Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:32]([O:33][CH3:34])=[CH:31][C:7]2[CH2:8][C:9](=[O:30])[N:10]([CH2:13][CH2:14][CH2:15][N:16]([CH3:29])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1.[Mn]([O-])(=O)(=O)=[O:36].[K+].N>C(OC(=O)C)(=O)C.CC(C)=O>[ClH:1].[CH3:2][O:3][C:4]1[C:32]([O:33][CH3:34])=[CH:31][C:7]2[C:8](=[O:36])[C:9](=[O:30])[N:10]([CH2:13][CH2:14][CH2:15][N:16]([CH3:29])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: N
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
1.98 gm (4.0 mmols) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane hydrochloride were suspended in 50 ml of acetic anhydride; the suspension was mixed with 2.5 gm of potassium permanganate, and the mixture was stirred for 20 minutes at 20° C. The reaction mixture was poured into ice water and made alkaline with concentrated ammonia. The precipitated manganese dioxide was suction-filtered off, and the filtrate was extracted several times with methylene chloride. The extract was dried over magnesium sulfate, evaporated in vacuo, and the residue was purified on a silica gel column with methylene chloride +1% of ethanol as the eluant. The product thus obtained was dissolved in acetone, and the hydrochloride was precipitated with ethereal hydrochloric acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])(O)[CH3:28])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36][CH3:37])=[CH2:28])[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C(C)(O)c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1)c1ccccc1OC
Yield: 0.1 %

Procedure:
A solution of crude 33 (3.96 mol) in toluene (150 mL) was treated with p-toluenesulfonic acid (100 mg) and refluxed under a Dean-Stark trap for 3 hr. After cooling, the reaction mixture was diluted with ethyl acetate (80 mL) and washed with saturated sodium bicarbonate (80 mL) and water (2×80 mL). The organic extract was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (80 g) with 2% ethyl acetate in heptane (2 L) to afford 34 (1.15 g, 62%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=O)[N:9]3CC[C@H:10]3[C:11]3[N:12](C=NC=3/C=C\Cl)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[OH2:33]>CN(C)C=O>[N:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]2[C:6]=1[C:5](=[O:33])[CH:4]=[CH:3][CH:2]=2
Reactant: O=C1c2c(Cl)cccc2-n2cnc(/C=C\Cl)c2[C@@H]2CCN12
Reactant: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=c1cccc2cnccnc1-2

Procedure:
2.21 g (6.9 mmol) of (S)-8-chloro-1-[(Z)-2-chlorovinyl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was heated to boiling under reflux for 4 hours together with 1.23 ml (8.3 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 30 ml of N,N-dimethylformamide. The reaction mixture was subsequently poured into 300 ml of water and extracted five times with methylene chloride. The organic extracts were washed four times with water, dried over magnesium sulphate and evaporated. After chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there was obtained (S)-8-chloro-1-ethynyl-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4benzodiazepin-9-one of melting point 249°-250°.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:10][NH:11][S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:9][C:3]1[C:2](/[CH:16]=[CH:15]/[S:12]([NH:11][CH3:10])(=[O:14])=[O:13])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1
Reactant: C=CS(=O)(=O)NC
Reactant: Nc1ncc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CNS(=O)(=O)/C=C/c1cc(Cl)cnc1N
Temperature: 25 °C
Yield: 25 %

Procedure:
A mixture of 3-bromo-5-chloro-2-pyridinamine (414 mg, 2 mmol), N-methyl ethene sulphonamide (266 mg, 2.2 mmol) and triethylamine (555 μl, 4 mmol), palladium acetate (18 mg, 0.08 mmol) and tri-o-tolylphosphine (50 mg, 0.16 mmol) in DMF (0.5 ml) in a Teflon™ pressure vessel was microwaved for 30 sec (full power), allowed to cool to RT and irradiated for a further 30 sec. After allowing to cool, the reaction mixture was diluted with water, extracted with EtOAc and the organic phase washed with saturated brine, dried over MgSO4, and concentrated to a brown semi-solid. Purification by column chromatography on silica gel eluting with methylene chloride—methanol (95:5), and then crystallisation from methanol gave the title compound (130 mg, 0.5 mmol):
