Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[S:7])[CH3:4].N1C=CC=CC=1.NOS(O)(=O)=O>C(O)C.CO>[CH3:4][C:3]1[N:5]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[S:7][N:2]=1
Reactant: CC(=NC(=S)C1CCCN(C(=O)OC(C)(C)C)C1)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CCO
Solvent: CO
Solvent: c1ccncc1
Product: Cc1nsc(C2CCCN(C(=O)OC(C)(C)C)C2)n1
Reaction time: 2.5 h

Procedure:
Compound 10a (1.5 g, 4.78 mmol) was stirred in ethanol (20 mL) and treated with pyridine (0.76 g, 9.6 mmol). A solution of hydroxylamine-O-sulfonic acid (0.65 g, 5.74 mmol), in methanol (4 mL) was added and stirring continued for 2.5 hours. The mixture was allowed to stand overnight at 4° C. The mixture was condensed under vacuum and extracted with dichloromethane and deionized water. The organic layer was dried (Na2SO4) and condensed under vacuum. The product was filtered through a plug of silica gel, with hexane:EtOAc (8:2) to remove low Rf impurities, and dried to 0.92 g of clear oil. MS (ESI) m/z 322 [M+K]+. 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.59-1.68 (m, 1H) 1.71-1.88 (m, 2H) 2.12-2.22 (m, 1H), 3.02-3.12 (t, 1H) 3.15-335 (m, 2H), 3.81-3.90 (dt, 1H), 4.14 (bs, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Si:5]([CH3:35])([CH3:34])[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12.[NH:36]1[CH:40]=[N:39][CH:38]=[N:37]1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:34][Si:5]([CH3:35])([CH2:4][CH2:3][CH2:2][N:36]1[CH:40]=[N:39][CH:38]=[N:37]1)[CH2:6][CH2:7][C:8]1[C:20]2[CH2:19][N:18]3[C:13](=[CH:14][C:15]4[C@:25]([CH2:27][CH3:28])([OH:26])[C:24](=[O:29])[O:23][CH2:22][C:16]=4[C:17]3=[O:21])[C:12]=2[N:11]=[C:10]2[CH:30]=[CH:31][CH:32]=[CH:33][C:9]=12
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCn1cncn1
Yield: 61 %

Procedure:
A solution of Compound 11 (50 mg), 1,2,4-triazole (31 mg) and NaHCO3 (15 mg) in dry N,N-dimethylformamide (1 mL) was heated at 70° C. for 5 hours under argon. The N,N-dimethylformamide was removed from the reaction mixture under vacuum and the residue was directly eluted on a silica gel column using 4% ethanol in dichloromethane to obtain the required product in 61% yield (30 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CO>[CH3:14][N:15]([CH3:17])[CH:16]=[N:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: COC(OC)N(C)C
Reactant: CSc1cccc(C(N)=O)c1
Solvent: CO
Product: CSc1cccc(C(=O)N=CN(C)C)c1

Procedure:
8.5 g of 3-methylsulfanylbenzamide and 18 ml of dimethylformamide dimethyl acetal were heated at 120° C. while the formed methanol was eliminated by distillation. After heating for 3 h, the volatiles were removed in vacuo. The crude product was purified by flash chromatography (300 g silica gel; DCM/MOH, gradient from 100:0 to 95:5). 8 g of the title compound were obtained as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:14]#[C:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: CCC#C[C@@H](CC(=O)OC)c1ccc(O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC[C@@H](CC(=O)OC)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
To a stirred solution of 24.1 (0.071 g, 0.3 mmol) in EtOAc (3 mL) at 23° C. was added palladium on carbon (0.03 g, 0.3 mmol). The reaction was placed under an atmosphere of hydrogen and then stirred at room temperature. After 5 hours, the reaction mixture was filtered through a pad of silica and then concentrated. After concentration, the residue was purified on silica gel (0%-20% EtOAc/hexane) to give 30.1 (0.06 g, 83%). MS ESI (pos.) m/e: 237.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CN1CCN(c2cccc(Br)n2)CC1
Product: CN1CCN(c2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide and 1-(6-bromopyridin-2-yl)-4-methylpiperazine as the starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:29]1[C:33](=[O:34])[NH:32][CH2:31][CH:30]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:32]4[CH2:31][CH:30]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:29][C:33]4=[O:34])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: O=C1CC(c2ccccc2)CN1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4CC(c5ccccc5)CC4=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-phenyl-2-pyrollidinone.
Reaction SMILES: C[C:2]1([CH3:20])[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=O)=[C:4]([C:17](O)=O)[CH2:3]1>CC(C)=O>[CH3:13][C:14]1[C:10](=[O:12])[C:9]2[C:8](=[CH:16][CH:15]=1)[C:5]1[C:4](=[CH:3][C:2]([CH3:20])=[CH:7][CH:6]=1)[CH:17]=2
Reactant: CC1(C)C=CC(c2ccccc2C(=O)O)=C(C(=O)O)C1
Solvent: CC(C)=O
Product: CC1=CC=C2C(=Cc3cc(C)ccc32)C1=O
Temperature: 25 °C

