Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C@@H:6]1([O:37][P:38]([OH:41])([OH:40])=[O:39])[C@@H:11]([O:12][P:13]([OH:16])([OH:15])=[O:14])[C@H:10]([O:17][P:18]([OH:21])([OH:20])=[O:19])[C@@H:9]([O:22][P:23]([OH:26])([OH:25])=[O:24])[C@@H:8]([O:27][P:28]([OH:31])([OH:30])=[O:29])[C@H:7]1[O:32][P:33]([OH:36])([OH:35])=[O:34]>>[CH:8]1([O:27][P:28]([OH:31])([OH:30])=[O:29])[CH:9]([O:22][P:23]([OH:25])([OH:26])=[O:24])[CH:10]([O:17][P:18]([OH:20])([OH:21])=[O:19])[CH:11]([O:12][P:13]([OH:16])([OH:15])=[O:14])[CH:6]([O:37][P:38]([OH:41])([OH:40])=[O:39])[CH:7]1[O:32][P:33]([OH:35])([OH:36])=[O:34]
Reactant: O=P(O)(O)O[C@H]1[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H]1OP(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=P(O)(O)OC1C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C1OP(=O)(O)O
Temperature: 90 °C
Reaction time: 24 h
Yield: 137.9 %

Procedure:
First, 0.33 kg of calcium carbonate was slowly added, in increments of 0.1 kg, to 0.87 kg of phytic acid liquid. The mixture was heated and refluxed for about one hour at about 90° C. The two solids were separated and filtered. The white solid, which was calcium phytate, was collected. About 1 kg of the calcium phytate was dissolved into 2.0 liters of water and heated to about 89° C. for about 10-15 minutes until calcium phytate was completely dissolved in the water solution. About 0.9 kg of citric acid was then added to and stirred in the calcium phytate solution until the citric acid was completely dissolved. The heat source was removed and the resulting mixture was left sat at no more than 40° C. or in a refrigerated environment at a temperature of about 5-10° C. to allow the newly formed phytic hexa-citrate to crystallize for approximately 6 to 8 hours or until crystallization has ceased. The mixture was allowed to dry out at room temperature until no liquid was visible. The crystals were spread in a drying pan for approximately 24 hours at a temperature of no more than 40° C., which yielded approximately 1.2 kg of hexa-citrated phytate.
Reaction SMILES: [Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Zn+].Br[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][C@H:24]([O:27][C:28]4[CH:33]=[C:32]([F:34])[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:30][C:29]=4[F:39])[C:23]3=[O:40])[CH2:18][CH2:17]2)=[N:14][CH:15]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Zn].[Pd]>[F:39][C:29]1[CH:30]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[C:32]([F:34])=[CH:33][C:28]=1[O:27][C@H:24]1[CH2:25][CH2:26][N:22]([CH:19]2[CH2:20][CH2:21][N:16]([C:13]3[N:12]=[CH:11][C:10]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)=[CH:15][N:14]=3)[CH2:17][CH2:18]2)[C:23]1=[O:40]
Reactant: CS(=O)(=O)c1cc(F)c(O[C@H]2CCN(C3CCN(c4ncc(Br)cn4)CC3)C2=O)cc1F
Reactant: [Zn+]c1ccccn1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCN(C3CCN(c4ncc(-c5ccccn5)cn4)CC3)C2=O)cc1F
Temperature: 55 °C
Reaction time: 6 h
Yield: 56.2 %

Procedure:
Pyridin-2-yl zinc(II) bromide (0.5M; 632 μL, 0.316 mmol) was added to a nitrogen purged flask. Pd(PPh3)4 (17.4 mg, 0.0151 mmol) was added followed by (S)-1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one (Example 90; 80 mg, 0.151 mmol) dissolved in THF (1 mL). The reaction was stirred at ambient temperature for 1 hour and 55° C. for 6 hours. Additional zinc reagent and palladium were added and the reaction stirred at 55° C. overnight. The reaction was partitioned between aqueous NH4Cl and CH2Cl2, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (95% EtOAc in hexanes) to afford (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1-(1-(5-(pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (44.9 mg, 0.0848 mmol, 56.3% yield) as a pale yellow solid. Mass spectrum (apci) m/z=530.2 (M+H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][NH2:14]>>[CH3:13][NH:14][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(O)CCOc1ccccc1
Product: CNCCCOc1ccccc1

