Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][C:19]1[CH:64]=[CH:63][C:22]([O:23][CH2:24][C@@H:25]([OH:62])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41](C4CCCCN4C(NCCCCCCCC)=O)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)(Cl)Cl.[CH3:69][OH:70]>>[CH2:28]([NH:27][C:69]([N:38]1[CH2:37][CH2:36][CH:35]([C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:60]=[CH:61][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:62])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:64][CH:63]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])[CH2:40][CH2:39]1)=[O:70])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:60][CH3:61]
Reactant: CO
Reactant: CCCCCCCCNC(=O)N1CCCCC1C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)CC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)CC1

Procedure:
4-((4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinylcarbonyl)-N-octyl-1-piperidinecarboxamide (0.160 g, 0.180 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.02 g, 0.03 mmol).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]([O:22][CH2:23][CH2:24][OH:25])=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:26][C:27]1[C:32](Cl)=[N:31][CH:30]=[CH:29][N:28]=1.O>O1CCOCC1>[Cl:26][C:27]1[C:32]([O:25][CH2:24][CH2:23][O:22][C:17]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11][CH2:12]3)=[N:21][CH:20]=[CH:19][N:18]=2)=[N:31][CH:30]=[CH:29][N:28]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2nccnc2Cl)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
NaH (50% in mineral oil; 0.153 g, 3.50 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2) and 2,3-dichloropyrazine (1.0 g, 6.71 mmol) in dioxane (10 mL). The reaction was stirred in a sealed tube at 100° C. overnight. The reaction mixture was poured into water and extracted with diethyl ether. The ether phase was dried (MgSO4), concentrated and purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent to give 0.823 g (61%) of the title product: Pos-EI-MS shows M+ and 14 ions supporting the stated structure. HRMS m/z calcd for C19H25CIN6O4 (M)+436.1626, found 436.1606.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]1([C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:5]1([C:11](=[O:19])[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:1][OH:3])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cc1ccccn1)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C(=NO)c1ccccn1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 8.75 g (127 mmol) of sodium nitrite in water was added dropwise to a solution of 25 g (127 mmol) of 1-phenyl-2-pyridin-2-ylethanone in 250 ml of water/conc. hydrochloric acid (8:1) at room temperature. After 2 h, the solution was neutralized with sodium carbonate. The product crystallized out overnight to result in 25.3 g of 1-phenyl-2-pyridin-2-ylethane-1,2-dione 2-oxime.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:18]1([C:21]2[C:26]([C:27](O)=[O:28])=[CH:25][N:24]=[C:23]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[N:22]=2)[CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:27]([C:26]2[C:21]([CH:18]3[CH2:20][CH2:19]3)=[N:22][C:23]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=3)=[N:24][CH:25]=2)=[O:28])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CN)c1
Product: CCOC(=O)C(C)(C)Oc1cccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 52B]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[3-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless amorphous solid.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][CH:10]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14]1.[Cl-].[NH4+].Cl>O.C1COCC1>[C:1]1([C:7]([CH2:8][CH2:9][CH:10]=[CH2:11])=[C:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]C1C=CC=C1
Reactant: C=CCCC(=O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=C1C=CC=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 L round bottomed flask was charged with 1-phenyl-4-penten-1-one (49.1 g, 307 mmol), THF (200 mL), and a stir bar, and cooled in an ice bath. Cyclopentadienyl magnesium chloride (330 mL of approximately 1 M solution in THF, 330 mmol) was added dropwise over 1 hour. The pale red solution was stirred overnight while warming to room temperature. The solution was then refluxed for 4.5 hours, during which time the red color intensified. After being stirred overnight at room temperature again, the solution was acidified by first adding 5.5 g of ammonium chloride in 100 mL of water, and then adding 50 mL of 1 M HCl. The product was extracted with pentane, and the pentane extracts were collected, washed with water, and dried over sodium sulfate. Elution through silica with heptane and concentration under vacuum afforded 38.6 g (55% isolated and purified yield) of the product 6-phenyl-6-(3-butenyl)fulvene as a red oil.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:21]=[C:19]([OH:20])[C:17]([OH:18])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[CH2:23]([N+:27]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>CO>[CH2:36]([N+:27]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38][CH3:39].[OH:20][C:19]1[CH:21]=[C:14]([CH2:13][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:10]([O-:12])=[O:11])[CH:15]=[CH:16][C:17]=1[OH:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)[O-]
Temperature: 4 °C
Yield: 83 %

