Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrCC(C1C=CC=C2C=1N=C(NC1(C)CC1)C(C)=N2)=O.C(OC(NC1(C(=O)CC(OCC)=O)CC1)=O)(C)(C)C>CCO.CC(O)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:12]2[NH:13][C:14]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[N:24]=[C:25]([NH:33][C:34]3([CH3:36])[CH2:35][CH2:37]3)[C:26]([CH3:32])=[N:27]4)=[CH:15][C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Agent: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: Cc1nc2cccc(C(=O)CBr)c2nc1NC1(C)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC4(C)CC4)nc23)[nH]c1C1(NC(=O)OC(C)(C)C)CC1
Yield: 76 %

Procedure:
This compound (930 mg, 1.84 mmol, 76% yield) as a yellow amorphous solid was prepared according to the procedures described for Intermediate 324b, using 2-bromo-1-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)ethanone (611) (810 mg, 2.42 mmol), ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (789 mg, 2.91 mmol) as the starting materials, followed by the subsequent treatment of the resulting 329a (m/z (ESI, +ve) 525.2 (M+H)+) with NH4OAc (1.12 g, 14.54 mmol) in 3 mL of EtOH and 1.5 mL of HOAc at 50° C. for 4 h. m/z (ESI, +ve) 506.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:17][CH2:18][CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:8][CH2:7]1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of the product from Example 1 step (ii) (2.0 g), 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (1.61 g) and triethylamine (2.5 ml) in dichloromethane (40 ml) was heated under reflux for 48 h. The reaction mixture was partitioned between ethyl acetate/water, the organic layer dried and evaporated under reduced pressure. Purification was by chromatography eluting with 4% methanol/dichloromethane. Yield 0.839 g
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[F:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:21][C:22]1[N:26]2[N:27]=[C:28]([C:31](=O)[CH3:32])[CH:29]=[CH:30][C:25]2=[N:24][CH:23]=1>>[F:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:21][C:22]1[N:26]2[N:27]=[C:28](/[C:31](=[N:2]/[N:3]3[CH2:7][C:6](=[O:8])[NH:5][C:4]3=[O:9])/[CH3:32])[CH:29]=[CH:30][C:25]2=[N:24][CH:23]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Product: C/C(=N\N1CC(=O)NC1=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 39 %

Procedure:
The title compound was prepared from 1-aminoimidazolidine-2,4-dione hydrochloride and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 39% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.39 (s, 1H), 8.91 (dd, 1H), 8.40 (d, 1H), 8.24 (d, 1H), 8.04 (d, 1H), 7.94 (m, 2H), 7.82 (d, 1H), 7.55 (q, 1H), 4.64 (s, 2H), 4.50 (s, 2H), 2.40 (s, 3H). LCMS (method A): [MH]+=418, tR=4.62 min.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[OH:5][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:25])[CH2:18][CH2:17]4)[CH2:14][C@H:13]([CH3:26])[C:12]1=[CH:11][C:10](=[O:27])[CH2:9][CH2:8]2.[C:28](O)(=[O:30])[CH3:29].[OH:32][CH2:33][C@@:34]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CC[C:39]1=[CH:38][C:37](=O)[CH2:36][CH2:35]2>>[C:1]([O:4][CH2:26][C@@:13]12[C@@H:14]3[C@H:37]([C@H:36]4[C@@:23]([CH2:24][CH2:15]3)([CH3:22])[C@@H:33]([OH:32])[CH2:34][CH2:35]4)[CH2:38][CH2:39][C:12]1=[CH:11][C@@H:10]([OH:27])[CH2:9][C@H:8]2[CH3:7])(=[O:3])[CH3:2].[C:28]([O:5][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C@@H:19]([OH:25])[CH2:18][CH2:17]4)[CH2:14][C@H:13]([CH3:26])[C:12]1=[CH:11][C@@H:10]([OH:27])[CH2:9][CH2:8]2)(=[O:30])[CH3:29]
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C=C12
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: CC(=O)O
Product: CC(=O)OC[C@@]12C(=C[C@@H](O)C[C@H]1C)CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Product: CC(=O)OC[C@]12CC[C@H](O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
Substituting 19-hydroxy-1β-methyl-4-androstene-3,17-dione acetate and 19-hydroxy-6α-methyl-4-androstene-3,17-dione acetate for 19-hydroxyandrost-4-ene-3,17-dione acetate in the above procedure results in the formation of 1β-methyl-4-androstene-3β,17β,19-triol 19-acetate and 6α-methyl-4-androstene-3β,17β,19-triol 19-acetate.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12.[Br:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:19][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1c2ccccc2-n2cncc2[C@@H]2CCCN12
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(Br)c2[C@@H]2CCCN12

