Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([O:5][CH2:6][C:7]1[C:8]2[C:15](C)=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)=[O:4].[C:19]1(C)C=CC=CC=1>>[F:18][C:2]([F:1])([F:17])[C:3]([O:5][CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][C:13]([CH3:19])=[CH:12][C:9]=2[S:10][CH:11]=1)=[O:4]
Reactant: Cc1ccccc1
Reactant: Cc1cccc2scc(COC(=O)C(F)(F)F)c12
Product: Cc1ccc2c(COC(=O)C(F)(F)F)csc2c1

Procedure:
A mechanical stirrer, a 200-mL dropping funnel and an internal thermometer were attached to a 3000-mL three neck flask. A solution obtained by dissolving the mixture (300.00 g) of the (4-methylbenzo[b]thiophen-3-yl)methyl 2,2,2-trifluoroacetate and the (6-methylbenzo[b]thiophen-3-yl)methyl 2,2,2-trifluoroacetate obtained by the reaction in Example 3 in 1500 mL of toluene was introduced into the flask, which was dipped in a water bath. Into the flask, was introduced 30.00 g of sodium borohydride. Methanol (150 mL) was introduced into the dropping funnel. The dropping was carried out for 60 minutes, and the mixture was intactly stirred at room temperature for 60 minutes. Water (1000 mL) was added to the flask and the resulting mixture was filtered through Celite. An organic layer was separated from an aqueous layer, and the aqueous layer was extracted with 500 mL of toluene. The organic layer was washed with 1000 mL of a saturated brine twice. The organic layers were dried with anhydrous magnesium sulfate, filtered and concentrated to obtain a yellow oil, a mixture (295.12 g) of the (4-methylbenzo[b]thiophen-3-yl)methan-1-ol and the (6-methylbenzo[b]thiophen-3-yl)methan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>C1COCC1>[CH3:32][N:33]([CH3:37])[C:34]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:35]
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2

Procedure:
1-(6-Aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (3 g) was dissolved in THF (50 ml) and triethylamine (2 g) was added. At 5° C. dimethylcarbamoylchloride (1 g) in THF (15 ml) was added dropwise. After completed addition the mixture was refluxed for 1.5 hours. THF was evaporated. Water was added and extraction with dichloromethane (2×50 ml) and work-up as above of the combined organic phases yielded crude title product, which was purified by column chromatography on silica gel (eluted with 4% triethylamine in a 1:1 mixture of ethyl acetate and heptane). The pure title compound 6a crystallized from diethyl ether. Yield: 1.4 g, mp: 141-144° C. 1H NMR (CDCl3): 81.65-2.55 (m, 10H); 2.70 (dd, 1H); 2.70-2.95 (m, 2H); 2.95-3.05 (m, 1H); 3.05 (s, 6H); 3.15 (broad d, 1H); 3.35 (qui, 1H); 6.25 (s, 1H); 6.95-7.25 (m, 6H); 7.45 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O.C(=O)([O-])[O-].[K+].[K+].[C:28]([C:30]1[CH:31]=[CH:32][C:33]([O:40][CH3:41])=[C:34]([S:36](Cl)(=[O:38])=[O:37])[CH:35]=1)#[N:29]>O1CCCC1>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([O:40][CH3:41])=[C:34]([S:36]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=2[NH:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:38])=[O:37])[CH:35]=1)#[N:29]
Reactant: COc1ccc(C#N)cc1S(=O)(=O)Cl
Reactant: CCOC(=O)C(=O)Nc1cc(C(C)C)ccc1CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)Nc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.7 %

Procedure:
To a solution of 0.125 g of ethyl N-[2-(2-aminoethyl)-5-isopropylphenyl]oxalamate in tetrahydrofuran (4 mL)-water (2 mL) were added successively 0.149 g of potassium carbonate and 0.125 g 5-cyano-2-methoxybenzenesulfonyl chloride, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.21 g of ethyl N-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]oxalamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[C:18]1([CH2:24][C:25](O)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:25](=[O:26])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1
Reactant: O=C(O)Cc1ccccc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Solvent: CN1CCCC1=O
Product: O=C(Cc1ccccc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 72.5 %

