Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:36]([O:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=O)=[C:46]([CH3:52])[CH:45]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)(C)C>[CH2:9]([O:8][C:6](=[O:7])/[C:5](/[O:4][CH2:2][CH3:3])=[CH:48]/[C:47]1[CH:50]=[CH:51][C:44]([O:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:45][C:46]=1[CH3:52])[CH3:10]
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)O
Product: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)cc1C)OCC
Temperature: 60 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
(Ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride (3.79 g, 8.8 mmol) and potassium carbonate (1.46 g, 10.6 mmol) were added to a solution of 4-benzyloxy-2-methyl-benzaldehyde (0.8 g, 3.5 mmol) in isopropanol (10 ml) at 10° C. under an argon atmosphere [for the preparation of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride see: K. K. Bach, H. R. El-Seedi, H. M. Jensen, H. B. Nielsen, I. Thomson, K. B. G. Torssell, Tetrahedron 1994, 50, 7543-7556]. The suspension was heated to 60° C. After 12 h and after 20 h (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride (each time 3.79 g, 8.8 mmol) and potassium carbonate (each time 1.46 g, 10.6 mmol) were added again. After 36 h the suspension was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed with saturated aqueous ammonium chloride and ice water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, dichloromethane) to give 0.7 g (2.1 mmol, 58%) of the title compound as yellow liquid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([NH2:21])[CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([NH:21][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:13]=1
Reactant: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)CCCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)CCCCCl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 124.6 %

Procedure:
5-Chlorovaleryl chloride (2.64 g, 17 mmol, 1.1 equiv) in CH2Cl2 (5 ml) was added over 2 min to a stirred solution of 3-amino-5-nitro-benzoic acid methyl ester (D1) (3 g, 15.3 mmol, 1 equiv) and NEt3 (2.6 ml, 18 mmol, 1.2 equiv) in CH2Cl2 (30 ml). The resulting mixture was stirred for 1 h at room temperature then washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with CH2Cl2 to give 3-(5-Chloro-pentanoylamino)-5-nitro-benzoic acid methyl ester D3 (6 g, 112%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:21]2[C:20]([Cl:22])=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1.[OH-].[Na+]>CC(C)=O.O>[Br:12][C:13]1[C:21]2[C:20]([Cl:22])=[N:19][CH:18]=[N:17][C:16]=2[N:15]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:14]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Methylbenzenesulfonyl chloride (5.21 g, 27.3 mmol) was added to a suspension of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (6.34 g, 27.3 mmol) in acetone (70 mL). After addition of an aqueous solution of sodium hydroxide (1.11 g, 27.8 mmol in 15 mL water), the reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water (125 mL), stirred for 10 minutes, and filtered. The collected solids were washed with water to afford the product as a solid, Yield: 8.88 g, 23.0 mmol, 84%. LCMS m/z 385.9, 387.9, 389.8 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.42 (s, 1H), 8.06 (br d, J=8.4 Hz, 2H), 7.46-7.51 (m, 2H), 2.37 (br s, 3H).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([C@@H:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([C@@H:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)[C@H](CC1CCCC1)c1ccc(-c2ccccc2)cc1
Yield: 60.1 %

