Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:22][O:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[C:30]([NH2:33])[CH:31]=2)[NH:26][N:25]=1.[CH2:34]([N:36]([C:42]1[C:43]([F:52])=[C:44]([C:48]([F:51])=[CH:49][CH:50]=1)[C:45](O)=[O:46])[S:37](=[O:41])(=[O:40])[NH:38][CH3:39])[CH3:35]>CN(C=O)C.CCOC(C)=O.C(Cl)Cl>[CH2:34]([N:36]([C:42]1[C:43]([F:52])=[C:44]([C:48]([F:51])=[CH:49][CH:50]=1)[C:45]([NH:33][C:30]1[CH:31]=[C:32]2[C:24]([O:23][CH3:22])=[N:25][NH:26][C:27]2=[N:28][CH:29]=1)=[O:46])[S:37](=[O:40])(=[O:41])[NH:38][CH3:39])[CH3:35]
Reactant: CCN(c1ccc(F)c(C(=O)O)c1F)S(=O)(=O)NC
Reactant: COc1n[nH]c2ncc(N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(c1ccc(F)c(C(=O)Nc2cnc3[nH]nc(OC)c3c2)c1F)S(=O)(=O)NC
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
HOBt (0.017 g, 0.13 mmol), EDCI (0.054 g, 0.28 mmol), and 3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine (0.046 g, 0.28 mmol) was added to 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluorobenzoic acid (0.075 g, 0.25 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (6 mL) and washed with brine (3×5 mL). The organic layers were dried over sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 5% MeOH:DCM to afford 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (0.055 g, 0.12 mmol, 49% yield). 1H NMR (400 MHz, CD3OD) δ 8.60-8.63 (m, 1H), 8.50-8.52 (m, 1H), 7.63-7.70 (m, 1H), 7.09-7.15 (m, 1H), 4.09 (s, 3H), 3.18-3.25 (m, 2H), 2.83 (s, 3H), 1.09-1.14 (m, 3H); m/z (APCI-neg) M−1=439.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C@@H:8]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:25](=[O:26])[CH2:24][C:23]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:22]=3[CH2:21][CH2:20]1)[CH2:7]2.C=O.[CH3:37]C1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.Cl.C([BH3-])#N.[Na+]>CO.ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C@@H:8]([CH2:14][N:15]([CH3:37])[CH2:16][CH2:17][CH2:18][N:19]1[C:25](=[O:26])[CH2:24][C:23]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:22]=3[CH2:21][CH2:20]1)[CH2:7]2
Reactant: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCNC[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Reaction time: 0.5 h
Yield: 58 %

