Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:5]1=[O:33])[CH2:2][CH3:3].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:34]([O:40][CH2:41][N:29]1[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:6]3[C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][C:9](=[O:10])[N:4]([CH2:1][CH2:2][CH3:3])[C:5]3=[O:33])=[CH:17][CH:18]=2)=[N:32][N:31]=[N:30]1)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CCCOc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.6 %

Procedure:
A mixture of 3-propyl-6-propyloxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.1 g), pivaloyloxymethyl iodide (90 mg) and sodium bicarbonate (35 mg) in DMF (2 ml) was stirred at room temperature for 20 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in chloroform-water. The chloroform layer was dried and evaporated in vacuo to give a syrup. The syrup was column-chromatographed on silica gel to give a colorless syrup (0.1 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][NH:10]1.F[C:21](F)(F)S(OC)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]1[CH3:21]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)c1c[nH]n(-c2c(Cl)cccc2Cl)c1=O
Product: CCOC(=O)c1cn(C)n(-c2c(Cl)cccc2Cl)c1=O
Yield: 87 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 2-(2,6-dichlorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.7 g, 12 mmol) and methyl trifluoromethanesulfonate (3 mL) as starting materials, the title compound (3.4 g, 87%) was obtained as a pale-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][CH:15](Cl)[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(C(Cl)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCl)cc2)CC1
Yield: 47.2 %

Procedure:
To a CH3CN (250 mL) solution of piperazine-1-carboxylic acid tert-butyl ester (19.8 g) and alpha,alpha-dichloro-p-xylene (18.6 g) was added DIPEA (18.5 mL) under a N2 atmosphere, then the resultant mixture was stirred at room temperature for 3 days. The reaction mixture was poured into saturated aqueous NaHCO3 (600 mL) and extracted with AcOEt (900 mL). The organic layer was washed with saturated aqueous NaCl (300 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1) to afford tert-butyl 4-[4-(chloromethyl)benzyl]piperazine-1-carboxylate (16.3 g) as a white powder.
Reaction SMILES: [C:1]([C:3]1([O:18][CH3:19])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[CH:2].C(C1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1)#C.C(C1(C#C[C:68]#[C:69][C:70]2([O:85][CH3:86])[CH2:75][CH2:74][CH:73]([CH:76]3[CH2:81][CH2:80][CH:79]([CH2:82][CH2:83][CH3:84])[CH2:78][CH2:77]3)[CH2:72][CH2:71]2)CCC(C2CCC(CCCCC)CC2)CC1)CCCC>N1C=CC=CC=1.CO.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Cu]I>[CH3:19][O:18][C:3]1([C:1]#[C:2][C:68]#[C:69][C:70]2([O:85][CH3:86])[CH2:75][CH2:74][CH:73]([CH:76]3[CH2:81][CH2:80][CH:79]([CH2:82][CH2:83][CH3:84])[CH2:78][CH2:77]3)[CH2:72][CH2:71]2)[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: C#CC1(OC)CCC(C2CCC(CCC)CC2)CC1
Reactant: CCCCCC1CCC(C2CCC(C#CC#CC3(OC)CCC(C4CCC(CCC)CC4)CC3)(CCCCC)CC2)CC1
Agent: [Cu+2]
Agent: [Cu]I
Agent: C#CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: CCCC1CCC(C2CCC(C#CC#CC3(OC)CCC(C4CCC(CCC)CC4)CC3)(OC)CC2)CC1

