Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N=C=N.C1C=CC2N(O)N=NC=2C=1.[O:14]=[C:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]1[CH:21]=[C:22]([C:32](O)=[O:33])[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=1.[CH3:35][C:36]([CH3:57])([CH3:56])[CH2:37][CH2:38][NH:39][C:40](=[O:55])[C@H:41]([CH3:54])[CH2:42][C@H:43]([OH:53])[C@@H:44]([NH2:52])[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(O)C(N)(CO)CO.[N-]=C=O>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH2:45]([C@H:44]([NH:52][C:32](=[O:33])[C:22]1[CH:23]=[C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:25]=[C:20]([N:16]2[CH2:17][CH2:18][CH2:19][C:15]2=[O:14])[CH:21]=1)[C@@H:43]([OH:53])[CH2:42][C@H:41]([C:40](=[O:55])[NH:39][CH2:38][CH2:37][C:36]([CH3:56])([CH3:35])[CH3:57])[CH3:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NCCC(C)(C)C
Reactant: O=C(O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Polystyrene linked carbodiimide (21 mg, 1.7 mmol/g, 0.036 mmol) was placed in a vial with DCM (1 ml). To this was added HOBT (5 mg, 0.036 mmol) in 1 ml DCM/DMF=4:1, 5-(2-oxo-pyrrolidin-1-yl)-biphenyl-3-carboxylic acid (D11) (10 mg, 0.036 mmol) in 1 ml DCM/DMF=4:1, and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (3,3-dimethylbutyl)amide (D2) (in 1 ml DCM). The mixture was stirred at room temperature overnight. Scavenger resins trisamine (˜100 mg) and isocyanate (˜100 mg) were added and the mixture was stirred for another 1.5 hours. The resins were filtered and the solvent evaporated in vacuo. Column chromatography on silica gel (5% MeOH in DCM) gave E6 (5 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:12][CH:13]([CH3:14])[N:9]3[C:10]=2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]3)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1>CN(C)P(=O)(N(C)C)N(C)C>[S:23]1[CH2:24][CH2:25][N:20]([C:2]2[C:11]3[CH2:12][CH:13]([CH3:14])[N:9]4[C:10]=3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]4)=[CH:4][C:3]=2[F:19])[CH2:21][CH2:22]1
Reactant: CC1Cc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C1CSCCN1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1Cc2c(N3CCSCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 8.9 %

Procedure:
A mixture of 28 g of 9-chloro-8-fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid, 5 g of thiomorpholine and 30 ml of hexamethylphosphoric triamide in a stainless steel autoclave was reacted at 150° C. for 7 hours. After completion of reaction, hexamethylphosphoric triamide was distilled off under reduced pressure and the residue was recrystallized from dimethylformamide to give 1.5 g of 9-thiomorpholino-8-fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid. m.p. not lower than 300° C., slightly yellow rhombic crystals.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]([O:15]CC)=O)[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][NH2:24])[CH3:19].[ClH:27]>CN(C=O)C.C(O)C.CCOCC>[ClH:27].[CH2:18]([N:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][NH:24][C:13](=[O:15])[CH2:12][N:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=[N:10]1)[CH3:19]
Reactant: CCOC(=O)Cn1nccc1-c1ccccc1
Reactant: CCN(CC)CCCN
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCN(CC)CCCNC(=O)Cn1nccc1-c1ccccc1

Procedure:
By procedure analogous to that of example 4, but omitting the DMF solvent, the free base of N-[3-(diethylamino)propyl]-5-phenyl-1H-pyrazole-1-acetamide hydrochloride was prepared from 1.0g 4.3 mmol) of ethyl 5-phenyl-1H-pyrazole-1-acetate and 3-(diethylamino)propanamine. The hydrochloride salt was prepared by dissolving the free base (an oil) in ethanol, adding a solution of hydrogen chloride in anhydrous ether, and recrystallizing the resulting solid from ethanol-ether. Upon drying, the white, crystalline product collapsed to a brownish, amorphous solid.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:22])([F:21])[C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:8]2=[N:9][CH:10]=1.CC[C:25]([O-:27])=[O:26]>O.C(O)C>[F:22][C:4]([F:21])([F:3])[C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:25]([OH:27])=[O:26])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:8]2=[N:9][CH:10]=1
Reactant: CCC(=O)[O-]
Reactant: FC(F)(F)c1cnc2c(ccn2Cc2ccncc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1ccncc1
Reaction time: 4 h
Yield: 73.4 %

