Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](O)=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].C(N(CC)CC)C.C1C=CC(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:36]=[N+:37]=[N-:38])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc(/C=C/C(=O)O)ccc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/C(=O)N=[N+]=[N-])ccc1F
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a solution of (E)-3-(4-fluoro-3-methoxyphenyl)acrylic acid (5 g, 25.5 mmol) in benzene (30 ml) was added triethylamine (5.16 g, 51 mmol) followed by DPPA (7.01 g, 25.5 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desire compound as white solid (4 g, 71%). 1H NMR (400 MHz, CDCl3): δ ppm 7.70-7.66 (d, J=16 Hz, 1H), 7.12-7.07 (m, 3H), 6.35-6.31 (d, J=16 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1([OH:19])[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH:7]=[C:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][O:21][CH2:22][C:23]([CH2:32][O:33][CH3:34])([CH3:31])[C:24]([NH:26][CH2:27][CH2:28][CH:29]=O)=[O:25].C([BH3-])#N.[Na+]>C(Cl)Cl.CC(O)=O>[OH:19][C@@:5]1([CH2:4][CH2:3][N:2]([CH3:1])[CH2:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[C:23]([CH2:32][O:33][CH3:34])([CH3:31])[CH2:22][O:21][CH3:20])[CH2:10][C@H:9]2[CH2:11][CH2:12][C@@H:6]1[CH:7]=[C:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNCCC1(O)CC2CCC1C=C2c1ccccc1
Reactant: COCC(C)(COC)C(=O)NCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCC(C)(COC)C(=O)NCCCN(C)CC[C@]1(O)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55 %

Procedure:
50 mg of rac-(1R*,2R*,4R*)-2-(2-methylamino-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol were dissolved in DCM/AcOH. 46 mg of 3-methoxy-2-methoxymethyl-2-methyl-N-(3-oxo-propyl)-propionamide and 50 mg of sodium cyanoborohydride were added. The reaction mixture was stirred for 3 days at room temperature, quenched with sat.-NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using EtOAc/MeOH/NEt3 90/10/1 as eluant to yield 49 mg of rac-N-(3-{[2-((1R*,2R*,4R*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-amino}-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as a yellow oil.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([NH:9][C:17](=[O:18])[C:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][C:13]=1[O:20][CH3:21])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc(Br)ccc1C(=O)Cl
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Br)ccc1C(=O)NCCc1ccccc1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
Phenethylamine (0.79 mL, 6.31 mmol) was added slowly to a mixture of 4-Bromo-2-methoxy-1-benzenecarbonyl chloride (1.5 g, 6.01 mmol) and triethylamine (1.3 mL, 9.02 mmol) in dichloromethane (60 mL). After 2 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography using dichloromethane/ethyl acetate (97:3) as mobile to give N1-phenethyl-4-bromo-2-methoxybenzamide (1.81 g, 90%). 1H NMR (DMSO-d6) δ 2.83 (m, 2H), 3.50 (m, 2H), 3.84 (s, 3H), 7.31 (m, 7H), 7.65 (d, J=8.28 Hz, 1H), 8.15 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:45][N:46]2[CH:50]=[N:49][CH:48]=[N:47]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:43])[CH:40]([OH:42])[CH3:41])[C:35]5=[O:44])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.[Cl:51][CH2:52][C:53](Cl)=[O:54].N1C=CC=CC=1>C(Cl)Cl>[Cl:51][CH2:52][C:53]([O:42][CH:40]([CH3:41])[CH:39]([N:36]1[C:35](=[O:44])[N:34]([C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:12]5[CH2:11][O:10][C:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])([CH2:45][N:46]6[CH:50]=[N:49][CH:48]=[N:47]6)[O:13]5)=[CH:17][CH:18]=4)[CH2:27][CH2:26]3)=[CH:33][CH:32]=2)[CH:38]=[N:37]1)[CH3:43])=[O:54]
Reactant: CC(O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(OC(=O)CCl)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Temperature: 25 °C

