Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[C:59]([O:65][CH3:66])[C:19]=1[CH:20]=[CH:21][CH:22]([S:32]([CH:35]([CH:45]=[CH:46][C:47]1[C:52]([O:53][CH3:54])=[CH:51][C:50]([O:55][CH3:56])=[CH:49][C:48]=1[O:57][CH3:58])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([NH2:44])[CH:37]=1)(=[O:34])=[O:33])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([NH2:31])[CH:24]=1>O1CCCC1>[CH3:66][O:65][C:59]1[CH:60]=[C:61]([O:63][CH3:64])[CH:62]=[C:18]([O:17][CH3:16])[C:19]=1/[CH:20]=[CH:21]/[CH:22]([S:32]([CH:35](/[CH:45]=[CH:46]/[C:47]1[C:48]([O:57][CH3:58])=[CH:49][C:50]([O:55][CH3:56])=[CH:51][C:52]=1[O:53][CH3:54])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([NH:44][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH:37]=1)(=[O:34])=[O:33])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([NH:31][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH:24]=1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)c(OC)c1
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3,5-dinitrobenzoyl chloride (10 mmol) in tetrahydrofuran (40 mL) was added drop wise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution was stirred overnight and the completion of the reaction was monitored by TLC. The solvent was removed and the residue was taken up in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to give (E)-2,4,6-trimethoxystyryl-3-(3,5-dinitrobenzamido)-4-methoxy-benzylsulfone in 80% yield (m.p. 277-279° C.). NMR (DMSO-d6) δ 3.80 (s, 3H), 3.82 (s, 6H), 3.86 (s, 3H), 4.35 (s, 2H), 6.3 (s, 2H), 7.15-9.1 (m, aromatic+vinylic), 9.8 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([NH2:19])=[CH:17][C:6]2[CH2:7][CH2:8][CH:9]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:38]3[CH2:37][N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:35][C:34](=[O:43])[NH:33][C:32]=3[CH:31]=[CH:30][C:29]=2[O:44][CH3:45])[C:24]([Cl:46])=[CH:23][N:22]=1>>[Cl:46][C:24]1[C:25]([NH:27][C:28]2[C:38]3[CH2:37][N:36]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:35][C:34](=[O:43])[NH:33][C:32]=3[CH:31]=[CH:30][C:29]=2[O:44][CH3:45])=[N:26][C:21]([NH:19][C:18]2[C:3]([O:2][CH3:1])=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:8][CH2:7][C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: COc1ccc2c(c1Nc1nc(Cl)ncc1Cl)CN(S(C)(=O)=O)CC(=O)N2
Reactant: COCCNC1CCc2cc(N)c(OC)cc2CC1
Product: COCCNC1CCc2cc(Nc3ncc(Cl)c(Nc4c(OC)ccc5c4CN(S(C)(=O)=O)CC(=O)N5)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 3-Methoxy-N*7*-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and 6-(2,5-Dichloro-pyrimidin-4-ylamino)-4-methanesulfonyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one in an analogous manner to example 730 (0.017 g, 11%). Mp110-114° C.; LCMS (m/e) 660 (M); 1H-NMR (DMSO, 400 MHz) δ 10.28 (br, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 7.20-7.14 (q, 2H, J=5.81 Hz), 6.70 (s, 1H), 6.56 (s, 1H), 6.39 (s, 1H), 4.40-4.24 (br, 3H), 3.74 (s, 3H), 3.70 (s, 6H), 3.98-3.45 (q, 3H, J=5.05 Hz), 3.25 (s, 2H), 2.80 (s, 2H), 2.79-2.70 (br, 2H), 2.70-2.57 (br, 2H), 2.35-2.10 (br, 2H), 1.98-1.81 (br, 3H), 1.25-0.90 (br, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[C:8]([Cl:16])[CH:7]=1)=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:17][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[C:8]([Cl:16])[CH:7]=2)=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)cc1Cl
Product: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)cc1Cl

