Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C.Cl[C:30]1[C:39]2[C:34](=[CH:35][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1>C(O)C>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:30]3[C:39]4[C:34](=[CH:35][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:12][CH2:13]1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: COc1ccccc1N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: CC(=O)Cl
Solvent: CCO
Product: COc1ccccc1N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.8 %

Procedure:
To 1.73 g (0.00498 n) of 1-[(p-aminophenyl)sulfonyl]-4-(o-methoxyphenyl)piperazine in absolute ethanol is added 0.35 ml acetyl chloride in 5 ml ethanol (source of hydrogen chloride). After stirring for 5 minutes, 1.15 g (0.00498 m) of 4-chloro-7-trifluoromethylquinoline is added. The reaction mixture is stirred at reflux for 3 hours and at room temperature overnight. The solvent is then removed in vacuo and the residue is extracted with methylene chloride/aqueous sodium bicarbonate. The organic layer is filtered through anhydrous sodium sulfate and taken to dryness and the product mixture is chromatographed on silica gel, once with 4% methanol: 96% methylene chloride as eluant, and a second time with methylene chloride as the eluant. Crystallization from methylene chloride/Skelly-solve® B hexanes gives 1.61 g (61%) of 1-(2-methoxyphenyl)-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine of melting point 146°-148° C.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])([O-:7])=[O:6]>>[CH:3]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N+:5]([O-:7])=[O:6])=[CH:2][CH3:1]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccccc1O
Product: CC=COc1ccccc1[N+](=O)[O-]

Procedure:
Allyl bromide was reacted with o-nitrophenol to yield 2-prop-1-en-oxynitrobenzene; which was reduced to the corresponding aniline; then reacted with 5-methyl-N-chloromethyl-2-pyrrolidone to form the corresponding 5-methyl-N'-methylene-2-pyrrolidonyl derivative.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:21]([OH:23])=[O:22])[CH2:9][C:10]([C@@H:12]([NH2:20])[CH2:13][CH2:14][CH2:15][N:16]=[C:17]([NH2:19])[NH2:18])=[O:11])=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].[CH2:30]([O:37][C:38](SC1N=C(C)C=C(C)N=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>O1CCOCC1.O>[CH2:30]([O:37][C:38]([NH:20][CH:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[NH:18])[C:10](=[O:11])[CH2:9][CH:8]([CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:21]([OH:23])=[O:22])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(N)=NCCC[C@H](N)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)NCCCC(NC(=O)OCc1ccccc1)C(=O)CC(Cc1ccccc1)C(=O)O
Yield: 60.7 %

Procedure:
Arphamenine A hydrochloride (150 mg), sodium hydrogen carbonate (176 mg) and S-benzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (230 mg) were dissolved in 20 ml of dioxane-water (1:1), and the resultant solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was adjusted to pH 2.0 with 1N hydrochloric acid, followed by extraction with n-butanol. The extract in n-butanol was washed with water and concentrated to dryness. The residue obtained was chromatographed in a column of silica-gel (20 g) by eluting with a mixture of chloroform and methanol, while changing the ratio of chloroform to methanol in said mixture gradiently from 15:1 to 2:1. The desired reaction product was eluted out in fraction Nos. 60 to 120 [in chloroformmethanol (2:1)] of the eluate. These fractions were combined together and concentrated to dryness to afford 116 mg of the titled compound as a colorless powder. This product gave a value of m/z 455 (MH+) in mass spectrometry.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[CH2:10][C@@H:9]([NH2:11])[CH2:8]1)=[O:6])[CH3:3].[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)[O:24][N:23]=2)=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([CH2:31][NH:11][C@@H:9]4[CH2:10][C@H:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8]4)=[CH:33][CH:34]=3)[O:24][N:23]=2)=[CH:20][CH:21]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Cc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1
Reactant: CCOC(=O)[C@H]1C[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1C[C@@H](NCc2ccc(-c3nc(-c4ccc(CC(C)C)cc4)no3)cc2)C1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
cis-3-Amino-cyclobutanecarboxylic acid ethyl ester hydrochloride (0.193 g, 1.35 mmol) was added to a solution of 4-[3-(4-isobutylphenyl)-1,2,4-oxadiazol-5-yl]benzaldehyde (0.333 g, 1.08 mmol), acetic acid (2 mL) and THF (18 mL) and stirred for 30 minutes. Sodium triacetoxyborohydride (0.500 g, 2.36 mmol) was added to the reaction mixture, stirred at room temperature for 16 hours, and concentrated in vacuo to give a white solid. The solid was triturated with water, filtered and dried to give the title compound (0.260 g, 55% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:9])[N:6]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)(=[O:25])=[O:9])[N:6]=1
Reactant: Nc1ccc(S(=O)Cc2csc(N)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)Cc2csc(N)n2)cc1
Temperature: 0 °C
Yield: 95.7 %

