Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:56][CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)=[O:21])=[CH:17][N:16]=1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (98 mg, 0.3 mmol) and TBTU (105 mg, 0.33 mmol) in DMF (1 mL) was added DIPEA (261 μL, 1.49 mmol). Then 4-aminotetrahydropyran (34 μL, 0.33 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (108 mg, 88%) as a white solid after recrystallisation from ethyl acetate/heptane. MS: m/e=412.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:20]=[C:19](SCC2C=CC=C(F)C=2F)[C:18]2[N:17]=[CH:16][C:15](=[O:31])[NH:14][C:13]=2[N:12]=1.[NH2:32][C@@H:33]([CH2:35][OH:36])[CH3:34]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:20]=[C:19]([NH:32][C@H:33]([CH3:34])[CH2:35][OH:36])[C:18]2[N:17]=[CH:16][C:15](=[O:31])[NH:14][C:13]=2[N:12]=1
Reactant: C[C@@H](N)CO
Reactant: O=c1cnc2c(SCc3cccc(F)c3F)nc(SCc3cccc(F)c3F)nc2[nH]1
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Yield: 11.7 %

Procedure:
The product of example 2, step (g) (2.3 g) and D-alaninol (5 g) were microwaved at 150° C. for 5 min. The resulting solution was partitioned between ethyl acetate and aqueous ammonium chloride and the organic layer was washed with ammonium chloride (2×50 ml). The organic layer was evaporated to dryness and purified twice by silica gel chromatography using first 20:1 DCM:methanol and then 1:1 DCM:ethyl acetate to yield the titled compound (220 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][CH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][C:21]3[CH:22]=[C:23]([CH2:31][OH:32])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=3)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:32][CH2:31][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=1)[CH2:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[CH:11]([NH:10][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])[CH2:12][CH2:13]2
Reactant: NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21)c1cccs1
Yield: 35.9 %

Procedure:
2-thiophenesulfonyl chloride (23 mg, 0.126 mmol) was added to a solution of (3-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)phenyl)methanol (40 mg, 0.124 mmol) and triethylamine (34 μL, 0.244 mmol) in DCM (2 mL). The reaction was stirred at rt for 24 h before aq. sat. NaHCO3 (2 mL) was added to the mixture and the whole was filtered over a phase separator. The organic filtrate was evaporated to dryness in a Genevac. The crude material was purified by prep. LCMS to afford the title compound (20.8 mg, 35.7%). MS (ESI): m/z [M−H]− 466.0.
Reaction SMILES: N=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[NH:11])[NH:3]1.[Br-:12].[CH3:13][C:14]1[S:15][C:16]2[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=2[N+:18]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22]>O>[Br-:12].[NH:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH:13]=[C:14]2[NH+:18]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:17]3[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=3[S:15]2)=[N:3]1
Reactant: Cc1sc2ccccc2[n+]1CCC(=O)O
Reactant: N=C1NC(=N)c2ccccc21
Agent: [Br-]
Solvent: O
Product: N=C1N=C(C=C2Sc3ccccc3[NH+]2CCC(=O)O)c2ccccc21

Procedure:
Three grams (0.02 mole) of 1,3-diiminoisoindoline was dissolved in 25 ml of warm water. Three grams (0.01 mole) of 2-methyl-3-carboxyethyl benzothiazolium bromide was added to the solution. A molar excess of 1,3-diiminoisoindoline was employed to avoid bis substitution. The solution was stirred and heated on a steam bath for 10 minutes. An orange solid separated from the solution. The solution was then cooled and the solid collected by filtration. The dye was redissolved in hot water with the aid of sodium hydroxide. The solution was filtered, and the filtrate was acidified with excess acetic acid to reprecipitate the dye. The dye was washed with water and methanol and vacuum dried at 70° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.O>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCN1CCCC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCN1CCCC1
Yield: 84.1 %