Procedure:
2-Chloro-N-(3-chloro-4-sulphamoylphenyl)-acetamide (28.3 g) and aniline (19 ml) were heated together for 30 min on a water bath (90°) and the product worked up as in Example 1(b) to yield 25 g, m.p. 192°-194°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH3:20])=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:41])=[C:33]([S:35]([NH:38][O:39][CH3:40])(=[O:37])=[O:36])[CH:34]=1.CO>ClCCl>[CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH3:20])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([CH3:41])=[C:33]([S:35]([NH:38][O:39][CH3:40])(=[O:36])=[O:37])[CH:34]=4)[N:22]=3)=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CONS(=O)(=O)c1cc(N)ccc1C
Reactant: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Cl)n1
Solvent: ClCCl
Solvent: CO
Product: CONS(=O)(=O)c1cc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3ccccc3)n4C)n2)ccc1C

Procedure:
The title compound was prepared following the procedure of Example 2 with N2-benzyl-N5-(2-chloropyrimidin-4-yl)-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (50 mg, 0.13 mmol) and 5-amino-N-methoxy-2-methylbenzenesulfonamide (30 mg, 0.14 mmol) as a white solid (58 mg, 0.10 mmol) after silica gel chromatography with methanol in dichloromethane. 1H NMR (300 MHz, d6-DMSO) δ 10.3 (s, 1H), 9.42 (s, 1H), 8.73 (s, 1H), 7.76-7.80 (m, 2H), 7.40-7.23 (m, 8H), 7.09 (br s, 1H), 6.84 (d, J=7.4 Hz, 1H), 5.61 (d, J=5.3 Hz, 1H), 4.60 (br s, 2H), 4.34 (s, 2H), 3.58 (s, 6H), 3.46 (s, 3H). MS (ESI) m/z=559 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:18]2[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=S1(=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCS(=O)(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
8.6 g (40 mmol) of 4-nitrobenzylbromide are dissolved in 100 ml of acetone. 6.9 g (50 mmol) of potassium carbonate and 5.4 g (40 mmol) of thiomorpholine-1,1-dioxide are added. The reaction solution is stirred for 7 hours at ambient temperature. After the undissolved solids have been filtered off, the solution is concentrated by evaporation. The residue is divided between ethyl acetate and water. The organic phases are freed from solvent in vacuo. The product is triturated with ether and dried.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]([C:25]4[CH:34]=[CH:33][C:32]([O:35]CC5C=CC=CC=5)=[C:31]5[C:26]=4[CH:27]=[CH:28][C:29](=[O:43])[NH:30]5)[OH:24])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl>CO.O1CCCC1.[Pd]>[C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]([C:25]4[CH:34]=[CH:33][C:32]([OH:35])=[C:31]5[C:26]=4[CH:27]=[CH:28][C:29](=[O:43])[NH:30]5)[OH:24])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=c1ccc2c([C@@H](O)CNCCc3cccc(OCC45CC6CC(CC(C6)C4)C5)c3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CNCCc3cccc(OCC45CC6CC(CC(C6)C4)C5)c3)ccc(O)c2[nH]1
Yield: 86.6 %

Procedure:
To a solution of Intermediate 43 (0.075 g, 0.13 mmol) in a mixture of methanol (3 mL) and tetrahydrofuran (1 mL) was added some drops of hydrogen chloride 1.25M in methanol and palladium on charcoal (10%, 0.015 g). The reaction mixture was hydrogenated under a balloon pressure overnight. The catalyst was filtered through Celite® and the solvent removed under reduced pressure. The crude was treated with ether and collected by filtration to obtain the title compound as a yellow solid (0.055 g, 82%).
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:33]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:33]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCC1CCCC(N)C1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCC1CCCC(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)C1

Procedure:
A solution of 590 mg (1.5 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2; Example 77A), 400 mg (1.8 mmol) of methyl 3-(3-aminocyclohexyl)propanoate hydrochloride (mixture of isomers), 1.05 ml (6.0 mmol) of N,N-diisopropylethylamine and 857 mg (2.26 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) in 13 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the reaction mixture was poured onto ice-water, whereupon the target compound precipitated in the form of white crystals. After filtration, the crystals obtained were washed three times with water and then dried overnight at 40° C. in a vacuum drying cabinet. This gave 830 mg (1.58 mol, 98% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.[F:16]C1C=CC(C)=C(C=1)C(O)=O>>[Br:1][C:2]1[NH:3][C:4]2[CH:5]=[C:6]([F:16])[CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Reactant: Cc1ccc(F)cc1C(=O)O
Product: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23