Procedure:
4,4-Dimethyldiphenic acid (20.0 g, 74.0 mmol) was heated in a sand bath at 300°-330° C. for 2 hr until decarboxylation was over (no gas was evolved). The reaction mixture was cooled down to room temperature and the cake obtained was dissolved in acetone. Evaporation of the acetone produced a black material which was extracted with 25% solution of ethyl acetate in hexane. Evaporation of the solvents afforded the crude ketone which was further purified on a short path chromatography (silica, a. hexane, b. 5% ethyl acetate in hexane). This afforded 10.1 g (65.4%) of 2,7-dimethylfluorenone.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]2[CH2:18][C@H:17]([S:19][C:20]3[C@H:21]([CH3:44])[C@@H:22]4[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:23]4[C:24]=3[C:25]([O:27]CC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:16][N:15]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:13])[CH2:7][CH2:6]1)(=[O:3])[NH2:2].[ClH:58]>O1CCCC1.O>[ClH:58].[C:1]([CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]2[CH2:18][C@H:17]([S:19][C:20]3[C@H:21]([CH3:44])[C@@H:22]4[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:23]4[C:24]=3[C:25]([OH:27])=[O:26])[CH2:16][NH:15]2)=[O:13])[CH2:7][CH2:6]1)(=[O:3])[NH2:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(CC(N)=O)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCCN(CC(N)=O)CC4)C3)[C@H](C)[C@H]12

Procedure:
200 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-[(2S, 4S)-2-(4-carbamoylmethyl-1-homopiperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.18 ml of 1N aqueous hydrochloric acid were added to the mixture, which was then hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 0.3 g of 10% w/w palladium-on-charcoal. The catalyst was then filtered off, and the filtrate was extracted with diethyl ether. The aqueous layer was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through a Lobar column (a product of Merck, LiChroprep RP-8, size B), using water as the eluent. Those fractions containing the title compound were combined, concentrated by evaporation under reduced pressure and lyophilized, to give 30 mg of the title compound as a colorless powder.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:28][C:29]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][NH:35]4)=[CH:31][CH:30]=3)=[C:21]([C:26]#[N:27])[CH:22]=[N:23]2)=[CH:18][C:17]=1[O:38][CH3:39])C1C=CC=CC=1>>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([NH:28][C:20]3[C:19]4[C:24](=[CH:25][C:16]([OH:15])=[C:17]([O:38][CH3:39])[CH:18]=4)[N:23]=[CH:22][C:21]=3[C:26]#[N:27])[CH:37]=2)[CH2:33][CH2:34]1
Reactant: COc1cc2c(Nc3ccc4c(c3)NCC4)c(C#N)cnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc4c(c3)NCC4)c(C#N)cnc2cc1O
Reaction time: 1 h
Yield: 66 %