Procedure:
A solution of N-Boc-(L)-Dopa (175 g, 0.59 mol) in methanol (1 L) was cautiously mixed with a methanolic solution of tetrabutylammonium hydroxide (1.0 M, 0.55 L) at 0° C. for 30 min. The mixture was then concentrated under reduced pressure and dried by azeotroping twice with toluene. The residue was crystallized after cooling at 4° C. for 16 h. The resulting crystalline solid was washed with acetone (400 mL×3), collected on a Buchner funnel, and then dried under high vacuum to afford 245 g (83% yield) of the title compound 1a. 1H NMR (400 MHz, DMSO-d6): δ 0.94 (t, J=7.6 Hz, 12H), 1.30 (m, 17H), 1.60 (m, 8H), 3.18 (m, 8H), 4.58 (m, 1H), 5.68 (d, J=5.6 Hz, 1H), 6.30 (d, J=7.6 Hz, 1H), 6.46 (d, J=8.0 Hz, 1H), 6.51 (s, 1H), 8.85 (s, 1H); 8.94 (s, 1H).
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][C@@H:11]([N:32]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[CH:33]1)[C:12]([NH:14][C@H:15]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:16][O:17]C(OCC1C=CC=CC=1)=O)=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:29][C:28]([CH3:31])([CH3:30])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:32]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)=[CH:33]1)[CH2:10][C:9]([OH:49])=[O:8])[CH2:16][OH:17]
Reactant: CC(C)(C)[C@H](COC(=O)OCc1ccccc1)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A mixture of N-(1-benzyloxycarbonyloxy-3,3-dimethylbut-2(R)-yl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester (140 mg, 0.212 mmol) and Pd(OH)2 (60 mg of 20% Pd by content) in MeOH (1mL) and EtOAc (9 mL) was stirred under H2 atmosphere for 3 hours. The catalyst was filtered onto Celite and rinsed with 10% MeOH/CHCl3 (75 mL). The filtrate was concentrated in vacuo to provide a yellow solid, which was precipitated from hot CHCl3 solution with hexane to furnish 68 mg (95%) of N-[2,2-dimethyl-1(S)-(hydroxymethyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow solid, mp 192-4° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](O)=O.[NH2:10][C:11]1[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:16]=1[NH2:17]>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[C:16]3[N:17]=[C:7]([CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[NH:10][C:11]=3[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14]2=[O:29])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=C(O)Cc1cccs1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3cccs3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 2-thiopheneacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine.
Reaction SMILES: [OH-].[K+].[CH3:3][CH2:4][OH:5].Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1.Cl>CS(C)=O>[CH2:4]([O:5][C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1)[CH3:3]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOc1ccc(C(=O)O)cn1
Temperature: 25 °C
Yield: 71 %

