Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C.O>[CH2:16]([O:15][C:13]([C:12]1[CH:18]=[CH:19][C:9]([O:8][C:3]2[C:2]([C:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1)=[O:14])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOC(=O)c1ccc(Oc2ncccc2Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1ccc(Oc2ncccc2C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 135 °C

Procedure:
Four glass microwave reaction vessels were charged with ethyl 4-(3-bromopyridin-2-yloxy)benzoate (1.025 g, 3.18 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.195 g, 3.86 mmol), sodium carbonate (1.725 g, 16.28 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.140 g, 0.199 mmol). DME (6 mL), Water (3 mL) and Ethanol (2 mL) were added and the reaction mixtures were sealed under argon and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 135° C. for 15 min. The reaction mixtures were combined and partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (120 gram)) eluting with EtOAc:hexanes (0:1→1:4) to give a light-yellow crystalline solid. MS m/z: 425.1 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24]Cl)=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:26])[CH:12]=3)=[CH:10][C:3]=12.[I-:37].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][I:37])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:26])[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCCl
Reactant: [I-]
Agent: [Na+]
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI

Procedure:
4-Chloro-2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 147c, but using 1.15 g of 4-chloro-2-[1-methyl-5-methoxy-6-(2-chloroethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.950 g of sodium iodide. After purification by flash chromatography (silica, 40/60 by volume ethyl acetate/cyclohexane as eluents, argon), 1.21 g of 4-chloro-2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained, the characteristics of which are as follows:
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH:9]([S:35]CC1C=CC(OC)=CC=1)[CH2:10][NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:28]([O:30]C(C)(C)C)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.Cl>O>[NH2:7][CH:8]([CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH:9]([SH:35])[CH2:10][NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(CSC(CN[C@@H](Cc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(S)C(N)Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-[N-[(3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-[[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]-L-phenylalanyl]-L-leucine, 1,1-dimethylethyl ester (780 mg, 1.06 mmol), anisole (1.0 ml) and trifluoroacetic acid (14 ml) was stirred at room temperature under argon. After 1 hour, the reaction was cooled to 0° C. and mercuric trifluoroacetate (497 mg, 1.1 eq) was added. The reaction was stirred for 1 hour at 0° C. and then concentrated to a red oil. The oil was triturated with ether/hexane and a nearly colorless solid was collected and washed with hexane. The solid was dissolved in degassed 80% aqueous acetic acid (20 ml) and hydrogen sulfide was bubbled through the solution for 30 minutes. The black reaction mixture was filtered through a pad of Celite followed by a Millipore filter (Teflon). The filtrate was concentrated to an amber oil. The oil was diluted with degassed double distilled water (20 ml) and 1N hydrochloric acid (3.2 ml, 1.5 eq) and the mixture filtered (Millipore, Metricel). The clear, colorless filtrate was lyophilized and relyophilized twice from water to yield the title compound as a fluffy, colorless solid: 490 mg (0.87 mmol); Rf =0.70 (silica gel, N-butanol:water:acetic acid, 4:1:1); Rf =0.75 (silica gel, chloroform:methanol:acetic acid, 4:1:1); fast atom bombardment mass spectrum: (M+H)+ m/e=458, (M-H)- m/e=456; melting point 123°-160° C.; [α]D =-12.8° (c=1.23, methanol). Analysis: C25H35N3O3S.1.8 mole HCl.2.2 mole H2O: C, 53.34; H, 7.38; N, 7.46; S, 5.69; SH 5.87; Cl, 11.33. Found: C, 53.06; H, 7.15; N, 7.12; S, 5.39; SH, 5.86; Cl, 11.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[NH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CCN(CC)CCOCCN
Product: CCN(CC)CCOCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12

Procedure:
Following the general procedure of Example 1 and making non-critical variations, but using 6,9-dichloro-2-methoxyacridine and commercially available 2-(2-aminoethoxy)-N,N-diethylethanamine, the title compound was obtained; MS (Found M+1=402).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:30])[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:29].Cl>O.CO>[C:19]1([CH2:18][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH2:8][CH2:7][C:6]([OH:30])=[O:5])[C:10]2=[O:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Reaction time: 6 h
Yield: 98.2 %

Procedure:
Lithium hydroxide monohydrate (31 mg, 0.75 mmol) is dissolved in water (3.5 mL) and this solution is added into 3-(3-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (180 mg, 0.5 mmol) in methanol (3.5 mL) at room temperature. The mixture is stirred for 6 hr and 1.0 M HCl aqueous solution (1.5 mL) is added along with water (25 mL). Then the mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried over MgSO4 and concentrated to give 170 mg of crude 3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid which is used in the following step without further purification.
Reaction SMILES: CO[C:3]1[C:4](=[O:12])[CH:5]=[CH:6][CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.[NH3:13]>CO>[NH2:13][C:3]1[C:4](=[O:12])[CH:5]=[CH:6][CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: N
Reactant: COc1cccc(=O)c(OC)c1
Solvent: CO
Product: COc1cccc(=O)c(N)c1
Temperature: 80 °C

