Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(N2C3C=C(F)C(F)=CC=3N=C2C2C(OC)=NC(OC)=CC=2)C(O)=O)CCCCC1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]([CH:44]([CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:45](O)=[O:46])[C:42]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:41]=3[N:40]=2)=[CH:35][CH:34]=1.Cl.N[C@H]1CC[C@H](O)CC1.C([O:71][C:72]([C@H:74]1[CH2:79][CH2:78][C@H:77]([NH2:80])[CH2:76][CH2:75]1)=[O:73])C>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]([CH:44]([CH:48]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]3)[C:45]([NH:80][C@H:77]3[CH2:76][CH2:75][C@H:74]([C:72]([OH:71])=[O:73])[CH2:79][CH2:78]3)=[O:46])[C:42]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:41]=3[N:40]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Agent: Cl
Agent: N[C@H]1CC[C@H](O)CC1
Product: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to example 8 replacing cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acid with [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 22, intermediate c) and trans-4-amino-cyclohexanol hydrochloride with trans-4-amino-cyclohexanecarboxylic acid ethyl ester ([CAS RN 1678-68-8]), followed by subsequent ester hydrolysis in analogy to example 10. Purification was conducted with chiral preparative HPLC (Chiralpak-AD column) eluting with a gradient of ethanol (+0.5% formic acid)/heptane. MS (ES+): 530 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[C:6]([CH3:20])=[CH:5]2.C(Cl)(Cl)Cl.[OH:25]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:25])=[CH:16][CH:17]=1)[C:6]([CH3:20])=[CH:5]2
Reactant: OO
Reactant: CSc1ccc(CC2C(C)=Cc3cc(F)ccc32)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC1=Cc2cc(F)ccc2C1Cc1ccc(S(C)=O)cc1
Reaction time: 1 h

Procedure:
500 mg. (1.755 mm) of 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene is dissolved in 5 ml. of chloroform. To this solution is added 30% hydrogen peroxide (equivalent to 2.645 mm). The reaction mixture is aged for 1 hour at room temperature followed by the addition of 5 ml. of glacial acetic acid and aged for an additional hour. The reaction mixture is then diluted with 25 ml. of 1:1 benzene-ether and extracted with 6 × 25 ml. of 3% aqueous sodium chloride. The solution is then dried over sodium sulfate and evaporated in vacuo to yield an oil. Recrystallization from ice-cold isopropanol gives 5-fluoro-2-methyl-1-(p-methylsulfinylbenzyl)-indene.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH3:17])[C:7]=1[CH2:8]O>C1C=CC=CC=1.O>[CH3:5][C:6]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH3:17])[C:7]=1[CH2:8][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(C)C)cc(C)c1CO
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C(C)C)cc(C)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Thionyl chloride (0.63 g, 5.28 mmol) was added to a solution of 2,6-dimethyl-4-isopropylbenzyl alcohol (Example 2a) (0.47 g, 2.64 mmol) in dry benzene (20 mL). The reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under reduced pressure to give a yellow oil. The crude oil was suspended in water (10 mL) and extracted with ether (3×10 mL). The solvent was removed under reduced pressure to give 0.51 g (98%) of the title compound as a white liquid.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8]1>>[Cl:1][C:2]1[S:3][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)O1
Reactant: Clc1cccs1
Product: O=C(O)CCC(=O)c1ccc(Cl)s1
Yield: 74 %