Procedure:
A mixture of intermediate 2a (0.01 mol) and chloroacetyl chloride (0.0115 mol) in CH2Cl2 (200 ml) was stirred at room temperature. Pyridine (0.02 mol) was added and the mixture was stirred for 2 hours, washed with water, dried, filtered and the solvent was evaporated. The residue was crystallized from MIK/DIPE. The precipitate was filtered off and dried, yielding 6.7 g (87%) [2S-[2α,4α[(R*,R*)]]]-2-[4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]-1-methylpropyl chloroacetate. (interm.3)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([CH3:23])[O:22][C:18]=2[CH:17]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:23]/[C:21]2[O:22][C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:25]=[CH:24][C:19]=3[N:20]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(OCCCCl)cc1
Reactant: COc1ccc2nc(C)oc2c1
Product: COc1ccc2nc(/C=C/c3ccc(OCCCCl)cc3)oc2c1
Yield: 69 %

Procedure:
The procedure of Example 8 was followed starting with 4-chloropropoxybenzaldehyde of Example 8 (1.9 g, 10 mmol) and using 6-methoxy-2-methylbenzoxazole in place of 2-methylbenzoxazole (1.6 ml, 10 mmol) to give 2.4 g (69% yield) of (E)-2-[2-(4-chloropropoxyphenyl)ethenyl]-6-methoxybenzoxazole as an amber oil. 1H NMR (CDCl3): δ 8.29-6.99 (m, 9H), 4.22 (t, J=5.4 Hz, 2H), 3.93 (s, 3H), 3.24 (m, 2H), 2.51 (m, 2H).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)=[O:46]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)=[O:46])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3ccc(Cl)cc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(4-chlorophenyl)ethanone and isolated as light-yellow solid. MS(m/e): 435.3 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=O)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:27][S:28][CH2:29][CH2:30][CH2:31][O:32][NH2:33]>C(Cl)Cl.CO>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:33]/[O:32][CH2:31][CH2:30][CH2:29][S:28][CH3:27])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CSCCCON
Solvent: ClCCl
Solvent: CO
Product: CSCCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
The title compound was obtained by a procedure similar to that in Step B of Example 9 using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 as a starting material and O-(3-methylsulfanyl-propyl)-hydroxylamine obtained in Step B as a reagent. Namely, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (76 mg, 0.158 mmol) was dissolved in a mixed solvent of methylene chloride (5 mL) and methanol (1 mL). O-(3-Methylsulfanyl-propyl)-hydroxylamine (100 μL) was added thereto, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to give a pale yellow crude product. The residue was triturated with a proper amount of ethyl acetate:hexane (1:9) to give (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-propoxyimino)-methyl]-benzamide (88.8 mg, 96%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:42])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[C:34]([F:41])[CH:33]=1)([CH3:27])([CH3:26])[CH3:25].CCN(CC)CC>ClCCCl>[C:24]([O:28][C:29](=[O:42])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:40])=[C:34]([F:41])[CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)CCc1ccc(N=C=O)c(F)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with 3-(3-fluoro-4-isocyanato-phenyl)-propionic acid tert-butyl ester in 1,2-dichloroethane in the presence of Et3N for 3 days under reflux conditions to give the title compound as brown oil. MS: m/e=591.3 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:24]=[C:25]1[NH:29][C@H:28]([CH2:30][O:31]C(=O)C2C=CC=CC=2)[CH2:27][O:26]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:29]4[C@H:28]([CH2:30][OH:31])[CH2:27][O:26][C:25]4=[O:24])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3)CC2)c(C)c1
Yield: 48.9 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (2.1 g) described in Preparation Example 77 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.3 g), the title compound (1 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=3[Cl:31])[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:33]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[C:22]=3[Cl:31])[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2)(=[O:35])[CH3:34]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1Oc1ccc2nc(N)sc2n1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(F)(F)F)c4Cl)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 28 h
Yield: 74.6 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-2-chloro-3-(trifluoromethyl)benzamide (200 mg, 0.417 mmol) produced in Example C78(iv) in pyridine (5 mL) were added acetyl chloride (118 μL, 1.67 mmol) and N,N-dimethylpyridine-4-amine (6.2 mg, 0.0507 mmol), and the mixture was stirred at room temperature for 28 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and filtered through a pad filled with basic silica gel. The solvent was concentrated under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate to give the title compound (162 mg, 74%) as white crystals.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].C1C(=O)N([Br:31])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[S:11]([N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:22])[F:23])[CH2:10][CH2:9]1)(=[O:12])=[O:13]
Reactant: Cc1ccc(F)cc1S(=O)(=O)N1CCN(C(=O)C(F)(F)F)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(N1CCN(S(=O)(=O)c2cc(F)ccc2CBr)CC1)C(F)(F)F