Procedure:
To a solution of N-(5-pyrrolidin-1-ylpentyl)phthalimide (3) (3.27 g, 11.42 mmol) dissolved in ethanol (100 ml) was added NH2NH2.H2O (hydrazine monohydrate) (5.54 ml, 114.19 mmol) at room temperature, and the reaction mixture was refluxed for 24 hours. After the reaction was completed, the resulting reaction mixture was filtered under reduced pressure to give the target compound (1.50 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19][CH3:20])=[N:15][CH:16]=2)[NH:11][C:10]1=[O:21].[H-].[Na+].Br[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19][CH3:20])=[N:15][CH:16]=2)[N:11]([CH:25]([CH3:27])[CH3:26])[C:10]1=[O:21]
Reactant: CSc1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N(C(C)C)C(=O)N(c1c(Cl)cccc1Cl)C2
Temperature: 90 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A solution, cooled in ice, of 100 mg (0.27 mmol) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 6 ml of dimethylformamide was treated with 13 mg (0.33 mmol) of sodium hydride (60% w/w). After 30 minutes the mixture was treated with 0.03 ml (0.3 mmol) of 2-bromopropane and then heated to 90° C. for 2 hours, cooled and left to stand for 3 days. The mixture was evaporated and the residue was treated with 30 ml of dichloromethane and 30 ml of water. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to give 60 mg (54%) of 3-(2,6-dichlorophenyl)-1-isopropyl-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid. [Mass spectrum (ESI) MH+ =383].
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[NH:27][C:26]([CH3:28])=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:24]=1[CH3:34])=O>>[CH3:28][C:26]1[NH:27][C:23](/[CH:21]=[C:14]2\[C:15](=[O:20])[NH:16][C:17]3[C:13]\2=[CH:12][C:11]([S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:19][CH:18]=3)=[C:24]([CH3:34])[C:25]=1[CH2:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CCC(=O)O

Procedure:
5-Phenylmethanesulfonyl-1,3-dihydro-indol-2-one was condensed with 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])[CH:5]=[N:6][CH:7]=1.I[CH2:17][CH3:18].[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:10]([CH2:17][CH3:18])[S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CCI
Reactant: CCS(=O)(=O)NC(C)c1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: CCN(C(C)c1cncc(Br)c1)S(=O)(=O)CC

Procedure:
In analogy to the procedure described for the preparation of intermediate A-42, N-(1-(5-bromopyridin-3-yl)ethyl)ethanesulfonamide (intermediate A-37) was reacted with iodoethane in presence of NaH (60% in mineral oil) to give the title compound as a yellow oil. MS: 321.0 and 323.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7](C3C=C(C(F)(F)F)C=CC=3C([O-])=O)[CH:8]=[C:9]([O:12]C)[CH:10]=2)[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)[CH:3]=1.C(Cl)Cl.B(Br)(Br)Br.[OH2:43]>>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([OH:43])[CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5](=[O:27])[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[CH:3]=1
Reactant: COc1ccc(-n2cc(Br)c3cc(OC)cc(-c4cc(C(F)(F)F)ccc4C(=O)[O-])c3c2=O)cc1
Reactant: O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c2c(O)cc(O)cc2c(Br)cn1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
4-Bromo-6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-dihydroisoquinolin-8-yl-4-(trifluoromethyl)benzoate (0.47 g, 0.86 mmol) was placed in a dry 250 mL single-necked round-bottomed flask fitted with a stirring bar and sealed with a septa. Anhydrous methylene chloride (20 mL) was added via a syringe at room temperature. BBr3 (8.60 mL of 1.0 M CH2Cl2 solution, 8.60 mmol) was added drop wise with stirring at room temperature. The resulting solution was heated to reflux for 20 hours and then stirred at room temperature for 3 days. 20 mL of water was added to quench the reaction. CH2Cl2 layer was separated and the aqueous layer was extracted with EtOAc (3×20 mL). The organic layers were combined and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.05 g, 16.7% yield. MS: m/e 347.8 [M−H]−. 1H NMR (DMSO-d6, 300 MHz): δ 13.12 (s, 1H), 10.78 (s, 1H), 9.81 (s, 1H), 7.75 (s, 1H), 7.28 (d, 2H, J=8.7 Hz), 6.85 (d, 2H, J=8.7 Hz), 6.61 (d, 1H, J=2.1 Hz), 6.37 (d, 1H, J=2.1 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[CH3:20][NH:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=1)=[O:23]>>[N:14]1([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[CH:30][CH:29]=3)[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 11 %

Procedure:
The title compound was prepared by following the procedure of example 473 step 2 using 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine and 1-Methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 13 mg, 11% yield; HPLC: Rt=1.98 min; MS 400 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[F:31])[CH2:24][NH:23][C:21]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:1]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:7]=1[CH:18]([CH3:20])[CH3:19])=[O:22]
Reactant: BrCCCCBr
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N3CCCC3)cc2n1Cc1ccccn1
Temperature: 110 °C

Procedure:
To a solution of 6-amino-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 182, 64 mg, 0.15 mmol) in toluene (2 ml) was added 1,4-dibromobutane (19 μl, 0.16 mmol) and i-Pr2NEt (77 μl, 0.44 mmol). The reaction was heated at 110° C. for 16 h, and was purified directly by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)cccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(Cl)cccc1CBr
Temperature: 25 °C