Procedure:
A solution of 2,4-dimethoxy-2,4,6-cycloheptatrien-1-one [described above in(b),2.4 g] in methanol (70 ml) is cooled to -25° C. and saturated with ammonia gas. The solution is heated in a pressure bottle at 80° C. for 4 hours and cooled to -70° C. The pressure bottle is opened and the solvent is evaporated to give 2-amino-4-methoxy-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[CH2:12](Br)/[CH:13]=[CH:14]/[CH3:15].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:1][C:2]([F:10])([F:11])[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:12]/[CH:13]=[CH:14]/[CH3:15])=[O:8])=[O:4]
Reactant: C/C=C/CBr
Reactant: O=C(O)CNC(=O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: C/C=C/COC(=O)CNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
A mixture of 143.1 g (836 mmol) of N-trifluoroacetylglycine in 1 L of DMF is chilled to −8° C. as 100 mL (844 mmol) of E-crotyl bromide is added dropwise, followed by addition of 140 mL (937 mmol) of DBU at −5° C. After 1.5 h at −5° C. and 2 h at −2° C. the mixture is allowed to warm to 25° C. The mixture is cooled to 0° C. and 40 mL more DBU is added. After warming to 25° C. the mixture is concentrated in vacuo. 1 L of 1:1 ether-water is added. The organic layer is separated, washed with water, 1 N HCl, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. Drying and concentration in vacuo is followed by trituration of the oil with hexanes-EtOAC to provide a solid. Chromatography on silica gel (elution with 3:1 hexanes-EtOAc) affords 49.96 g of (2E)-2-buten-1-yl N-trifluoroacetylglycinate as an oil.
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(F)c(Cl)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3-chloro-4-fluorophenylboronic acid (217 mg, 1.24 mmol) were coupled to yield 2-(3-chloro, 4-fluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 217 mg (61%), as a pale-yellow solid. mp 234-235° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.04 (m, 2H), 3.39 (m, 2H), 7.24 (app t, 1H, J=7.8 Hz), 7.57 (dd, 1H, J=8.1, 0.9 Hz), 7.61 (m, 2H), 7.69 (dd, 1H, J=7.5, 0.9 Hz), 7.85 (dd, 1H, J=7.2, 2.1 Hz), 8.10 (br t, 1H), 11.68 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H13ClFN2O: 315.0700, Found: 315.0704; Anal. (C17H12ClFN2O.1.0 H2O.0.5 MeOH) C, H, N.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[O:26]([C:23]1[CH:22]=[CH:21][C:20]([C:17]2[N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[O:19][N:18]=2)=[CH:25][CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(COc2ccc(-c3nc(-c4ccc(Oc5ccccc5)cc4)no3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)no2)cc1
Temperature: 55 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
To 5-(4-(benzyloxy)phenyl)-3-(4-phenoxyphenyl)-1,2,4-oxadiazole (50 mg, 120 μmol) was added 10% Pd/C (1 mg, 8 μmol) and the mixture was suspended in methanol (3.0 mL) and THF (3.0 mL). The solution was stirred under H2 at 55° C. for 24 hours. The solution was filtered through Celite and the solvent was removed under reduced pressure and then purified by column chromatography EtOAc/Hex (1:6→1:4) to give the product as a white solid (12 mg, 31%). 1H NMR (500 MHz, CDCL3) δ(ppm): 5.83 (1H, bs), 6.98 (2H, d, J=8.2 Hz), 7.09 (4H, m), 7.18 (1H, t, J=7.6 Hz), 8.12 (2H, t, J=7.7 Hz), 8.12 (2H, d, J=6.8 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 116.3 (CH), 117.2, 118.6 (CH), 119.9 (CH), 121.8, 124.4 (CH), 129.5 (CH), 130.2 (CH), 130.6 (CH), 156.4, 159.8, 160.3, 168.5, 175.7. MS (FAB+): 331 (MH+). HRMS for C20H14N2O3 (MH+): calculated: 331.1083; found 331.1056.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(OC(=O)C)(=O)C.[Br:16]Br>C(O)(=O)C>[Br:16][C:5]1[CH:4]=[CH:3][C:2]([NH2:7])=[C:1]([NH2:8])[CH:6]=1
Reactant: BrBr
Reactant: Nc1ccccc1N
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1N
Temperature: 65 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
In 64 ml of acetic acid, 8.0 g of o-phenylene diamine was dissolved, to which 15.3 ml of acetic anhydride was added drop-wise under cooling. Then the mixture was heated for 30 minutes in an oil bath at 65° C. After cooling to room temperature, a solution of bromine (4.6 ml bromine in 16 ml acetic acid) was quickly added, followed by heating for 40 minutes in an oil bath at 50° C. About 10 minutes after adding bromine, crystals started to precipitate. The reaction mixture was cooled to room temperature, and poured into 300 ml ice water containing 4.0 g sodium hydrogen sulfite. The resulting white precipitates were collected by filtration, washed with water and dried under reduced pressure (14.0 g; yield 70%). Into a 150 ml solution of water:methanol (2:1) containing 33.6 g potassium hydroxide, the white solid was dissolved and heated with stirring for 12 hours in an oil bath at 75°-80° C. After cooling the reaction mixture, and adding 400 ml water thereto, the mixture was extracted with 100 ml ether five times. The ether phase was washed with 200 ml of saturated salt water two times, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) so as to obtain compound 13 as colorless crystals (5.5 g, total yield 40%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2ccccn2)ccn1
Yield: 88.3 %