Procedure:
To 5 ml of trifluoroacetic acid was added 206 mg 7-benzyloxy-4-(2,3-dihydro-1H-indol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile and the reaction was refluxed for 1.5 h. The TFA was removed under vacuum and the resulting film was dissolved in 7 ml of methanol followed by the addition of 50 ml of ice cold saturated sodium bicarbonate. The solution was allowed to stand at 10° C. for 1 h. The resulting solid was isolated, washed with excess water and dried under vacuum at 80° C. to yield 107 mg of 4-(2,3-dihydro-1H-indol-6-ylamino)-7-hydroxy-6-methoxy-quinoline-3-carbonitrile. This compound was taken directly on to the next step without purification.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([S:11][CH2:12][CH2:13][CH3:14])[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:5]1=[O:52])[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=[O:61])C=1>ClCCl>[CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([S:11]([CH2:12][CH2:13][CH3:14])=[O:61])[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:5]1=[O:52])[CH2:2][CH3:3]
Reactant: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCn1c(=O)cc(S(=O)CCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution of 3-propyl-6-propylthio-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.6 g) in dichloromethane (10 ml) was added m-chloroperbenzoic acid (0.16 g) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with an aqueous sodium bicarbonate solution and water, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless powders (0.27 g, 44%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:28]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:28][CH3:29])=[CH:32][CH:33]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-ethoxyphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.25 g, 93%).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[N:21]1([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN1CCCC1=O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:28]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1cccc(N2CCOCC2)c1
Solvent: CN1CCCC1=O
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCOCC4)c3)nn12
Temperature: 140 °C
Yield: 9.3 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000261 mol) and 3-Morpholin-4-yl-phenylamine (93.0 mg, 0.000522 mol) were dissolved in N-Methylpyrrolidinone (2.0 mL) and the reaction was heated at 140° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 9.70 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3-morpholin-4-yl-phenyl)-amine as a lyophilated powder. (M+H)=402.20. 1H NMR (400 MHz, DMSO, d6) δ 9.23 (s, 1H), 8.94 (s, 1H), 7.70 (d, 1H, J=7.84 Hz), 7.46 (m, 1H), 7.34 (s, 1H), 7.19 (d, 1H, J=7.83 Hz), 7.08 (m, 3H), 6.90 (m, 2H), 6.87 (m, 1H), 3.75 (s, 3H), 3.63 (m, 4H), 2.83 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][N:4]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC.O>CC(N(C)C)=O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][N:4]=1)[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CNc1ccc(I)cn1
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)c1ccc(I)cn1
Temperature: 90 °C
Yield: 56.9 %

Procedure:
The obtained 2-(N-monomethylamino)-5-iodopyridine (99, 1.00 g, 4.27 mmol), potassium carbonate (2.95 g, 21.36 mmol) and iodomethane (145 mg, 8.546 mmol) were dissolved in dimethylacetamide (30 mL), and the reaction mixture was heated at 90° C. for 24 hours, followed by adding water. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-(N,N-dimethylamino)-5-iodopyridine (100, 603 mg, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=2)=[C:4]([F:23])[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:37])[CH2:33][C:34](O)=[O:35])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[F:23][C:4]1[CH:3]=[C:2]([NH:1][C:34](=[O:35])[CH2:33][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:37])[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cc2F)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)ncn1
Yield: 80.1 %

Procedure:
The title compound was prepared from tert-butyl 6-(4-amino-2-fluorophenoxy)pyrimidin-4-ylcarbamate (8 mg, 0.025 mmol) and (4-fluorophenylamino)-3-oxopropanoic acid (6 mg, 0.031 mmol, Compound B of Example 1), TBTU (11 mg, 0.034 mmol), and DIPEA (6 μL, 0.030 mmol) using a similar procedure described for the preparation of Compound C, Example 1. Flash chromatography using 1-1.5% MeOH in CH2Cl2 as the eluent gave the title compound as a white solid (10 mg, 80%). 1H NMR (DMSO-d6) δ 10.48 (s, 1H), 10.46 (s, 1H), 10.25 (s, 1H), 8.39 (s, 1H), 7.74-7.77 (m, 1H), 7.62 (d, 1H, J=5.5 Hz), 7.61 (d, 1H, J=4.9 Hz), 7.36-7.30 (m, 2H), 7.17-7.13 (m, 2H), 3.48 (s, 2H), 1.46 (s, 9H); MS(ESI+) m/z 500.12 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]([OH:13])[CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.C(NC(C)C)(C)C.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>ClCCl.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:9][C@@H:10]([CH2:11][Cl:12])[O:13][C:25]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O[C@H](CCl)CNCc1ccccc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: O=C1O[C@H](CCl)CN1Cc1ccccc1
Temperature: 45 °C
Yield: 66.5 %

Procedure:
To a 250 ml round bottom flask was added (2S)-1-(benzylamino)-3-chloropropan-2-ol (1.0 g, 5 mmol, INTERMEDIATE 12), chloroform (15 ml), and diisopropylamine (3.23 g, 25 mmol). To this was added carbonyldiimidazole (1.63 g, 10 mmol), and the mixture was heated to 45° C. for 15 h. The reaction then was diluted with dichloromethane (25 ml) and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to provide a pale tan residue. The product was isolated on silica gel eluting with a gradient of ethyl acetate in hexanes from 0% to 100% to provide 750 mg of product as colorless oil. Mass spectrum (ESI) 226.1 (M+1).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18]CC)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[CH:25]([NH2:27])=[NH:26].C[O-].[Na+].C(O)(=O)C>CO.[OH-].[Na+]>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2[N:26]=[CH:25][NH:27][C:16](=[O:18])[C:11]=2[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Temperature: 85 °C