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH3:10])[CH:4]=1)[CH3:2].[Mg+2].[Cl-].[Cl-].Cl.C[CH2:16][O:17]C(C)=O>CC#N.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:10])[C:6]([OH:9])=[C:7]([CH:8]=1)[CH:16]=[O:17])[CH3:2]
Reactant: CCc1ccc(O)c(C)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: CC#N
Product: CCc1cc(C)c(O)c(C=O)c1
Yield: 53 %

Procedure:
To a solution of the phenol of Example 150 Step 1 (5.0 g, 36.7 mmol) in 200 mL CH3CN, was added MgCl2 (5.25 g, 55.1 mmol), TEA (13.9 g, 19.2 mL, 137.6 mmol), and (CHO)N (8.3 g, 280 mmol). The reaction was heated at reflux for 3 h. After cooling, the reaction was diluted with EtOAc (500 mL) and acidified with aqueous 2N HCl until the reaction was pH 4. The reaction was diluted with 300 mL H2O. The organic layer was washed with H2O, with brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (on SiO2, hexane/EtOAc=94/6) to give 3.2 g (53%) of the desired product as a clear oil.
Reaction SMILES: [CH:1]([N:14]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=[C:15]1[SH:23])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH3:27]I>C(Cl)Cl.CO>[CH:1]([N:14]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=[C:15]1[S:23][CH3:27])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CI
Reactant: COC(=O)c1cnc(S)n1C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc(SC)n1C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
3.2 g (0.01 mol) of 1-benzhydryl-2-mercapto-5-methoxycarbonyl-imidazole (Example 1a) were introduced into a mixture of 30 cc of water, 15 cc of methanol, 15 cc of methylene chloride, 10 cc of 2 N sodium hydroxide solution and 1.3 cc of methyl iodide. Stirring was continued for 30 minutes. During this time the temperature of the reaction mixture rose to 39° C. After cooling, 3 g (90% of the theory) of 1-benzhydryl-5-methoxycarbonyl-2-methylthio-imidazole, m.p. 118° C. were isolated from the organic phase.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:10])=[CH:28][CH:27]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C(/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)NCCCCc1cccnc1
Yield: 81.4 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (6.35 g) and 3-pyridinebutanamine (2.7 g) in tetrahydrofuran (75 mL) was stirred for 2 hours at 25° C. and was worked up in the usual fashion. The crude material was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to give 5.3 g of (E)-5,5-bis(4-chlorophenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 146°-147° C. Anal. Calculated for C26H24Cl2N2O: C, 69.18; H, 5.36; Cl, 15.71; N, 6.21 Found: C, 69.00; H, 5,57; Cl, 15.71; N, 6.21.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:22][F:23])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1.C(Cl)Cl.[C:27]1([CH3:40])[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=1[S:35]([O:38][NH2:39])(=[O:37])=[O:36]>CCOCC>[C:27]1([CH3:40])[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=1[S:35]([O-:38])(=[O:37])=[O:36].[NH2:39][N+:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]([CH2:2][F:1])([CH2:22][F:23])[CH:8]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1ccccc1C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Yield: 71.7 %

Procedure:
To a mixture of 200 mg of 2,2-bisfluoromethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran and 2 ml of methylene chloride was added dropwise a mixture of 135 mg of (O-mesitylenesulfonyl)hydroxylamine and 3 ml of methylene chloride at room temperature with stirring. The mixture was stirred for 1 hour and ether was added thereto. The separated crystal was collected by filtration to obtain 240 mg of N-amino-2-(2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl)pyridinium mesitylenesulfonate. To a mixture of 60 mg of the above-obtained N-amino-2-(2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl)pyridinium mesitylenesulfonate and 1 ml of dimethylformamide was added 5 mg of sodium hydride and 36 mg of cyano bromide under ice-cooling with stirring. The mixture was stirred under ice-cooling for 1 hour. Water was added thereto and the mixture was extracted with ether. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =5:95) to obtain 11 mg of 2-(2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl)pyridine N-cyanoimine represented by the following formula having a melting point of 212°-214° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:39]=[CH:38][C:15]([CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][C@@H:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C@H:24]([OH:36])[CH2:23]3)[C:18]2=[O:37])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:11][C:12]1[CH:39]=[CH:38][C:15]([CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:24](=[O:36])[CH2:23]3)[C:18]2=[O:37])=[CH:14][CH:13]=1