Procedure:
A solution of 1-chloro-2-methoxy-3-methyl-benzene (13.40 g, 85.60 mmol), NBS (15.30 g, 86.00 mmol) and a catalytic amount of benzoyl peroxide (150 mg) in CCl4 was refluxed for 30 minutes. The reaction mixture was cooled to room temperature and filtered. The precipitate was washed with pentane. The solvent was distilled off and the residue was purified by column chromatography using pentane as the eluant to afford the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H), 4.56 (s, 2H), 7.04 (t, J=7.62 Hz, 1H), 7.29 (dd, J=7.62 Hz, 1H), 7.34 (dd, J=7.92 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:48])=[C:6]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:31](=[O:43])(=[O:42])[NH:32][C:33](=[O:41])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])=[CH:21][CH:20]=3)[C:10]([CH2:44][CH2:45][CH2:46][CH3:47])=[N:9]2)[CH:7]=1.[C:49](Cl)(=[O:54])[CH2:50][CH2:51][CH2:52][CH3:53]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:44]([C:10]1[C:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:42])(=[O:43])[NH:32][C:33](=[O:41])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])=[CH:23][CH:24]=2)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:49](=[O:54])[CH2:50][CH2:51][CH2:52][CH3:53])[CH:3]=[CH:4][C:5]=2[Cl:48])[N:9]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CCCCC(=O)Cl
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc(Cl)c(-n2nc(CCCC)c(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3)c2C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a mixture of 150 mg (0.213 mmol) of ethyl 1-(5-amino-2-chlorophenyl)-3-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]-biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylate (from Step I), 26 mg (0.213 mmol) of 4-(dimethylamino)pyridine (DMAP), and 1.75 mL of dry pyridine was added 126 μL (128 mg, 1.06 mmol) of valeryl chloride. The mixture was stirred under N2 at room temperature overnight and then partitioned between H2O and ethyl acetate. The organic layer was washed twice with H2O and then with brine. Next, the ethyl acetate phase was dried over Na2SO4, filtered, and rotary-evaporated in vacuo. The yellow-orange residual oil was flash chromatographed on silica gel (gradient elution with 0.5-3% MeOH in CH2Cl2) to give 123 mg (72%) of the title compound as a slightly yellow solid, mp>95° C. (gradual); homogeneous by TLC in 95:5 CH2Cl2 -- MeOH; mass spectrum (FAB) m/e 827 (M+K)+. 400 MHz 1H NMR (CDCl3) δ0.87 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H), 1.02 (t, J=7.1 Hz, 3H), 1.29-1.40 (m, 4H), 1.57 (m, 2H), 1.67 (m, 2H), 2.32 (t, J=7.6 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 4.05-4.15 (m, 4H), 7.06 (d, J=8.2 Hz, 2H), 7.21-7.66 (m, 10H), 7.75 (d, J=2.4 Hz, 1H), 8.27 (s, 1H), 8.34 (dd, J=8.0, 1.3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][Mg]Cl.O>C1COCC1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([OH:3])([CH3:12])[CH3:1])=[CH:5][CH:6]=1
Reactant: C[Mg]Cl
Reactant: COc1ccc(C(C)=O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)(C)O)cc1
Temperature: 12.5 °C
Yield: 93.9 %