Procedure:
Using the method of Example 3, Step A, pyridine-2-thiol (0.526 g, 4.73 mmol), 60% sodium hydride in mineral oil (189 mg, 4.73 mmol), and 2-chloro-4-nitropyridine (0.750 g, 4.73 mmol) were reacted to provide 2-chloro-4-(pyridin-2-ylthio)pyridine (0.93 g, 88% yield) as a clear oil. 1H NMR (CDCl3) δ 8.61 (d, 1H), 8.25 (d, 1H), 7.71 (d, 1H), 7.44 (d, 1H), 7.31 (s, 1H), 7.25 (m, 1H), 7.19 (d, 1H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][CH:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CS(C)=O>C(#N)C>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:45][CH:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH3:37])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: CC(N)c1ccccc1
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NC(C)c4ccccc4)n3Cc3ccccc32)cc1C

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 (2 mmol), α-methylbenzylamine (4.2 mmol) in dimethylsulfoxide (7 mmol) and acetonitrile (15 mL) was stirred at 80° C. for 18 hours. The solvents were evaporated and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated. The compound was purified by HPLC (normal phase, Luna® CN bonded packing (Phenomenex, Torrance, Calif.)) and crystallized from ethyl acetate/hexane. (0.93 g), m.p. 118-124°C. MS [(+)ESI, m/z]: 538 [M+H]+Anal. Calcd for C36H33N2O2: C, 80.12; H, 6.16; N, 7.79. Found: C, 79.97; H, 6.27; N, 7.78.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH:11]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>CO>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH:11]=[C:21]([N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: CC[N+](=O)[O-]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=Cc1[nH]c2ccccc2c1C)[N+](=O)[O-]

Procedure:
A mixture of 3-methyl-2-indolecarbaldehyde (7.0 g), ammonium acetate (1.4 g) and nitroethane (10.5 ml) in methanol (35 ml) was refluxed for an hour. After the solvent was removed, the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was pulverized with isopropyl ether to give 3-methyl-2-(2-nitro-1-propenyl)indole (4.29 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]([NH2:11])=[S:10])=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=[CH:4][CH:3]=1.[CH3:18][I:19]>CO>[IH:19].[CH3:18][S:10][C:9](=[NH:11])[NH:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cccc(N2CCCCC2)c1NC(N)=S
Reactant: CI
Solvent: CO
Product: CSC(=N)Nc1c(C)cccc1N1CCCCC1
Product: I

Procedure:
A mixture of 1-(6-methyl-2-piperidinophenyl)thiourea (7 g) and methyl iodide (4.38 g) in dry methanol (100 ml) was heated under reflux for 3 hours to give 2-methyl-1-(6-methyl-2-piperidinophenyl)-2-thiopseudourea hydroiodide as a pale yellow solid, (m.p. 204°-205° C.).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:13]=[C:14]([C:32](=[O:34])[CH3:33])[CH:15]=[C:16]([N:20]2[CH2:24][C@H:23]([O:25][CH2:26][O:27][CH3:28])[C@@H:22]([O:29][CH2:30][CH3:31])[CH2:21]2)[C:17]=1[O:18][CH3:19])([CH3:11])([CH3:10])[CH3:9].[Br:35]N1C(=O)CCC1=O>O1CCCC1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Br:35][CH2:33][C:32]([C:14]1[CH:15]=[C:16]([N:20]2[CH2:24][C@H:23]([O:25][CH2:26][O:27][CH3:28])[C@@H:22]([O:29][CH2:30][CH3:31])[CH2:21]2)[C:17]([O:18][CH3:19])=[C:12]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:13]=1)=[O:34]
Reactant: CCO[C@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@@H]1OCOC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCO[C@H]1CN(c2cc(C(=O)CBr)cc(C(C)(C)C)c2OC)C[C@@H]1OCOC
Reaction time: 0.42 h
Yield: 101.4 %