Procedure:
A solution of 0.39 g (6.87 mmol) of potassium hydroxide in 2 mL of water is added to a solution, in 30 mL of ethanol, of 0.8 g (2.29 mmol) of 5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate, obtained in Stage 9.1. The mixture is stirred for four hours under reflux. After this time the reaction mixture is concentrated at reduced pressure, and is then taken up in 40 mL of water. The reaction mixture is acidified to pH 5 by successive additions of concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and then dried at reduced pressure. In this way we isolate 0.54 g of the expected product, in the form of a white powder, which is used as it is in the next stage.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[H-].[Na+].[CH2:35]([SH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:4]3=[N:5][CH:6]=[CH:7][C:2]([S:42][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[C:3]3[CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: SCc1ccccc1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(SCc4ccccc4)ccnc32)CC1
Yield: 8 %

Procedure:
A mixture of the title compound from Example 250 (0.25 grams), sodium hydride (0.11 grams, 60% in mineral oil), benzyl mercaptan (0.13 mL) and anhydrous DMF (15 mL) was stirred while being irradiated with a 200 W lamp for 10 days. Isolation and purification as in Example 257 provided the title compound (0.02 grams, 8%, MH+ 552).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:21]([O:30]CC3C=CC(OC)=CC=3)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:16][C:15]=2[CH3:40])=[CH:6][CH:5]=1.ClC(Cl)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O>ClCCl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:40])=[CH:16][C:17]([C:21]([OH:30])([C:22]([F:23])([F:24])[F:25])[C:26]([F:28])([F:29])[F:27])=[CH:18][C:19]=2[CH3:20])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCCOc2c(C)cc(C(OCc3ccc(OC)cc3)(C(F)(F)F)C(F)(F)F)cc2C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCOc2c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc2C)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To 105 mg (0.2 mmol) of 4-(2-{2,6-dimethyl-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-benzoic acid methyl ester in 5 mL of dichloroethane 61 mg (0.3 mmol) of DDQ and a drop of water were added. The reaction mixture was stirred at 70° C. overnight, cooled to room temperature and was diluted with dichloromethane and EtOAc, dried (Na2SO4) and evaporated. Column chromatography on ISOLUTE Flash NH2 with EtOAc/n-heptane 1:1 gave 21 mg (25%) of 4-{2-[2,6-dimethyl-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-benzoic acid methyl ester as a light yellow solid, MS: 465 (M−H)−.
Reaction SMILES: [OH-:1].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][Br:10]>C(#N)C>[Br:10][C:9]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:1][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Br:10])[CH:4]=1
Reactant: [OH-]
Reactant: BrCCCCCCBr
Agent: [Na+]
Solvent: CC#N
Product: Brc1cccc(OCCCCCCOc2cccc(Br)c2)c1
Yield: 273.2 %

