Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1>C1COCC1>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[C:36]([C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Solvent: C1CCOC1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 571.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2ccc(F)cc2NC1=O
Product: CC(C)(CC(=O)NC1CCc2ccc(F)cc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step E by the procedure described in Example 1, Step F. 1H NMR (300 MHz, CDCl3): 1.35 (s,6H), 1.41 (s,9H), 1.93 (m,1H), 2.4-2.9 (m,5H), 4.54 (m,1H), 5.19 (br s,1H), 6.73 (m,2H), 6.88 (dt;2,8 Hz;1H), 7.19 (dd;6,8 Hz;1H), 8.07 (m,1H). FAB-MS: calculated for C20H28FN3O4 393; found 394 (M+H,56%).
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:24][CH:23](O)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:26])[CH:21]=3)[O:16]2)[CH:12]=[CH:13][CH:14]=1.FC(F)(F)C(O)=O>ClCCl>[F:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:26])[CH:21]=3)[O:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cccc(F)c1)O2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylsilane (960 μl) was added slowly into a solution of 2-(3-fluorophenyl)chroman-4,6-diol (195 mg) in dichloromethane (4 ml). Trifluoroacetic acid (1.9 ml) was then added dropwise into a reaction mixture and it was stirred at room temperature for 5 hours. The reaction mixture was poured on ice-water and extracted with dichloromethane. The residue was evaporated under reduced pressure with toluene to obtain 2-(3-fluorophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 8.78 (s, 1H), 7.43 (m, 1H), 7.28-7.25 (m, 2H), 7.14 (m, 1H), 6.66 (d, 1H, J 8.5 Hz) 6.52 (dd, 1H, J 8.5, 2.7 Hz), 6.49 (d, 1H, J 2.7 Hz), 5.03 (dd, 1H, J 9.9, 2.1 Hz), 2.86 (m, 1H), 2.63 (m, 1H), 2.13 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: [OH:1][C:2]1([C:18]2[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=2)[C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]1=2.[CH3:26]I>>[CH3:26][N:22]1[CH:23]=[C:18]([C:2]2([OH:1])[C:8]3[N:9]=[C:10]([CH3:12])[O:11][C:7]=3[CH2:6][CH2:5][C:4]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]2=3)[C:19](=[O:25])[NH:20][C:21]1=[O:24]
Reactant: CI
Reactant: Cc1ccc2c(c1)CCc1oc(C)nc1C2(O)c1c[nH]c(=O)[nH]c1=O
Product: Cc1ccc2c(c1)CCc1oc(C)nc1C2(O)c1cn(C)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of example 14 step (vi) (1.55 g) and methyl iodide (0.284 ml) according to the method of example 15 step (i). Purification was by flash column chromatography eluting with 5% methanol in ethyl acetate.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[NH:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=O)[CH2:15][CH2:14]1>>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[NH:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)[CH:23]=1
Reactant: CC(=O)c1c(O)cc(C)[nH]c1=O
Reactant: O=Cc1cccc(OCCN2CCOCC2)c1
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCCN3CCOCC3)c2)c(=O)[nH]1
Yield: 10.8 %

Procedure:
According to the same manner as that of Example 16 except that 1.09 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone, and 1.68 g of 3-(2-morpholinoethoxy)benzaldehyde was used in place of 3-(methoxycarbonyl)benzaldehyde, 0.27 g of 4-hydroxy-3-[3-[3-(2-morpholinoethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (3a-39)] was obtained as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:38]([C:36]5[O:35][N:34]=[C:33]([O:32][CH3:31])[CH:37]=5)=[O:39])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)no1
Product: COc1cc(C(=O)NC2(C(=O)NC3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)cnc43)CC2)on1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 37) has been coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light grey solid. MS: 553.1 (MH+, 1Cl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]=[O:16]>Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:15][OH:16])[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc(-c2cccc(Br)c2)n[nH]1
Reactant: C=O
Agent: Cl
Solvent: CO
Product: O=c1ccc(-c2cccc(Br)c2)nn1CO
Reaction time: 8 h
Yield: 40 %