Procedure:
A mixture of Intermediate 1 (0.028 g) and phenylacetic acid (0.015 g) was treated with 1-methyl-2-pyrrolidinone (0.015 ml) then heated in a 600 W microwave oven, at full power, for 4 min. The crude mixture was purified by chromatography on silica gel (Varian Bond-Elut, 1 g) eluting with cyclohexane/ethyl acetate (4:1 followed by 2:1) to give the title compound as a colourless gum (0.029 g).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH:14]=2)=[CH:9][CH:8]=1.C(O)(=O)C>O.O1CCCC1>[CH2:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][N:20]1[CH2:19][C:15]1[CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:29])=[O:4])=[CH:12][CH:11]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(-c2cccc(CN3Cc4ccccc4C3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2cccc(CN3Cc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
Lithium hydroxide (126 mg) in water (5 mL) was added to a solution of [3′-(1,3-dihydro-iso-indol-2-ylmethyl)-biphenyl-4-yl]-acetic acid methyl ester (0.47 g) in tetrahydrofuran (10 mL) and stirred at room temperature for 72 hour. The reaction mixture was acidified with glacial acetic acid and evaporated. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous was separated and extracted with ethyl acetate (2×20 mL). The combined organics were washed with brine (20 mL), dried (sodium sulfate) and evaporated to give a the subtitle compound as a brown oil (450 mg).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](N3CCCC3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[F:24][C:25]1([F:30])[CH2:29][CH2:28][NH:27][CH2:26]1.Cl>CO>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:27]3[CH2:28][CH2:29][C:25]([F:30])([F:24])[CH2:26]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10]
Reactant: FC1(F)CCNC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: CO
Product: Nc1ccc(N2CCC[C@@H](C(=O)N3CCC(F)(F)C3)C2)nc1N

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 1, but using 3,3-difluoropyrrolidine instead of pyrrolidine for Step 1 and a solution of hydrogen chloride in methanol (1.25 M) for Step 2. MS (ES+) (M+H) 326.1; LCMS retention time: 0.26 minutes (Method M). 1H NMR (DMSO, 400 MHz): δ 1.45-1.62 (m, 2H), 1.65-1.72 (m, 1H), 1.82-1.90 (m, 1H), 2.30-2.45 (m, 2H), 2.76-2.91 (m, 2H), 3.46-3.54 (m, 1H), 3.64-3.78 (m, 2H), 3.84-3.92 (m, 1H), 3.95-4.04 (m, 2H), 4.06-4.13 (m, 1H), 4.13-4.62 (m, 6H), 6.14 (d, 1H), 7.24 (d, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH3:29])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[CH:18]=3)=[CH:11][CH:10]=1)(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:6]=[S:5]1(=[O:7])[NH:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH3:29])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[CH:18]=3)=[CH:11][CH:10]=1
Reactant: CCn1c(-c2ccc(NS(=O)(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2ccc(N3CCNS3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of N-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl]sulfamide (100 mg, 0.241 mmol) in anhydrous DMF (1.25 mL), is added potassium carbonate (71.0 mg, 0.514 mmol). The mixture is stirred at room temperature for 17 h, then diluted with water (7.5 mL). The reaction mixture is extracted with ethyl acetate (3×2 mL) and the extract is washed with water (2×2 mL), dried over MgSO4 and concentrated to give 2-[4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, compound 725, as a white solid (84 mg, 88% yield).
Reaction SMILES: Br.[OH:2][CH2:3][C:4]1[C:5]([C:10]2[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[Si:24]([O:2][CH2:3][C:4]1[C:5]([C:10]2[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: O=[N+]([O-])c1cccc(-c2ncccc2CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Br
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 131.9 %