Procedure:
A suspension of 37 (7.13 g, 41.22 mmol) and NaOH (1.52 g, 38.10 mmol) in acetonitrile (309 ml) was stirred under reflux for 1 h before 1,6-dibromohexane (2.51 g, 10.31 mmol) was added in one portion. The reaction mixture was stirred under reflux for another 22 hours before the precipitates were removed by filtration. The filtrate was quenched with water and extracted with methylene chloride. The extracts were combined, washed with water and dried over MgSO4. Upon evaporating off the solvent, the crude product was purified by gradient column chromatography on silica gel with hexanes/ethyl acetate 19:1 to 9:1 (v/v) as the eluent to yield 38 (4.02 g, 91%) as a white powder. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 7.15-7.11 (m, 2H), 7.07-7.04 (m, 4H), 6.83-6.80 (m, 2H), 3.96-3.93 (t, 4H), 1.82-1.79 (t, 4H), 1.55-1.51 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][N:24]=2)[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl.Cl.[NH2:37][CH2:38][CH2:39][C:40]([O:42]C)=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.O.O.[OH-].[Li+]>C1COCC1.O>[CH:1]1([CH2:4][CH:5]([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:28])=[CH:25][N:24]=2)[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CCN
Reactant: COC(=O)c1ccc(NC(CC2CC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCNC(=O)c1ccc(NC(CC2CC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
To a solution of methyl 6-(2-cyclopropyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)ethylamino)nicotinate (60 mg, 0.14 mmol) in THF (3.0 mL) was added 170 μL of a 2M aqueous solution of sodium hydroxide (0.34 mL). The reaction solution was stirred at 60° C. overnight. The mixture was acidified to pH 3 by addition of 1N aqueous HCl. The mixture was extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with water, brine, then dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in DMF (3 mL). methyl 3-aminopropionate hydrochloride (32.7 mg, 0.234 mmol) was added. HATU (134 mg, 0.351 mmol) was added. The mixture was stirred for 15 mins. Diisopropylethylamine (60.5 mg, 0.468 mmol) was added. The resulting mixture was stirred 2 h at room temperature. The reaction mixture was poured into water and the phases separated. The aqueous layer was extracted with ethyl acetate (3 mL×3). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. This solid was dissolved in THF (1.5 mL). A solution of lithium hydroxide dihydrate (14.7 mg, 0.351 mmol) in water (1.5 mL) was added. The reaction mixture was stirred for 1 h at room temperature. The mixture was acidified to pH 3 by addition of 1N aqueous HCl. The mixture was extracted with ethyl acetate (5 mL*3), and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to dryness. Purification by HPLC (column: Kromasil Eternity-5-C18 150×30 mm×5 μm; modifier 0.0685% TFA; gradient 10 to 80% acetonitrile in water) gave 3-(6-(2-cyclopropyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)ethylamino)nicotinamido)propanoic acid (7.00 mg) as a colorless solid. 1H NMR (400 MHz, Methanol-d4) δ 8.32 (s, 1H), 7.72-7.67 (m, 3H), 7.60 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.43 (d, J=8.8 Hz, 1H), 4.90-5.00 (m, 1H), 3.40-3.48 (m, 2H), 2.40-2.45 (m, 2H), 1.83-1.74 (m, 1H), 1.65-1.55 (m, 1H), 0.75-0.60 (m, 1H), 0.45-0.28 (m, 2H), 0.18-0.00 (m, 2H). MS (M+1)=498.3.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:22])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:28](B(O)O)=[C:27]([CH3:32])[O:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>COCCOC.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(Cl)(Cl)Cl.CN(C=O)C>[CH3:23][C:24]1[C:28]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([OH:22])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:8](=[O:13])[N:9]3[CH3:12])=[CH:4][CH:3]=2)=[C:27]([CH3:32])[O:26][N:25]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)CNC(=O)c1c(O)c2ccc(-c3c(C)noc3C)cc2n(C)c1=O
Temperature: 75 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (400 mg, 1084 μmol), 3,5-dimethylisoxazol-4-ylboronic acid (305 mg, 2167 μmol) and Pd(PPh3)4 (125 mg, 108 μmol) in 8 ml 1,2-dimethoxyethane (or DMF) and 1.6 ml 2M aqueous Na2CO3 was heated to 75° C. and stirred for 12 hours. The mixture was cooled to 24° C., treated with 1M aqueous HCl and CHCl3, after which solids precipitated. The organic layer was separated and the solids were collected by filtration, and washed with MeOH.
Reaction SMILES: C([O-])(=O)/C=C/C([O-])=O.[NH2:9][C:10]1[C:38]([Cl:39])=[CH:37][C:13]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]4[CH2:36][CH2:35][CH2:34][O:33]4)=[O:31])[CH2:26][CH2:25]3)[CH2:19][CH2:18]2)=[O:15])=[C:12]([O:40][CH3:41])[CH:11]=1>>[NH2:9][C:10]1[C:38]([Cl:39])=[CH:37][C:13]([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([C@H:32]4[CH2:36][CH2:35][CH2:34][O:33]4)=[O:31])[CH2:28][CH2:29]3)[CH2:21][CH2:22]2)=[O:15])=[C:12]([O:40][CH3:41])[CH:11]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)[C@@H]3CCCO3)CC2)CC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)[C@H]3CCCO3)CC2)CC1