Procedure:
Synthesized according to typical procedures C and D from 3-phenoxypropionic acid and methylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].O>CC(C)=O>[CH3:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23].[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Clc1ccc2c(c1)[nH]c1cc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCC

Procedure:
To a solution of 3.00 g of compound 8 (12.7 mmol) in 50 mL of anhydrous acetone was added 3.51 g (25.4 mmol, Aldrich Co.) of K2CO3 and 8.47 g (25.4 mmol, Aldrich Co.) of 1-bromooctadecane. The solution was refluxed 24 h under argon. The mixture was poured into 100 mL of distillated water and the aqueous layer was extracted with three portions of diethyl ether. The combined organic fractions were washed with brine and dried over magnesium sulfate. The solvent was removed under vacuum. Recristallization from methanol followed by a recristallization in hexanes afforded 4.77 g of the title product as a white solid. M. P. 72-74° C. (Yield=86%).
Reaction SMILES: C[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccc(-c3nnnn3C)cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nnnc1-c1ccc2scc(Br)c2c1
Yield: 62.4 %

Procedure:
Following the procedure of Example 11, Step 6, 0.666 g (2.89 mmol) 3-methyl-5-(1-methyltetrazol-5-yl)benzo[b]thiophene was reacted with 0.515 g (2.89 mmol) of N-bromosuccinimide and 38.1 mg of benzoyl peroxide in 30 ml of carbon-tetrachloride. The reaction mixture was evaporated in vacuo and chromatographed on flash silica, eluting with 0-3% methanol/dichloromethane to give 0.532 g of crude 3-bromo-5-(1-methyltetrazol-5-yl) benzo[b]thiophene.
Reaction SMILES: [OH-].[Li+].[NH2:3][C@@H:4]([CH2:13][CH2:14][CH2:15][N:16]1[C:24]([S:25][C:26]2[C:34]([I:35])=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:36])[C:5]([O:7]C1CCCC1)=[O:6].O>O1CCCC1.O.C(O)(=O)C>[NH2:3][C@@H:4]([CH2:13][CH2:14][CH2:15][N:16]1[C:24]([S:25][C:26]2[C:34]([I:35])=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:36])[C:5]([OH:7])=[O:6]
Reactant: Nc1ncnc2c1nc(Sc1cc3c(cc1I)OCO3)n2CCC[C@H](N)C(=O)OC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1I)OCO3)n2CCC[C@H](N)C(=O)O
Reaction time: 12 h
Yield: 34.1 %

Procedure:
Lithium hydroxide (2.88 mg, 0.12 mmol) was added to a solution of (S)-cyclopentyl 2-amino-5-(6-amino-8-(6-iodobenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)pentanoate (14.0 mg, 0.02 mmol) in tetrahydrofuran (1 ml) and water (3 drops). After stirring for 12 h, 5 drops of acetic acid and water (0.1 ml) were added to the reaction mixture. The solid was collected by filtration and dried in vacuo to afford the title compound (3.6 mg) as a white solid. m/z 529 [M+H]+, 527 [M−H]−. 1H NMR (400 MHz, DMSO-d6), δ: 8.1 (1H, s), 7.4 (1H, s), 7.3 (2H, bs), 6.8 (1H, s), 6.0 (2H, s), 4.1 (2H, m), 3.1 (1H, m), 1.8-1.4 (5H, m).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]1[C:19](=[O:34])[CH2:20][C:21]1[NH:26][C:25](=[O:27])[CH:24]=[C:23]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:22]=1.O.ClCCl>C(Cl)(Cl)Cl>[Cl:1][C:24]1[C:25](=[O:27])[NH:26][C:21]([CH2:20][C:19]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18][C@@H:10]2[CH3:9])=[O:34])=[N:22][C:23]=1[N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)c(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
37.6 mg of N-chlorosuccinimide are added to a solution of 100 mg of 2-{2-[(2S)-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one in 4 ml of chloroform. The reaction medium is stirred at ambient temperature for 2 hours. 5 ml of water and 20 ml of dichloromethane are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 99/01 then 98/02 then 97/03 dichloromethane/methanol, so as to give 69 mg of 5-chloro-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]3[C:22]=2[O:21][C:20](=[O:23])[CH:19]=[C:18]3[NH:24][C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=2[Cl:32])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: c1nc[nH]n1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCn1cncn1