Procedure:
2.5 g (10.4 mmol) of (S)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 20 ml of dimethylformamide are stirred at room temperature for 30 minutes with 1.86 g (10.4 mmol) of N-bromosuccinimide. The solution is poured into water and extracted with chloroform. The chloroform extracts are washed several times with water, dried over magnesium sulphate and evaporated. After two-fold recrystallization from ethyl acetate, there is obtained (S)-1-bromo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 225°-226°.
Reaction SMILES: [C:1]1([CH:7]([CH3:27])[CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[BH4-].[Na+].[OH-].[Na+].[CH3:33]O>>[CH3:33][N:10]([CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:27])[C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]2[CH:26]=[CH:25][C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)[CH2:15][CH2:16]1
Reactant: CO
Reactant: CC(CCN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CCN(C)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1)c1ccccc1
Reaction time: 2 h

Procedure:
To a stirred solution of 6-{trans-4-[3-phenylbutylamino]-cyclohexyl}-3H-benzoxazol-2-one (638 mg, 1.75 mmol) in MeOH (10 mL) containing water (0.5 mL) was added p-formaldehyde (263 mg, 8.76 mmol). The reaction mixture was stirred for 2 hours, and NaBH4 (519 mg, 2.45 mmol) was added. The reaction mixture was stirred for 3 hours. The reaction was treated with solid NaOH until a clear solution resulted and concentrated under reduced pressure. Purification by flash chromatography (95:5:1 CH2Cl2:MeOH:NH4OH) gave 6-[trans-4-(methyl-3-phenylbutylamino)cyclohexyl]-3H-benzoxazol-2-one (231 mg, 35%), as a white solid: mp 61-70° C.; IR (KBr): 2928, 1774 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 7.29-7.12 (m, 7H), 6.97 (s, 1H), 2.76 (m, 1H), 2.49-2.26 (m, 5H), 2.14 (s, 3H), 1.77 (m, 4H), 1.67 (m, 2H), 1.43 (m, 2H), 1.27 (m, 2H), 1.17 (d, J=4 Hz, 3H); API-MS (m/z): 379 [M+H]+; HPLC: method A, 5.99 minutes (94.3%); HPLC: method B, 10.97 minutes (>99%); Anal. Calcd for C24H30N2O2.0.5H2O: C, 74.39; H, 8.06; N, 7.23. Found: C, 74.41; H, 7.90; N, 7.31.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[N:17]=[C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]4)[S:19][CH:20]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1.[OH-].[Li+]>O1CCCC1.CO.CC1CCCO1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[N:17]=[C:18]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]4)[S:19][CH:20]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: CCOC(=O)C1CCN(c2nc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)cs2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC1CCCO1
Product: O=C(O)C1CCN(c2nc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)cs2)CC1
Temperature: 50 °C
Yield: 100 %