Reactant: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(F)cc4)C3=O)C[C@H]2O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(C2CCN(C3CCN(Cc4ccc(F)cc4)C3=O)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of DMSO (0.14 mL, 2 mmol) and DCM (20 mL) at −78° C. under nitrogen was added oxalyl chloride (0.18 mL, 2 mmol) and the reaction mixture was stirred for 10 min. Then 1-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)-piperidin-1-yl)pyrrolidin-2-one (320 mg, 0.8 mmol) was added and the reaction was stirred for one hour at same temperature. Triethylamine (0.56 mL, 4 mmol) was then added, and the reaction mixture was allowed to warm to rt. The mixture was then partitioned between water (100 mL) and DCM (200 mL). The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to give afford the crude product, which was taken on to step D without further purification. LCMS (method Q) RT 0.68 min (47% AP), m/z 397.1 (M+H+).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[C:10]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:10]([NH:14][C:15](=[O:23])[C:16]1[C:21]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
92 ml (92 mMol) o-Tolylmagnesium chloride solution (1M in THF) were added over 15 minutes to a solution of 5.0 g (23 mMol) N-tert.-butyl-6-chloro-nicotinamide in 25 ml THF cooled to 0° C. The reaction mixture was stirred 18 hours at 30° C. and cooled again to 0° C. 5.6 ml (138 mMol) Methanol were added over 30 minutes, stirring was pursued for 10 minutes and 6.3 g (27 mMol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were added. After 1 hour at room temperature, the reaction mixture was concentrated to 50 g under reduced pressure, heated to 50° C. and 100 ml tert.-butyl-methylether were added. The resulting suspension was refluxed for 30 minutes, cooled to room temperature and, after 1 hour, filtered off. The filtrate was concentrated and dried under high vacuum to yield 6.3 g (90%) of N-tert.-butyl-6-chloro-4-o-tolyl-nicotinamide as an orange foam.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][CH:13]([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)C(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CC(C)C(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl 2-methylpropanoate (603 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 44 (486 mg, 71% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 8H), 1.06 (d, J=6.8 Hz, 3H), 1.08 (d, J=7.2 Hz, 3H), 1.16-1.38 (br. m, 3H), 1.64-1.73 (br. m, 2H), 1.82-1.92 (br. m, 3H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.52 (hept., J=6.8 Hz, 1H), 2.74-2.87 (br. m, 2H), 6.42 (d, J=5.2 Hz, 1H), 7.40 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 366.08 (M+Na)+; 342.04 (M−H)−.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#N.[OH-:22].[Na+].C[OH:25]>C(O)C>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:3]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)([C:1]([OH:25])=[O:22])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccnc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2cccnc2)CC1

Procedure:
A flask was charged with tert-butyl 4-cyano-4-(pyridin-3-yl)piperidine-1-carboxylate (7.5 g, 26.1 mmol) and NaOH (50% in water, 100 mL) in ethanol (100 ml) and heated at reflux for 6 h. The ethanol was removed, and the resulting solution was acidified to pH=5 using concentrated hydrochloric acid. The desired product was collected by filtration, and dried overnight to yield 4.1 g (51%). Mass Spec.: 307.18 (MH)+. LC tr=1.31 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([NH:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1)[CH3:16]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)N
Product: CC(C)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 1A starting with 4-fluoro-2-(trifluoromethyl)benzonitrile and isopropyl amine: MS (ES) m/z 229 (M+1).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([CH3:29])[C@H:6]([C@H:15]1[CH2:19][O:18]C(C)(C)[N:16]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[N+:2]=[N-:3].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CCN(C(C)C)C(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CCO>[N:1]([CH2:4][C@H:5]([CH3:29])[C@@H:6]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10])[C@H:15]([NH:16][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:19][OH:18])=[N+:2]=[N-:3]
