Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@H:3]([OH:7])[C:4]([OH:6])=[O:5].CCN(CC)CC.Cl[C:23]([C:25]1[C:26]([CH3:35])=[C:27]([O:31][C:32](=[O:34])[CH3:33])[CH:28]=[CH:29][CH:30]=1)=[O:24].Cl.[Na+].[Cl-]>C1COCC1.O>[C:32]([O:31][C:27]1[C:26]([CH3:35])=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:23]([NH:1][C@@H:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@H:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:24])(=[O:34])[CH3:33]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Oc1cccc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)O)c1C
Temperature: 6 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
(2S,3S)-3-Amino-2-hydroxy-4-phenyl-butyric acid (185 g; 948 mmol) was added to a 5-L flask and was suspended in THF (695 mL). H2O (695 mL) was poured in, followed by NEt3 (277 mL; 1990 mmol). After stirring for 45 min, the solution was cooled to 6° C. A solution of acetic acid 3-chlorocarbonyl-2-methyl-phenyl ester (201 g; 948 mmol) in THF (350 mL) was then added dropwise. One-half hour later, the pH was adjusted from 8.7 to 2.5 with 6 N HCl (˜170 mL). Solid NaCl (46 g) was added, the ice bath was then removed and the mixture was stirred vigorously while warming to room temperature. The mixture was transferred to 4-L separatory funnel, using 1:1 THF/H2O (50 mL) for the transfer, and the lower aqueous phase was then removed. The organic fraction was transferred to a 5-L distillation flask, and was then diluted with fresh THF (2.5 L). The solution was azeotropically dried and concentrated to a volume of 1.3 L by distillation of THF at one atmosphere. To complete the azeotropic drying, fresh THF (2.0 L) was added and the solution was concentrated to 1.85 L by distillation at one atmosphere and was then held at 55° C. n-Heptane (230 mL) was added dropwise via addition funnel and the solution was then immediately seeded. After crystallization had initiated, additional n-heptane (95 mL) was added dropwise. The resulting crystal slurry was stirred vigorously for 7 min. Additional n-heptane (1.52 L) was then added as a slow stream. The crystal slurry was then allowed to cool to room temperature slowly and stir overnight. The suspension was vacuum-filtered and the filter cake was then washed with 1:1 THF/n-heptane (700 mL). After drying in a vacuum oven at 45–50° C., 324 g (92%) of (2S,3S)-3-(3-acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyric acid was obtained as a crystalline solid: mp=189–191° C., 1H NMR (300 MHz, DMSO-d6) δ 12.65 (br s, 1H), 3.80 (d, J=9.7 Hz, 1H), 7.16–7.30 (m, 6H), 7.07 (dd, J=1.1, 8.0 Hz, 1H), 7.00 (dd, J=1.1, 7.5 Hz), 4.40–4.52 (m, 1H), 4.09 (d, J=6.0 Hz, 1H), 2.92 (app dd, J=2.9, 13.9 Hz, 1H), 2.76 (app dd, J=11.4, 13.9 Hz, 1H), 2.29 (s, 3H), 1.80 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 174.4, 169.3, 168.1, 149.5, 139.7, 139.4, 129.5, 128.3, 127.9, 126.5, 126.3, 124.8, 123.3, 73.2, 53.5, 35.4, 20.8, 12.6; MS (CI) m/z 372.1464 (372.1447 calcd for C20H22NO6, M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:4])O.[H-].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21]Cl)=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:12]=2[CH:29]=1>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21][N:2]([CH3:4])[CH3:1])=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:12]=2[CH:29]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reactant: CN(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 16, a solution of N,N-dimethylhydroxylamine in dimethylformamide is treated with sodium hydride suspended in mineral oil, and the mixture is treated with 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s--triazolo[4,3-a][1,4]benzodiazepine to give 8-bromo-1-[(dimethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)[CH2:3][CH2:2]1.[NH2:19][CH:20]1[CH:27]2[CH2:28][C:23]3([OH:30])[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2>>[OH:30][C:23]12[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:29][CH:21]([CH:20]3[NH:19][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([O:9][CH2:8][CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:11]=3)[CH2:22]1)[CH2:24]2
Reactant: O=C(O)c1cccc(OCCC2CCOCC2)c1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCCC2CCOCC2)c1

Procedure:
Prepared from 3-(tetrahydro-pyran-4-ylethoxy)-benzoic acid and 4-amino-1-hydroxyadamantane. LC-MS (m/z): 400 (M).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)(=[O:33])=[O:32])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)CCCCCCNCc1ccc(-c2nccs2)cc1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Product: COC(=O)CCCCCCN(Cc1ccc(-c2nccs2)cc1)S(=O)(=O)c1ccccn1