Procedure:
A mixture of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (50.0 g, 0.168 mol), formamidine acetate (16.2 g, 0.201 mol), 4.37 M of sodium methoxide in methanol (190 mL) and methanol (200 mL, 5 mol) was heated to 85° C. for 16 hour in a 350 ml sealed reaction vessel. The mixture was allowed to cool and reduced in vacuo. The residue was dissolved in 1N NaOH (150 ml) and poured over ice. Glacial acetic acid was added to the mixture until the pH of the mixture was 7 and a tan solid precipitated out the solid was filtered, washed with water and cold ether, and dried on high vacuum to yield the title compound as a tan solid; (26.2 g, 61.4%).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[N:11][C:12]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:14]=2)[N:9]=1.C(O)C>O>[O:18]([C:12]1[N:11]=[C:10]2[C:15]([CH:16]=[CH:17][C:8]([NH:7][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])=[N:9]2)=[CH:14][CH:13]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)C1CC1
Temperature: 4 °C
Yield: 49.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with cyclopropanecarboxylic acid (4.8 g), N,N'-carbonyldiimidazole (9.07 g) and 2-amino-7-phenoxy-1,8-naphthyridine (10 g). The product produced by precipitation in water (11.2 g; m.p. approximately 170° C.) is dissolved in boiling ethanol (200 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)cyclopropanecarboxamide (6.4 g) is produced, m.p. 190° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10](S)[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[Br:14]Br>CO.Br>[Br:14][C:10]1[NH:9][C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[N:11]=1
Reactant: O=[N+]([O-])c1ccc2nc(S)[nH]c2c1
Reactant: BrBr
Agent: Br
Solvent: CO
Product: O=[N+]([O-])c1ccc2nc(Br)[nH]c2c1
Temperature: 7.5 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
A suspension of 5.0 g (25.61 mmol) of 6-nitro-1H-benzimidazole-2-thiol in 30 ml of methanol and 10 ml of hydrogen bromide (48% in water) was cooled to 5-10° C. and admixed with 5.7 ml (111 mmol) of bromine. Subsequently, the mixture was stirred at 5-10° C. for 1.5 hours and poured onto ice-water. The red precipitate was filtered off with suction, washed with water and dried at 40° C. under reduced pressure. 4.82 g (78%) of the desired product were obtained.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:53][O:54][CH3:55])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:35]3[C:39]([O:41]C(C)(C)C)=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:53][O:54][CH3:55])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CCOC(=O)CSC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2CS1
Solvent: O=CO
Product: CCOC(=O)CSC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)C2CS1
Temperature: 50 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A mixture of 200 mg of the product of Step B dissolved in 4 ml of 66% formic acid was stirred at 50° C. for 2 hours, after which the solution was cooled and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was re-dissolved in ethanol. The solvent was evaporated and 20 ml of ether were added with stirring for 30 minutes. Then, the crude products was separated and chromatographed on silica and eluted with a mixture of methylene chloride and methanol (8-2). After crystallization from ether, 70 mg of racemic 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(ethoxycarbonylmethylthio)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid melting at >210° C. (decomposes) were obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[O:23][C:13]2=[C:14]3[C:19](=[CH:20][CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]3)=O)(C)(C)C.[ClH:24]>O1CCCC1>[NH2:8][CH2:9][CH:10]1[O:23][C:13]2=[C:14]3[C:19](=[C:20]([Cl:24])[CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]3
Reactant: CC(C)(C)OC(=O)NCC1Cc2ccc3[nH]c(=O)ccc3c2O1
Reactant: Cl
Solvent: C1CCOC1
Product: NCC1Cc2cc(Cl)c3[nH]c(=O)ccc3c2O1

Procedure:
2-(t-Butoxycarbonyl)aminomethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (416 mg) was dissolved in tetrahydrofuran (8.8 ml), to which 6N-HCl (2.2 ml) was added. The mixture was refluxed for 30 minutes while heating. After completion of the reaction, the mixture was dried to solidity under reduced pressure. The residue was subjected to recrstallization with a solvent mixture of methanol-ether to obtain 265 mg of a hydrochloric acid salt of 2-aminomethyl-5-chloro-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as light yellow powdery crystals (79.6%,