Procedure:
2.51 g of 6-(3-bromophenyl)-3(2H)-pyridazinone, 5 ml of a 37% formalin and 2 drops of concentrated hydrochloric acid were dissolved in 50 ml of methanol, and then the solution was heated under reflux for about 7 hours. The mixture was then left to stand overnight, after which it was filtered and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was extracted with a 1:1 by volume mixture of ethyl acetate and acetone. After distilling the solvent from the extract, there were obtained 1.13 g (yield 40%) of the desired Compound No. 1 in the form of a white solid melting at 228°-229° C.
Reaction SMILES: C(Cl)Cl.[SH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:8]=2[N:9]=1.Br[CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]([OH:21])=[O:20]>C(N(CC)CC)C>[N+:14]([C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:5]([S:4][CH:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([OH:21])=[O:20])[S:6][C:7]=2[CH:13]=1)([O-:16])=[O:15]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Sc1nc2ccc([N+](=O)[O-])cc2s1)c1ccccc1
Yield: 18.4 %

Procedure:
A methylene chloride solution of 5.0 g (0.235 m) 2-mercapto-6-nitrobenzothiazole, 5.2 g (0.235 m) α-bromophenylacetic acid and 5.0 g (0.05 m) triethylamine is heated to gentle reflux overnight. The solution is washed twice with a dilute hydrochloric acid solution and once with water. The solution is dried over anhydrous MgSO4 and then concentrated. The residue is recrystallized once from benzene and then from acetonitrile. 1.5 g (18% yield) of title compound, having a melting point of 152°-5° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=3[F:24])[C:10]=2[N+:25]([O-])=O)=[CH:4][C:3]=1[NH:28][S:29](=[O:32])(=[O:31])[NH2:30].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[NH2:25][C:10]1[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:28][S:29](=[O:31])(=[O:32])[NH2:30])[CH:4]=1
Reactant: NS(=O)(=O)Nc1cc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])ccc1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1ccc(F)c(NS(N)(=O)=O)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 96.7 %

Procedure:
597 mg crude N-(2-fluoro-5-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-nitrophenoxy}phenyl)sulfuric diamide (1.028 mmol, 1 eq.) were dissolved in 20 mL THF, warmed to 50° C., treated with a solution of 3.044 g sodium dithionite (17.484 mmol, 17 eq.) in 16 ml of water dropwise over a period of 30 minutes. The resulting mixture was stirred at this temperature for another 5 h. Upon cooling to rt the phases separated. The organic layer was separated, concentrated in vacuo and redissolved in ethyl acetate. The aqueouse layer was diluted with saturated sodium bicarbonate solution and then extracted twice with ethyl acetate. The combined organic layers were washed once with half saturated brine and once with brine saturated, dried, filtered and concentrated in vacuo, providing 547 mg of crude product which was used in the subsequent transformations without further purification.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:12]2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([NH2:41])[N:3]=1.[F:42][B-](F)(F)F.[H+]>>[CH2:14]([O:13][C@H:12]1[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:30]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:31][C@H:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([F:42])=[N:3][C:4]=2[NH2:41])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reactant: F[B-](F)(F)F
Agent: [H+]
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
The process of claim 1 wherein in addition the 2-amino group of (V) is replaced with a 2-fluoro group by reaction with fluoroboric acid in an organic solvent for the reaction to form 9-(2,3,5 tri-O-benzyl-beta-D-arabinofuranosyl)-2-fluoroadenine (VI) and wherein (VI) is treated in a reaction mixture with hydrogen and palladium chloride in an organic solvent and in a sealed vessel under pressure to produce 9-beta-D-arabinofuranosyl-2-fluoroadenine (VII) which is separated from the reaction mixture.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]=12.[CH3:14][NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH:16]1([N:15]([CH3:14])[C:2]2[C:3]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][CH:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CNC1CCCCC1
Reactant: O=[N+]([O-])c1c[nH]c2nccc(Cl)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccnc2[nH]cc([N+](=O)[O-])c12)C1CCCCC1