Procedure:
To a solution of ethyl 1-[4-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (38 mg, 0.08 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added 1M aqueous lithium hydroxide (0.5 mL, 0.5 mmol). The reaction was heated to 50° C. for 2 hours. The mixture was then cooled to room temperature, diluted with 2-methyltetrahydrofuran (30 mL), and washed with 0.1N aqueous hydrochloride acid (30 mL) and brine (30 mL). The aqueous fractions were further extracted with 2-methyltetrahydrofuran (30 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to provide 1-[4-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylic acid (36 mg, 0.08 mmol, quantitative) as a light blue solid. MS APCI: [M+H]+ m/z 450.1. 1H NMR (400 MHz, DMSO): δ 10.23 (s, 1H); 8.82 (d, J=4.9 Hz, 1H); 8.38 (s, 1H); 7.61 (d, J=7.8 Hz, 1H); 7.50 (d, J=7.8 Hz, 1H); 7.32 (t, J=7.8 Hz, 1H); 7.27 (d, J=5.0 Hz, 1H); 7.15 (s, 1H); 6.65 (s, 2H); 3.93 (d, J=12.3 Hz, 2H); 3.22-3.08 (m, 2H); 1.95 (d, J=13.1 Hz, 2H); 1.65 (d, J=14.4 Hz, 2H). rhSyk=++.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH2:30])=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH:30][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][C:2]([F:14])([F:13])[F:1])=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccccc2OC(F)(F)F)sc1C(=O)NCc1ccccc1
Yield: 30 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-trifluoromethoxybenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 30% yield; m.p. 140-141° C.; 1H NMR (CDCl3, 300 MHz) δ 7.98 (dd, J=1.8, 7.8 Hz, 1H), 7.60 (ddd, J=1.8, 7.6, 8.2 Hz, 1H), 7.43 (dt, J=1.0, 7.6 Hz, 1H), 7.46-7.25 (m, 6H), 5.98 (t, J=5.3 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.1 (s, 3H); MS (ES+) m/z 436 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:16]=1.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C([O-])(=O)/C=C/C([O-])=O>CC(OC)(C)C.C(O)C.CO>[CH3:18][O:17][C:3]1[C:2]([O:1][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[CH:16][C:6]2[C:7]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)cc(C(F)(F)F)c2cc1O
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: CCO
Product: COc1cc2oc(=O)cc(C(F)(F)F)c2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 45 %

Procedure:
Method D (3 h at 85° C.); starting materials: 6-hydroxy-7-methoxy-4-(trifluoromethyl)-2H-1-benzopyran-2-one (example 104) and 1-(3-chloropropyl)-4-phenylpiperidine; yield 45%; fusion point 125°-126° C. (from TBME and methanol). Fumarate: method E; yield 59%; fusion point 176°-179° C. (from ethanol and TBME).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[F:26])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[ClH:25].[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:12]2[C:11]3[C:16](=[CH:17][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[C:9]([O:27][CH3:28])[CH:10]=3)[N:15]=[CH:14][N:13]=2)=[C:20]([F:26])[CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOCCBr
Reactant: CN1CCNCC1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOCCN1CCN(C)CC1
Product: Cl
Temperature: 100 °C
Yield: 28 %