Procedure:
Potassium hydroxide powder (0.373 g, 12.005 mmol) and EtOH (0.3 mL, 6.002 mmol) were added to a solution of 6-chloropyridine-3-carboxylic acid (0.473 g, 3.001 mmol) in DMSO (12 mL) at room temperature. The reaction mixture was heated at 100 C for 21 h, and cooled to room temperature. A 1M aqueous solution of HCl was added. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to afford the title compound (356 mg, 71%). Method B HPLC-MS: MH+ requires m/z=168. Found: m/z=168, Rt=1.50 min (95%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10](=[O:20])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:9][C:10]2=[O:20]
Reactant: O=c1[nH]n(Cc2ccccc2)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)c(=O)[nH]n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 1-benzyl-5-nitro-1,2-dihydro-indazol-3-one (0.44 g) in MeOH (50 mL) was added Pd/C(10%) catalyst (0.1 g) and the reaction mixture was stirred for four hours at ambient temperature under a hydrogen atmosphere using a balloon. After this time the reaction mixture was filtered through Celite® which was washed with more EtOAc. The combined organic solution was evaporated in vacuo for afford the desired 5-amino-1-benzyl-1,2-dihydro-indazol-3-one (0.39 g) which was taken into the next reaction without further purification. MS (ESI+): 240.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21]OC4CCCCO4)[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[S:11][C:10]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH2:21][O:52][C:51](=[O:57])[C:53]([F:56])([F:55])[F:54])[C:14](=[O:29])[N:13]([CH3:30])[C:12]=3[S:11][C:10]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:40])([F:41])[F:42])[CH:33]=2)=[CH:6][CH:7]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
To a solution of 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 21, Step 2, 30 mg, 0.047 mmol) in TFA (2 mL) was added triethylsilane (1 mL). The reaction was stirred at RT for 3 h then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenoxy)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propyl2,2,2-trifluoroacetate (25 mg, 83.9% yield) as an oil. LCMS: MH+ 637 and TR=2.274 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[F:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][NH:22]2)=[CH:18][CH:17]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[C:16]([F:15])[CH:24]=2)[CH2:20][CH2:21]1)=[O:14]
Reactant: O=C(O)CSc1nc2ccccc2s1
Reactant: Fc1ccc2c(c1)NCC2
Product: O=C(CSc1nc2ccccc2s1)N1CCc2ccc(F)cc21
Yield: 70 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 6-fluoroindoline to yield 43 as a white solid (70%): MS m/z: 345 (M+H)+. Anal. Calcd. For, C17H13N2FOS2: C, 59.28; H, 3.80; N, 8.13; S, 18.62; F, 5.52. Found: C, 59.51; H, 3.85; N, 8.13; S, 18.73; F, 5.37.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][C:17]1[C:18]([CH3:25])=[C:19]([CH:23]=O)[NH:20][C:21]=1[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:23][C:19]1[NH:20][C:21]([CH3:22])=[C:17]([CH2:16][CH2:15][CH2:14][N:13]([CH3:12])[CH3:26])[C:18]=1[CH3:25]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1CCCN(C)C
Yield: 71 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one was condensed with 4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) using method B to give 284.9 mg (71%) of 5-bromo-3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one as a red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2([CH3:14])[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:16].N#N>>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]2([CH3:14])[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc(C2(C)CC2)ccc1C(=O)O
Agent: N#N
Product: Cc1cc(C2(C)CC2)ccc1C(=O)Cl
Temperature: 25 °C
Yield: 81.8 %

Procedure:
2-Methyl-4-(1-methyl-cyclopropyl)-benzoic acid (2.139 g, 11.243 mmol) and phosphoruspentachloride (2.575 g, 12.37 mmol) were charged into a 50 ml flask under stirring. These both solids dissolved at 100° C. The reaction mixture was stirred 2 hours at 120° C. with an reflux condenser in a N2 atmosphere. After that the resulting phosphorus oxylchloride was distilled off at 140° C. from the reaction mixture. The whole reaction mixture was cooled to room temperature and the reaction mixture still remained as a solution. The desired product was distilled by Kugelrohr distillation (150° C./4 mbar) to give 2-Methyl-4-(1-methyl-cyclopropyl)-benzoyl chloride (1.92 g, 9.2 mmol)
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)N1C(=O)Cc2cc(N)ccc21
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1C(=O)Cc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reaction time: 2 h

Procedure:
20.0 g (105 mmol) of 1-acetyl-5-amino-2-indolinone are placed in 200 ml of pyridine, combined with 15.3 ml (120 mmol) of benzenesulphonic acid chloride while cooling with ice and stirred for 2 hours. Then the mixture is poured onto 1.8 l of water and suction filtered. The crude product is stirred into acetone, suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][CH:6]([NH:21][OH:22])[C:5]1=[O:23].[CH2:24]([N:27]=[C:28]=[O:29])[CH2:25][CH3:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:7][C:6](=[N:21][O:22][C:28]([NH:27][CH2:24][CH2:25][CH3:26])=[O:29])[C:5]1=[O:23]
Reactant: COCN1C(=O)C(NO)CN(c2ccccc2)c2ccccc21
Reactant: CCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNC(=O)ON=C1CN(c2ccccc2)c2ccccc2N(COC)C1=O
Yield: 63.8 %