Procedure:
Triethylamine (0.52 ml, 3.7 mmol) and tert-butyl dimethylsilyltrifluoromethanesulfonate (0.51 ml, 2.2 mmol) were added dropwise in that order to a solution of 1-{3-(tert-butyl)-5-[(3S,4S)-3-ethoxy-4-(methoxymethoxy)tetrahydro-1H-1-pyrrolyl]-4-methoxyphenyl}-1-ethanone (650 mg, 1.71 mmol) in tetrahydrofuran (7 ml) while cooling on ice, and the mixture was stirred at the same temperature for 25 minutes. N-bromosuccinimide (427 mg, 2.40 mmol) was then added and stirring was continued at the same temperature for 25 minutes. After completion of the reaction, the reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate and ethyl acetate and the organic layer was separated. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (795 mg, 100%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C>[NH2:9][C:4]1[N:5]=[C:6]([Cl:8])[C:7]([Br:15])=[C:2]([Cl:1])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(Cl)c(Br)c(Cl)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a stirred mixture of 4,6-dichloro-pyrimidin-2-yl-amine (2.46 g, 15.0 mmol) and sodium acetate (6.15 g, 75.0 mmol) in acetic acid (150 ml) was added bromine (3.24 g, 20.25 mmol) dropwise. The mixture was then stirred at 60° C. for 2 hours. Volatiles were evaporated under reduced pressure. The residue was stirred with water (500 ml) for 1 hour, filtered, and dried under reduced pressure to provide 2-amino-4,6-dichloro-5-bromo-pyrimidine (3.2 g, 88% yield) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([Cl:23])[CH:14]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[Cl:23][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[C:3]([OH:24])=[O:2])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: COC(=O)C(CC1CCC(=O)CC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid methyl ester (590 mg, 1.58 mmol) in methanol (7.0 mL) and water (3.0 mL) was treated with lithium hydroxide (980 mg, 31.6 mmol). The reaction mixture was stirred at 25° C. for 2 h and then concentrated in vacuo to remove methanol. The remaining aqueous layer was diluted with water (25 mL) and washed with ethyl acetate (2×50 mL). The aqueous layer was then acidified to pH=3 with a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(3-chloro-4-methylsulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (550 mg, 97%) as a colorless gum: EI-HRMS m/e calcd for C16H19ClO5S (M+Na)+ 381.0534, found 381.0537.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[CH3:6][C:7]1([CH3:16])[CH2:12][CH:11]([NH2:13])[CH2:10][C:9]([CH3:15])([CH3:14])[NH:8]1.C1(C)C=CC(S([CH:26]([N+:34]#[C-:35])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:6][C:7]1([CH3:16])[CH2:12][CH:11]([N:13]2[C:1]([C:2](=[O:3])[CH3:4])=[C:26]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[N:34]=[CH:35]2)[CH2:10][C:9]([CH3:15])([CH3:14])[NH:8]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)c1c(-c2ccc(F)cc2)ncn1C1CC(C)(C)NC(C)(C)C1
Reaction time: 23 h
Yield: 75.1 %

Procedure:
a solution of pyruvaldehyde (40% w/w solution in water, 7.56 mL, 8.91 g, 49.5 mmol) in 90 mL of DMSO at room temperature was added dropwise 2,2,6,6-tetramethyl-4-amino-piperidine (9.24 mL, 8.43 g, 65.4 mmol). After 10 min α-(p-toluenesulfonyl)-4-fluorobenzylisonitile (13.0 g, 44.95 mmol) and K2CO3 (7.46 g, 53.95 mmol) were added. After 23 h, the solution was diluted with 250 mL of EtOAc and washed with 2×200 mL of 3N HCl. The aqueous layers were combined and basified with excess solid K2CO3 until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2×250 mL of EtOAc. The combined organics were washed with 3×100 mL of water and concentrated in vacuo to yield the title compound (11.6 g, 75%) as a brown oil, which could be recrystallized from CHCl3 /hexanes: mp=134-36° C.; IR (KBR) 3430, 3144, 1659, 1653, 1219 cm-1 ; 1H NMR (CDCl3) δ7.76 (1H, s), 7.43 (2H, m), 7.12 (2H, t, J=8.7 Hz), 5.39 (1H, tt, J=3.1, 12.5 Hz), 2.11 (3H, s), 2.10 (2H, m), 1.50 (2H, t, J=12.2 Hz), 1.37 (6H, s), 1.22 (6H, s); 13C NMR (CDCl3) δ190.77, 164.69, 161.41, 149.79, 137.42, 131.47, 131.36, 127.03, 115.57, 115.29, 52.02, 50.57, 46.20, 34.61, 30.45, 28.06.