Procedure:
fumarate (an enantiomer of Compound 2)
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH:5]1([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([S:18]([C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23])(=[O:20])=[O:19])=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:7][CH2:6]1>ClCCl>[CH:5]1([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16]([S:18]([C:21]([CH3:26])([CH3:25])[C:22]([N:2]([CH3:3])[CH3:1])=[O:23])(=[O:20])=[O:19])=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:7][CH2:6]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)Cl)ccc2n1CC1CC1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)C(C)(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 1.5 h
Yield: 47 %

Procedure:
To a solution of dimethylamine (2 mol/L tetrahydrofurane solution, 0.950 mL, 1.90 mmol) in dichloromethane (3 mL) was added 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoyl chloride hydrochloride (Step A, 175 mg, 0.380 mmol) in dichloromethane (2 mL) at room temperature. After stirring at the same temperature for 1.5 h, the mixture was diluted with dichloromethane. The whole was washed with saturated sodium hydrogencarbonate aqueous solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (ODS, gradient elution with acetonitrile/0.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (75 mg, 47%) as an amorphous.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.C1(C[C@H]2NC(=O)N([C@H](C3NC(C4C=CC(I)=CC=4F)=C(C)N=3)[C@H](C3C=CC=CC=3)C)C2=O)CC1.N[C@H](C1C=CC(OC(CO)CO)=CC=1)C([NH:63][C@H:64]([C:73]1[NH:74][C:75]([C:79]2[CH:84]=[CH:83][C:82]([I:85])=[CH:81][C:80]=2[F:86])=[C:76]([Cl:78])[N:77]=1)[C@H:65]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH3:66])=O>>[Cl:78][C:76]1[N:77]=[C:73]([C@@H:64]([N:63]2[C:10](=[O:12])[C@@H:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH:20]([CH2:21][OH:22])[CH2:23][OH:24])=[CH:17][CH:18]=3)[NH:8][C:6]2=[O:7])[C@H:65]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH3:66])[NH:74][C:75]=1[C:79]1[CH:84]=[CH:83][C:82]([I:85])=[CH:81][C:80]=1[F:86]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC(CO)CO)cc1)c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC(CO)CO)cc1
Agent: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Product: C[C@@H](c1ccccc1)[C@@H](c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1)N1C(=O)N[C@H](c2ccc(OC(CO)CO)cc2)C1=O

Procedure:
Prepared by the same method as described in example 1 except that (i) (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetic acid (prepared as described in steps 57-V, 57-W and 57-X) was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 75-G and (ii) cyclization of (R)-2-amino-N-{(1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetamide in step 75-H was performed as described in step 34-H. HR-MS: calcd for C30H27ClFlN4O5 [M+H+] 705.0772. Found 705.0772.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([OH:14])[CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1.C(OCC)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@H](Oc1ccc(Cl)cc1O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H](Oc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 90 °C