Procedure:
A mixture of 7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (150 mg, 0.32 mmol) in 1-methylpiperazine (2 ml) was heated at 100° C. for 1 hour. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was separated and washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/methanol (85/15 followed by 80/20). The purified solid product was dissolved in methylene chloride/methanol (1/1) and 2.9M ethereal hydrogen chloride was added. The volatiles were removed by evaporation and the solid was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-[4-methylpiperazin-1-yl]ethoxy)ethoxy)quinazoline hydrochloride (54 mg, 28%).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].[C:30]([O:34][C:35](=[O:45])[NH:36][CH2:37][C:38]1[N:43]=[CH:42][C:41](Cl)=[CH:40][N:39]=1)([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C(O)(C)C.O>[C:30]([O:34][C:35](=[O:45])[NH:36][CH2:37][C:38]1[N:43]=[CH:42][C:41]([C:15]2[CH:16]=[CH:17][C:12]([C@H:8]3[O:7][C:6]([CH3:27])([CH3:28])[N:5]([C:3](=[O:4])[CH:2]([F:29])[F:1])[C@@H:9]3[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:40][N:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CC(C)(C)OC(=O)NCc1ncc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ncc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 140 °C
Yield: 36.4 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.286 g, 0.694 mmol) and (5-Chloro-pyrimidin-2-ylmethyl)-carbamic acid tert-butyl ester (0.2 g, 0.694 mmol) in isopropylalcohol:water (2:1, 6 mL) is added K2CO3 (0.287 g, 2.083 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 20 minutes followed by addition of Pd(dppf)Cl2.CH2Cl2 (0.028 g, 0.035 mmol). The resulting reaction mixture is heated to 140° C. for 20 minutes in a microwave. Solvent is evaporated in vacuo and the crude material is diluted using water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by column chromatography using Combi-flash eluting with 75% ethyl acetate in hexane to afford the title compound (0.125 g): 1H NMR (400 MHz, DMSO-d6) δ: 1.40 (s, 9H), 1.52 (s, 3H), 1.60 (s, 3H), 4.36 (d, J=6.16 Hz, 2H), 4.54-4.58 (m, 0.5H), 4.66-4.73 (m, 1H), 4.82-4.85 (m, 0.5H), 4.91-4.95 (m, 1H), 5.28 (d, J=3.52 Hz, 1H), 6.64 (t, J=52.44 Hz, 1H), 7.32 (t, J=6.04 Hz, 1H), 7.62 (d, J=8.04 Hz, 2H), 7.86 (d, J=8.04 Hz, 2H), 9.10 (s, 2H). LC-MS (m/z): [M+H]=495.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[O:38][C:39]2[C:45]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:44][CH:43]=[CH:42][C:40]=2[CH:41]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[O:38][C:39]3[C:45]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:44][CH:43]=[CH:42][C:40]=3[CH:41]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1cccc2cc(CCl)oc12
Product: COCCCOc1cccc2cc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)oc12

Procedure:
Analogously to Method D, 0.339 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.215 g of 2-chloromethyl-7-(3-methoxypropoxy)benzofuran are reacted. The title compound is obtained as a yellow oil. Rf=0.37 (1:2 EtOAc-heptane); Rt=6.26.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][C:4]([N+:8]([O-:10])=[O:9])=[N:3]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:24][C:25]1[N:29]([CH2:30][CH2:31][CH3:32])[CH:28]=[N:27][CH:26]=1>O>[CH3:1][N:2]1[C:6]([S:7][CH2:24][C:25]2[N:29]([CH2:30][CH2:31][CH3:32])[CH:28]=[N:27][CH:26]=2)=[N:5][C:4]([N+:8]([O-:10])=[O:9])=[N:3]1
Reactant: CCCn1cncc1CCl
Reactant: Cn1nc([N+](=O)[O-])nc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cncc1CSc1nc([N+](=O)[O-])nn1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
1-methyl-3-nitro-1,2,4-triazol-5-thiol (0.66 g) was dissolved in. DMF (13.2 ml), potassium carbonate (1.7 g) and 5-chloromethyl-1-propylimidazole hydrochloride (1.1 g) were added to the mixture, and the mixture was stirred for 18 hours at room temperature. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed, to give 1-methyl-3-nitro-5-[[(1-propylimidazol-5-yl)methyl]thio]-1,2,4-triazole (0.55 g).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.Br.[NH2:15][C:16]1([CH3:24])[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C(N(CC)CC)C>CN(C)C=O>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:13])[N:15]([C:16]1([CH3:24])[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])[CH2:11]2
Reactant: CC1(N)CCC(=O)NC1=O
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(N2Cc3cc(Br)ccc3C2=O)CCC(=O)NC1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (3.0 g, 10.0 mmol), 3-amino-3-methyl-piperidine-2,6-dione hydrobromide (2.2 g, 10.0 mmol) and triethylamine (2.0 g, 20 mmol) in N,N-dimethylformamide (10 mL) was heated to 90° C. under nitrogen. After 1 h, the mixture was cooled to rt and the solvent was removed in vacuo. The crude residue was purified by column chromatography (95:5 CH2Cl2: MeOH) providing 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-3-methyl-piperidine-2,6-dione (2.0 g, 61% yield); 1H NMR (DMSO-d6) δ 1.67 (s, 3H), 1.87-1.93 (m, 1H), 2.54-2.80 (m, 3H), 4.64 (d, J=17.9 Hz, 1H), 4.73 (d, J=17.9 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.69 (dd, J=8.1, 1.5 Hz, 1H), 7.88 (d, J=1.5 Hz, 1H), 10.89 (s, 1H).
Reaction SMILES: [H-].[Na+].C([C:5]([CH2:15][CH3:16])(P(O)(O)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:17]([C:21]1[CH:26]=[CH:25]C(C=O)=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30])([CH3:20])([CH3:19])[CH3:18]>CCCCCC.CN(C)C=O.C(OCC)C>[C:17]([C:21]1[CH:26]=[CH:25][C:16](/[CH:15]=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C(CC)(CC)P(=O)(O)O
Reactant: CC(C)(C)c1ccc(C=O)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.1 %

