC2)OCCO3)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC1(OCCO)CCN(Cc2ccccc2)CC1
Yield: 71.5 %

Procedure:
87.5 g of ethyl bromide dissolved in 100 ml of ether were added dropwise over 30 minutes to 19.2 g of magnesium in 100 ml of ether refluxing in a flask and the resulting solution was cooled. A solution of 46.6 g of 8-benzyl-1,4-dioxa-8-aza-spiro [4,5] decane in 250 ml of benzene was added thereto and the ether was evaporated off. 250 ml. of benzene were added and the mixture was refluxed for 20 hours. The mixture was cooled and hydrolyzed with a saturated aqueous ammonium chloride solution. The benzene phase was decanted and the aqueous phase was extracted with methylene chloride. The methylene chloride phase was washed with water until neutral, dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was distilled to obtain 37.6 g of 2-(1-benzyl-4-ethyl-4-piperidyloxy)-ethanol as a colorless oil boiling at 152°-156° C at 0.5 mm Hg which was used as is for the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[CH3:12][O:13][C:14]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COc1c(N)cccc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: COc1c(F)cccc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-methoxy-3-fluoroaniline to yield 2-[(2-methoxy-3-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: N[C@@H]([CH2:7][C:8]1[CH:13]=CC(OCCCC)=C[CH:9]=1)C(NC)=O.N[C@@H](CC1C=CC(OCCCC)=CC=1)C(OC)=O.[CH2:37]([O:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][C@H:49]([NH:54][C:55]([C@@H:57](/[CH:67]=[CH:68]/[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][C:75]([F:84])([F:83])[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[C@@:58]([OH:66])([CH2:62][CH2:63][O:64][CH3:65])[C:59]([OH:61])=[O:60])=[O:56])[C:50](=[O:53])[NH:51][CH3:52])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]>>[CH2:37]([O:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:48][C@H:49]([NH:54][C:55]([C@@H:57](/[CH:67]=[CH:68]/[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][C:75]([F:83])([F:84])[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[C@@:58]([OH:66])([CH2:62][CH2:63][O:64][CH3:65])[C:59]([O:61][C:8]([CH3:13])([CH3:9])[CH3:7])=[O:60])=[O:56])[C:50](=[O:53])[NH:51][CH3:52])=[CH:46][CH:47]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOc1ccc(C[C@H](N)C(=O)NC)cc1
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)NC)[C@@](O)(CCOC)C(=O)O
Agent: CCCCOc1ccc(C[C@H](N)C(=O)OC)cc1
Product: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)NC)[C@@](O)(CCOC)C(=O)OC(C)(C)C

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (PSI (LC/MS positive mode) ink 739 (M+H); Rt 2.72 min.) was synthesized using (S)-2-amino-3-(4-butoxy-phenyl)-N-methyl-propionamide and the conditions at 50° C. for 2.5 days instead of methyl (S)-2-amino-3-(4-butoxy-phenyl)-propionate and the conditions in Step B-7′. (E)-(2S,3S)-3-[(S)-2-(4-Butoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (No. 5514404) was synthesized under conditions similar to those in the following Step B-8′.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:14])[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:15]1([CH3:33])[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=[C:23]([C:29]([F:32])([F:31])[F:30])[N:22]=2)[CH:16]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:14])[C:11]([NH:28][CH2:27][C:26]2[C:21]([C:17]3[CH:16]=[C:15]([CH3:33])[CH:20]=[CH:19][CH:18]=3)=[N:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(C#N)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.6 %

Procedure:
To a stirred solution of 2-(3-chloro-4-cyanophenyl)propanoic acid (95 mg, 0.454 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (121 mg, 0.454 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (131 mg, 0.681 mmol), 1-hydroxybenzotriazole (92 mg, 0.681 mmol) and triethylamine (0.16 mL, 1.135 mmol). The reaction mixture was stirred for 15 h at room temperature. The residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(3-chloro-4-cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (182 mg) was obtained as 88% yield.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH2:32]>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:35]([Cl:36])=[C:28]([Cl:27])[CH:29]=1)([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: CCOC(OCC)P(=O)(C[C@@H](O)CCl)OCC
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(OCC)P(=O)(C[C@@H](O)CNCc1ccc(Cl)c(Cl)c1)OCC