Procedure:
The title compound was prepared in a manner similar to that used for 2-bromo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, starting from 5-fluoro-2-methylbenzoic acid. 2-Bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one was isolated as an orange solid: m.p. 203-204° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 2.79 (m, 2H), 3.41 (m, 2H), 7.29 (dd, J=8.7, 1.2 Hz, 1H), 7.74 (dd, J=10.8, 1.5 Hz, 1H), 8.23 (br t, 1H), 12.12 (br s, 1H). MS (electrospray, [M+Na]+) 305/307.
Reaction SMILES: [OH2:1].[OH-].[K+].Cl[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12](=[O:21])[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20]>C(O)C>[CH3:10][N:9]1[C:5]([OH:1])=[C:6]([C:12](=[O:21])[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[C:7]([CH3:11])=[N:8]1
Reactant: Cc1nn(C)c(Cl)c1C(=O)c1c(Cl)cccc1Cl
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C)c(O)c1C(=O)c1c(Cl)cccc1Cl
Yield: 48 %

Procedure:
In 5 ml. of water is dissolved 0.56 g. of potassium hydroxide and a solution of 1.52 g. of 5-chloro-4-(2,6-dichlorobenzoyl)-1,3-dimethylpyrazole in 10 ml. of ethanol is added thereto. The mixture is heated under reflux for 12 hours. After completion of the reaction, the reaction mixture is allowed to cool and extracted with benzene. An aqueous layer is separated and 2N HCl solution is added to adjust the pH to 3-4, whereby crystalline substance is separated out. The resulting crystalline substance is recovered by filtration and recrystallized from ethanol to give 0.68 g. of the desired product as colorless needles melting 249.5°-250.5° C. Yield 48.0%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[F:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccccc1F
Reactant: Nc1ccc(Br)cn1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Fc1ccccc1CNc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
In a round bottom flask, 5-bromo-pyridin-2-ylamine (38, 4.05 g g, 23.4 mmol) was combined with 70.0 mL of acetonitrile, 2-fluoro-benzaldehyde (39, 2.45 mL, 23.4 mmol), triethylsilane (20.0 mL, 125 mmol) and trifluoroacetic acid (10.0 mL, 130 mmol). The reaction was stirred at 80° C. for 3 hours. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-60% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (40, 5.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:22]=[C:23]1[NH:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])[CH:25]=[CH:24]1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]=[C:10]([CH2:14][N:28]3[C:23](=[O:22])[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[C:32]#[N:33])=[N:27]3)[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: N#Cc1cccc(-c2ccc(=O)[nH]n2)c1
Reactant: BrCc1cccc(-c2ncc(Br)cn2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(Br)cn4)n3)n2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
2.3 54.6 mg (0.166 mmol) of 5-bromo-2-(6-bromomethylpyridin-2-yl)-pyrimidine and 54.1 mg (0.166 mmol) of caesium carbonate are added to a suspension of 32.7 mg (0.166 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile in 0.5 ml of DMF, and the mixture is stirred for 18 hours at 80° C. The reaction mixture is added to water. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving 3-{1-[6-(5-bromopyrimidin-2-yl)pyridin-2-ylmethyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile as slightly brownish crystals; ESI 445, 447;
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[OH:13])[NH:9][C:8](=[O:14])[CH2:7]2)(=O)[CH3:2].[N:15]1C=CC=CC=1.O>CN(C)C=O>[CH3:2][C:1]1[C:4]2[CH:5]=[C:6]3[CH2:7][C:8](=[O:14])[NH:9][C:10]3=[CH:11][C:12]=2[O:13][N:15]=1
Reactant: c1ccncc1
Reactant: CC(=O)c1cc2c(cc1O)NC(=O)C2
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc2cc3c(cc12)CC(=O)N3
Yield: 64.9 %