Procedure:
As described for Example 1, 0.3 mole of 2-chlorothiophene is reacted with succinic anhydride to give 4-(5-chloro-2-thienyl)-4-ketobutyric acid (74%), m.p. 121°-123° C. The preceding compound is coupled to L-proline to give 1-[3-(5-chloro-2-thenoyl)propionyl]-L-proline (94%) as crystals, m.p. 131°-133° C. The above compound is reacted with bromine in acetic acid to give 1-[3-bromo-3-(5-chloro-2-thenoyl)-propionyl]-L-proline as a glass. As for Example 1, reaction of the preceding compound with sodium thioacetate in ethanol gives the desired product (84%) as a glass.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][N:10](COCC[Si](C)(C)C)[C:7]2=[N:8][CH:9]=1)[CH3:2].O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:12]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cnc2c(n1)c(C(=O)C(C)(C)C)cn2COCC[Si](C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of crude 1-[2-ethoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.075 g, 0.20 mmol) in 2 mL of dichloromethane and 2 mL of trifluoroacetic acid was stirred for 3 h, then concentrated, chasing with toluene. The resulting residue was dissolved in 3 mL of ethanol and treated with sodium acetate trihydrate (0.270 g, 1.98 mmol). The mixture was stirred overnight, then concentrated to a residue. Column chromatography (0→30% EtOAc/hexanes) afforded 0.039 g (80%) of 1-(2-ethoxy-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one as a white solid.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](=O)[CH3:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:18][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH2:20][NH2:21].CO.[ClH:31]>ClCCl.C(OCC)C>[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:21][CH2:20][CH:19]([OH:18])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH3:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:31].[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:21][CH2:20][CH:19]([OH:18])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH3:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CC(Cc1ccc(OC2CCCCC2)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
N-[2-(4-cyclohexyloxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine was prepared from 1-(4-cyclohexyloxyphenyl)propan-2-one (2.5 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (2.1 g) by an analogous procedure to that described in Example 1. After chromatography on silica gel eluting with 1% methanol in dichloromethane the purified amine was dissolved in diethyl ether, cooled and hydrogen chloride passed through the solution. Evaporation of the solvent and recrystallisation of the crude hydrochloride gave N-[2-(4-cyclohexyloxyphenyl)-1methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride m.p. 164°-166° C. (ethyl acetate-hexane) as a 48:52 mixture of diastereoisomers.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH2:18]([NH:20][S:21](Cl)(=[O:23])=[O:22])[CH3:19].CCN(CC)CC>C(Cl)(Cl)Cl>[F:1][C:2]([F:16])([F:17])[C:3]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][S:21]([NH:20][CH2:18][CH3:19])(=[O:23])=[O:22])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: CCNS(=O)(=O)Cl
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNS(=O)(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
To 5.18 g (20 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)aniline and 3.44 g (24 mmole) N-ethylsulfamoyl chloride in 30 ml CHCl3, add 2.18 g (24 mmole) Et3N in 20 ml CHCl3 and stir for 16 hours. Dilute with CHCl3 and wash with 1N HCl. Dry, concentrate and recrystallize from Et2O-hexane to yield the product; m.p. 178°-179° C.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl.C(N=C=NCCCN(C)C)C.[CH3:29][C:30]([CH3:65])([CH3:64])/[CH:31]=[CH:32]/[C@H:33]1[O:38][C:37]([CH3:40])([CH3:39])[O:36][C@@H:35]([C@@H:41]([O:61][CH3:62])[C:42]([NH:44][C@H:45]2[CH2:51][CH2:50][C@@H:49](O)[CH2:48][N:47]([CH2:53][C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[C:46]2=[O:60])=[O:43])[C@@H:34]1[OH:63]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:29][C:30]([CH3:65])([CH3:64])/[CH:31]=[CH:32]/[C@H:33]1[O:38][C:37]([CH3:39])([CH3:40])[O:36][C@@H:35]([C@@H:41]([O:61][CH3:62])[C:42]([NH:44][C@@H:45]2[C:46](=[O:60])[N:47]([CH2:53][C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[CH2:48][C@H:49]([O:15][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:50][CH2:51]2)=[O:43])[C@@H:34]1[OH:63]
Reactant: CO[C@@H](C(=O)N[C@H]1CC[C@@H](O)CN(Cc2cccnc2)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]1O
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)O[C@@H]1CC[C@H](NC(=O)[C@H](OC)[C@@H]2OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]2O)C(=O)N(Cc2cccnc2)C1
Reaction time: 16 h
Yield: 29.4 %

