Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:12]1[CH2:11][CH2:10][CH:9]([C:4]2[C:3]([C:2]([F:15])([F:1])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13]1)(=[O:26])=[O:25]
Reactant: FC(F)(F)c1cccnc1C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1Cl)N1CCC(c2ncccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of the amine from Step 13BE (100 mg, 0.43 mmol) in CH2Cl2 (2.9 mL) was added 2-chlorobenzenesulfonyl chloride (113 mg, 73 μl, 0.52 mmol) and sat. NaHCO3 (1.4 mL). The biphasic mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (3 mL) and poured into a Phase Separator cartridge. The organic phase was concentrated and purified by flash chromatography (elution with 0-20% EtOAc-hex). Lyophilization then afforded the title compound (121 mg), a white solid, in 70% yield. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.79 (d, J=13.6 Hz, 2H), 2.09-2.23 (m, 2H), 2.82-2.92 (m, 2H), 3.08 (t, J=11.9 Hz, 1H), 4.02 (d, J=12.4 Hz, 2H), 7.21-7.27 (m, 1H), 7.37-7.44 (m, 1H), 7.46-7.52 (m, 1H), 7.53-7.59 (m, 1H), 7.89 (dd, J=8.0, 1.6 Hz, 1H), 8.09 (d, J=6.3 Hz, 1 H), 8.73 (d, J=3.5 Hz, 1H). HRMS: calcd for C17H16ClF3N2O2S+H+, 405.06458. found (ESI-FTMS, [M+H]1+), 405.0652.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](O)=[O:7].C1(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)C=CC=CC=1.N#N>C1COCC1>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([N:27]=[N+:28]=[N-:29])=[O:7]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1C=CC(=O)O
Agent: N#N
Solvent: C1CCOC1
Product: Cc1ccccc1C=CC(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.4 %

Procedure:
To a stirred solution of o-methylcinnamic acid (Intermediate-1) (30 g, 185 mmol) in dry THF (100 mL) was added TEA (51.5 mL, 37 mmol) and diphenylphosphoryl azide (DPPA) (56 g, 204 mmol) slowly under N2 atmosphere and the mixture was stirred at room temperature for 2-3 h. It was quenched with cold water, extracted with EtOAc (3×200 mL), washed with water (2×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. It was recrystallized from MeOH to obtain the desired compound (23 g, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH2:28])[C:19]2=[O:29])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CO>C(O)C>[CH:30]1([C:33]([NH:28][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[C:26](=[O:27])[N:18]([C@@H:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:19]3=[O:29])=[O:34])[CH2:32][CH2:31]1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Solvent: CCO
Solvent: CO
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A stirred mixture of 2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-aminoisoindoline-1,3-dione (1.3 g, 3.1 mmol) and cyclopropane carbonyl chloride (3 mL) was heated to reflux for 45 min. To the cooled mixture was added methanol (10 mL) at 0° C. and the mixture stirred for 30 min. The solvent was removed in vacuo to give an oil. The oil was stirred in ethanol (10 mL) for 2 h to give a suspension. The suspension was filtered and the solid washed with ethanol to give cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}carboxamide as a white solid (1.3 g, 86% yield); mp, 140-141° C.; 1H NMR (CDCl3) δ 0.92-0.99 (m, 2H, 2CHH), 1.11-1.17 (m, 2H, 2CHH), 1.48 (t, J=6.9 Hz, 3H, CH3), 1.61-1.71 (m, 1H, CH), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.12 (q, J=7.1 Hz, 2H, CH2), 4.57 (dd, J=10.4, 14.3 Hz, 1H, CHH), 5.89 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.84-6.88 (m, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.48 (d, J=7.2 Hz, 1H, Ar), 7.65 (t, J=7.4 Hz, 1H, Ar), 8.76 (d, J=8.5 Hz, 1H, Ar), 9.69 (s, 1H, NH); 13C NMR (CDCl3) δ 8.71, 14.62, 16.16, 41.58, 48.59, 54.60, 55.89, 64.50, 111.49, 112.44, 114.83, 117.91, 120.26, 124.99, 129.27, 130.99, 136.02, 137.77, 148.63, 149.76, 167.49, 169.52, 172.79; Anal Calcd for C24H26N2O7S: C, 59.25; H, 5.39; N, 5.76. Found: C, 58.92; H, 5.21; N, 5.56.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]3OC(C)(C)C(C)(C)O3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[N:38]=C(Cl)[S:40][CH:41]=2)=[O:36])[CH3:33])[CH:23]=[C:24]([F:31])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:31][C:24]1[CH:23]=[C:22]([CH:32]([NH:34][C:35]([C:37]2[N:38]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)[S:40][CH:41]=2)=[O:36])[CH3:33])[CH:21]=[C:20]([F:19])[C:25]=1[NH:26][S:27]([CH3:30])(=[O:28])=[O:29]
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC1(C)OC(c2cccc(C3CC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1csc(-c2cccc(C3CC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 37 %