Procedure:
A solution of 2(R)-biphenyl-4-yl-3-cyclopentylpropionic acid (36.9 mg, 0.13 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (52.3 mg, 0.14 mmol), N,N-diisopropylethylamine (66 μL, 0.38 mmol), and 2-aminothiazole (25.1 mg, 0.25 mmol) in dry N,N-dimethylformamide (627 μL) was stirred at 25° C. under nitrogen for 13 h. The reaction mixture was concentrated in vacuo to remove the N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (100 mL). The organic layer was washed with a 10% aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded (2R)-2-biphenyl-4-yl-3-cyclopentyl-N-thiazol-2-yl-propionamide (29.4 mg, 62%) as a white foam: mp 132-134° C.; FAB-HRMS m/e calcd for C23H24N2OS (M+H)+ 377.1687, found 377.1696.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13]C3N=CNC=3)[CH2:11][CH2:10][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)C=CC=3)=O)[CH2:8][C:7]=2[CH:31]=1.[OH-].[Na+].C(Cl)(=[O:36])C>ClCCl>[C:10]([N:9]1[CH2:8][C:7]2[CH:31]=[C:3]([Br:2])[CH:4]=[CH:5][C:6]=2[NH:12][CH2:13][CH:19]1[CH2:21][C:30]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:36])[CH3:11]
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Br)ccc2NCC1Cc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of Compound B (200 mg, 0.63 mmol), dichloromethane (5 mL), and aqueous sodium hydroxide (1 ml, 1N) was combined and cooled to 0° C. Acetyl chloride (66 mL, 0.94 mmol) was added to the mixture, and after stirring for 2 hour at 0° C. aqueous sodium hydroxide (20 ml, 1N) and dichloromethane (50 mL) were added, followed by extraction with dichloromethane (50 mL). The organic portions were combined, dried (Na2SO4), and concentrated to a crude oil (230 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18](OC)=[O:19])[CH2:13][C:14]([F:17])([F:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[BH4-].[Na+]>C(O)C.O.Cl>[F:16][C:14]([F:17])([CH3:15])[CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:18][OH:19]
Reactant: COC(=O)[C@H](CC(C)(F)F)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(F)(F)C[C@@H](CO)NC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of methyl N-((benzyloxy)carbonyl)-4,4-difluoro-L-norvalinate (1.59 g, 5.29 mmol) in ethanol (50 mL) was added lithium chloride (919 mg) and the mixture was stirred for 10 minutes. Sodium borohydride (820 mg) was added slowly, the mixture stirred for 2 hours. Then, another portion of sodium borohydride (100 mg) was added and stirring continued for 30 minutes. The mixture was diluted with water (20 mL) and neutralized slowly with 1N HCl followed by the addition of another aliquot of water. The mixture was extracted with ethyl acetate (2×), washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated under vacuum to afford benzyl (1S)-3,3-difluoro-1-(hydroxymethyl)butylcarbamate.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1cccc(Cl)c1
Product: N#Cc1cc(-c2cccc(Cl)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (73 mg, 91%), MS (ISP) m/z=322.4 [(M+H)+], mp 241.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1>C1(C)C(C)=CC=CC=1.[Pd]>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)[nH]c1cnccc12

Procedure:
To a solution of the crude tetrahydro β-carboline 3 in xylene (10 ml) was added 10% Pd/C (50-100 mg) and the mixture refluxed overnight. The reaction mixture was then cooled and filtered through celite and washed with MeOH (5-10 ml). Evaporation of the xylene/MeOH filtrate under reduced pressure yielded a crude β-carboline residue. The crude residue was subjected to flash chromatography (30% ethyl acetate in hexanes) to obtain pure β-carbolines 4 in 50-75% overall yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N+:4]([CH2:49][CH2:50][CH2:51][CH2:52][CH:53]([NH:61]C(OCC2C=CC=CC=2)=O)[C:54]([O:56]C(C)(C)C)=[O:55])[CH:5]=[C:6]([CH2:28][CH2:29][CH:30]([NH:38]C(OCC2C=CC=CC=2)=O)[C:31]([O:33]CCCC)=[O:32])[C:7]=1[CH2:8][CH:9]([NH:17]C(OCC1C=CC=CC=1)=O)[C:10]([O:12]C(C)(C)C)=[O:11].Br>>[CH:5]1[N+:4]([CH2:49][CH2:50][CH2:51][CH2:52][C@@H:53]([NH2:61])[C:54]([O-:56])=[O:55])=[CH:3][C:2]([OH:1])=[C:7]([CH2:8][C@H:9]([NH2:17])[C:10]([OH:12])=[O:11])[C:6]=1[CH2:28][CH2:29][C@H:30]([NH2:38])[C:31]([OH:33])=[O:32]
Reactant: CCCCOC(=O)C(CCc1c[n+](CCCCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc(O)c1CC(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: Br
Product: N[C@H](CCCC[n+]1cc(O)c(C[C@H](N)C(=O)O)c(CC[C@H](N)C(=O)O)c1)C(=O)[O-]

Procedure:
reacting the pyridinium salt prepared in step (c) with HBr in an appropriate solvent to provide deoxypyridinoline.
Reaction SMILES: [CH2:1]([S:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25]CC)=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[Li+].[OH-].Cl>C(O)C.O>[CH2:1]([S:21][C:22]([CH3:28])([CH3:29])[C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)(C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)(C)C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
Ethyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenylthio)-2-methylpropanoate (209 mg, 0.50 mmol) was dissolved in ethanol (2.5 mL) and added to a solution of LiOH×H2O (168 mg, 4.0 mmol) in water (2.5 mL). The resulting turbid solution was stirred at 70° C. under inert atmosphere for 2 hours, cooled and added water (10 mL) and 1 M HCl (5 mL) to pH=1-2. The mixture was extracted three times with heptane (3×20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give 101 mg of the title compound as crude oil. Purification by flash chromatography on silica gel using gradient elution (starting with pure heptane and increasing stepwise to heptane:EtOAc (with 5% HOAc) 80:20) afforded 78 mg (40%) of the title compound as oil.
Reaction SMILES: [C:1]1(=[O:13])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[C:4](=[O:12])[CH:3]=[CH:2]1.[NH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15].C(Cl)CCl>C(Cl)Cl>[O:13]=[C:1]1[CH:2]=[CH:3][C:4](=[O:12])[N:5]1[CH2:6][CH2:7][CH2:8][C:9]([NH:15][NH:14][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:11]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)CCCN1C(=O)C=CC1=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)CCCN1C(=O)C=CC1=O
Yield: 84.7 %