Procedure:
The title compound was prepared from 1,2,4-triazole and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 98. 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.81 (s, 2H), 8.50 (s, 1H), 7.94 (d, 1H), 7.93 (s, 1H), 7.19 (d, 1H), 4.64 (s, 1H), 4.19 (t, 2H), 3.96 (t, 2H), 3.90 (s, 3H), 1.84 (m, 2H), 1.69 (m, 2H), 1.43 (m, 2H); MS (ESI): 489.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([S:32]([C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:33])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)CCCCCCNCc1ccc(-c2ncccn2)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCN(Cc1ccc(-c2ncccn2)cc1)S(=O)(=O)c1cccnc1

Procedure:
The title compound of Step B was prepared from 7-(4-pyrimidin-2-yl-benzylamino)-heptanoic acid methyl ester of Step A and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.07 (d, 1H), 8.80 (m, 3H), 8.37 (d, 2H), 8.10 (m, 1H), 7.46 (m, 1H), 7.37 (d, 2H), 7.19 (m, 1H), 4.43 (s, 2H), 3.62 (s, 3H), 3.15 (t, 2H), 2.20 (t, 2H), 1.48 (m, 2H), 1.38 (m, 2H), 1.14 (m, 4H); MS 469 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].N[C:20]1C=CC(O)=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[CH3:20])[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Nc1ccc(O)cc1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Product: CNC(=O)c1cc(Oc2ccc(N)cc2C)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide, substituting 4-amino-2-methylphenol for 4-aminophenol. 1H-NMR (DMSO-d6) δ 8.73 (br q, J=4.8 Hz, 1H), 8.43 (d, J=5.4 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.02 (dd, J=5.7, 2.7 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 6.52 (d, J=3 Hz, 1H), 6.47 (dd, J=8.7, 2.7 Hz, 1H), 5.09 (s, 2H), 2.78 (d, J=3.3 Hz, 3H), 1.91 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][S:12][CH3:13])[CH:5]=1.[OH:14]O>C(O)(=O)C.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>[CH3:13][S:12]([CH2:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:2][CH3:1])=[O:14]
Reactant: OO
Reactant: CNCc1cccc(OCSC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCc1cccc(OCS(C)=O)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Compound from step 3 (592 mg, 3.00 mmol) was dissolved in glacial acetic acid (4 mL) and cooled to 0° C. H2O2 (0.34 mL, 3.00 mmol) was added drop-wise. The mixture was allowed to stir for 6 h. The mixture was then diluted with CH2Cl2 and neutralized with K2CO3. The solids were filtered off. The filtrate was dried over Na2SO4 and concentrated in vacuo to give 640 mg (quant) of a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:16]([O-])([O-:18])=[O:17].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([F:15])=[C:4]2[C:9]([NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2)=[C:10]([N+:16]([O-:18])=[O:17])[C:11]=1[F:12]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(F)c(Cl)c(F)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(F)c(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.4 %