Procedure:
A solution of 7.2 g of 3-chloro-2(R)-hydroxy-propyl-(diethoxymethyl)phosphinic acid ethyl ester, 3.6 g of Hunig base and 6.5 g of 3,4-dichlorobenzylamine in 20 ml of anhydrous ethanol is heated at reflux for 4 days. The mixture is concentrated to dryness by evaporation and the residue is partitioned between dichloromethane and water. The organic phase is separated off, dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel, yielding 3-[N-(3,4-dichlorobenzyl)amino]-2(S)-hydroxy-propyl(diethoxymethyl)phosphinic acid ethyl ester in the form of a yellowish oil; 1H-NMR (CD3Cl3 /D2O): δ=7.43 (1H, m, phenyl), 7.39 (1H, m, phenyl), 7.15 (1H, m, phenyl), 4.70 (1H, s, CHP), 4.20 (3H, m, CHO+CH2OP), 3.83 (2H, m, CH2OC), 3.70 (4H, m, CH2 phenyl+CH2OC), 2.65 (2H, m, CH2N), 2.20-1.71 (2H, m, CH2P), 1.40-1.26 (6H, m, 3xCH3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1.O.[Cl-].[Na+].O>[C:11]([O:10][C:9]([NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:2][CH2:3]1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CN1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl piperidine-4-ylmethyl-carbamate (2.00 g) is dissolved in tetrahydrofuran (10 ml), and thereto is added triethylamine (1.69 ml), followed by an addition dropwise of ethyl bromoacetate (1.24 mL) in water bath and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure, and to the resulting crystalline residue is added isopropylether and the mixture is filtered to give ethyl [4-(tert-butoxy-carbonylamino-methyl)-piperidin-1-yl]-acetate (1.87 g). MS (m/z): 301 [M+H]+
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[OH2:31].Cl>N1C=CC=CC=1>[S:26]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][O:19][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:27])=[O:31])([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: O
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
To a solution of 1.48 g (5.24 mmol) of hexaethylene glycol in dry pyridine (30 ml) was added 2.19 g (11.5 mmol) of p-toluenesulfonyl chloride in an atmosphere of argon, and the mixture was allowed to react at room temperature for 15 hours. To the solution was added water followed by addition of conc. hydrochloric acid to adjust the pH to 4, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-methanol (100:1) yielded 2.85 g (4.82 mmol) of O,O'-ditosyl-3,6,9,12,15-pentaoxaheptadecane-1,17-diol.
Reaction SMILES: [CH:1]1([N:4]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])[C:5]([C:7]2[C@@H:8]([CH2:28][O:29][CH2:30][O:31][CH3:32])[N:9]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][CH2:11][C:12]=2OS(C(F)(F)F)(=O)=O)=[O:6])[CH2:3][CH2:2]1.[OH:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH:1]1([N:4]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])[C:5]([C:7]2[C@@H:8]([CH2:28][O:29][CH2:30][O:31][CH3:32])[N:9]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:10][CH2:11][C:12]=2[C:46]2[CH:47]=[CH:48][C:43]([OH:42])=[CH:44][CH:45]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: COCOC[C@@H]1C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)=C(OS(=O)(=O)C(F)(F)F)CCN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COCOC[C@@H]1C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)=C(c2ccc(O)cc2)CCN1C(=O)OC(C)(C)C