Procedure:
To a stirred solution of tetradecanoic acid (0.39 g 1.7 mmol) and 4-dimethylaminopyridine (0.21 g, 1.7 mmol) in CH2Cl2(15 mL) is added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride (0.34 g, 1.7 mmol) at room temperature. After 30 min (R)-2-[(4R,5R,6R)-6-((E)3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-N-((3S,6R)-6-hydroxy-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl)-2-methoxy-acetamide (0.74 g, 1.4 mmol) is added and stirred for 16 h. The reaction is concentrated and chromatographed on silica (98% CH2Cl2/2% CH3OH) to give 0.3 g (28.8%) of tetradecanoic acid (3R,6S)-6-{(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetylamino}-7-oxo-1-pyridin-3-ylmethyl-azepan-3-yl ester as a white solid. 1H NMR 300 MHz δ 8.54(s, 2H), 7.88 (d, 1H), 7.63 (d, 1H), 7.29 (m, 1H), 5.77 (d, 1H), 5.54(dd, 1H), 5.06 (d, 1H), 4.75 (m, 1H), 4.50 (m, 1H), 4.29 (m, 2H), 4.08 (d, 1H), 3.90 (d, 1H), 3.52 (s, 3H), 3.50 (m, 1H), 3.25 (d, 1H), 2.27 (t, 2H), 2.15 (m, 2H), 2.00 (m, 1H), 1.60 (m, 3H), 1.46 (d, 2H), 1.25 (m, 24H), 1.04 (s, 9H), 0.88 (t, 3H); MS (ESI) 730.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])=[CH:5][C:4]=1[F:22])#[CH:2].[N:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N+:24]=[N-:25].N1C(C)=CC=CC=1C>C(#N)C.[Cu](I)I>[CH2:26]([N:23]1[CH:2]=[C:1]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:13][C@H:12]([CH2:14][N:15]4[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]4)[O:11][C:10]3=[O:21])=[CH:5][C:4]=2[F:22])[N:25]=[N:24]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1ccc(N2C[C@H](Cn3cc(C)nn3)OC2=O)cc1F
Agent: I[Cu]I
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4cn(Cc5ccccc5)nn4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Yield: 26 %

Procedure:
(5R)-3-(4-Ethynyl-3-fluorophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (Intermediate 9, 40 mg, 0.133 mmol), azidomethyl-benzene(21.2 mg, 0.16 mmol), copper iodide (2.5 mg, 0.013 mmol) and 2,6-lutidine were mixed in dry acetonitrile (2 mL) and stirred at room temperature for over night. The reaction mixture was filtered through a 0.45 μm membrane, the filtrate was concentrated to an oil and purified by reverse phase chromatography with 5%˜95% MeCN in H2O (0.1% TFA). The product was obtained as a colourless solid (15 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[C:6]([CH:17]=1)[CH2:7][N:8](C)[C:9](=O)OC(C)(C)C.[ClH:23].O1CCOCC1>CCOC(C)=O>[ClH:23].[CH2:21]([S:18]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:17][C:6]=1[CH2:7][NH:8][CH3:9])(=[O:19])=[O:20])[CH3:22]
Reactant: CCS(=O)(=O)c1ccc(N)cc1CN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(N)cc1CNC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 3B (2 g, 6.09 mmol) in EtOAc (30 mL) was added 4.0 N HCl in dioxane (30.4 mL, 122 mmol) and the mixture was stirred at r.t. for 2 h. Solvent was removed under reduced pressure to give 3C (1.8 g, 6.27 mmol, 99% yield) as a off white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.79 (d, J=8.79 Hz, 1H) 7.03 (d, J=2.20 Hz, 1H) 6.96-7.02 (m, 1H) 4.33 (s, 2H) 3.24 (q, J=7.47 Hz, 2H) 2.75 (s, 3H) 1.24 (t, J=7.47 Hz, 3H).
Reaction SMILES: O[C@:2]12[CH2:19][CH:18]=[CH:17][CH2:16][C@:15]1([CH3:20])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C:9]([Br:21])=[CH:8][CH2:7]3)[CH2:4][C@H:3]2[OH:22].CS(Cl)(=O)=O.O[C@]12CC=CC[C@]1(C)[C@@H]1[C@H]([C@H]3[C@@](CC1)(C)C(Br)=CC3)C[C@H]2Cl>>[O:22]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:14]([C@@:15]4([CH3:20])[CH2:16][CH:17]=[CH:18][CH2:19][C@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[CH2:7][CH:8]=[C:9]1[Br:21]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H](O)[C@@]4(O)CC=CC[C@]34C)[C@@H]1CC=C2Br
Agent: CS(=O)(=O)Cl
Agent: C[C@]12CC[C@H]3[C@@H](C[C@@H](Cl)[C@@]4(O)CC=CC[C@]34C)[C@@H]1CC=C2Br
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45CC=CC[C@]35C)[C@@H]1CC=C2Br
Temperature: 25 °C
Yield: 89 %