Procedure:
A mixture of the oxime acetate formed in step c (4.48 g, 18.0 mmol) and pyridine (14.6 mL, 180 mmol) in dimethylformamide (DMF) (660 mL) was heated at 125°-130° C. for 4 hours. The cooled reaction mixture was poured over water and extracted with EtOAc (4 times). The combined organic layer was washed with water and brine and dried (MgSO4), filtered, and concentrated. Purification by silica gel flash chromatography (50% EtOAc/hexanes→100% EtOAc) gave the title compound (2.20 g, 65%) as a pale yellow-orange solid.
Reaction SMILES: Br.[CH2:2]([N:20]([CH2:22][CH:23]([OH:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH:11]([OH:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])C>>[CH2:2]([NH:20][CH2:22][CH:23]([OH:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:10][CH:11]([OH:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC(O)CN(C)CCCCCCN(C)CC(O)CCCCCCC
Agent: Br
Product: CCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCC

Procedure:
In a manner similar to that of Example 22, methylation of N,N'-(1,6-hexylene)-bis[2-hydroxynonylamine] (36 g.) and treatment of the resulting product (25 g., b.p. 172°-176° C./0.05 mm.) with hydrogen bromide gave N,N'-(1,6-hexylene)-bis-[N-methyl-2-hydroxynonylamine] (I: R = CH3 (CH2)6, R' = CH3, X = (CH2)6, Z = H) dihydrobromide (26.3 g., m.p. 176.0°-177.0° C.).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][OH:5].CCN(C(C)C)C(C)C.Br[CH:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21]>CN(C=O)C>[OH:5][CH2:4][CH2:3][CH2:2][S:1][CH:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21]
Reactant: OCCCS
Reactant: O=C1OCCC1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1OCCC1SCCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-mercapto-propan-1-ol (1685 μmol) in DMF (2 ml) were added DIEA (1.5 eq) and 3-bromo-dihydro-furan-2-one (1 eq). The reaction mixture was stirred at RT for 4 hours. The precipitate was filtered and the solvent was removed under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][O-:23].[Na+].CO>COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[N:5]=[C:4]([O:23][CH3:22])[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(-c2cc(Cl)nc(S(C)(=O)=O)n2)cc1OC
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COc1nc(Cl)cc(-c2ccc(OC)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A mixture of 4-chloro-6-(3,4-dimethoxy-phenyl)-2-methanesulfonyl-pyrimidine [5.05 g, 0.0154 mol, Intermediate (49)] in ethylene glycol dimethyl ether (100 mL) is chilled to 0° C. and added 25 wt % sodium methoxide in MeOH (1.32 mL, 0.0231 mol). After 15 minutes the reaction is allowed to warm to ambient temperature and stirred overnight. The mixture is concentrated to afford 4-chloro-6-(3,4-dimethoxy-phenyl)-2-methoxy-pyrimidine [4.3 g, 100%, Intermediate (50)]
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][Cl:15])[C:8]([OH:10])=[O:9])[N:6]=1.[C:16](OC(=O)C)(=[O:18])C.C(O)=O>O1CCCC1>[CH:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][Cl:15])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(C(=NOCCCl)C(=O)O)cs1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1nc(C(=NOCCCl)C(=O)O)cs1
Yield: 80.3 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 15 g.), acetic anhydride (24.5 g.), formic acid (11.0 g.) and tetrahydrofuran (50 ml.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 13.4 g.), mp 155° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:30])[N:16]2[C@H:19]2[C:28]3[C:23](=[C:24]([F:29])[CH:25]=[CH:26][CH:27]=3)[O:22][CH2:21][CH2:20]2)=[C:12]([Cl:31])[N:11]=1.[CH3:32]OC(OC)OC.CS(O)(=O)=O>CO>[Cl:31][C:12]1[N:11]=[C:10]([N:9]2[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[N:1]=[CH:32]2)[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:30])[N:16]2[C@H:19]1[C:28]2[C:23](=[C:24]([F:29])[CH:25]=[CH:26][CH:27]=2)[O:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(F)cc1Nc1nc(Cl)c2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