Procedure:
Into a 20 mL microwave vial was added 4G (1.33 g, 2.05 mmol) and 4-hydroxyphenyl boronic acid (425 mg, 3.1 mmol, 1.5 eq). Dioxane (12 mL) and saturated sodium bicarbonate (4 mL) was added and the mixture was degassed by bubbling N2 through the solution for 10 minutes. After degassing, 1,1′-bis-diphenyl phosphinoferrocene dichloro palladium (II) (Pd(dppf)Cl2) (150 mg, 206 μmol, 0.05 eq) was added and the reaction was capped. The reaction was microwaved at 150° C. for 20 minutes, and the reaction was transferred to a round bottom and the solvent was removed under vacuum. Saturated ammonium chloride (25 mL) and ethyl acetate (25 mL) was added to the residue and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2×25 mL). The organic layers were combined and dried over sodium sulfate. Solution was filtered and the solvent was removed under vacuum. The residue was purified by column chromatography (40% ethyl acetate/hexanes) to give 4H (948 mg, 37%). ESI-MS:m/z 591.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([O-:31])=[O:26].[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1Cl
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1-carboxylate (Intermediate 2, 2.9 g, 7.7 mmol) in 15 ml DCM was added 15 ml TFA. The solution was stirred at room temperature for 30 minutes before evaporating off solvent under reduced pressure. Solid dark product was obtained in quantitative yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Zn](CC)CC.[CH3:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([CH3:25])[CH:19]=[CH:18][C:17]=1I>CN1C(=O)N(C)CCC1.C1COCC1.Cl[Cu]>[CH3:25][C:20]1[C:21]([N+:22]([O-:24])=[O:23])=[C:16]([CH3:15])[CH:17]=[CH:18][C:19]=1[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1ccc(I)c(C)c1[N+](=O)[O-]
Reactant: CCOC(=O)CCCBr
Agent: Cl[Cu]
Agent: CC[Zn]CC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1ccc(C)c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
A three-necked flask equipped with a thermometer, a gas inlet, and a magnetic stirring bar was charged under argon with MnBr2 (320 mg, 1.5 mmol) in DMPU (25 ml). CuCl (85 mg, 1 mmol), ethyl 4-bromobutyrate (5.85 g, 30 mmol) and Et2Zn (2.7 ml, 27 mmol) were successively added. The reaction mixture turned dark red and was stirred for 4 h at 25° C. After cooling to −30° C., a solution of Cl2Pd(dppf) (0.925 g, 10 mmol) and 2,4-dimethyl-3-nitroiodobenzene (6.93 g, 25 mmol) in anhydrous THF (25 ml) was slowly added. The reaction mixture was warmed to 25° C. for 30 min and was then stirred at 65° C. overnight and quenched with an aqueous 2N HCl solution (100 ml). This mixture was extracted with CH2Cl2 three times, and the organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the crude residue obtained was purified by Biotage (hexane/EtOAc, 0-30%, 40 min) to give 4.5 g of yellow oily products (68%). 1H-NMR δ (CDCl3, 300 MHz): 7.13 (d, J=7.8 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 2.64 (t, J=7.8 Hz, 2H), 2.34 (t, J=7.8 Hz, 2H), 2.23 (s, 3H), 2.20 (s, 3H), 1.86 (m, J=7.8 Hz, 2H), 1.24 (t, J=7.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[CH:3]1[O:8][CH:7]([C:9](Cl)([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([C:17](OCC)=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.O.[NH2:25][NH2:26]>C(O)C>[Cl:10][C:9]([Cl:11])=[C:7]1[C:6]2[CH:13]=[C:14]([C:17]([NH:25][NH2:26])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4][CH:3]([C:2]([Cl:23])([Cl:22])[Cl:1])[O:8]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2c(c1)C(=C(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
A mixture of ethyl 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylate (6.4 g.), 100% hydrazine hydrate (3 ml.) and ethanol (30 ml.) was warmed on the steam bath for 30 hours. The reaction mixture was cooled, and then evaporated to dryness under reduced pressure. The oily residue was triturated with petroleum ether (b.p. 60°-80° C.) and the solid product thus obtained was crystallised from ethanol, to give 4-dichloromethylene-2-trichloromethylbenzo[1,3]dioxin-6-carbohydrazide, m.p. 182°-183° C.
Reaction SMILES: [C:1](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[F:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:58]=1[NH:57][C:56](=[O:59])[N:55]([CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:54]2.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:58]=1[NH:57][C:56](=[O:59])[N:55]([CH:60]1[CH2:65][CH2:64][N:63]([C:1]([O:2][C@H:3]([CH2:18][C:19]3[CH:27]=[C:26]([CH3:28])[C:25]4[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[N:24]=4)[CH:20]=3)[C:4](=[O:17])[N:5]3[CH2:6][CH2:7][CH:8]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[CH2:9][CH2:10]3)=[O:37])[CH2:62][CH2:61]1)[CH2:54]2
Reactant: O=C1Nc2c(F)cccc2CN1C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 8-fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (84.2 mg, 1.50 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (79 μL, 0.45 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 78 mg (45%) as a colorless film. Mass spec.: 776.58 (MH)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:27])=O>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1[nH]c(=O)c2cc(OCCCC)ccc2c1O
Reactant: O=P(Br)(Br)Br
Product: CCCCOC(=O)c1nc(Br)c2cc(OCCCC)ccc2c1O

Procedure:
0.150 g of 7-butoxy-4-hydroxy-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester, were allowed to react with phosphorous oxybromide analogously to Example D-46 b) to give 0.105 g of an off-white solid: Proton NMR (200 MHz, chloroform-d): δ 11.82 (s, 1H), 8.68 (s, 1H), 8.26 (d, 1H), 7.35 (dd, 1H), 7.19 (d, 1H), 4.49 (t, J=7 Hz, 2H), 4.12 (t, J=7 Hz, 2H), 1.95-1.75 (m, 4H), 1.70-1.40 (m, 4H), 1.05-0.95 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:12])=[C:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1F.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11](=[O:12])[N:13]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:25]4[C:20]([C:5]=3[C:4]=2[CH:3]=1)=[CH:21][CH:22]=[CH:23][CH:24]=4
Reactant: CN(C)CCCNC(=O)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1c(=O)c2[nH]c3ccc(Cl)cc3c2c2ccccc21

Procedure:
Under the same conditions as described above, reaction of 17.7 g. of 5-chloro-N-(3-dimethylaminopropyl)-3-(2-fluorophenyl)-indole-2-carboxamide with 6.8 g. sodium hydride suspension in 250 ml. of dimethylformamide yielded after recrystallization from boiling dimethylformamide 13.5 g. (81 percent) of 10-chloro-5-(3-dimethylaminopropyl)-7H-indolo[2,3-c]quinolin-6(5H)-one, having a melting point of 286°-288°.