Procedure:
The title compound of Step B was prepared following the procedure described in Step B of Example 1 from 7-(4-thiazol-2-yl-benzylamino)-heptanoic acid methyl ester, of Step A and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47. 1H NMR (400 MHz, CDCl3) δ 9.06 (d, 1H), 8.81 (m, 1H), 8.10 (m, 1H), 7.91 (d, 2H), 7.86 (m, 1H), 7.46 (m, 1H), 7.34 (m, 3H), 4.39 (s, 2H), 3.62 (s, 3H), 3.15 (t, 2H), 2.21 (t, 2H), 1.48 (m, 2H), 1.37 (m, 2H), 1.15 (m, 4H); MS 474 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]=[C:16]([N:27]3[CH2:41][CH2:40][C:30]4([CH2:34][NH:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31]4)[CH2:29][CH2:28]3)[N:15]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:42]2[CH:46]=[CH:45][C:44]([CH3:47])=[N:43]2)[CH:3]=1.[Li+].[OH-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:17]=[C:16]([N:27]3[CH2:28][CH2:29][C:30]4([CH2:34][NH:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31]4)[CH2:40][CH2:41]3)[N:15]=2)[C:9]([F:11])([F:10])[F:12])=[C:4]([N:42]2[CH:46]=[CH:45][C:44]([CH3:47])=[N:43]2)[CH:3]=1
Reactant: CCOC(=O)C1CC2(CCN(c3nc(Oc4ccccc4)cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(Oc3ccccc3)nc(N3CCC4(CC3)CNC(C(=O)O)C4)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of ethyl 8-(4-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-phenoxypyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[N:16]=[CH:17][N:18]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1)CCC>>[C:33]1([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:18]2[CH:19]=[C:15]([C:2]3[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=3)[N:16]=[CH:17]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: N#Cc1ccnc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Yield: 77 %

Procedure:
The title compound was prepared in 77% yield from 2-chloro-4-pyridinenitrile and 4-(tributylstannyl)-1-tritylimidazole according to the procedure for Example 1, part A. 1H NMR (400 MHz, DMSO-d6): δ 7.17 (5H, m), 7.40-7.47 (10H, m), 7.49 (1H, d, J=1.2 Hz), 7.62 (1H, d, J=1.3 Hz), 7.65 (1H, dd, J=1.5 Hz and 5.0 Hz), 8.13 (1H, s), 8.67 (1H, d, 5.0 Hz).
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C@H:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[NH2:13])=[CH:3]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(OC(C)C)(C)C>C(O)(C)C>[C:19]1([C:17]2[N:18]=[C:14]([C@H:12]3[CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[NH:2][C:3]=4[C:35]4([CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)[NH:13]3)[NH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N[C@@H](c1nc(-c3ccccc3)c[nH]1)Cc1c2[nH]c2ccccc12
Yield: 79.8 %

Procedure:
To a solution of (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine hydrochloride (14 g, 35 mmol) in isopropanol (210 ml) was added 1-tert-butoxycarbonyl-4-piperidone (35 g, 170 mmol) and the mixture refluxed for about two hours. The solvent was evaporated under reduced pressure. Water (150 ml) was added to the residue followed by 10% NaHCO3 solution until neutral pH and extracted by ethyl acetate (4×50 ml). The combined organic extracts were washed with water (2×50 ml) and dried over MgSO4. The solvent was removed under reduced pressure to afford an oil which solidified on addition of diisopropyl ether (150 ml). The precipitate was collected by filtration, washed with diisopropyl ether and dried to afford 13.5 g of the desired product. Melting point: 118-120° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4]Cl.[CH3:7][N:8]=[C:9]=[O:10].[OH-].[K+]>C(Cl)Cl.C(N(CC)CC)C.C(O)C>[Cl:1][CH2:2][CH:3]1[O:6][C:9](=[O:10])[N:8]([CH3:7])[CH2:4]1
Reactant: OC(CCl)CCl
Reactant: CN=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CC(CCl)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A solution of 64.5 g (0.5 mole) of 1,3-dichloro-2-propanol in 200 ml of methylene chloride was treated with 28.5 g (0.5 mole) of methyl isocyanate and a few drops of triethylamine and allowed to stir at ambient temperature overnight. The solution was concentrated and the residue was dissolved in 200 ml of 95% ethanol and treated with a solution of 33.6 g (0.6 mole) of potassium hydroxide in 300 ml of 95% ethanol. The mixture was stirred at ambient temperature for 3.5 hr and then concentrated. The residue was partitioned between 250 ml of benzene and 100 ml of water. The organic layer was washed successively with 50 ml of a 2N hydrochloric acid solution and 100 ml of brine, dried over anhydrous sodium sulfate and concentrated to give 50.5 g of oil as residue. The oil was subjected to vacuum distillation to yield 36.9 g (49%) of clear oil, b.p. 131°-133° C. at 0.3 mm.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O-:15])=O)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]([Cl:26])=[O:15])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])c1nnnn1Cc1ccccc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Cl)c1nnnn1Cc1ccccc1
Temperature: 15 °C