Procedure:
2-(3-Cyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3]dioxolane (63 mg, 0.26 mmol) and 2-chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (55 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (23 mg, 38%) after purification by flash chromatography on silica gel (% EtOAc in hexane=25%˜100%).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:40]=[C:39]([N:41]4[CH2:46][CH2:45][N:44]([CH2:47][C:48]5[CH2:53][CH2:52][C:51]([CH3:55])([CH3:54])[CH2:50][C:49]=5[C:56]5[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=5)[CH2:43][CH2:42]4)[CH:38]=[CH:37][C:13]=3[C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[C:22]([N+:34]([O-:36])=[O:35])[CH:21]=3)(=[O:19])=[O:18])=[O:15])[CH:9]=2)[NH:4][CH:3]=1.C([OH:65])C>Cl>[Cl:62][C:59]1[CH:58]=[CH:57][C:56]([C:49]2[CH2:50][C:51]([CH3:55])([CH3:54])[CH2:52][CH2:53][C:48]=2[CH2:47][N:44]2[CH2:45][CH2:46][N:41]([C:39]3[CH:38]=[CH:37][C:13]([C:14]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[C:22]([N+:34]([O-:36])=[O:35])[CH:21]=4)(=[O:18])=[O:19])=[O:15])=[C:12]([O:11][C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[NH:4][C:3](=[O:65])[CH2:2]5)[CH:40]=3)[CH2:42][CH2:43]2)=[CH:61][CH:60]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]cc(Cl)c5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: CCO
Agent: Cl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5c(c4)CC(=O)N5)c3)CC2)=C(c2ccc(Cl)cc2)C1
Temperature: 25 °C