Procedure:
4.00 g of 4-ethynyl-4-methoxy-4′-propylbicyclohexyl, 5.04 g of 4-ethynyl-4,4′-dipentylbicyclohexyl, 10.65 g of copper(II) acetate monohydrate and 0.145 g of copper(I) iodide are refluxed overnight in a mixture of 25 ml of pyridine and 25 ml of methanol. Conventional work-up gives a mixture of the three coupling products 4-[4-(4,4′-dipentylbicyclohexyl-4-yl)buta-1,3-diynyl]-4-methoxy-4′-propylbicyclohexyl (C 76 N 136 I, Δε=0.95, Δn=0.006), 4-[4-(4,4′-dipentylbicyclohexyl-4-yl)buta-1,3-diynyl]-4,4′-dipentylbicyclohexyl and 4-[4-(4-methoxy-4′-propylbicyclohexyl-4-yl)buta-1,3-diynyl]-4-methoxy-4′-propylbicyclohexyl (C 121 N (80) I, Δε=−1.77, Δn=−0.002), which can easily be separated by chromatography.
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[S:6])([CH3:3])[CH3:2].Br[CH2:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=O>C1COCC1>[CH:1]([NH:4][C:5]1[S:6][CH:9]=[C:10]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[N:7]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: CC(C)NC(N)=S
Solvent: C1CCOC1
Product: CC(C)Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Isopropyl-thiourea (2.47 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.47 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The volume was reduced to 5 mL and the mixture was then cooled to −20° C. and filtered. The solid was washed with a small amount of diethylether and dried. m/z=263.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[N:6][C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[Cl:10][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)=[N:6][C:7]=1[Cl:11]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Reactant: Nc1ccc(CCO)cc1
Product: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 34 from 3-nitro-2,5,6-trichloropyridine (Horn, U.; Mutterer, F.; Weis, C. D. Helv. Chim. Acta., 1976, 59, 190.) and 4-aminophenylethyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[CH2:23]Br)=[O:4].[C:25]([CH2:27][NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])#[N:26].[H-].[Na+]>C1COCC1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[CH2:23][N:28]([CH2:27][C:25]#[N:26])[S:29]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)(=[O:31])=[O:30])=[O:4]
Reactant: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncccc12
Reactant: Cc1ccc(S(=O)(=O)NCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
To a cooled (0° C.) mixture of 1-benzenesulfonyl-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (1.64 g, 4.00 mmol) and N-cyanomethyl-4-methyl-benzenesulfonamide (0.93 g, 4.40 mmol) in dry THF (10 mL) was added sodium hydride (0.176 g, 60% dispersion in mineral oil, 4.40 mmol) in two equal portions. The reaction mixture was stirred at 0° C. for 15 minutes then allowed to warm to room temperature. After 66 h the reaction mixture was diluted with DCM (60 mL) and saturated aqueous sodium carbonate solution (25 mL). The layers were separated and the aqueous phase was extracted with DCM (2×25 mL). The combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with THF (5 mL) and the resultant solid dried in vacuo to afford the title compound as a beige solid (1.72 g, 80%). LCMS (Method B): RT=3.91 min, M+H+=539.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:7][C:8]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:12]=2.C1C(=O)N([I:38])C(=O)C1>CC(C)=O>[I:38][C:17]1[C:16]2[C:11](=[CH:12][C:13]([CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:8]1[CH:7]=[C:6]([C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[N:5]=[N:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CN3CCCCC3)cc2[nH]1
Solvent: CC(C)=O
Product: COc1nnc(-c2ccncc2)cc1-c1[nH]c2cc(CN3CCCCC3)ccc2c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
1.05 g 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-piperidin-1-ylmethyl-1H-indole are suspended in 30 mL acetone and 690 mg NIS is added. After stirring for 30 minutes at rt, the solvent is removed in vacuo. HPLC purification affords 560 mg (43%) 3-iodo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-6-piperidin-1-ylmethyl-1H-indole and 287 mg (27%) starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1cccc(CC(=O)Cl)c1
Product: COc1cccc(CC(=O)Nc2ccc(OC)nc2)c1
Yield: 98.9 %

Procedure:
The title compound was prepared as described in Example 1.A, using 3-methoxyphenylacetyl chloride (4.8 g, 26.0 mmol) and 5-amino-2-methoxypyridine (3.23 g, 26.0 mmol) to afford the title compound (7.0 g, 99% yield): ES−MS (m/z) 272.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:29])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([CH:27]=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:1]([O:8][NH:9][C:10](=[O:29])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([CH2:27][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=Cc1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(CN2CCOCC2)co1)NOCc1ccccc1
Yield: 61.5 %

Procedure:
Method and purification as for preparation 157 using (3R)-N-(benzyloxy)-6-cyclohexyl-3-(4-formyl-1,3-oxazol-2-yl)hexanamide (preparation 156) (180 mg, 0.45 mmol) and morpholine (40 μl, 0.45 mmol) as starting materials to afford the title compound as a colourless oil (130 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:35])[C:33]#[CH:34]>N(CC)CC.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:34]#[C:33][CH2:32][OH:35])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(C#CCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide (0.200 g), PdCl2(PPh3)2 (0.012 g) and CuI (0.029 g) in 10 mL Et2NH and 5 mL CH2Cl2 is added propargyl alcohol (0.021 g). The mixture is allowed to stir overnight at room temperature. The solvents are evaporated and the residue is partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed (Biotage flash 40S, eluent 1% MeOH/CH2Cl2 then 2% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The resulting solid is recrystallized from CH2Cl2/Et20 to yield 0.114 g (66%) of the desired product as a white solid.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH2:15][CH2:16][C:17]([CH3:20])(C)C)[CH3:12])(C)(C)C.C1(N)CCC1.[F:36][C:37]1[C:60]([N:61]2[CH2:65][CH2:64][CH2:63][C:62]2=[O:66])=[CH:59][C:58]([N:67]2[CH2:71][CH2:70][CH2:69][C:68]2=[O:72])=[CH:57][C:38]=1C(N[C@H]([C@@H]1C[C@@H](C)C(=O)O1)CC1C=CC=CC=1)=O>>[CH2:23]([C@H:8]([NH:7][C:6](=[O:30])[C:38]1[CH:57]=[C:58]([N:67]2[CH2:71][CH2:70][CH2:69][C:68]2=[O:72])[CH:59]=[C:60]([N:61]2[CH2:65][CH2:64][CH2:63][C:62]2=[O:66])[C:37]=1[F:36])[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])[NH:14][CH:15]1[CH2:16][CH2:17][CH2:20]1)[CH3:12])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCC(C)(C)C
Reactant: C[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)c2cc(N3CCCC3=O)cc(N3CCCC3=O)c2F)OC1=O
Agent: NC1CCC1
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1F)C(=O)NC1CCC1