Procedure:
To a solution of 2-amino-4-(4-aminophenylsulfinylmethyl)thiazole (2.8 g) in N,N-dimethylformamide (30 ml) was added portionwise the 3-chloroperbenzoic acid (2.6 g) at 5° C. with stirring. The mixture was stirred at room temperature for 2 hours and then the solution was poured into ice-water. The precipitates were collected by filtration, washed with aqueous sodium bicarbonate, washed with water and dried in vacuo to give 2-amino-4-(4-aminophenylsulfonylmethyl)thiazole (2.85 g, yield 95.6%). mp: 204°-208° C. (dec.)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([NH:16][NH2:17])=O)=O)(C)(C)C.[O:18]=[C:19]1[NH:24][C:23]2[CH:25]=[C:26]([C:29](N)=[NH:30])[CH:27]=[CH:28][C:22]=2[O:21][CH2:20]1.C(O)(=O)C>CN(C=O)C>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[NH:16][N:17]=[C:29]([C:26]2[CH:27]=[CH:28][C:22]3[O:21][CH2:20][C:19](=[O:18])[NH:24][C:23]=3[CH:25]=2)[N:30]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)NN
Reactant: N=C(N)c1ccc2c(c1)NC(=O)CO2
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1COc2ccc(-c3n[nH]c(C4CCCCN4)n3)cc2N1
Temperature: 120 °C

Procedure:
1.5 mmol of 2-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 3 ml DMF. 1 eq of 3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxamidine and 90 ul acetic acid were added and the reaction mixture heated to 120° C. overnight. The solvent was evaporated and the crude extracted from ethylacetate/water. The resulting oil was taken up in 15 ml DCM and treated with 3 ml TFA. The reaction mixture was reduced to dryness.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:15]([OH:19])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:38](Cl)([CH3:41])(=[O:40])=[O:39].O>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22][CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:21])=[C:15]([O:19][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS(=O)[C@H]12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
To a solution of benzhydryl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate-1-oxide (40 g) in pyridine (120 ml) was added mesyl chloride (13 g) under ice-cooling. The reaction mixture was stirred at ambient temperature for an hour. The resulting suspension was poured into water (1 l). The precipitates were collected by filtration, washed with water and methanol, dried under reduced pressure to give benzhydryl 7-phenylacetamido-3-mesyloxy-3-cephem-4-carboxylate-1-oxide (37.0 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([NH:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:34]([CH2:35][CH2:36][C@:19]12[CH3:20])[C@:32]1([CH3:33])[C:27]([CH:28]=[C:29]([C:37]#N)[CH2:30][CH2:31]1)=[CH:26][CH2:25]3)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C(C(C(O)=O)O)[OH:41]>C1(C)C=CC=CC=1>[C:11]([NH:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:34]([CH2:35][CH2:36][C@:19]12[CH3:20])[C@:32]1([CH3:33])[C:27]([CH:28]=[C:29]([CH:37]=[O:41])[CH2:30][CH2:31]1)=[CH:26][CH2:25]3)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2 ml of a 1M solution of diisobutyl aluminum hydride in toluene were added at 0° C. to 10 ml of a dry solution of toluene containing 380 mg of N-t-butyl-3-cyanoandrosta-3,5-diene-17β-carboxamide (prepared as described in Preparation 2). The reaction mixture was then stirred at 0° C. for 30 minutes, after which 30 ml of an aqueous solution of 1.5 g of tartaric acid were added to the mixture. The reaction mixture was then stirred at room temperature for 2 hours, and rhea extracted with methylene chloride three times. The combined organic extracts were washed with water and with a saturated aqueous solution of sodium chloride, in that order. They were then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 50 g of silica gel and using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 1:99 to 4:96 by volume as the eluent, to give 325 mg of the title compound.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[N:6]=1.[F:15][B-](F)(F)F.[H+].F[B-](F)(F)F.N#[O+]>C(OCC)C>[F:15][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[N:6]=1
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)C1CCc2sc(N)nc21
Agent: N#[O+]
Agent: [H+]
Solvent: CCOCC
Product: CCOC(=O)C1CCc2sc(F)nc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 19.3 %