Procedure:
A solution of EXAMPLE 265E (38 mg) in ethanol (5 mL) and 1 N aqueous HCl (5 mL) was stirred at 85° C. for 7 hours. The mixture was cooled to ambient temperature and concentrated. The residue was purified on reverse-phase HPLC on a C18 column using a water-acetonitrile gradient with ammonium acetate buffer to give the title compound. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.30 (br s, 1H), 10.33 (s, 1H), 8.61 (t, 1H), 8.54 (d, 1H), 7.84 (dd, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.18 (d, 1H), 7.06 (d, 2H), 6.84 (s, 1H), 6.80 (d, 1H), 6.74 (d, 1H), 6.67 (dd, 1H), 6.20 (d, 1H), 3.85 (dd, 2H), 3.43 (s, 2H), 3.27 (t, 2H), 3.10 (br.s, 4H), 2.77 (br.s, 2H), 2.25-2.10 (m, 6H), 1.97 (br.s, 2H), 1.90 (m, 1H), 1.62 (dd, 2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s, 6H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:14]2[CH:26]=[CH:27][O:28][C:13]=2[CH2:12]1)=O)(C)(C)C.[ClH:29].C(OCC)(=O)C>CO>[ClH:24].[ClH:29].[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:14]2[CH:26]=[CH:27][O:28][C:13]=2[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCN1Cc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCN1Cc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(2-[(tert-Butoxycarbonyl)amino]ethyl)-4-(3,4-di-chlorophenyloxy)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine (35 mg) prepared in the step 1 was dissolved in 2 mL of dehydrated methanol, 20 equivalents of a hydrochloric acid/ethyl acetate solution was dropped thereinto and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo to evaporate the solvent and excess hydrochloric acid. To the resulting residue was added 2 mL of diethyl ether, the mixture was stirred and the solid separated out therefrom was filtered and dried to give 8 mg of the objective compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[S:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([Li])(CC)C.C(O[B:38]1[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]1)(C)C>C1COCC1.C1CCCCC1>[CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[S:21][C:22]5[C:27]([B:38]6[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]6)=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3sc3ccccc34)cc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3sc3c(B5OC(C)(C)C(C)(C)O5)cccc34)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Into a solution of 4-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]thiophene (10.637 g, 28.3 mmol) in THF (200 ml), a solution of sec-butyllithium 1.4 M (27.2 ml, 38.1 mmol) in cyclohexane at −78° C. was added slowly. The resulting mixture was stirred at −78° C. for 2 hours before quenching with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.65 ml, 42.4 mmol) added at one portion. The mixture was gradually warmed to room temperature, stirred overnight, and then quenched with methanol. The solvent was evaporated. The residue was purified by column chromatography on silica gel with a heptane/DCM (4/1 to 1/1) eluent and then precipitation in MeOH to yield 2-(6-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]thiophen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.3 g, 65.5% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:25][OH:26])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CC=CC=1.[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1>O1CCOCC1>[CH3:1][C:2]1[NH:3][C:4]([CH2:25][O:26][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(C)NC(COC(=O)CCC(=O)O)=C(C(=O)OCC)C1c1ccccc1Cl
Yield: 87.4 %

Procedure:
A mixed solution of diethyl 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.3798 g), pyridine (0.791 g) and succinic anhydride (0.1501 g) in dioxane (5 ml) was refluxed for 4.5 hours. The resultant solution was concentrated, acidified with dilute hydrochloric acid and extracted with diethyl ether. The extract was washed with dilute hydrochloric acid and water in turn. The diethyl ether extract was back-extracted with an aqueous saturated sodium bicarbonate solution and the aqueous solution was washed with diethyl ether. The aqueous solution was acidified with dilute hydrochloric acid to precipitate crystals. The crystals were collected by filtration, washed with water and then dried to give diethyl 2-methyl-4-(2-chlorophenyl)-6-(3-carboxypropionyl)oxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (419.3 mg), m.p. 130° to 131° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N+:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]>>[C:16]([NH:15][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=2)(=[O:34])=[O:35])[CH:3]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)c1cccc(N)c1
Product: CCOC(=O)CC(NC(=O)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1

Procedure:
Corresponding to Example 3c, 2.60 g of (4b) were reacted with 3-nitrophenylsulphonyl chloride. A solid was obtained (yield: 1.76 g).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH:10]12[O:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2>>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[CH2:11][CH:10]3[O:17][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[N:7]=1
Reactant: C1CC2CNCC1O2
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(N2CC3CCC(C2)O3)n1
Yield: 47 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 3 using cyanuric chloride and 8-oxa-3-azabicyclo[3.2.1]octane. Yield 10 g, 47% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:7]=[CH:6][C:3]=1[C:4]1[NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][C:26]=2[N:31]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Reactant: CN1CCN(CCCOc2ccc(C=O)c(Cl)c2)CC1
Product: CN1CCN(CCCOc2ccc(-c3nc4cc(OC(F)(F)F)ccc4[nH]3)c(Cl)c2)CC1
Yield: 24.8 %