Procedure:
Prepared in an analogous manner to D1 from cyclobutylamine and 2-fluoro-N-[(S)-1-((2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl)-2-phenylethyl]-3,5-bis-(2-oxopyrrolidin-1-yl)benzamide (D50).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.[N:20]1([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:14]1([C:9]2([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:23]4[CH2:22][CH2:21][N:20]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:24]4)=[CH:4][CH:5]=3)[O:13][CH2:12][CH2:11][O:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CN1CCNCC1
Reactant: BrCc1ccc(C2(c3ccccc3)OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1CCN(Cc2ccc(C3(c4ccccc4)OCCO3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a round-bottom flask were added 13 (2.57 g, 8.05 mmol, 1.0 equiv.), 10 (2.09 g, 12.1 mmol, 1.5 equiv.), K2CO3 (3.35 g, 24.2 mmol, 3.0 equiv.), and acetone (40 mL, 0.2 M). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetone. The filtrate was concentrated and purified by silica gel column chromatography (gradient, 50-100% EtOAc/hexanes) to yield 14 (2.54 g, 77%) as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 7.52-7.50 (m, 2H), 7.44 (d, 2H, J=8.5 Hz), 7.34-7.25 (m, 5H), 4.17 (q, 2H, J=7.0 Hz), 4.09-4.06 (m, 2H), 4.05-4.02 (m, 2H), 2.57 (br s, 4H), 2.50 (br s, 4H), 1.26 (t, 3H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.3, 142.1, 140.9, 137.9, 128.9, 128.1, 128.0, 126.1, 126.0, 109.4, 64.8, 62.6, 60.6, 59.5, 53.1, 52.7, 14.2.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:24]([CH3:26])[CH3:25])[C:10]([S:12][CH2:13][C@H:14]([NH:20][C:21](=[O:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:8][C@@H:9]([CH:24]([CH3:25])[CH3:26])[C:10]([S:12][CH2:13][C@H:14]([NH:20][C:21](=[O:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11]
Reactant: CCOC(=O)[C@H](CSC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)NC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@H](CSC(=O)[C@@H](N)C(C)C)NC(C)=O
Reaction time: 5 h
Yield: 90 %

Procedure:
ethyl (2R)-3-{[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoyl]sulfanyl}-2-acetamidopropanoate (570 mg) was dissolved in a solution of hydrogen chloride (4N) in 1,4-dioxane (15 mL) and the reaction was stirred for 5 hours. The reaction mixture was concentrated at reduced pressure, triturated with ethyl acetate (15 mL) for 1 hour, filtered and dried to give the product as a white solid (430 mg, 90%). 1H NMR (300 MHz, DMSO) δ=8.63-8.48 (m, 4H), 4.41 (dt, J=5.3, 8.4 Hz, 1H), 4.17-4.04 (m, 4H), 3.55-3.45 (m, 2H), 3.12 (dd, J=8.6, 13.6 Hz, 1H), 2.17 (dt, J=5.0, 6.9 Hz, 1H), 1.83 (s, 3H), 1.21-1.15 (m, 3H), 0.96 (d, J=7.0 Hz, 3H), 0.93 (d, J=7.0 Hz, 3H). MS (ESI) m/z 291 (M+1)′.
Reaction SMILES: [Cl-].[CH:2](=O)[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:5].[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>CO>[CH:14]1[CH:13]=[C:12]([NH:17][CH:2]=[C:3]2[C:4](=[O:5])[CH:6]=[CH:7][CH:8]=[CH:9]2)[C:11]([NH:18][CH:2]=[C:3]2[C:4](=[O:5])[CH:6]=[CH:7][CH:8]=[CH:9]2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1O
Reactant: Nc1ccccc1N
Agent: [Cl-]
Solvent: CO
Product: O=C1C=CC=CC1=CNc1ccccc1NC=C1C=CC=CC1=O

Procedure:
chloride (compound 29). Two equivalents of salicylaldehyde (2.2 g, 18.1 mmol) was mixed with one equivalent of o-phenylenediamine (920 mg, 8.4 mmol) in methanol that resulted in light orange precipitate of salphen ligand (L8). This ligand (500 mg, 1.6 mmol) was complexed with one equivalent of Fe(III) chloride (295 mg, 1.8 mmol) to obtain compound 29 (65% yield). Observed m/z value for compound 29: 370.18 (M+, —Cl). CHN analysis: Calculated (for C20H14N2O2FeCl. 2.5H2O) C: 53.37%, H, 4.26%, N, 6.22%. Observed: C: 53.32%, H, 3.88%, N, 6.00%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:32]Br.O.[Cl-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:32][C:16]1[CH:15]=[CH:14][C:13]2[N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2c2ccccc2)cc1
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2c2ccccc2)cc1
Temperature: 25 °C
Yield: 27.6 %

Procedure:
A stirred suspension of 5-[(4-methoxyphenyl)sulfonyl]-6-phenyl-5,6-dihydrophenanthridine (4.27 g, 10 mmol) was heated to 50° C. in glacial acetic acid (20 mL) and treated drop-wise over three hours with excess bromine (8.0 g, 50 mmol). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the precipitate filtered. The organic phase filtrate was washed sequentially with a saturated, aqueous, sodium thiosulfate solution, a 1 N hydrochloric acid solution, and water. The organic phase was further washed sequentially with a 2.5 N aqueous sodium hydroxide solution until a basic extract was obtained, water, and a saturated, aqueous, sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and the solvent removed in vacuo to afford a crude yellow solid (4.0 g, 7.9 mmol, 79%). The crude solid was purified by repetitive preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with dichloromethane at a flow rate of 25 mL/min; to afford, after evaporation of the appropriate fractions, a monobromo compound and a dibromo compound, both as solids. Crystallization of the monobromo compound from a mixture of dichloromethane-diethyl ether-hexane yielded the title compound (1.4 g, 2.76 mmol, 28%) as a homogeneous, colorless, crystalline solid, m.p. 209-211° C.;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:27])[CH3:26]>>[CH2:25]([NH:27][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22])[CH3:26]
Reactant: CCN
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Product: CCNC(=O)c1cc(/C=C/c2c(-c3ccc(F)cc3)noc2C)nn1C
Yield: 74 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using ethylamine instead of isopropylamine, to the title compound (30 mg, 74%) which was obtained as a colorless gum. MS: m/e=355.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([O:25][CH3:26])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].N1C=CC=CC=1.C1(C)C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1([OH:19])[CH:20]=[CH:21][CH:22]=[CH:23][CH:17]1[C:16]([O:25][CH3:26])=[O:24])(=[O:5])=[O:4]
Reactant: COC(=O)c1ccccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1C=CC=CC1(O)OS(=O)(=O)C(F)(F)F
Temperature: -40 °C
Reaction time: 16 h

Procedure:
Trifluoromethanesulfonic anhydride (28.4 mL, 169 mmol, 1.1 eq) was added to a solution of methyl salicylate (20 mL, 154 mmol) and pyridine (31 mL, 385 mmol, 2.5 eq) in dichloromethane (150 mL) maintained at an internal temperature about −40° C., under nitrogen. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 hours. Toluene (150 mL) was added causing precipitation. The solids were removed by filtration and washed with toluene (20 mL). The organic solutions were combined and washed with 2 N HCl (aq) (2×50 mL), water (100 mL), saturated aqueous sodium carbonate solution (100 mL) and brine (100 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. Yield 41.93 g, 96%
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)(=O)[CH3:2]>CC(O)=O>[Cl:11][C:7]1[C:6]2[N:12]([C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[C:1]([CH3:2])=[N:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1cccc(Cl)c1N[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: CC(=O)O
Product: Cc1nc2cccc(Cl)c2n1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Yield: 42 %

Procedure:
Crude (R)-tert-butyl 3-((2-acetamido-6-chlorophenyl)amino)pyrrolidine-1-carboxylate (148 mg) was dissolved in glacial HOAc (20 mL) and heated at 70° C. for 1 day. The mixture was concentrated. The residue was taken up in EtOAc (100 mL), washed with satd aq NaHCO3 (10 mL) and brine (10 mL), and dried over Na2SO4. Removal of the solvent left a brown oil (133 mg) which was purified by chromatography on a 12-g silica gel cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-(7-chloro-2-methyl-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate (59 mg, 18%) as a brown oil. LC-MS Method 1 tR=1.42 min, m/z=336.