Procedure:
To a stirred suspension of 3-(3-hydroxymethylpyridin-2-yl)-nitrobenzene hydrobromide (0.3 g) and imidazole (106 mg) in N,N-dimethylformamide (3 ml) was added tert-butyldimethylsilyl chloride (216 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 3-(3-tert-butyldimethylsilyloxymethylpyridin-2-yl)nitrobenzene (438 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].C([O:24][P:25]([CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[C:37]([CH3:39])[C:36]([CH:40]=O)=[C:35]([CH3:42])[CH:34]=1)(=[O:29])[O:26]CC)C>>[CH3:42][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][CH2:30][P:25](=[O:24])([OH:29])[OH:26])[CH:38]=[C:37]([CH3:39])[C:36]=1[C:40]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:18]=[CH:19][C:20]=2[N:21]=1
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Reactant: CCOP(=O)(C/C=C/c1cc(C)c(C=O)c(C)c1)OCC
Product: Cc1cc(CCCP(=O)(O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide and [(E)-3-(4-formyl-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester analogous to Example 6-32. 1H NMR (Methanol-d4, 400 MHz): δ 8.42 (m, 3H), 8.05 (dd, 1H), 7.94 (dd, 2H), 7.79 (dd, 1H), 7.77 (m, 1H), 7.56 (m, 1H), 7.09 (s, 2H), 2.75 (t, 2H), 2.18 (s, 6H), 2.00 (m, 2H), 1.69 (m, 2H). MS (m/z) 543.2 (M+1); Retention time: 1.13 min (Method 10).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH3:11][N:12]1C(=O)O[C:15](=[O:16])[C:14]2=[CH:20][CH:21]=[C:22]([Cl:24])[CH:23]=[C:13]12>>[CH3:11][NH:12][C:13]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:14]=1[C:15]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:16]
Reactant: Oc1n[nH]c2ccccc12
Reactant: Cn1c(=O)oc(=O)c2ccc(Cl)cc21
Product: CNc1cc(Cl)ccc1C(=O)n1nc(O)c2ccccc21
Yield: 53.5 %

Procedure:
1H-Indazol-3-ol was reacted with N-methyl-4-chloroisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 53.5% yield; m.p. 209°-211° C.
Reaction SMILES: [NH2:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[C:7]=3[Br:21])=[CH:4][C:3]=1[F:22].N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30].[OH-].[Na+]>C(Cl)Cl.N1C=CC=CC=1.C(Cl)(=O)C.CCO>[C:29]([NH:1][C:2]1[C:14]([Cl:15])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:20])[C:7]=3[Br:21])=[CH:4][C:3]=1[F:22])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(N)c(Cl)c1C2
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(NC(C)=O)c(Cl)c1C2
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A partial solution of 7-amino-4-bromo-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.940 g, 2.44 mmol) in CH2Cl2 (7.5 mL) was cooled in an ice bath and treated successively with pyridine (0.202 mL, 2.5 mmol) and acetyl chloride (0.178 mL, 2.5 mmol). The reaction mixture was placed under a N2 atmosphere and stirred at room temperature. Additional pyridine (0.01 mL, 0.12 mmol and 0.039 mL, 0.48 mmol) was added after 4 and 5 hours, respectively; and additional acetyl chloride (0.009 mL, 0.12 mmol; 0.035 mL, 0.49 mmol; and 0.175 mL, 2.45 mmol) was added after 4, 5, and 5.5 hours, respectively. After stirring overnight at room temperature, the mixture was treated with EtOH (10 mL) and 5N NaOH (ca. 1 mL), stirred briefly, and then partitioned between EtOAc and water. The organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to provide 7-(acetylamino)-4-bromo-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.02 g, 98%) as an orange solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:15][C@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[C:28]([F:35])[CH:27]=3)[CH:19]=2)([O:16][CH3:17])[C@H:13]([OH:36])[C@@H:12]([OH:37])[C@@H:11]1[OH:38])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O>[CH2:41]([O:38][C@H:11]1[C@H:12]([O:37][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([O:36][CH2:14][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[C:28]([F:35])[CH:27]=3)[CH:19]=2)([O:16][CH3:17])[O:15][C@@H:10]1[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 199.6 %