Procedure:
95 g (0.258 mole) of 5α,6β-dihydroxy-17-bromo-androsta-2,16-diene obtained as described in section (b) of Example 2 are reacted with 21 ml (0.276 mole) of methanesulfonic acid chloride, as described in section (c) of Example 2, but with the difference that the mixture of products obtained after evaporation of the dichloro methane extract is dissolved in 16-fold amount (calculated on the starting material) of ethanol and the 12% aqueous solution of 19 g of sodium hydroxide is added to the ethanolic solution. The reaction mixture is heated to reflux for 10 minutes, then cooled to room temperature and the pH value is adjusted to 7 with acetic acid. The solvent is then distilled off, the evaporation residue is triturated with water. The precipitated product is filtered off, washed with water until the washings are neutral and dried over phosphorous pentoxide in vacuo. The obtained product is recrystallized from acetonitrile. Yield: 89% of 5α,6α-epoxy-17-bromo-androsta-2,16-diene; m.p. 146°-147° C; [α]D25 = - 18.3° (c = 1 in chloroform).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]1)=[O:9].CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][OH:43].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:43][CH2:42][C:41]1[CH:40]=[C:39]([CH:46]=[CH:45][CH:44]=1)[CH2:38][NH:37][C:19]([CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15]1)=[O:21]
Reactant: NCc1cccc(CO)c1
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a stirred solution of 3-[4-(Biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (0.5 g, 1.36 mmol; prepared as described in Preparation 11) in DCM (200 mL) was added DIPEA (10.7 mL, 6.12 mmol), 3-aminomethylbenzyl alcohol (0.33 g, 1.9 mmol), DMAP (0.14 g, 0.14 mmol) and EDCI (0.364 g, 1.9 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated, taken up in EtOAc (20 mL) and then washed with K2CO3 (3×10 mL), H2O (1×10 mL), brine (1×10 mL), dried over magnesium sulfate, filtered and concentrated. The mixture was purified on silica gel (7% MeOH/CHCl3) to afford 0.38 g of the title intermediate (57% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]2([CH3:21])[CH3:20])[C:3]1=[O:22].F[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[F:34].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[F:34][C:25]1[CH:26]=[C:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=[CH:29][C:24]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][C:8]2([CH3:21])[CH3:20])[C:3]1=[O:22]
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](N)C2=O)C(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Nc3ccc(S(C)(=O)=O)cc3F)C2=O)C(C)(C)C1
Temperature: 120 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
tert-Butyl 4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (0.40 g, 1.3 mmol) was dissolved in DMSO (5 mL). 1,2-Difluoro-4-(methylsulfonyl)benzene (0.32 g, 1.7 mmol) and powdered Na2CO3 (0.18 g, 1.7 mmol) were added. The reaction mixture was bubbled under nitrogen for 15 minutes. The mixture stirred overnight at 120° C. The reaction mixture was cooled to ambient temperature and partitioned between brine and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated. Flash chromatography of the crude material on silica gel followed by reverse phase HPLC purification gave tert-butyl 4-((S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (0.10 g, 0.21 mmol, 16% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O)=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:31])=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)CCCCc1ccc(CCCCCCO)c(CCC(=O)OCC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)CCCCc1ccc(CCCCCCBr)c(CCC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 75.9 %