Procedure:
This compound was prepared by the method described in General Procedure 3 using 2-chloro-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (200 mg, 0.68 mmol, 1.0 equiv), 4-trifluoromethoxy-benzene-1,2-diamine (119 mg, 0.62 mmol, 0.92 equiv) and Na2S2O5 (167 mg, 0.88 mmol, 1.3 equiv). Purification by Method 2 afforded 72 mg (23%) of the title compound. MS (electrospray): mass calculated for C22H24ClF3N4O2, 468.15; m/z found, 469.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.82 (d, J=8.7 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.55 (s, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.1 (dd, J=8.6, 2.2 Hz, 1H), 4.17 (t, J=5.7 Hz, 2H), 2.88-2.38 (m, 10H), 2.32 (s, 3H), 2.10-1.95 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C:22]1[N:23]=[C:24]([C:28](=O)[CH3:29])[S:25][C:26]=1[CH3:27].C([BH3-])#N>[Zn]>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:28]([C:24]3[S:25][C:26]([CH3:27])=[C:22]([CH3:21])[N:23]=3)[CH3:29])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CC(=O)c1nc(C)c(C)s1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [BH3-]C#N
Agent: [Zn]
Product: Cc1nc(C(C)Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)sc1C

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 1-(4,5-dimethyl-thiazol-2-yl)-ethanone with zinc-modified cyanoborohydride yielded a mixture of epimers of the title compound as a colorless solid. MS (ESI): m/z=418.4 [M+H]+.
Reaction SMILES: [F:1][C@@H:2]([CH3:27])[CH2:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23]COC)[CH2:19][CH2:18][CH2:17]2)[S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6].Cl.O1CCOCC1>CO>[F:1][C@@H:2]([CH3:27])[CH2:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[OH:23])[CH2:19][CH2:18][CH2:17]2)[S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6]
Reactant: COCOc1cc2c(cc1N(C[C@H](C)F)S(=O)(=O)c1nc(C)cs1)CCC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1csc(S(=O)(=O)N(C[C@H](C)F)c2cc3c(cc2O)CCC3)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 104.1 %