Procedure:
To a suspension of 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (57 mg) in 2-propanol (180 μl) were added N-methylcyclohexanamine (154 μl) and N,N-diisopropylethylamine (50 μl), and irradiated microwave at 120° C. for 15 minutes. The reaction mixture was purified by flash column chromatography over silica gel with a EtOAc/methanol (100:0-60:40) as eluant. then by preparative silica gel thin-layer chromatography with EtOAc as eluant to give a solid. The solid was washed with diisopropyl ether to give N-cyclohexyl-N-methyl-3-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (7.9 mg) as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[C@H:12]([C:13]([O-])=[O:14])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:6](=[O:30])[C@H:5]1[CH2:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2)(=[O:3])[CH3:2].C([N:45]1[C@H:53]([C:54]([O-:56])=[O:55])CC(=O)C2C=CC=CC=2N(CC2C=CC=CC=2)C(=O)[C@H]1CC12CC3CC(CC(C3)C1)C2)(=O)C>>[C:1]([N:4]1[C@H:12]([C:13]([NH:45][CH2:53][C:54]([OH:56])=[O:55])=[O:14])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:6](=[O:30])[C@H:5]1[CH2:31][C:32]12[CH2:39][CH:38]3[CH2:40][CH:34]([CH2:35][CH:36]([CH2:37]3)[CH2:41]1)[CH2:33]2)(=[O:3])[CH3:2]
Reactant: COc1ccc(CN2C(=O)[C@@H](CC34CC5CC(CC(C5)C3)C4)N(C(C)=O)[C@H](C(=O)[O-])CC(=O)c3ccccc32)cc1
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Product: COc1ccc(CN2C(=O)[C@@H](CC34CC5CC(CC(C5)C3)C4)N(C(C)=O)[C@H](C(=O)NCC(=O)O)CC(=O)c3ccccc32)cc1

Procedure:
The compound was prepared by an identical route to that used to prepare example 22 except that (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-(4-methoxybenzyl)-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate was used in step a in place of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[CH:15]=[C:14]([C:23](=[O:31])[NH:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)[CH:13]=2)=[CH:7][N:6]=1)=[O:4].[NH:32]1[CH2:35][CH2:34][CH2:33]1>CC(O)=O>[CH3:30][N:27]1[CH:28]=[CH:29][C:25]([NH:24][C:23]([C:14]2[CH:13]=[C:12]([O:11][C:8]3[CH:7]=[N:6][C:5]([C:3]([N:32]4[CH2:35][CH2:34][CH2:33]4)=[O:4])=[CH:10][N:9]=3)[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[CH:15]=2)=[O:31])=[N:26]1
Reactant: C1CNC1
Reactant: COC(=O)c1cnc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1
Solvent: CC(=O)O
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyrazine-2-carboxylic acid methyl ester (396a) and azetidine. 1H NMR (400 MHz, CDCl3) δ 8.86 (d, J=1.26 Hz, 1 H) 8.35 (d, J=1.26 Hz, 1 H) 8.30 (s, 1 H) 7.23-7.32 (m, 1 H) 7.18 (d, J=1.26 Hz, 1 H) 7.12 (d, J=1.26 Hz, 1 H) 6.79 (d, J=2.27 Hz, 1 H) 4.70 (t, J=7.83 Hz, 2 H) 4.27 (t, J=7.83 Hz, 2 H) 3.81 (s, 3 H) 2.85 (s, 2 H) 2.31-2.46 (m, 2 H) 1.49 (s, 6 H); LCMS for C23H24N6O4 m/z 449.20 (M+H+); Anal. Calcd. for C23H24N6O4.0.18 AcOH: C, 61.09; H, 5.43; N, 18.30. Found: C, 61.21; H, 5.64; N, 18.31.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH2:14][CH2:15][OH:16])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CNCCO
Solvent: ClC(Cl)Cl
Product: CN(CCO)S(=O)(=O)c1ccc(Br)cc1
Reaction time: 2.5 h