Procedure:
4-Maleimidobutyric acid (245 mg, 1.33 mmol), tert-butyl hydrazinecarboxylate (201 mg, 1.52 mmol) and EDC (400 mg, 2.08 mmol) in 5 ml of CH2Cl2, were stirred overnight under Ar, washed with 1 M NaH2PO4/NaCl (conc), dried over MgSO4, filtered, evaporated and purified on SiO2 chromatography eluted with MeOH/DCM (1:25) to afford 335 mg (85%) of the title compound. 1H NMR (CDCl3), 7.83 (br, 1H), 6.65 (s, 2H), 6.50 (br, 1H), 3.58 (t, 2H, J=6.3 Hz), 2.15 (t, 2H, J=7.0 Hz), 1.90 (dt, 2H, J=6.8, 13.4 Hz), 1.40 (s, 9H); 13C NMR 171.30, 155.61, 134.41, 82.00, 37.13, 31.38, 28.36, 24.95; MS m/z+320.2 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([OH:40])[CH2:37][NH:38][CH3:39])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:38]([CH2:37][CH:36]([OH:40])[C:33]4[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][OH:26])=[CH:31][CH:32]=4)[CH3:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc(OCCO)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(O)c2ccc(OCCO)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-[4-(2-hydroxyethoxy)phenyl]-2-(methylamino)ethanol (Preparation 83) (70 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 4 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (82 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:35][O:36][CH:37]1[CH2:40][NH:39][CH2:38]1>CN1C(=O)CCC1>[CH3:35][O:36][CH:37]1[CH2:40][N:39]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:38]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: COC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CC(OC)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-mopholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-methoxy-azetidine hydrochloride in NMP. ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: [CH:1]([N:4]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:5](=[O:37])[CH2:6][N:7]1[C:13](=[O:14])[C:12](=[N:15]NC2C=CC=CC=2)[C:11](=[O:23])[N:10]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)([CH3:3])[CH3:2]>C(O)(=O)C.[Zn]>[NH2:15][CH:12]1[C:13](=[O:14])[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)=[O:37])[C:8]2[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=2[N:10]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:11]1=[O:23]
Reactant: COc1ccc(Cn2c(=O)c(=NNc3ccccc3)c(=O)n(CC(=O)N(c3ccc(OC)cc3)C(C)C)c3ccccc32)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C(N)C(=O)N(CC(=O)N(c3ccc(OC)cc3)C(C)C)c3ccccc32)cc1
Yield: 73.5 %

Procedure:
To a stirred solution of N-Isopropyl-2-[5-(4-methoxy-benzyl)-2,4-dioxo-3-(phenyl-hydrazono)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-(4-methoxy-phenyl)-acetamide (4.55 g, 7.51 mmol) in acetic acid (50 mL) was added zinc dust (4.50 g) and the resultant mixture was stirred 4 hours at ambient temperature. The zinc was separated by filtration, the filtrate was concentrated in vacuo, and the resultant oil partitioned between water (150 mL) and ethyl acetate (250 mL). The pH was adjusted to 8 with 6N sodium hydroxide and the phases separated. The aqueous phase was extracted with ethyl acetate (2×80 mL) and the organics combined, dried with magnesium sulfate, filtered and concentrated in vacuo to a brown oil. The crude product was purified via flash chromatography on silica gel (70 g) eluting successively with EtOAc/Hexanes (2:1, 500 mL) and methylene chloride/methanol (19:1, 500 mL). Appropriate fractions were combined and concentrated to give the title compound (2:85 g, 5.52 mmol) as a brown oil: 1H NMR (300 MHz, CDCl3): d 7.43 (d, J=7.3 Hz, 1H), 7.30-7.19 (m, 4H), 7.05-6.90 (m, 5H), 6.59 (d, J=8.8 Hz, 2H), 5.13 (d, J=15.1 Hz, 1H), 5.00 (m, 1H), 4.86 (d, J=15.1 Hz, 1H), 4.25 (s, 1H), 4.21 (d, J=16.6 Hz, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 3.48 (d, J=16.6 Hz, 1H), 1.09 (m, 6H); TLC (CH2 Cl2 /CH3OH (29:1)): Rf =0.11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12]C)=[O:11].Br[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:16]1([S:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:14])[C:10]([OH:12])=[O:11])=[C:2]([F:1])[CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrC1CCCC1
Reactant: COC(=O)C(C)c1ccc(S)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(SC2CCCC2)cc1F
Yield: 95.4 %