Procedure:
To a solution of (2S)-2-(4-chloro-2-hydroxyphenoxy)-propanoic acid (0.216 g) and 1-fluoro-4-nitro-benzene (0.127 g) in NMP (3 ml) was added potassium carbonate (0.276 g) and the reaction heated at 90° C. for 2 h. After cooling to RT, water and diethylether were added. The aqueous layer was separated and extracted again with diethylether. The aqueous layer was isolated, acidified to pH 2 and extracted with diethylether. This later extract was dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30-50% ethylactate/isohexane+1% AcOH, yield 0.2 g
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[I:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][NH2:20]>C(O)C>[CH3:19][NH:20][CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[I:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCC[C@@H](Oc1ccccc1I)c1ccccc1
Reactant: CN
Solvent: CCO
Product: CNCC[C@@H](Oc1ccccc1I)c1ccccc1
Yield: 97.4 %

Procedure:
Compound 1-A (2.68 g, 7.2 mmole) was dissolved in an aqueous solution of ethanol (80 ml) and methylamine (160 ml), and heated to reflux for 30 h. After cooling, the solution was extracted with chloroform (100 ml, twice), and an organic layer was decanted. The organic layer was dried over anhydrous sodium sulfate, and dried by evaporation under vacuum, to obtain the product as oil (2.75 g, 97.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:31])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:30])[CH2:20]CC2C=CC(OC)=CC=2)[CH2:14][CH2:13]1.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH2:35]Cl.COC1C=CC(CCl)=CC=1>>[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH2:35][CH2:20][CH:19]([OH:30])[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:31])[CH2:13][CH2:14]1
Reactant: COc1ccc(CCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1
Reactant: Fc1cccc(F)c1CCl
Agent: COc1ccc(CCl)cc1
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CCc2c(F)cccc2F)CC1

Procedure:
Compound 17 was prepared in a manner similar to that of compound 16 substituting 2,6-difluorobenzyl chloride for 4-methoxybenzyl chloride. (M+1)=432.2
Reaction SMILES: [F:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[CH2:12][NH2:13])=[CH:7][N:6]=1)([F:4])[CH3:3].[Cl:22][C:23]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].C1COCC1.CCN(C(C)C)C(C)C>>[Cl:22][C:23]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:13][CH2:12][CH:11]([C:8]1[CH:7]=[N:6][C:5]([C:2]([F:1])([F:4])[CH3:3])=[N:10][CH:9]=1)[N:14]1[CH2:19][CH2:18][C:17]([F:20])([F:21])[CH2:16][CH2:15]1)=[O:26]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: CC(F)(F)c1ncc(C(CN)N2CCC(F)(F)CC2)cn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)c1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(F)(F)CC2)cn1
Yield: 47.4 %

Procedure:
2-(2-(1,1-Difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethanamine (34 mg, 0.044 mmol, 40% pure) and 2,3-dichlorobenzoyl chloride (65 mg, 0.31 mmol), was dissolved in anhydrous THF (4400 mg, 5 ml, 61.0 mmol), DIPEA (111 mg, 0.15 ml, 0,859 mmol) was added and stirred over night. The solution was concentrated and purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) followed by HPLC, to afford 2,3-dichloro-N-(2-(2-(1,1-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1-yl)ethyl)benzamide (10 mg, 47% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[N+:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24])([O-:13])=[O:12]>>[OH:24][C:17]1([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[O:9][CH3:10])[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)[NH:19][C:18]1=[O:23]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Reactant: COc1ccc(C)cc1Br
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc([N+](=O)[O-])cc21
Yield: 95.8 %

Procedure:
With 10.0 g of 2-bromo-4-methyl anisole and 6.00 g of 5-nitroisatin as starting materials, 9.40 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:30])([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][C:16]([F:15])([F:30])[CH:17]([F:18])[F:19])=[CH:22][CH:23]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CC(N)c1ccc(OC(F)(F)C(F)F)cc1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1ccc(OC(F)(F)C(F)F)cc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 75 %

Procedure:
The title compound is prepared in 75% yield (165 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine hydrochloride (155 mg, 0.57 mmol, Amine-29, single enantiomer) in a similar manner to Intermediate-2.