Procedure:
Ethyl 2-amino-5,6-dihydro-4H-cyclopenta[d][1,3]thiazole-4-carboxylate (2.0 g, 9.4 mmol), (see i-13, step A) was dissolved in fluoroboric acid (5.17 g, 28.3 mmol) and the mixture cooled to the point just above it freezes (˜5° C.). Nitrosonium tetrafluoroborate (1.1 g, 9.4 mmol) was added portionwise and mixture stirred at 0° C. for 20min. Diethyl ether (60 ml) added and mixture stirred at −50° C. for 30 min. Filtered and the solid washed with diethyl ether and air dried. The solid was taken up in toluene (70 ml) and warmed to 90° C. for 30 min. The mixture was cooled and evaporated, and the crude residue purified by MPLC (eluent: gradient rising from 100% Hexanes to 40% EtOAc in Hexanes) to give the title compound 390mg (19%) as a yellow oil. 1H NMR (500 MHz CDCl3) δ; 4.22 (q, J=7.1, 2H), 3.93 (dd, J=7.0 and 5.0, 1H), 3.08 (m, 1H), 2.91 (m, 1H), 2.71 (m, 2H), 1.31 (t, J=7.1, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34]C1C=CC=CC=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20](C(OC)=O)[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:34][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([NH:12][CH:13]([C:14]([N:42]([CH3:41])[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:6]([OH:7])=[O:5])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCNC
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CCCCCN(C)C(=O)C(Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 59.7 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and N-methylamylamine (29 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (33 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 7.5-7.15 (m, 6H), 7.04 (d, 1H), 5.02 (m, 1H), 4.81 (s, 2H), 4.28 (m, 1H), 3.25-2.7 (m, 9H), 1.10-1.5 (m, 15H), 0.89 (t, 3H); HRMS m/z 613.2982 (calc. of monoisotopic mass for C32H43N3O9 gives 613.2999).
Reaction SMILES: [OH:1][CH:2]=[C:3]([CH2:8][C:9]1[N:10]([CH3:18])[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4](OC)=O.[NH2:19][C:20]([NH2:22])=[S:21]>CO>[CH3:18][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:9]1[CH2:8][C:3]1[C:2](=[O:1])[NH:19][C:20](=[S:21])[NH:22][CH:4]=1
Reactant: NC(N)=S
Reactant: COC(=O)C(=CO)Cc1cc2ccccc2n1C
Solvent: CO
Product: Cn1c(Cc2c[nH]c(=S)[nH]c2=O)cc2ccccc21
Temperature: 50 °C
Yield: 56.7 %

Procedure:
To a solution of methyl 3-hydroxy-2-[(1-methyl-1H-indol-2-yl)methyl]-2-propenoate (0.363 g, 1.482 mmol) in MeOH (5 mL) was added thiourea (0.30 g, 3.94 mmol). The mixture was heated at 50° C. for 6 h. Purification via MDAP then afforded the title compound (240 mg, 0.840 mmol, 56.7% yield). LCMS: rt=2.40 min, [M+H+]=272
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 53 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.58 (s, 1H), 7.49 (br s, 1H), 7.28–7.21 (m, 10H), 6.91 (m, 1H), 4.77 (s, 1H), 3.38 (dd, 2H, J=6.0, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.46 (m, 1H), 2.41 (t, 2H, J=6.0 Hz), 2.31 (t, 2H, J=7.2 Hz), 1.96 (dt, 2H, J=1.6, 12.0 Hz); 1.82–1.66 (m, 6H), 1.58–1.54 (m, 2H), 0.98 (t, 3H, J=7.6 Hz); ESMS m/e: 566.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1)=[O:27]>C(Cl)Cl.CO>[CH3:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:5]3[N:6]=[CH:7][C:2]([C:31]4[CH:32]=[CH:33][C:28]([CH:26]=[O:27])=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)=[CH:11][CH:12]=2)[CH2:20][CH2:21]1
Reactant: O=Cc1ccc(OB(O)O)cc1
Reactant: CC1CCN(CCOc2ccc(C#Cc3ccc(Br)cn3)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(C=O)cc4)cn3)cc2)CC1

Procedure:
The product was obtained analogously to Example 1.1e starting from 5-bromo-2-{4-[2-(4-methylpiperidin-1-yl)ethoxy]phenylethynyl}pyridine and 4-formylphenylboric acid. Yield: 0.20 g (47% of theoretical); C28H28N2O2 (M=424.534); calc.: molpeak (M+H)+425; found: molpeak (M+H)+: 425; Rf value: 0.40 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]([F:38])([F:37])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]C(O)=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:9][CH2:10][N:5]([C:3]([CH:2]2[CH2:33][CH:32]2[C:29]2[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:37])[F:38])=[CH:31][CH:30]=2)=[O:4])[CH2:6][CH2:7]1)(=[O:13])=[O:12]
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CC1c1ccc(C(F)(F)F)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.086 g, 0.27 mmol) and 3-(4-(trifluoromethyl)phenyl)propanoic acid (60 mg, 0.27 mmol) in dry DCM (20 mL), DIPEA (72 mg, 1.37 mmol) followed by HATU (208 mg, 0.55 mmol) was added at room temperature and stirred overnight. The mixture was then diluted with DCM washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound AGI-604 (0.118 g, 90.07%) as solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)=[N:14][C:13]=1[CH:27]=C.O.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.[Os](=O)(=O)(=O)=O.O>[CH:27]([C:13]1[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)[S:16][C:12]=1[C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:29])[CH3:30])[CH:11]=[CH:10][N:9]=1)=[O:33]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1nc(-c2ccnc(NC(C)=O)c2)sc1-c1nccn1COCC[Si](C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(C=O)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.3 %