To a round bottom flask containing (R)-2-(2-amino-5-fluorophenylamino)-6-chloro-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one (0.65 mmol) was added anhydrous methanol (45 mL), followed by anhydrous trimethylorthoformate (5 mL) and methane sulfonic acid (0.1 mL) and the reaction mixture was stirred under Ar at room temperature until it was complete (HPLC monitoring). Preparative HPLC purification, after evaporation of solvent and drying, provided the desired product (184 mg, 62% yield on two steps), as a white solid. 1H NMR (300 MHz, CDCl3) δ, ppm: 9.38 (br s, 1H), 9.01 (s, 1H), 7.84-7.79 (m, 1H), 7.64-7.60 (m, 1H), 7.20-7.13 (m, 1H), 7.10-7.03 (m, 1H), 6.79-6.67 (m, 2H), 5.97-5.92 (m, 1H), 4.68-4.62 (m, 1H), 4.51-4.40 (m, 1H), 2.95-2.83 (m, 1H), 2.41-2.36 (m, 1H); MS (EI) m/z 454.9 (MH)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:57][CH3:58])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:34]=[CH:35][CH:36]=2)[C:16]([N:18]([CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[C:27]([O:29]C(C)(C)C)=[O:28])[CH3:19])=[O:17])=[O:12])=[C:6]([C:37]2[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)[CH:40]=[CH:39][N:38]=2)[CH:5]=1)[CH3:2].Cl>C(Cl)Cl.O1CCOCC1>[CH2:57]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:34]=[CH:35][CH:36]=2)[C:16]([N:18]([CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[C:27]([OH:29])=[O:28])[CH3:19])=[O:17])=[O:12])=[C:6]([C:37]2[CH:42]=[C:41]([C:43](=[O:56])[NH:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:53])[F:54])[CH:47]=3)[CH:40]=[CH:39][N:38]=2)[CH:5]=1)[CH3:58]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (S)-tert-butyl 1-(2-(3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)-N-methylbenzamido)ethyl)pyrrolidine-2-carboxylate in DCM (3 mL) was added 4M HCl in dioxane (40 mL). The mixture was stirred at room temperature for 3 h and concentrated to give a yellow solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[NH3:14]>C(O)C>[NH2:14][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N
Reactant: N#Cc1cc([N+](=O)[O-])c(F)cc1F
Solvent: CCO
Product: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a mixture of 2,4-difluoro-5-nitrobenzonitrile (2 g, 10.86 mmol, prepared as described in: [Ohmori, J.; Sakamoto, S. et. al. J. Med. Chem., 1994, 37(4), 467-475.]) in ethanol (1.25 ml) was added ammonia (6.25 mL, 10.86 mmol) at r.t. The mixture was stirred overnight. Filtered to collect the precipitate, washed w/H2O (3×). The solid was dried in vacuo for 24 hrs to afford 1.9 g of 4-amino-2-fluoro-5-nitrobenzonitrile (1.8 g, 9.44 mmol, 87% yield), which was used in the next reaction without further purification. 1H-NMR (CD3OD, 500 MHz): δ 8.55 (1H, s), 6.82 (1H, s). m/e (M+H): 182.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[C:3]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Solvent: CN(C)C=O
Product: Cn1c(N)c(Br)c(=O)[nH]c1=O
Temperature: 80 °C
Yield: 81.8 %

Procedure:
A mixture of 6-amino-1-methyluracil (14.0 g, 100 mmol), N-bromosuccinimide (21.0 g, 118 mmol), and dry DMF (250 mL) was heated at 80° C. for 3 h. The reaction mixture was evaporated in vacuo and the residue was slurried with ice-cold 50% aqueous ethanol (150 mL) and filtered. The resulting off-white solid was washed with ethanol, then ether and dried to yield 18.0 g 2a (83%). mp 274° C. dec; UV pH 1 λmax 276 nm; NMR δ (DMSO-d6) 3.26 (s, 3H, CH3), 7.02 (s, 2H, NH2), 10.89 (s, 1H, NH).