Procedure:
A solution of compound (9) (0.53 g, 2.5 mmol), bromocyclopentane (0.32 mL, 3.0 mmol), and potassium carbonate (1.2 g, 8.8 mmol) in dry DMF (5 mL) was treated in the same manner as in Example 7. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution followed by conventional hydrolysis to give 0.64 g (90%) of compound (17) of interest as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[S:17][C:16]([C:18](O)=O)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:35][C:36]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([NH2:40])=[O:39]>N1C=CC=CC=1.CN(C=O)C>[C:38]([C:37]1[C:36]2[N:35]=[C:18]([C:16]3[S:17][C:13]([CH:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:14][CH:15]=3)[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)(=[O:39])[NH2:40]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(C(=O)O)s1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 34C (2.4 g) in pyridine (100 mL) and DMF (100 mL) was added CDI (1.6 g). The mixture was heated at 40° C. for 1 hour, treated with 2,3-diaminobenzamide dihydrochloride (1.8 g), stirred at ambient temperature overnight and concentrated. The concentrate was heated in acetic acid (50 mL) at 80° C. overnight and concentrated. The concentrate was flash chromatographed on silica gel with ethyl acetate.
Reaction SMILES: B.[Na].S(=O)(=O)(O)O.Cl.[OH-].[Na+].[CH2:11]([N:18]1[C:22](=O)[CH2:21][C@H:20]([OH:24])[C:19]1=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>COCCOC.O.C1(C)C=CC=CC=1.CO>[CH2:11]([N:18]1[CH2:22][CH2:21][C@H:20]([OH:24])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C[C@H](O)C(=O)N1Cc1ccccc1
Agent: B
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: O[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
158 g (approximately 0.745 mole) crude (S)-1-benzyl-3-hydroxy-2,5-pyrrolidinedione (IIa) were obtained. It was dissolved in 800 ml DME to which 85.1 g (2.25 moles) sodium boron hydride were then added. A solution of 60.3 ml (1.125 moles) sulfuric acid in 200 ml DME was added dropwise to the thick suspension produced at 20°-32° C. within 2.5 h and subsequently agitated 3 h at 70° C. After cooling off, 200 ml methanol were added dropwise and the batch was subsequently rotated in to dryness. The residue was taken up in 700 ml water, compounded under ice cooling with 180 ml conc. hydrochloric acid and agitated 1 h until the end of the development of gas. Then, 270 ml sodium hydroxide solution and 1 1 toluene were added. After the mixture was heated to 70° C. the toluene phase was separated and the aqueous phase subsequently extracted with 300 ml toluene. After the rotating in of the organic phase the residue began to gas, so that it was taken up in 600 ml water and 600 ml toluene and agitated overnight at room temperature with 90 ml conc. hydrochloric acid. The mixture was then made basic again and extracted and rotated in as above, yielding 131.3 g (99.4%) crude (S)-1-benzyl-3-hydroxypyrrolidine (IIIa).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)=[CH:15][N:16]3[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:14]2[C:13]3[C:17](=[CH:18][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[CH:11][CH:12]=3)[N:16]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[CH:15]=2)=[CH:26][CH:27]=1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1cccc(-c2ccc3c(-c4ccc(O)cc4)cn(-c4ccncc4)c3c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN(C)CCOc1ccc(-c2cn(-c3ccncc3)c3cc(-c4cccc([N+](=O)[O-])c4)ccc23)cc1

Procedure:
The target compound was prepared as in Example 18 using 4-(6-(3-nitrophenyl)-1-(pyridin-4-yl)-1H-indol-3-yl)phenol (32 mg, 0.079 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (34 mg, 0.237 mmol) and cesium carbonate (154 mg, 0.237 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: COc1cccc(CN)c1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccc(OC)c1
Yield: 85 %

Procedure:
The compound prepared in Example 3 was reacted with 3-methoxy-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 85%).