Procedure:
15 8.0 g (0.18 mol) of sodium hydride (as a 55% w/w dispersion in mineral oil) was washed twice with hexane and suspended in 250 ml of dimethyl-formamide. A solution of 31 ml (0.16 mol) of ethyl diethyl-phosphonoacetate in 50 ml of dimethylformamide was then added, with ice-cooling, to the suspension, and the resulting mixture was stirred at room temperature for 40 minutes. At the end of this time, the mixture was ice-cooled and a solution of 27 g (0.13 mol) of 2-t-butyl-5-formyl-1-nitrobenzene [prepared as described in step (i) above] in 50 ml of dimethylformamide was added thereto over a period of 30 minutes, after which the mixture was stirred for 1 hour. The reaction mixture was then diluted with diethyl ether, and the diluted solution was washed with a 10% w/w aqueous solution of hydrochloric acid and with water, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 20.6 g of the title compound as crystals, melting at 77°-78° C. (from ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@H:17]([C:26]([OH:28])=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[C:26]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([OH:28])=[O:27]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(O)cc1)C(=O)O
Yield: 71 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with L-tyrosine (2 eq.) to provide the title compound in 71% yield as yellow needles (recrystallization from acetone/water).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][OH:6].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][O:6][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.5 %

Procedure:
A solution of 3-bromo-5-nitrobenzyl alcohol (5 g, 21.5 mmol), in N,N-dimethylformamide (5 mL) was treated with tert-butyldimethylsilyl chloride (4.9 g, 32.3 mmol) and imidazole (2.5 g, 36.6 mmol) and stirred at room temperature for 14 h. The reaction was quenched with water and extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica (0-75% ethyl acetate inhexanes) afforded [(3-bromo-5-nitrobenzyl)oxy](tert-butyl)dimethylsilane (7.32 g, 20.1 mmol, 93% yield) as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[O:13][CH3:14])=[O:3].[CH3:15][CH:16]([OH:21])[CH2:17][CH:18]([OH:20])[CH3:19]>>[CH3:14][O:13][C:6]1[CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:20][CH:18]([CH2:17][CH:16]([OH:21])[CH3:15])[CH3:19])=[O:3]
Reactant: COc1cc(C=O)ccc1OC(=O)Cl
Reactant: CC(O)CC(C)O
Product: COc1cc(C=O)ccc1OC(=O)OC(C)CC(C)O

Procedure:
The reaction of 2-methoxy-4-formylphenyl chloroformate with 2,4-pentanediol is conducted on a 0.02 mole scale employing the same conditions as described in Example I. A 2.9 g yield of the pure product is obtained as an oil.