Procedure:
To 1-methoxymethyl-2-oxo-3-hydroxyamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (41.4 g) in absolute tetrahydrofuran (500 ml) were added n-propyl isocyanate (28.3 g) and triethylamine (33.7 g). The resultant mixture was refluxed for three hours with heat. The reaction mixture was concentrated under reduced pressure, and the residue was crushed in isopropyl ether and collected by filtration, to thereby obtain 33.4 g of the title compound (yield: 63.3%).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Br:20])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Br:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][CH3:13])[C:9]=2[CH:14]=1
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)c(Br)cc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1CNCCc2cc(OC)c(Br)cc21
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.561 g, 1.48 mmol) in methanol (30 mL) was treated with 15% aqueous NaOH (30 mL), and stirred overnight at 20 C. The product mixture was diluted with brine (100 mL), extracted twice with EtOAc (200 mL), dried with MgSO4, and concentrated to give 0.412 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.24 (s, 1H), 6.76 (s, 1H), 3.83 (s, 3H), 3.02 (m, 3H), 2.91 (s, 1H), 2.85-2.76 (m, 3H), 2.63 (m, 1H), 1.78 (m, 1H), 1.72 (m, 1H), 0.94 (dd, J=8, 8 Hz, 3H). MS calculated for C13H18BrNO+H: 284, observed: 284.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[CH:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20](O)[CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[C:1]([S:4][CH2:5][CH:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]([NH:9][CH2:10][C:11]([O:13][C:20]1[CH:19]=[CH:18][C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1)=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
N-[2-[(Acetylthio)methyl]-4-methyl-1-oxopentyl]glycine (0.5 g) is dissolved in 30 ml of ethyl acetate along with p-nitrophenol (0.2 g). This solution is cooled to 5° C., N,N'-dicyclohexylcarbodiimide (0.4 g) is added portionwise and the reaction mixture is stirred at 5° for about 16 hours. The dicyclohexyl urea is filtered off and the filtrate is concentrated thoroughly in vacuo. Isopropyl ether is added to the residue and allowed to sit for about 16 hours. The crystalline solid is filtered to yield 0.4 g of product, melting point 95°-100° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:38][CH2:39][C@@H:40]1[C@@H:44]([OH:45])[C@@H:43]([OH:46])[CH2:42][N:41]1[CH2:47][CH2:48][OH:49]>>[OH:45][C@H:44]1[C@@H:43]([OH:46])[CH2:42][N:41]([CH2:47][CH2:48][OH:49])[C@@H:40]1[CH2:39][NH:38][C:32]([N:12]1[C@@:13]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)([CH3:24])[C@@:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=1[O:35][CH2:36][CH3:37])=[O:33]
Reactant: NC[C@@H]1[C@@H](O)[C@@H](O)CN1CCO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC[C@@H]1[C@@H](O)[C@@H](O)CN1CCO

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (2R,3R,4S)-2-aminomethyl-1-(2-hydroxy-ethyl)-pyrrolidine-3,4-diol (AFID Therapeutics) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O5 [(M+H)+] 698.2871, observed 698.2873.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH3:15])=[C:10]([C:12]([OH:14])=O)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:27][O:28][C:29](=[O:51])[C@@H:30]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH:31]([CH3:33])[CH3:32]>N1C=CC=CC=1>[CH3:27][O:28][C:29](=[O:51])[C@@H:30]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:45]=[CH:46][C:47]([NH:50][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[C:9]=3[CH3:15])=[O:14])=[CH:48][CH:49]=2)=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH:31]([CH3:33])[CH3:32]
Reactant: COc1cccc2oc(C(=O)O)c(C)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To 110 mg (0.53 mmol) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 2 mL of oxalyl chloride and the resulting mixture was refluxed for 4 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 2 mL of dichloromethane and was added to a mixture of 232 mg (0.64 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were removed under vacuum. Column chromatography on silica gel gave 95 mg (33% yield) of (S)-2-{4′-[(4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as off white solid.