Procedure:
This was synthesized using a synthesis based on that described by Archer et al., J. Org. Chem., Vol. 42, No. 13, 1977, page 2282, column 2 (see synthesis of (22)). A solution of 4-methoxy acetophenone (151.18 g, 1 mol) in 300 ml of anhydrous THF was added for 1 h to the solution of 1N methyl magnesium chloride (1360 ml, 1.36 mol) in THF while maintaining the internal temperature at 10-15° C. After completion of the addition, the reaction mixture was heated for about 4.5 hrs. After completion of the reaction (as determined by TLC), 0.2 L of water was slowly added during 3 hrs to quench the reaction while maintaining the internal temperature at <15° C. The reaction mixture was decanted from the precipitate and evaporated under vacuum. The remaining white residue was washed with methyl t-butyl ether (MTBE) (2×200 mL) and evaporated. The combined residue was dissolved in 400 mL of MTBE and 200 mL of water was added. The organic layer was extracted and the aqueous layer was washed with MTBE (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness to afford 156 g of 2-(4-Methoxy-phenyl)-propan-2-ol as yellow oil (94% yield, 96% purity by HPLC).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:10])[C:7]=1[O:8]C.B(Br)(Br)[Br:12].CO>C(Cl)Cl>[NH2:10][C:6]1[C:5]([Br:12])=[CH:4][CH:3]=[CH:2][C:7]=1[OH:8]
Reactant: BrB(Br)Br
Reactant: COc1c(N)cccc1Br
Solvent: CO
Solvent: ClCCl
Product: Nc1c(O)cccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To an ice cooled solution of 6-bromo-2-anisidine (1.01 g, 5 mmol) in methylene chloride (30 mL) was slowly added a 1.0 M solution of boron tribromide in methylene chloride (10 mL, 10 mmol) via syringe. The reaction was slowly warmed to room temperature and stirred overnight. Methanol (10 mL) was added and the solvents removed by rotoevaporation to give the title compound (0.87 g, 92% yield).
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].CS([O-])(=O)=O.Cl.[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33][C:34](=[O:36])[NH2:35])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CO.N1C=CC=CC=1>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=3)[C:29]=2[CH2:33][C:34](=[O:36])[NH2:35])=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2CC(N)=O)cc1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
100 Milliliters of 20% hydrous pyridine was added to 3.0 g of 4-guanidinobenzoic acid.methanesulfonate, 3.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride and 4.5 g of DCC, followed by stirring for 2 hours under cooling with ice and then 2 days at room temperature. The precipitate was filtered and 1 g of active carbon was added to the filtrate, followed by stirring for 30 minutes under cooling with ice, and insoluble matter was filtered off. The filtrate was slowly added dropwise to 4 liters of ether under cooling with ice, followed by stirring for 2 hours. The precipitate was collected by filtration and washed with 100 ml of acetone to obtain a crude product. Then, the product was dissolved in 150 ml of methanol. Thereafter, 2.5 g of active carbon was added to the solution, followed by stirring for 30 minutes under cooling with ice, and insoluble matter was filtered off. The filtrate was slowly added dropwise to 1 liter of acetone under cooling with ice, followed by stirring for 2 hours. The precipitate was collected by filtration to obtain 2.9 g of the desired product.
Reaction SMILES: CO[C:3]1[C:8]([C:9]([C:11](=[C:17](SC)SC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:7][N:6]=[C:5]([S:22][CH3:23])[N:4]=1.[NH2:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([NH:29][CH3:30])=[O:28]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:11]1[C:9](=[O:10])[C:8]2[CH:7]=[N:6][C:5]([S:22][CH3:23])=[N:4][C:3]=2[N:24]2[C:17]=1[N:29]([CH3:30])[C:27](=[O:28])[C:26]1[CH:31]=[CH:32][CH:33]=[CH:34][C:25]2=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(C(=O)c1cnc(SC)nc1OC)=C(SC)SC
Reactant: CNC(=O)c1ccccc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(=O)c2cnc(SC)nc2n2c3ccccc3c(=O)n(C)c12
Temperature: 140 °C
Yield: 3.7 %

Procedure:
A solution of ethyl 2-(4-methoxy-2-(methylthio)pyrimidine-5-carbonyl)-3,3-bis(methylthio)acrylate (775 mg, 2.069 mmol) and 2-amino-N-methylbenzamide (475 mg, 3.163 mmol) in toluene (5 mL) was heated over stream of nitrogen allowing toluene to evaporate and continued heating as neat at 140° C. for over night. Cooled to rt and precipitate formed from DCM (10 mL) was filtered off. The solvent of mother liquor was removed under reduced pressure and repeated the precipitation process with Et2O (10 mL). Trituration in methanol (10 mL) afforded the desired product as a yellow solid (30 mg, 4 %). MS (m/z): 397 (MH+). 1H NMR (CDCl3) δ: 9.37 (s, 1H), 8.37 (d, 1H), 8.26 (dd, 1H), 7.70 (m, 1H), 7.49 (m, 1H), 4.46 (q, 2H), 3.61 (s, 3H), 2.60 (s, 3H), 1.43 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=1[CH3:23])=[O:9]
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 107.9 %

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid (2.0 g, 0.008 mol) in CH2Cl2 (20 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (1.28 g, 0.0072, see preparation 12) and N,N-diisopropylethylamine (4.12 g, 0.032 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 7.63 g, 0.024 mol) is added via syringe and stirred at 50° C. After 16 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted twice with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 12% ethyl acetate in hexane to give the title compound as a white solid (2.9 g, 97%). Mass spectrum (m/z): 376.0 (M+1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]2=[CH:15][N:16]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[C:17]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]2[CH:12]=[N:11]1.O>CN(C)C=O>[Br:1][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[CH:24]=[C:17]1[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]3[CH:12]=[N:11][N:10]([CH3:9])[C:14]3=[CH:15][N:16]12
Reactant: CN1N=CN2C1=Cn1c(cc3ccccc31)-c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CN1N=CN2C1=Cn1c(cc3c(Br)cccc31)-c1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution of 2.41 g N-bromosuccinimide in 50 ml dimethylformamide was added dropwise to 3.53 g 1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine in 108 ml dimethylformamide. After the addition was complete, the reaction mixture was stirred for one hour at room temperature. Upon addition of water, a solid precipitated, which was collected, washed with water and dried. Recrystallization from water/methanol yielded 2.55 g solid;