Procedure:
(2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 4g (7.14 g, 12.5 mmol) was dissolved in 100 mL N,N-dimethyl formamide, followed by addition of 60% NaH (2.5 g, 62.5 mmol) in an ice bath. The reaction mixture was warmed and stirred for 40 minutes at room temperature. The mixture was stirred for 16 hours after benzyl bromide (7.5 mL, 62.5 mmol) was added. Thereafter, the reaction mixture was concentrated under reduced pressure after 20 mL methanol were added. The residue was dissolved in 200 mL ethyl acetate and 50 mL water and partitioned. The aqueous phase was extracted with ethyl acetate (50 mL). The organic extracts were washed with water (50 mL), then saturated sodium chloride (50 mL), combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethylsilane 4h (10.5 g, yellow grease), yield: 99.8%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:37]=[CH:36][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].C1COCC1.CO.[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:37]=[CH:36][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11]
Reactant: COC(=O)CCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCC(=O)O)sc34)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoate (98 mg, 0.19 mmol) in a mixture of solvents THF/MeOH (10 ml/10 ml) was added 2 ml of 1M NaOH (2 mmol) solution. The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. 2M HCl was added until pH=4. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propanoic acid as off-white solid. Yield: 90 mg, 95%.
Reaction SMILES: CC(O[C:6](=[O:20])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].[Cl:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[CH:40][C:41]([NH2:45])=[N:42]2)=[CH:37][CH:36]=1>>[NH2:45][C:41]1[CH:40]=[C:39]([N:46]2[CH2:47][CH2:48][N:49]([C:6]([NH:7][C@@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH3:18])=[O:16])[C:9]3=[O:19])=[O:20])[CH2:50][CH2:51]2)[C:38]2[C:43](=[CH:44][C:35]([Cl:34])=[CH:36][CH:37]=2)[N:42]=1
Reactant: CNC(=O)N1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCCC[C@@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3R)-hexahydro-1-[(methylamino)carbonyl]-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, K2CO3 (sat.) 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. 1H NMR (DMSO-d6): δ 1.2 (m, 1H), 1.6 (m, 1H), 1.71 (m, 2H), 1.84 (m, 2H), 2.73 (s, 3H), 2.98 (m, 4H), 3.31 (m, 2H), 3.58 (m, 4H), 4.57 (m, 1H), 4.64 (t, 1H), 6.22 (s, 1H), 6.45 (br. s, 1H), 6.78 (d, 1H), 7.11 (d, 1H), 7.37 (s, 1H), 7.76 (d, 1H), 8.84 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH3:21].[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][CH2:21][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:10]=2)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(C)=CC(C)(C)N2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Yield: 75.6 %

Procedure:
A mixture of 800 mg of 6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline and 90 mL of acetonitrile was treated with 510 mg of N-bromosuccinimide (NBS) at −20° C. for 2 minutes. The reaction was quenched with water and extracted with EtOAc three times. The organic layers were combined and washed with 10% aqueous sodium thiosulfate (Na2S2O3) solution, water, and brine and then dried over magnesium sulfate. The residue was purified by flash chromatography to yield 776 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline as a solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1I)(=[O:3])[CH3:2].C([Sn](CC[CH2:41][CH3:42])(CCCC)/C=C/[Sn](CCCC)(CCCC)CCCC)CCC.[I:43]I>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:42]=[CH:41]/[I:43])(=[O:3])[CH3:2]
Reactant: CCCC[Sn](/C=C/[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Reactant: CC(=O)OCCOc1ccccc1I
Reactant: II
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)OCCOc1ccccc1/C=C/I
Yield: 42.2 %

Procedure:
Under the conditions of example 2D, 612 mg of 2-(2-iodophenoxy)-ethyl acetate and 3.2 g of (E)-1,2-bis-(tri-n-butylstannyl)-ethylene (50%) is reacted in the presence of 47 mg of tetrakis-(triphenylphosphine)-palladium, treated with 1.02 g of iodine, worked up and chromatographed on silica gel with n-hexane/ethyl acetate=95/5. 280 mg of 2-[2-[(E)-2-iodovinyl]-phenoxy]-ethyl acetate is obtained as an oily crude product, which is used without further purification in the next stage.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:52])[CH:49]([CH3:51])[CH3:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:48](=[O:52])[CH:49]([CH3:51])[CH3:50])[CH2:42][CH2:41]1
Reactant: CC(C)C(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isobutyryl chloride as starting materials in 41% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 9.38 (s, 1H), 9.31 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 4.40 (m, 2H), 3.95 (m, 2H), 3.03 (m, 1H), 2.83 (m, 4H), 2.27 (m, 2H), 2.01 (m, 1H), 1.76 (m, 2H), 1.10 (m, 2H), 1.00 (m, 6H). LCMS for C29H34ClN6O2 (M+H)+: m/z=533.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][C:16]([CH3:29])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][C:16]([CH3:29])([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: CC(CN)(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: CC(CNC(=O)c1cccc(F)c1Cl)(CC1CC1)c1cnc(C(F)(F)F)nc1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound.