Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:31]([CH:32]=1)[CH2:30][C:8]1([CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24]C(C)(C)C)=[O:23])[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[O:7]2)([O-:3])=[O:2].[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39]O)=[CH:37][CH:36]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C=O)C>C(Cl)Cl.FC(F)(F)C(O)=O.O>[N+:1]([C:4]1[N:5]=[C:6]2[N:31]([CH:32]=1)[CH2:30][C:8]1([CH2:9][CH2:10][N:11]([C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:39][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:43])[F:44])=[CH:42][CH:41]=4)=[O:23])[CH2:18][CH2:17]3)[CH2:12][CH2:13]1)[O:7]2)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)Cn2cc([N+](=O)[O-])nc2O3)CC1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCN(C(=O)OCc2ccc(C(F)(F)F)cc2)CC1)N1CCC2(CC1)Cn1cc([N+](=O)[O-])nc1O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.5 %

Procedure:
Tert-butyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazol-2,4′-piperidin]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate prepared in Example 653 (300 mg, 0.67 mmol) was dissolved in methylene chloride (5 ml) To the solution, trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. To the residue, methylene chloride (1 ml) and triethylamine (1 ml) were added. The reaction mixture was stirred at room temperature for 5 minutes and concentrated under reduced pressure, and the residue was dissolved in DMF (15 ml). To the solution, a mixture of 4-trifluoromethylbenzyl alcohol (293 mg, 1.67 mmol), 1,1′-carbonyldiimidazole (270 mg, 1.67 mmol) and DMF (5 ml) stirred at room temperature for 3 hours was added followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution and dried over magnesium sulfate. After filtration, the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-isopropyl ether to afford 4-trifluromethylbenzyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidin]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate (324 mg, yield 88%) as a light pink powder.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:10]([CH3:12])=O)=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3].[C:13](OCC)(=[O:16])[NH:14][NH2:15]>C(O)(=O)C.C(O)CCC>[CH3:12][C:10]1[C:6]2[N:5]([C:4]([CH2:1][CH2:2][CH3:3])=[N:8][C:7]=2[CH3:9])[C:13](=[O:16])[NH:14][N:15]=1
Reactant: CCCc1nc(C)c(C(C)=O)[nH]1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Solvent: CC(=O)O
Product: CCCc1nc(C)c2c(C)n[nH]c(=O)n12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 59.7 g. of methyl 2-n-propyl-4-methyl-5-imidazolyl ketone, 41.14 g. of ethyl carbazate, 200 ml. of n-butanol and 4 drops of glacial acetic acid is warmed until solution is complete and then heated under reflux for 5 hours. The solution is concentrated in vacuo to an oily residue, 250 ml. of diphenyl ether are added and the resulting solution is heated with stirring in an oil bath for 30 minutes after the start of gas evolution. The temperature is maintained as closely as possible to the point at which gas evolution starts (150°-250° C.). The reaction is removed from the oil bath, cooled to 50° C. and diluted with 1-2 volumes hexane. The product is collected, washed with petroleum ether and then dissolved in 200 ml. of chloroform. This solution is filtered through 250 ml. of Magnesol® followed by an 800 ml chloroform wash. The filtrate is concentrated in vacuo and the residue is recrystallized from 250 ml. of ethyl acetate, giving 48.2 g. of the desired product as off-white crystals, m.p. 154°-155° C.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[O:11][C:12]([C@@H:14]1[CH2:27][C:26]2[CH:25]=[C:24]3[C:19]([O:20][C@@H:21]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=5)=[CH:32][CH:31]=4)[C:22](=[O:29])[N:23]3[CH3:28])=[CH:18][C:17]=2[CH2:16][NH:15]1)=[O:13])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH:52]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:53][CH3:54].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[O:11][C:12]([C@@H:14]1[CH2:27][C:26]2[CH:25]=[C:24]3[C:19]([O:20][C@@H:21]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=5)=[CH:34][CH:35]=4)[C:22](=[O:29])[N:23]3[CH3:28])=[CH:18][C:17]=2[CH2:16][N:15]1[C@H:52]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:53][CH3:54])=[O:13])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Reactant: CCC(Br)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 50 °C
Reaction time: 48 h

Procedure:
(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (3.5 g, 5.37 mmol) was dissolved in 10 mL DMF and sodium bicarbonate (21.5 mmol) and (1-Bromo-propyl)-benzene (10.7 mmol) added. The mixture was stirred at 50° C. for 20 h and room temperature for 48 hours. The mixture was poured onto diethyl ether and 10% sodium carbonate. The aqueous layer was extracted with ether and organic layers combined. The organic layer was dried over sodium sulfate and concentrated. The residue was purified over silica (EtOAc-hexanes-DCM-TEA, 0.5/5/4.5/0.02) to provide (3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (803 mg, 1H NMR (400 MHz, d6 acetone): 7.7 (d, 1H), 7.6 (d, 1H), 7.46 (d, 1H), 7.33 (m, 7H), 6.98 (m, 2H), 6.87 (s, 1H), 6.77 (s, 1H), 5.65 (s, 1H), 5.13 (s, 2H), 4.55 (m, 1H), 4.20 (s, 2H), 3.9 (m, 1H), 3.55 (m, 1H), 3.38 (s, 3H), 2.95 (m, 2H), 1.6 (m, 6H), 1.15 (m, 1H), 0.95 (m, 1H) 0.9 (m, 2H), 0.8 (m, 4H), 0.7 (d, 3H), 0.65 (m, 6H).
Reaction SMILES: COC([CH:5]1[C:20](=[O:21])[C:9]2([CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)[CH2:8][NH:7][C:6]1=[O:22])=O>C(#N)C.O>[C:16]([O:15][C:13]([N:11]1[CH2:12][C:9]2([C:20](=[O:21])[CH2:5][C:6](=[O:22])[NH:7][CH2:8]2)[CH2:10]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)C1C(=O)NCC2(CN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(CNC(=O)CC2=O)C1

Procedure:
7,9-Dioxo-2,6-diaza-spiro[3.5]nonane-2,8-dicarboxylic acid 2-tert-butyl ester 8-methyl ester (Example 156g)(8.3 g; 26.6 mmol) is dissolved in acetonitrile/water (170 ml; 9/1) and refluxed for 1 hour. The reaction mixture is evaporated to dryness and delivers the title compound as white crystals (6.35 g; 94%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][CH:13]([CH2:12][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:14]2)=[CH:19][CH:18]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1CCNC1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCC1)CC2

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), pyrrolidine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 295 (M+, 2), 131 (4), 85 (6), 84 (bp), 77 (3), 55 (4).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C@@H:16]([CH3:27])[CH2:15][NH:14]2.Cl[C:29]([O:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30]>ClCCCl>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([N:17]([C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[C@@H:16]([CH3:27])[CH2:15][N:14]2[C:29]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:30])=[CH:19][CH:20]=1
Reactant: O=C(Cl)OC1CCCC1
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
N,N-Diisopropylethylamine (0.486 mL, 2.79 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.300 g, 0.928 mmol) and cyclopentyl chloroformate (0.144 mL, 1.114 mmol) in 1,2-dichloroethane (6.0 mL), and the mixture stirred at 50° C. for 3 days. Additional N,N-diisopropylethylamine (0.486 mL, 2.79 mmol) and cyclopentyl chloroformate (0.28 mL, 2.22 mmol) were added, and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford an off-white solid. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-cyclopentyl 7-bromo-3-methyl-4-(2,2,2-trifluoroacetyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.390 g, 97%) as a yellow oil. MS (ESI, pos. ion) m/z 435, 437 [M+1]+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:31]=[C:32]([C:37](=[N:39]O)[NH2:38])[CH:33]=[C:34]([F:36])[CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:37]2[N:39]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:38]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1cc(F)cc(F)c1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cc(F)cc(F)c3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq.) of 3,5-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 75 mg (68% of theory)
Reaction SMILES: C(O[C@@H]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)OC1(CC1C=CC=CC=1)O)C1C=CC=CC=1.Cl[CH:49](Cl)[C:50]([OH:52])=[O:51]>[Cl-].C[N+](C)(C)C.C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:25]([O:24][C@@H:49]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:52][CH:50]1[O:51][CH2:14][CH2:15][OH:16])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: OC1(Cc2ccccc2)O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCCOC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-benzylgalactopyranose, 1.64 g (15 mmol) of tetramethylammonium chloride in 350 ml of toluene and 200 ml of 60% aqueous sodium hydroxide solution is cooled to 0° C. At 0° C., 52.7 g (130 mmol) of 2-(4,4′-dimethoxytriphenylmethyloxy)-ethylbromide, dissolved in 100 ml of toluene, is added in drops over 30 minutes while being stirred vigorously. It is stirred for three hours at 0° C. 300 ml of toluene is added, the organic phase is separated, and the aqueous phase is extracted twice with 200 ml of toluene. The solvent is distilled off in a vacuum. The residue is taken up in 500 ml of dichloromethane, and 25 g (194 mmol) of dichloroacetic acid is added. It is stirred for three hours at 35° C. The solution is washed three times with 300 ml of 10% aqueous sodium hydroxide solution, and the organic phase is evaporated to the dry state, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/ethanol=20:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.[CH3:22][N:23]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:34]3[CH2:35][CH2:36][C:31]4([C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][N:23]4[CH3:22])[CH2:32][CH2:33]3)=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CN1Cc2ccccc2C12CCNCC2
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Agent: CC(C)=C(Cl)N(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1Cc2ccccc2C12CCN(C(=O)c1c[nH]c3cc(Cl)ccc13)CC2
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of 0.040 g (0.20 mmol) 6-chloro-1H-indole-3-carboxylic acid in 3 ml dichloromethane were added 0.03 ml (0.22 mmol) 1-chloro-N,N,2-trimethyl-propenylamine at room temperature. After stirring for 1 h the reaction mixture was concentrated in vacuo. The residue was redissolved in 2 ml dry N,N-dimethylformamide. A solution of 0.041 g (0.20 mmol) 2-methyl-2,3-dihydrospiro[isoindole-1,4′-piperidine] and 0.043 ml (0.31 mmol) triethylamine in 1 ml dry N,N-dimethylformamide was added at room temperature. After stirring for 2 h the reaction mixture was quenched with 1 M aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (0.022 g, 23%) as an off-white solid with a purity of approx. 83% by LC-MS.
Reaction SMILES: C(O[C:9]([N:11](C)[N:12]1[C:21]([C:22](O)=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=O)C1C=CC=CC=1.[CH3:34][C:35]1[N:36]=[CH:37][S:38][C:39]=1[CH2:40][CH2:41][OH:42]>>[CH3:34][C:35]1[N:36]=[CH:37][S:38][C:39]=1[CH2:40][CH2:41][O:42][C:22]([C:21]1[N:12]([NH:11][CH3:9])[C:13](=[O:32])[C:14]2[C:19]([C:20]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=2)=[O:23]
Reactant: Cc1ncsc1CCO
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: CNn1c(C(=O)OCCc2scnc2C)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 207 and using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg) and 2-(4-methylthiazol-5-yl)ethanol. A colorless powder (41 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1F.C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:42][CH2:41]2)[CH2:36][CH2:35]1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:44][CH2:45]2)[CH2:36][CH2:35]1
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)c(Cl)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 104.4 %

Procedure:
1-Chloro-2-fluoro-4-(methyloxy)-5-nitrobenzene (2.0 g, 9.7 mmol), from a different batch than previously described, was dissolved in DMSO (50 mL) and K2CO3 (6.7 g, 49 mmol), and phenylmethyl 4-(4-piperidinyl)-1-piperazinecarboxylate bis(trifluoroacetate) salt (5.1 g, 9.7 mmol) were added. Reaction was stirred overnight. Poured into H2O and extracted (2×) with EtOAc. Combined organic layers were back-extracted (5×) with H2O and then dried over MgSO4, filtered, concentrated on to silica gel and flash chromatographed to give the title compound of step C (4.95 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (s, 1H), 7.00-7.52 (m, 5H), 6.76 (s, 1H), 5.03 (s, 2H), 3.90 (s, 3H), 3.54 (d, J=12.1 Hz, 2H), 3.17-3.47 (m, 4H), 2.76 (t, J=11.4 Hz, 2H), 2.23-2.63 (m, 5H), 1.82 (d, J=11.5 Hz, 2H), 1.54 (qd, J=11.7, 3.0 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C([Li])CCC.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>O1CCCC1>[OH:6][C:2]([CH3:3])([CH3:1])[C:4]#[C:5][C:12]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCCC1
Reactant: C#CC(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CC1(O)CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 2-methyl-3-butyne-2-ol (25 g, 0.297 mol) in tetrahydrofuran (250 ml) is cooled to −78° C. under a nitrogen atmosphere and n-butyl lithium (1.6 molar solution in hexanes, 410 ml, 0.65 mol) is added slowly over 1.5-2.0 hours. The reaction mixture is stirred for 1 hour at −78° C. and a solution of cyclopentanone (39 ml, 0.44 mol) in tetrahydrofuran (39 ml) is added. The reaction mixture is stirred at −78° C. for one hour and allowed to come to ambient temperature and stirred for 2-3 hours. The reaction mixture is cooled to 10° C. and quenched with ice cold water. The mixture is extracted with dichloromethane (3×250 ml), and the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 1-(3-hydroxy-3-methylbut-1-ynyl)-cyclopentanol (17 g) as colourless oil.
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.C[N+](C)=C.[I-].[C:17]([O:21][C:22]([C@@:24]1([CH2:38][CH2:39][CH:40]=[O:41])[CH2:28][C:27](=[O:29])[N:26]([C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].[Cl-].[NH4+]>ClCCl>[C:17]([O:21][C:22]([C@@:24]1([CH2:38][C:39](=[CH2:1])[CH:40]=[O:41])[CH2:28][C:27](=[O:29])[N:26]([C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C1CCC2=NCCCN2CC1
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCC=O)(C(=O)OC(C)(C)C)CC1=O
Agent: C=[N+](C)C
Agent: [Cl-]
Agent: [I-]
Solvent: ClCCl
Product: C=C(C=O)C[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,8-Diazabicyclo[5.4.0]-7-undecene (2.17 ml, 14.5 mmol) and Eschenmoser salt (3.66 g, 19.8 mmol) were added to a solution of (3S)-3-(3-oxo-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester in dichloromethane (88.0 ml) in a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hours. Thereafter, Eschenmoser salt (1.22 g, 6.59 mmol) was added, and the mixture was stirred at room temperature for three hours. A saturated ammonium chloride solution (150 ml) was added to the reaction solution, followed by extraction with chloroform (100 ml×1, 150 ml×1). The organic layer was washed with brine (200 ml) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→60:40→50:50→34:66) to give 3.14 g of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:18][C:19]([C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[CH:26][NH:27]3)=[CH:23][CH:22]=2)=[O:20])[CH2:9][O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:18][C:19]([C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[CH:26][NH:27]3)=[CH:23][CH:22]=2)=[O:20])[CH2:9][O:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH:31]([CH3:33])[CH3:30])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccc(F)cc1)c1ccc2cc[nH]c2c1
Reactant: CC(C)=O
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccc(F)cc2)CC1

Procedure:
Using alkylation method A, N-[1-(4-fluorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (900 mg, 2.3 mmol) and acetone (25 mL, 340 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 45 mg (5%) of the title compound.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9]([C:12]3[C:13]([F:22])=[C:14]([C:18]#[C:19][CH2:20]O)[CH:15]=[CH:16][CH:17]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([NH:30][O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:23]([O:27][C:28]([N:30]([CH2:20][C:19]#[C:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:9]2[O:10][CH2:11][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[C:13]=1[F:22])[O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: OCC#Cc1cccc(C2=N[C@H](c3ccccc3)CO2)c1F
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)ON(CC#Cc1cccc(C2=N[C@H](c3ccccc3)CO2)c1F)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a mixture of 3-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)-2-fluorophenyl]-2-propyn-1-ol (1.41 g, 4.8 mmol), N,O-bis(tert-butoxycarbonyl)hydroxylamine (1.11 g, 4.8 mmol) and triphenylphosphine (1.63 g, 6.2 mmol) in dry tetrahydrofuran (350 ml) was added dropwise a solution of diethyl azodicarboxylate (1.08 g, 6.2 mmol) in dry tetrahydrofuran (15 ml). The reaction mixture was stirred for 2 hours and volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (=1:10) to afford N,O-di(tert-butoxycarbonyl)-[3-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)-2-fluoro-phenyl]-2-propyn-1-yl]hydroxylamine (1.64 g, 67%) as pale yellow plates.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:8][C:7]3[C:2]([Br:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=3)(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Nc1cc(Br)cnc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(Br)cnc1Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2,5-dibromo-3-aminopyridine (0.51 g, 2.0 mmol) and 4-(4-chloro-phenoxy)-benzenesulfonyl chloride (0.76 g, 2.0 mmol) in dry CH2Cl2 (10 mL) was added pyridine (1 mL) at 0 C. The resulting mixture was allowed to warm to room temperature and stirred until TCL showed the completion of the reaction. The reaction mixture was diluted with CH2Cl2 and washed with aqueous HCl solution. After the pyridine was neutralized, the organics were washed with water, brine and dried over anhydrous Na2SO4. The filtration (Celite) and concentration under vacuo gave a crude material, which was purified by silica column (30% EtOAc/hexanes). MS: 516, 518 (M+H)+.