Procedure:
The potassium salt produced in Example 2, and pyridine are stirred at 6° C. in benzene followed by rapid addition of oxalyl chloride. After stirring one half hour at 15° C. the mixture is stripped at 15° C., and scrubbed with two portions of benzene at 15° C. to yield 1-benzyl-1H-tetrazole-5-carbonyl chloride.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[C:34]([CH3:36])[N:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[C:34]([CH3:36])[N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2nc(C)nn12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.5 g), rhodium(II) acetate (dimer) (0.0070 g) and toluene (15 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl 2-diazoacetate (1.6 g) in toluene (15 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.0 g, 56%).
Reaction SMILES: Cl[CH:2](Cl)[C:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.[CH2:29](O)CC>>[CH2:3]([O:5][CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])[CH2:2][CH3:29]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Reactant: CCCO
Product: CCCOCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 11.7 %

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (5 g., 12.9 mmoles) was refluxed in n-propanol (50 ml.) for 20 minutes. The solution was cooled and the precipitated brown solid was filtered off and discarded. The filtrate was treated with water (300 ml.) and the pH adjusted to 8.5 with aqueous sodium bicarbonate. The solution was extracted with ethyl acetate (2 × 20 ml.) and the extracts were discarded. The aqueous phase was acidified to pH 1.5 and extracted with ethyl acetate (3 × 20 ml.). After drying, the solution was removed and the residue dissolved in ethyl acetate (50 ml.), and ether (100 ml.) was added. The precipitated brown solid was filtered off and discarded, and the filtrate evaporated to dryness. The residue was twice recrystallised from aqueous ethanol to give the title compound as colourless needles (500 mg., 11.7%), m.p. 152°-154° (decomp) [α]D25 = 79.8° (c 1.0, tetrahydrofuran), λmax (pH6-phosphate buffer) 236 nm. (ε = 13,600), 260 nm. (ε = 8,700) (shoulder), νmax (Nujol) 3310 (--NH--), 1772 (β-lactam), 1724 (--COOH), 1665 and 1535 cm-1 (--CONH--). (Found: C, 51.3; H, 5.1; N, 6.9; S, 15.9. C17H20N2S2O5 requires: C, 51.5; H, 5.1; N, 7.1; S, 16.2%). N.M.R. (D2O-NaHCO3) 5.78, 6.60, 8.52, 9.13τ (--CH2OCH2CH2CH3), Rf 0.48 (System B); 0.54 (System C).
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:27])[NH:15][C:16](=[O:26])[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[Mg]>CO.C(OCC)(=O)C>[C:1]1([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:16](=[O:26])[NH:15][C:14]2=[O:27])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COc1cccc(C2=C(c3cn4c5c(cccc35)CCC4)C(=O)NC2=O)c1
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccc([C@@H]2C(=O)NC(=O)[C@H]2c2cn3c4c(cccc24)CCC3)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-methoxyphenyl)-1H-pyrrole-2,5-dione (0.73 g, 2.04 mmol), magnesium (0.89 g, 36.7 mmol) in anhydrous methanol was heated to reflux for 1.5 h. After cooling to room temperature, the light yellow solution was diluted with ethyl acetate (200 mL), washed with 1.0 M hydrochloric acid (2×50 mL), water (100 mL), dried over sodium sulfate and concentrated to provide a light brown solid. The residue was purified by column chromatography on silica gel eluting with 40-50% ethyl acetate in hexane to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-methoxyphenyl)pyrrolidine-2,5-dione as a light yellow solid. Mp 87-91° C.; 1H NMR (CDCl3) 400 MHz δ: 8.73 (s. I H), 7.25-7.30 (m, 1H), 7.14 (d, J-J=7.6 Hz, 1H), 6.93-7.01 (m, 3H), 6.77-6.86 (m, 3H), 4.36 (d, J=6.4 Hz, 1H), 4.24 (d, J=6.4 Hz, I H), 4.18 (t J=5.5 Hz, 2H), 3.78 (s, 3H), 2.97 (t, J=5.6 Hz, 2H), 2.19-2.24 (m, 2H).
Reaction SMILES: C([N:8]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]3)[CH:18]=2)[NH:13][C:12]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>[OH-].[OH-].[Pd+2].O>[CH3:34][C:29]1[CH:28]=[C:27]([C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH2:10][CH2:9][NH:8][CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:18][C:17]([N:20]2[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]2)=[CH:16][CH:15]=3)[CH:32]=[C:31]([CH3:33])[CH:30]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nnn(C)c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nnn(C)c4=O)cc3c2CCNCCCCc2cccnc2)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To a stirred solution of 1-[3-{2-[benzyl-(4-pyridin-3-yl-butyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-4-methyl-1,4-dihydrotetrazol-5-one (20 mg in 4 mL methanol) was added 15 mg of 10% palladium hydroxide on carbon catalyst followed by acetic acid (0.020 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 30 minutes the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 90:6.5:1) gave the title compound (16 mg). m/e=496 (M+H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:11]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:23]#[N:24].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:11][C:23]#[N:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC#N)c1ccccc1
Yield: 107.6 %