Procedure:
A solution of 4-bromobenzenesulfonyl chloride (1.10 g) in chloroform (10 mL) was stirred in an ice bath, during which N-methylethanolamine (5 mL) was slowly added dropwise thereto. The mixture was returned to room temperature and stirred for about 2.5 hours. The reaction solution was quenched with concentrated hydrochloric acid with stirring again in an ice bath. The mixed solution was poured into 6 M hydrochloric acid (10 mL) as such, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure to give a crude product of 4-bromo-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide as a colorless oil (1.339 g, quant.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:7]=[C:8]([CH:30]([C:44]3[CH:49]=[C:48]([O:50][CH2:51][CH3:52])[CH:47]=[C:46]([O:53][CH:54]([CH3:56])[CH3:55])[C:45]=3[F:57])[NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[N:42]=[C:41]([CH3:43])[O:40][N:39]=4)=[CH:34][CH:33]=3)[N:9]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH3:60]I>C1COCC1>[CH2:51]([O:50][C:48]1[CH:47]=[C:46]([O:53][CH:54]([CH3:56])[CH3:55])[C:45]([F:57])=[C:44]([CH:30]([C:8]2[N:9]([C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH3:60])[CH:3]=3)[N:7]=2)[NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:42]=[C:41]([CH3:43])[O:40][N:39]=3)=[CH:34][CH:33]=2)[CH:49]=1)[CH3:52]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3cn[nH]c3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3cnn(C)c3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of Intermediate 237.1 (30 mg, 0.04 mmol) in THF (1 mL) at 0° C. was added NaH (3.16 mg, 0.08 mmol), stirred at 0° C. for 30 min, then MeI was added and the reaction mixture was warmed up to rt over 1 h. The reaction mixture was then partitioned between EtOAc and sat. NH4Cl, the organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes, gradient) to afford 20 mg (62%) of Intermediate 237.2.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[O:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([NH:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCOCC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: C(#Cc1cnc(NC2CCOCC2)nc1)c1ccccc1

Procedure:
The title compound, MS: m/e=280.3 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine(example 1, step 2) and tetrahydro-pyran-4-ylamine
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].F[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]3[CH2:8]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc([N+](=O)[O-])nc3)CC2C1
Yield: 63.6 %

Procedure:
Following Example 188a, reaction of 404 mg of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2 mmol) and 566 mg 5-fluoro-2-nitropyridine (1.1 mmol) gave 335a as a yellow solid (234 mg, 35%). MS: [M+H]+ 335. 1H NMR (500 MHz, DMSO) δ 8.18 (d, J=9.0, 1H), 7.87 (d, J=3.5, 1H), 7.06 (dd, J=9.0, 1H), 3.66 (s, 2H), 3.55 (s, 2H), 3.36 (s, 2H), 3.18 (s, 2H), 3.05 (s, 2H), 1.39 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([F:31])[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([F:31])[CH:22]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)cc1F
Product: COC(=O)c1ccc(CNC(=O)c2cc(Cl)ccc2Oc2ccc(F)cc2)cc1F

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(4-fluorophenoxy)benzoic acid (step 2 of Example 67) and methyl 4-(aminomethyl)-2-fluorobenzoate: 1H-NMR (CDCl3) δ 8.22 (1H, d, J=2.6 Hz), 8.06–7.98 (1H, m), 7.86 (1H, t, J=7.7 Hz), 7.35 (1H, dd, J=8.9, 2.6 Hz), 7.13–6.98 (6H, m), 6.75 (1H, d, J=8.9 Hz), 4.69 (2H, d, J=5.9 Hz), 3.91 (3H, s); MS (ESI) m/z 432 (M+H)+, 430 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[O:8][N:7]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.CO>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(-c2ccco2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccco2)on1
Reaction time: 15 h
Yield: 90 %

Procedure:
To a solution of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester (4.14 g) in THF (130 mL) and methanol (25 mL) was slowly added 1N lithium hydroxide aqueous solution (80 mL). The resulting mixture was stirred for 15 hours, and then concentrated under reduced pressure. The remaining solution was acidified with 1N hydrochloric acid to form a solid, and the solid was filtered, washed with distilled water, dried to give 3.22 g of 5-furan-2-yl-isoxazole-3-carboxylic acid (yield: 90%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.N1C=CC=CC=1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl>[Br:19][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: BrBr
Reactant: COc1ccc2ncccc2c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2ncccc2c1Br
Temperature: 25 °C
Yield: 35.9 %

Procedure:
To a mixture of 6-methoxy-quinoline (13.0 g, 0.082 mol) and pyridine (13.2 mL, 0.164 mol) in CCl4 (130 mL) was added bromine (8.4 mL, 0.164 mol) dropwise. The mixture was heated to reflux for 2 hrs and cooled to room temperature. The liquid in the flask was decanted and washed with saturated aqueous NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water again and dried before being evaporated to dryness. The crude product was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1˜1/1) to give 7 g of 5-bromo-6-methoxy-quinoline as a red solid (36% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: CCCc1ccnc(C(=O)CBr)c1
Agent: Br
Product: CCCc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-4-propylpyridine hydrobromide*.