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of (R)-tert-butyl 4-((1R,2S)-3-azido-1-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.0 equiv.) in EtOH (0.1 M) was added PPTS (1.3 equiv.) and the mixture was refluxed for 2 days. The volatiles were removed under vacuo, the residue was dissolved in DCM (0.1 M) and DIEA (1.5 equiv.) and Boc2O (1.0 equiv.) were added to the reaction mixture. The solution was stirred for 3 hours at room temperature. The solvents were removed under reduced pressure and the residue was diluted with ethyl acetate, washed with water, aqueous NaHSO4, aqueous NaHCO3, sat. NaCl, the organic phase was dried with magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:3) to give tert-butyl (2R,3R,4S)-5-azido-3-(tert-butyldimethylsilyloxy)-1-hydroxy-4-methylpentan-2-ylcarbamate as the major isomer (5:2) in 70% yield. LC/MS=289.3 (M+H-Boc), Rt=0.76 min (Frac 65%-95% method).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[NH:17][CH:16]=[C:15]([C:18](O)=[O:19])[CH:14]=3)[CH:8]=2)=[CH:4][C:3]=1[NH:23][C:24]([C:26]1[O:27][CH:28]=[CH:29][C:30]=1[CH3:31])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[O:65]1[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][CH2:73][NH2:74])[CH2:67][CH2:66]1>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[NH:17][CH:16]=[C:15]([C:18]([NH:74][CH2:73][CH2:72][CH2:71][N:68]4[CH2:69][CH2:70][O:65][CH2:66][CH2:67]4)=[O:19])[CH:14]=3)[CH:8]=2)=[CH:4][C:3]=1[NH:23][C:24]([C:26]1[O:27][CH:28]=[CH:29][C:30]=1[CH3:31])=[O:25]
Reactant: NCCCN1CCOCC1
Reactant: Cc1ccoc1C(=O)Nc1cc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cc(Oc2ccnc(-c3cc(C(=O)NCCCN4CCOCC4)c[nH]3)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (Example 28) (150 mg, 0.36 mmol) in 10 ml of anhydrous DMF were added HATU (163 mg, 0.43 mmol) and N,N-diisopropylethylamine (102 mg, 0.79 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 3-morpholinopropylamine (104 mg, 0.72 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 10% methanol in chloroform to give 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 110 mg, 56%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]\[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]\[C:18]([N:42]=[N+:43]=[N-:44])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(/C=C\C(=O)O)c1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(/C=C\C(=O)N=[N+]=[N-])c1OCc1ccccc1
Temperature: 5 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2Z)-3-[2-(benzyloxy)-3-methylphenyl]prop-2-enoic acid (20 g, 74.54 mmol, 1.00 equiv), toluene (300 mL) and diphenylphosphoryl azide (25 g, 90.84 mmol, 1.20 equiv). This was followed by the addition of DBU (14 g, 91.96 mmol, 1.20 equiv) dropwise with stirring at 0-10° C. The resulting solution was stirred for 1 h at 0-10° C. in a water/ice bath. The resulting solution was diluted with 1 L of ethyl acetate. The resulting mixture was washed with 2×800 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40). This resulted in 13 g (59%) of (2Z)-3-[2-(benzyloxy)-3-methylphenyl]prop-2-enoyl azide as a white solid. Rf: 0.44 (in ethyl acetate:petroleum ether=1:5).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:20]1[N:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1F.[CH2:36]([OH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[H-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[CH2:36]([O:43][C:10]1[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:9]=1[CH2:8][N:7]([CH2:6][C:5]1[CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:4]=1)[C:20]1[N:21]=[CH:22][C:23]([Br:26])=[CH:24][N:25]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OCc1ccccc1
Reactant: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)c2ncc(Br)cn2)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (11.1 g) is dissolved in tetrahydrofuran (20 ml), and thereto are added benzyl alcohol (6 ml) and sodium hydride (60%) (2.32 g), and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=97:3→9:1) to give (2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (12.9 g). MS (m/z): 664/666 [M+H]+