Procedure:
A solution of methanesulfonic acid (S)-3-tert-butoxycarbonylamino-3-phenylpropyl ester (2.0 g) and sodium cyanide (0.97 g) in DMF (10 ml) was stirred at 70° C. for 16 hours. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (50 ml), and the aqueous phase was reextracted (2×50 ml). The combined organic phases were dried over magnesium sulfate and concentrated. This gave the product (1.7 g) with a molecular weight of 260.3 g/mol (C15H20N2O2); MS (ESI): m/e=261 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][CH:30]1[CH2:32][CH2:31]1>>[CH:30]1([CH2:29][N:22]2[CH2:21][C@@H:20]([CH3:25])[N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])[CH2:32][CH2:31]1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CN(CC3CC3)C2=O)CC1
Yield: 47 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 1-(bromomethyl)cyclopropane, to give the desired product as a light yellow oil (47%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1.Br[CH:17]([CH2:19][CH3:20])[CH3:18].O>CN(C=O)C>[CH3:18][CH:17]([S:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)[CH2:19][CH3:20]
Reactant: COc1ccc(S)cc1
Reactant: CCC(C)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Sc1ccc(OC)cc1
Reaction time: 8 h

Procedure:
Potassium t-butoxide (30.6 g, 275.0 mmol) is added to a solution of 4-methoxybenzenethiol (30.0 ml, 250.0 mmol) in 250 ml of DMF. The mixture is heated at 80° until homogeneous, after which 2-bromobutane (30.0 ml, 275.0 mmol) in 30 ml of DMF is added dropwise over approx. 30 min. The mixture is stirred at 60° overnight, after which it is cooled and is then poured into water and the aqueous phase is extracted with ether (3X). The combined ether extracts are washed with water, with 5% sodium hydroxide, with water and with brine, dried, and the solvent removed to give 4-(1-methylpropylthio)anisole.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1>CO.[Pd]>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)[C:9](=[O:11])[CH3:10])[CH2:13][C@@H:14]2[CH3:32])=[O:31])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccccc3)C[C@@H]2C)cc1
Reaction time: 8 h
Yield: 95.2 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (200 mg, 0.36 mmol) was dissolved in MeOH and a catalytic amount of Palladium on Carbon (10%) was added. The round bottom flask in which resided the resulting solution was evacuated and backfilled with hydrogen. The reaction was stirred under the hydrogen atmosphere overnight. The mixture was carefully filtered through a Celite® plug and concentrated to afford crude product. The crude product was purified by silica gel chromatography (hexanes/ethyl acetate system) to afford N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-phenylacetamide (142 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[O:8]C.S(=O)(=O)(O)O.[N+:19]([O-])([O-:21])=[O:20].[K+]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([N+:19]([O-:21])=[O:20])[C:7]=1[OH:8]
Reactant: COc1ccc(C(F)(F)F)cc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(F)c1O
Temperature: 0 °C
Yield: 86.2 %

Procedure:
The product from (c) (4.1 g) in 1,2-dichloro-ethane (25 ml) was chilled to -10° C. and concentrated sulphuric acid (25 ml) added. The mixture was stirred and kept at -5° to -10° C. while potassium nitrate (2.3 g) was added in portions over a period of 30 minutes. The mixture was stirred for a further 30 minutes at below 0° C. and then poured on to ice (150 ml). The mixture was extracted with chloroform (150 ml) and the extracts washed with water (100 ml), dried (MgSO4) and evaporated to give 3-fluoro-4-hydroxy-5-nitrobenzotrifluoride as a pale yellow liquid (4.1 g).