Procedure:
A mixture of Intermediate 2 (37.5 g, 105.9 mmol), NBS (19.4 g, 105.9 mmol) and AIBN (0.45 g, 2.8 mmol) in carbon tetrachloride (500 mL) was refluxed for 4 h. The mixture was cooled, concentrated and purified over silica gel eluting with EtOAc to give the title compound contaminated with starting material and dibrominated side-product as amber oil (41.0 g). LCMS (M+H) calcd for C13H14F4N2O3SBr: 433.97; found: 433.01.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([Cl:17])[CH:6]=2.CC(C)([O-])C.[K+]>CN(C)C=O.O>[Cl:17][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[NH:12][CH2:13][CH:14]([CH3:15])[O:16][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(O)CNc1c(Br)cnc2cc(Cl)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CNc2c(cnc3cc(Cl)ccc23)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.6 %

Procedure:
A solution of 11 g of 3-bromo-7-chloro-N-(2-hydroxypropyl)-4-quinolinamine in 33 ml of dimethylformamide was stirred and to it was added 4.3 g of potassium t-butoxide. The mixture was stirred at 130°-140° C. for three hours and then allowed to cool to room temperature. The reaction mixture was diluted with water and the organics were extracted into dichloromethane. Washing with water, drying over anhydrous magnesium sulfate and evaporation of solvents resulted in a crude oil which was purified by HPLC using 2:1 hexane/ethyl acetate as the eluent. Recrystallization from acetone yielded 2.5 g of solid with a melting point of 239°-241° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:25]1[CH2:26][CH2:27][CH2:28][CH:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:24]1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Yield: 99 %

Procedure:
Method 1 was followed using 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.0 eq), 3-(N-Boc-amino) piperidine (1.2 eq), and TEA (1.5 eq) at 55° C. for 1 hour yielding tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate (99%). LCMS (m/z): 390.1 (MH+); LC Rt=3.58 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[N:12]([CH3:13])[C@H:11]([CH3:14])[C@@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:9]1.C([Li:25])CCC>O1CCNC1.C1COCC1>[CH3:13][N:12]1[C@H:11]([CH3:14])[C@@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:9][C@@H:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Li:25]
Reactant: [Li]CCCC
Reactant: C[C@@H]1[C@@H](c2ccccc2)O[C@H](c2ccccc2Br)N1C
Agent: C1COCN1
Solvent: C1CCOC1
Product: [Li]c1ccccc1[C@H]1O[C@H](c2ccccc2)[C@@H](C)N1C
Reaction time: 2 h

Procedure:
In a separate flask, the oxazolidine in the form of the mixture of Example 1 (17.43 g, 52.62 mmol, 1 eq) was dissolved in 25 mL of THF under an argon atmosphere. The solution was cooled to -70° C. (internal temperature) and n-C4H9Li (n-BuLi) (21 mL, 52.5 mmol, 1 eq) was added dropwise over 10 min such that the internal temperature did not rise above -50° C. The reaction was brought back to -70° C., and stirred for 2 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[CH:35]=[C:34]([Cl:40])[C:33]([Cl:41])=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:33]1[C:34]([Cl:40])=[CH:35][C:36]2[C:37]3[CH2:38][CH2:39][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:27][CH2:28][C:29]=3[N:30]([CH2:42][C:43]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:44])[C:31]=2[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Reactant: COc1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)Cn2c3c(c4cc(Cl)c(Cl)cc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reaction time: 18 h
Yield: 32.6 %