Procedure:
630 mg of N-[(2S)-2-fluoropropyl]-N-[6-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-1,3-thiazole-2-sulfonamide was dissolved in 3.50 mL of methanol, and 1.50 mL of a 4 M hydrogen chloride/dioxane solution was added thereto, followed by stirring at room temperature for 6 hours. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain 586 mg of N-[(2S)-2-fluoropropyl]-N-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,3-thiazole-2-sulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][C:3]=1[O:11][C:12]1[C:17]([F:18])=[C:16]([N:19]([CH3:30])[C:20]2([C:25]([O:27]CC)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15]([F:31])=[C:14]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]3[N:40]([CH3:44])[CH2:41][CH2:42][N:43]=3)[CH:34]=2)[N:13]=1>Cl.C(#N)C.FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][C:3]=1[O:11][C:12]1[C:17]([F:18])=[C:16]([N:19]([CH3:30])[C:20]2([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15]([F:31])=[C:14]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]3[N:40]([CH3:44])[CH2:41][CH2:42][N:43]=3)[CH:34]=2)[N:13]=1
Reactant: CCOC(=O)C1(N(C)c2c(F)c(Oc3cccc(C4=NCCN4C)c3)nc(Oc3cc(C(=N)N)ccc3O)c2F)CCCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1CCN=C1c1cccc(Oc2nc(Oc3cc(C(=N)N)ccc3O)c(F)c(N(C)C3(C(=O)O)CCCC3)c2F)c1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine, trifluoroacet acid salt (0.80 g, 1.2 mmol) in 25 mL of 6 N aqueous HCl was stirred at 60° C. for 1 hour. It was then cooled to ambient temperature, diluted with acetonitrile and trifluoroacetic acid and purified by HPLC on a C18 Dynamax column with 20-80% acetonitrile in water gradient with 0.1% trifluoroacetic acid to afford 4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine, trifluoroacet acid salt as a white solid: NMR (DMSO-d6)/TFA) 10.2 (br s, 1), 9.0 (br s , 2), 8.8 (br s, 2), 7.3-7.6, (m, 6), 7.0 (d, 2), 4.1 (m, 2), 3.9 (m, 2), 3.2 (s, 3), 3.0 (s, 3), 2.9 (s, 3), 2.1 (m, 4), 1.6-1.8 n(m, 4) ppm.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1([CH3:37])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:33]2[C:27]3[O:26][C:25]([CH3:37])([CH3:24])[CH2:29][C:28]=3[CH:30]=[CH:31][CH:32]=2)=[O:35])=[O:10])[N:12]=1
Reactant: CC1(C)Cc2cccc(C(=O)O)c2O1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OC(C)(C)C3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid. LC-MS (basic): tR=0.97 min; [M+H]+=502.4.
Reaction SMILES: [C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=[O:28])=[N:21][CH:22]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([N:4]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([OH:29])=[O:28])=[N:21][CH:22]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)nc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}pyridin-2-yl)oxy]-2,2-dimethylbutanoic acid was prepared from methyl 4-[(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}pyridin-2-yl)oxy]-2,2-dimethylbutanoate. methyl 4-[(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}pyridin-2-yl)oxy]-2,2-dimethylbutanoate (0.005 g, 0.0086 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and methanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature overnight. The mixture was cooled to rt, acidified to pH=5 with 1N HCl to form a white precipitate (0.002 g, 42%). The solid was filtered to give 4-[(5-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}pyridin-2-yl)oxy]-2,2-dimethylbutanoic acid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:12]2[S:28][C:27]([NH2:29])=[N:26][C:13]=2[N:14]=[C:15]([S:17][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[N:16]=1.[NH2:30][C@H:31]([CH2:34][C:35]([F:38])([CH3:37])[CH3:36])[CH2:32][OH:33]>CN1C(=O)CCC1>[NH2:29][C:27]1[S:28][C:12]2[C:11]([NH:30][C@H:31]([CH2:34][C:35]([F:38])([CH3:37])[CH3:36])[CH2:32][OH:33])=[N:16][C:15]([S:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[N:14][C:13]=2[N:26]=1
Reactant: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1
Reactant: CC(C)(F)C[C@@H](N)CO
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Sc1nc(N[C@@H](CO)CC(C)(C)F)c2sc(N)nc2n1)c1ccccc1
Temperature: 120 °C
Reaction time: 22 h
Yield: 34.3 %

Procedure:
DIPEA (0.83 mL, 4.75 mmol) was added to a solution of 7-chloro-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-2-amine (0.49 g, 1.52 mmol) and (2R)-2-amino-4-fluoro-4-methylpentan-1-ol (2 mmol) in NMP (2 mL) and the reaction mixture was stirred at 120° C. for 22 h. HPLC purification provided the title compound (0.22 g, 17% yield).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:13])[N:6]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7](/[CH:13]=[CH:21]/[N:22]([CH3:24])[CH3:23])[N:6]=1
Reactant: Cc1nc(Oc2ccc(F)cc2F)ccc1C#N
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1nc(Oc2ccc(F)cc2F)ccc1C#N

Procedure:
A solution of 6-(2,4-difluorophenoxy)-2-methylnicotinonitrile (3.40 g, 14 mmol) in N,N-dimethylformamide dimethyl acetal (3.7 mL, 28 mmol) and DMF (5.00 mL) was heated at 140° C. in an oil bath for 18 h. The mixture was concentrated under reduced pressure to remove most of the DMF. The residue containing (E)-6-(2,4-difluorophenoxy)-2-(2-(dimethylamino)vinyl)nicotinonitrile (with some DMF) was used in the next step without further purification.