Procedure:
To a solution of 120 mg (5.16 mmol) of 6-chloro-5,7-difluoro-1,4-dihydroquinoxaline-2,3-dione in 1 mL of H2SO4 (97%) kept in ice bath was added portionwise 60 mg (0.59 mmol) of KNO3. The solution was stirred at room temperature for 14 h and 60 mg of KNO3 was added and it was stirred at room temperature for 24 h. It was diluted by ice-water (4 mL) and the mixture was filtered and washed by water, and dried to leave a yellow solid (94 mg, 65%). The solid was purified by NaOH/HCl precipitate to leave 63 mg of yellow solid, mp>250° C. 1H NMR (DMSO-d6), 12.11 (mb, 1), 12.503 (s, 1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][S:5]([C:8]1[CH:46]=[CH:45][C:11]([O:12][C:13]2[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([O:35]C3C=CC([N+]([O-])=O)=CC=3)=O)=[CH:15][C:16]3[NH:20][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[NH:18][C:17]=3[CH:27]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]>O1CCCC1>[CH3:1][N:2]([CH3:3])[C:33]([N:29]1[CH2:30][CH2:31][CH2:32][CH:28]1[C:14]1[C:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]([S:5]([CH3:4])(=[O:6])=[O:7])=[CH:46][CH:45]=2)=[CH:27][C:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[NH:20][C:16]=2[CH:15]=1)=[O:35]
Reactant: CNC
Reactant: CS(=O)(=O)c1ccc(Oc2cc3c(cc2C2CCCN2C(=O)Oc2ccc([N+](=O)[O-])cc2)NC(c2ccccn2)N3)cc1
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1 ml of dimethylamine (2.0 M tetrahydrofuran solution) was added to a tetrahydrofuran (1 ml) solution of 20 mg of 4-nitrophenyl 2-(6-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-5-yl)-pyrrolidin-1-carboxylate, and the reaction liquid was stirred overnight in a sealed tube at 100° C. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[N:6][C:7]=1[CH2:8][CH3:9].[CH3:18][O:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][CH2:26]2)=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH2:16]([C:4]1[C:5]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[N:6][C:7]([CH2:8][CH3:9])=[C:2]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][C:20]=2[O:19][CH3:18])[CH2:26][CH2:25][CH2:24]3)[N:3]=1)[CH3:17]
Reactant: CCc1nc(NC(CC)CC)c(CC)nc1Br
Reactant: COc1cc2c(cc1B(O)O)CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1nc(-c2cc3c(cc2OC)CCC3)c(CC)nc1NC(CC)CC
Temperature: 80 °C
Yield: 66.1 %