Procedure:
DMAP (60 mg, 0.49 mmol), p-anisidine (66 mg, 0.54 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reaction was diluted with EtOAc and washed with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc (gradient, 99:1 to 95:5) to give 81 mg of impure product. Then, crystallization from EtOAc/heptane gave 73 mg (29%) of a white solid: mp 151-151.5° C.; IR (diffuse reflectance) 3288, 1695, 1661, 1550, 1513, 1473, 1422, 1367, 1318, 1269, 1250, 1172, 1161, 1118, 831 cm−1; MS (CI) m/z 518 (M+H+), 222, 221, 220, 167, 166, 124, 59, 58, 52, 51; Anal. Calcd for C26H29Cl2N3O4: C, 60.24; H, 5.64; N, 8.10; found: C, 60.23; H, 5.73; N, 8.10.
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([OH:45])=O)=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl.CN(C)CCCN=C=NCC.[NH2:58][CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCN(CC)CC>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:58][CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])=[O:45])=[O:39])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of (C18H37)2NCOCH2OCH2COOH (1.0 g, 1.5 mmol) in CH2Cl2 (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.31 g, 1.6 mmol) and the reaction was stirred at room temperature. After 0.5 h, Gly-OCH2Ph.TsOH (0.53 g, 1.5 mmol) and Et3N (0.6 mL) were added and the mixture was stirred overnight. The reaction mixture was washed with water (20 mL), 0.5 M aqueous HCl (20 mL), water (20 mL), 10% aqueous Na2CO3 (20 mL), and brine (20 mL) then dried over MgSO4, evaporated and the residue crystallized from MeOH yielding (C18H37)2NCOCH2OCH2CO-Gly-OCH2Ph as a deliquescent white solid (0.86 g, 70%), mp 38–40° C. 1H-NMR (300 MHz, δ, CDCl3) 0.86 (6H, t, J=6.9 Hz), 1.24 (64H, m), 1.50 (4H, bs), 3.06 (2H, t, J=7.5 Hz), 3.28 (2H, t, J=7.5 Hz), 4.10 (2H, s), 4.12 (2H, s), 4.25 (2H, s), 5.15 (2H, s), 7.33 (5H, m), 8.20 (1H, t, J=5.7 Hz). 13C-NMR (75 MHz, 6, CDCl3): 14.2, 22.7, 26.9, 27.1, 27.6, 29.0, 29.39, 29.44, 29.5, 29.6, 29.7, 29.8, 32.0, 40.8, 46.3, 47.0, 67.1, 69.7, 71.8, 128.5, 128.6, 128.8, 135.3, 168.5, 169.8, 170.6.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH:14]([CH3:16])[NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:26][CH:27]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]([NH:15][CH2:27][CH:26]=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:16])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCC=C(c1ccccc1)c1ccccc1

Procedure:
The starting material is prepared as follows: The solution of 12 g of dl-p-benzyloxyamphetamine, and 10.4 g of β-phenyl-cinnamaldehyde in 300 ml of absolute ethanol is treated dropwse with the solution of 3 g of sodium borohydride in 6.7 ml of water while stirring. It is refluxed for 18 hours, concentrated to remove most of the ethanol and diluted with water. The mixture is extracted with ethyl acetate and the organic layer washed with brine, dried and evaporated, to yield the dl-1-(p-benzyloxyphenyl)-2-(3,3-diphenylallylamino)-propane; its maleate melts at 177°-178°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[F:20][C:21]([F:35])([F:34])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31].Cl>O1CCOCC1.O>[F:35][C:21]([F:20])([F:34])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:11]([NH:10][C:5]1[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([CH3:9])[N:6]=1)=[O:13])(=[O:32])=[O:31]
Reactant: NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CC(F)(F)F)n1
Reaction time: 3 h
Yield: 86.7 %

Procedure:
5.2 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-phenylcarbamate are added to a solution of 5 g of 2-(3,3,3-trifluoro-1-propen-1-yl)-phenylsulfonamide and 3.3 g of 1,5-diazabicyclo[5,4,0]undec-5-one in 80 ml of dioxan, and the mixture is stirred for 3 hours at 20°-25° C. The clear reaction solution is then taken up in 300 ml of water and the aqueous solution is acidified with 2N hydrochloric acid to pH 4-5. The resinous precipitate is extracted from the aqueous phase with ethyl acetate and the organic extract is dried and concentrated. The oily residue is crystallised from a 1:10 mixture of acetone/ether, affording 7.2 g of the title compound with a melting point of 159°-160° C.