Procedure:
N-{4-[5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-4-vinyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.650 g, 1.47 mmol) was dissolved in tetrahydrofuran (20 mL) and water (10 mL) at ambient temperature and 0.157 M osmium tetraoxide in water (93 uL, 0.014 mmol) was added. The mixture was stirred at room temperature for 5 minutes. Sodium metaperiodate (0.661 g, 3.09 mmol) was then added in portions over 20 minutes and the mixture was stirred at room temperature overnight. Solids were removed by filtration and washed with THF (2×50 mL) and ethyl acetate (2×5 mL). The filtrate was extracted with ethyl acetate (3×100 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Crude material was purified by silica gel chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.25 g, 38%). LCMS: (FA) ES+, 444. 1H NMR (400 MHz, CDCl3) δ: 8.75 (s, 1H), 10.21 (s, 1H), 8.41 (d, J=5.18 Hz, 1H), 8.20-8.07 (m, 1H), 7.76 (dd, J=5.21, 1.58 Hz, 1H), 7.30 (dd, J=2.87, 1.21 Hz, 2H), 5.32 (s, 2H), 3.50-3.33 (m, 2H), 2.26 (s, 3H), 0.93-0.78 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: O.Cl.[C:3]1([CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].O.C(O[CH:16](OCC)[CH2:17][CH:18](OCC)OCC)C>C(O)C>[C:3]1([CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:18]=[CH:17][CH:16]=[N:10]1
Reactant: Cc1ccccc1NN
Reactant: CCOC(CC(OCC)OCC)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-n1cccn1
Yield: 83 %

Procedure:
Into a 1 liter, 2-neck flask, fitted with a condenser and a magnetic stirrer, is successively added 90.0 g. (0.570 M.) of o-tolyl-hydrazine hydrochloride hydrate, 100 ml. of water, 63 ml. of 100% ethanol and 139.0 g. (0.633 M.) of 1,1,3,3-tetraethoxypropane. The reaction mixture is then heated slowly to between 80° C. and 90° C., and after maintaining the mixture at this temperature range for a period of about 3 hours, the reaction mixture is quenched on ice water and extracted with ethylacetate/ether. After drying the organic solution over anhydrous sodium sulfate, the solvents are evaporated to obtain a very dark liquid. Distillation in an air oven at a temperature between 110°-120° C. and a pressure of 1 mm. of Hg. yielded a light yellow oil (Yield: 83%).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH:1]1([O:6][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:16][CH:17]=2)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: OC1CCCC1
Solvent: c1ccncc1
Product: O=C(OC1CCCC1)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
Cyclopentanol (2.58g.; 0.03 m) was dissolved in pyridine (50 ml), 4-benzyloxybenzoyl chloride (6.76g; 0.03 m) was added and the mixture was boiled under reflux 6 hours. The resulting mixture was added to ice-water, extracted with ether, the organic extract washed with 2×100 ml. of 2N hydrochloric acid, 2×100 ml. saturated sodium bicarbonate solution and 1×100 ml. of water, dried (MgSO4) and evaporated. The ester was purified by elution from a column of silica in toluene.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:27]1[C:35]2[C:30](=[C:31](B3OC(C)(C)C(C)(C)O3)[C:32]([F:36])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)(C(C)(C)C)(C)C>>[F:36][C:32]1[C:31]([C:2]2[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]3[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:30]2[C:35](=[CH:34][CH:33]=1)[NH:27][CH:28]=[CH:29]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: OCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Product: OCc1ccc2nc(-c3c(F)ccc4[nH]ccc34)nc(N3CCOCC3)c2n1

Procedure:
(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanol 6 (0.1 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 73.4 mg of 108 following reverse phase HPLC purification. MS (Q1) 380.1 (M)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:12]=1)[CH3:2]
Reactant: CCOC(=O)CNc1nc(Cl)cc(Cl)n1
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 6.1 g. (0.024 mole) of N-(4,6-dichloro-2-pyrimidinyl)glycine ethyl ester, 3.4 g. (0.024 mole) of p-chlorobenzylamine and 2.6 g. (0.024 mole) of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hours. The reaction mixture was filtered and the filtrate on cooling gave a precipitate. The precipitate was collected and recrystallized twice from benzene to give 4.6 g. of product, m.p. 132°-135°C.