Procedure:
A mixture of 0.673 g (1.65 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-(6-hydroxyhexyl)benzenepentanoic acid ethyl ester from the preceding example, 1.1 g (3.3 mmol) of carbon tetrabromide, and 0.9 g (3.3 mmol) of triphenylphosphine in 25 mL of ether was stirred at room temperature for 23 hr. The mixture was diluted with 250 mL of ether, and the solution worked-up in the usual manner. The crude product was purified by flash chromatography on 80 g of silica gel, eluting with hexane-ethyl acetate (10:1). There was obtained 0.588 g (75.7%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([CH3:10])[C:3]=1[OH:11].Cl.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1>>[OH:9][CH2:8][C:7]1[C:2]([CH3:1])=[C:3]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[C:4]([CH3:10])=[N:5][CH:6]=1
Reactant: Cc1ncc(CO)c(C)c1O
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Product: Cc1ncc(CO)c(C)c1OCc1ccc(C#N)cc1
Yield: 80.3 %

Procedure:
The coupling of 4-deoxypyridoxine hydrochloride (5.0 g, 0.026 mol) and α-bromo-p-tolunitrile (5.2 g, 0.026 mol), as described in Example 3, gave 4-(5-hydroxymethyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (22) (5.6 g, 80% yield) as a colorless solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:13]2[CH2:25][CH2:24][C:23]3[N:22]4[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]4)=[CH:16][C:15]=3[C:14]2=[O:26])=[N:8][CH:9]=[CH:10][C:11]=1Cl)(=[O:3])[CH3:2].[B:27]1(B2OC(C)(C)C(C)(C)O2)[O:31]C(C)(C)C(C)(C)[O:28]1.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:13]2[CH2:25][CH2:24][C:23]3[N:22]4[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]4)=[CH:16][C:15]=3[C:14]2=[O:26])=[N:8][CH:9]=[CH:10][C:11]=1[B:27]([OH:31])[OH:28])(=[O:3])[CH3:2]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(=O)OCc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(B(O)O)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 65 °C
Yield: 108.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 244b (900 mg, 2.4 mmol), Pin2B2 (3.05 g, 12 mmol), Pd(dppf)Cl2 (98 mg, 0.12 mmol), X-phos (114 mg, 0.24 mmol), potassium acetate (720 mg, 7.2 mmol), and dioxane (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 65° C. for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with 5:1 petroleum ether/ethyl acetate (10 mL) to afford 244c as a yellow solid (1.0 g, purity: 60%). MS-ESI: [M+H]+ 384.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][N:8]=1.[C:22](OC(=O)C)(=[O:24])C>C(O)=O>[Cl:21][C:20]1[CH:19]=[CH:18][C:4]([CH2:5][NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:3][C:2]=1[NH:1][CH:22]=[O:24]
Reactant: Nc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1cc(CNc2ncnc3ccc(Cl)cc23)ccc1Cl
Temperature: 25 °C

Procedure:
0.90 g (2.82 mmol) of the 4-(3-amino-4-chlorobenzyl)amino-6-chloroquinazoline prepared in Example 151 was dissolved in 15 ml of formic acid, followed by the addition of 1 ml of acetic anhydride. The obtained mixture was stirred at room temperature for several hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate to give 0.64 g of the title compound as a pale yellow crystal.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:12][C:4]1[CH:3]=[C:2]([C:13]#[N:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)cc1Cl
Temperature: 90 °C

Procedure:
The product from Example 143 Part A (1.0 g, 4.0 mmol), Zn(CN)2 (0.52 g, 4.8 mmol), Pd(PPh3)4 (0.23 g, 0.2 mmol) were added together with 9 mL of DMF. The mixture was degassed and then heated at 90° C. for 6 h. Water and EtOAc were added to the reaction mixture. It was filtered to remove inorganic solids. The layers were separated and the EtOAc layer was washed with water and brine. It was dried over MgSO4, concentrated, and purified by flash chromatography (silica, EtOAc/hexane) to give 0.28 g of the desired product. MS: 196.1 (M+1)+.