Procedure:
A scintillation vial with a Teflon lined cap was charged with 5-bromo-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine (300.2 mg, 1 mmol), 6-methoxy-2,3-dihydro-1H-inden-5-ylboronic acid (211.2 mg, 1.1 mmol, Preparation 2), terakis(triphenylphosphine)palladium (0) (116 mg, 0.1 mmol), 2M Na2CO3 (1 mL, 2 mmol), and ethylene glycol dimethyl ether (6 mL). The reaction was heated on the orbital shaker to 80° C. for 30 hours. After cooling to ambient temperature, the reaction was partitioned between H2O and ethyl acetate. The aqueous layer was extracted one more time with ethyl acetate. The organics were combined, dried with Na2SO4, filtered and concentrated to 530 mg of a yellow crude oil. The crude was purified by Biotage MPLC (90 g column, 1.5% acetone in toluene) to give 243 mg (66%) of 3,6-diethyl-N-(1-ethylpropyl)-5-(6-methoxy-2,3-dihydro-1H-inden-5-yl)pyrazin-2-amine as a pale yellow oil. Rf 0.19 (10% ethyl acetate in heptane). IR (liq.) 2964, 2935, 2874, 1566, 1550, 1484, 1464, 1444, 1391, 1380, 1276, 1253, 1203, 1174, 1033 cm−1. OAMS supporting ions at: ESI+368.3. HRMS (ESI) calcd for C23H33N3O+H1 368.2702, found 368.2703. Anal. Calcd for C23H33N3O: C, 75.16; H, 9.05; N, 11.43. Found: C, 75.25; H, 9.15; N, 11.13.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[N:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)[CH:29]=[CH:30][CH:31]=2)O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)[CH:27]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[N:9][CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2cccc(-n3cccn3)c2)OC1(C)C
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccnnc1
Product: Nc1ncc(-c2cccc(-n3cccn3)c2)cc1C(=O)Nc1ccnnc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridazin-4-yl-nicotinamide (see step 1 in the synthesis of “A16”) and 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole gives the compound “A18”;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].C([Li])CCC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:12]([CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2Cl)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4,5-di-(2,4-dichlorophenyl)-1-methylimidazole (200 mg, 0.54 mmol) from Step C in THF (5 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.40 mL, 0.65 mmol). The reaction was stirred for 1 hr and then ethyl chloroformate (0.10 mL, 1.1 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (2×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[CH3:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[C:3]([CH3:19])[CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1N
Product: Cc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Method H3 was used with 4-(4-amino-3-methylphenoxy)-3-nitropyridin-2-amine and 4-chloro-3-trifluoromethyl-phenyl isocyanate to afford the title compound (582 mg, 78%. 1H-NMR (δ, ppm, DMSO-d6): 2.25 (s, 3H, CH3), 5.95 (d, 1H, HPy,5, J=5.7 Hz), 6.96 (m, 2H, Harom), 7.02 (m, 1H, Harom), 7.12 (s, 2H, NH2,Py), 7.48-7.68 (m, 2H, Harom), 7.73 (d, 1H, Harom), 7.95 (d, 1H, HPy,6, J=5.7 Hz), 8.13 (m, 1H, Harom), 8.65 (s, 1H, NHurea1), 9.99 (s, 1H, NHurea3). LC-MS (m/z): 482 (M+H, 100).
Reaction SMILES: [S:1]=[C:2]1[NH:14][C:13](=[O:15])[C:5]2=[CH:6][C:7]3[C:12]([N:4]2[NH:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CI.[C:18]([O-])(O)=O.[Na+]>O1CCCC1>[CH3:18][S:1][C:2]1[NH:14][C:13](=[O:15])[C:5]2=[CH:6][C:7]3[C:12]([N:4]2[N:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=C([O-])O
Reactant: O=c1[nH]c(=S)[nH]n2c1cc1ccccc12
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nn2c(cc3ccccc32)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Into a round-bottom flask 2-thioxo-2,3-dihydro-1H-[1,2,4]triazino[1,6-a]indol-4-one (9.25 g, 0.04 mol) and methyl iodide (3.42 mL, 0.0549 mol) were combined in tetrahydrofuran (200 mL). The reaction was stirred at 45° C. for one hour. The solvent was removed under vacuum to give a solid, which was next stirred for 30 minutes with saturated aqueous NaHCO3 (100 mL). The solid was filtered and washed with water, then dried on high vacuum and further by azeotrop distillation with toluene to give 2-methylsulfanyl-3H-[1,2,4]triazino[1,6-a]indol-4-one (7 g, 71%), which was used in the next step without further purification. 1H-NMR (DMSO-d6) δ 12.28 (br s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.43 (m, 1H), 7.28 (m, 1H), 7.18 (s, 1H), 2.64 (s, 3H).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([OH:19])([CH3:18])[CH3:17].[H-].[Na+]>C1COCC1>[NH:1]([C:8]1[N:9]=[C:10]([CH3:15])[CH:11]=[C:12]([O:19][CH:16]([CH3:18])[CH3:17])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)nc(Nc2ccccc2)n1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OC(C)C)nc(Nc2ccccc2)n1
Yield: 64.1 %

Procedure:
In the same manner as in Example 3, 3.1 g of 2-anilino-4-chloro-6-methylpyrimidine, 1.9 g of isopropyl alcohol and 0.7 g of NaH were added to 50 ml of THF and allowed to react at room temperature for 4 hours to obtain 2.2 g of 2-anilino-4-methyl-6-isopropoxypyrimidine (yield 65%). nD20 1.5931.