Procedure:
180 mg (0.36 mmol) of hydrochloride obtained in Step 1 are dissolved in a mixture of 10 mL of methanol and 5 mL of dichloromethane. To the resulting solution there are added 0.04 mL (0.54 mmol, 1.5 equivalents) of formaldehyde (37% in water) and a grain of bromocresol green. 1N aqueous hydrochloric acid solution is added until the pH is 4 (yellow-coloured solution) and then stirring is carried out at 25° C. for 30 minutes. There are then added 23 mg (0.36 mmol) of sodium cyanoborohydride, stirring is carried out at 25° C. for 12 hours whilst maintaining the pH at 4, and then evaporation to dryness is carried out. There are obtained 250 mg of an oil which is purified by flash chromatography on 100 g of silica (eluant=dichloromethane/ethanol/NH4OH: 90/10/1) to yield 100 mg of the title product in the form of a colourless oil which crystallises at ambient temperature.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].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.[F:59][C:60]1[CH:61]=[C:62]2[C:67](=[CH:68][CH:69]=1)[CH:66]=[C:65]([N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1)[CH:64]=[CH:63]2>ClCCl>[F:59][C:60]1[CH:61]=[C:62]2[C:67](=[CH:68][CH:69]=1)[CH:66]=[C:65]([N:70]1[CH2:71][CH2:72][N:73]([C:19](=[O:21])[CH2:18][O:17][CH:14]3[CH2:15][CH2:16][CH:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:24])([F:23])[F:25])[CH:6]=4)[CH2:12][CH2:13]3)[CH2:74][CH2:75]1)[CH:64]=[CH:63]2
Reactant: Fc1ccc2cc(N3CCNCC3)ccc2c1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(F)ccc3c2)CC1
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)-oxy]acetic acid (173 mg, 0.48 mmol, 1 eq) in dichloromethane (50 ml) was added DIEA (61.8 mg, 0.48 mmol, 1 eq), HATU (182 mg, 0.48 mmol, 1 eq) and 1-(6-fluoronaphthalen-2-yl)piperazine (110 mg, 0.48 mmol, 1 eq) at room temperature under an inert atmosphere of nitrogen. The resulting solution was stirred overnight. The reaction was then quenched by the addition of water (100 ml) and extracted with dichloromethane (3×50 ml) and the organic layers were combined and then dried over anhydrous sodium sulfate. The solids were filtered off. The resulting mixture was concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with 2% methanol in dichloromethane. The product-containing fractions were combined and concentrated under vacuum to afford 1-[4-(6-fluoronaphthalen-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (31.1 mg, 11%); (ES, m/z): [M−H]− 573.2; 1H NMR (300 MHz, DMSO/D2O): δ 8.05 (d, J=6.9 Hz, 1H), 7.77-7.82 (m, 2H), 7.53-7.56 (dd, J=1.8, 7.5 Hz, 1H), 7.43-7.46 (dd, J=1.5, 6.9 Hz, 1H), 7.28-7.33 (m, 1H), 7.25 (d, J=1.2 Hz, 1H), 7.06 (s, 1H), 6.83-6.86 (dd, J=1.8, 6.9 Hz, 1H), 4.21 (s, 2H), 3.63 (broad s, 4H), 3.37-3.52 (m, 2H), 3.21-3.26 (m, 4H), 1.94-2.05 (m, 4H), 1.34-1.39 (m, 2H), 1.23-1.29 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:20][CH2:21]CS([O-])(=O)=O)([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:8]1)=[O:6].Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[Cl:19][C:14]1[CH:13]=[C:12]([C:9]2([CH2:20][CH2:21][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:10][CH2:11][N:7]([C:5](=[O:6])[C:4]3[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:3]=3[O:2][CH3:1])[CH2:8]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1ccc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c(OC)c1
Yield: 36.4 %

Procedure:
2-[1-(2,4-Dimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (343 mg, 0.68 mmol) was dissolved in THF (8 mL) and the 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (170 mg, 0.71 mmol, 1.04 eq.), potassium carbonate (200 mg, 1.45 mmol, 2.1 eq.), and water (2 mL) were added and the solution was heated at reflux for 16 hours. The solution was concentrated in vacuo and the aqueous phase was extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (40 g) with a gradient of ethyl acetate to 6% methanol in dichloromethane to give 151 mg (36%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:17]([O:19]C)=[O:18])[S:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl.ClC1C=C(C2C(C(O)=O)=CSN=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:17]([OH:19])=[O:18])[S:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1snc(-c2cccc(Cl)c2)c1C(=O)OC
Agent: Cl
Agent: O=C(O)c1csnc1-c1cccc(Cl)c1
Agent: [Na+]
Product: O=C(O)c1snc(-c2cccc(Cl)c2)c1C(=O)O

Procedure:
Dimethyl 3-(m-chlorophenyl)-4,5-isothiazoledicarboxylate (14.51 g, 0.0504 mol) was hydrolyzed as given above with NaOH (10.08 g, 0.252 mol) and then acidified with HCl. The purified yellow solid had m.p. 185°-6° with decomposition (rapid heating of the sample produced normal decomposition in this temperature range; slow heating caused a color change to red and m.p. 217.5°-218.5° with decomposition. Infrared of material heated slowly to 190° showed that it was 3-(m-chlorophenyl)-4-isothiazolecarboxylic acid).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.II>CC#N>[CH:23]([N:6]1[CH:7]=[C:2]([I:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: II
Solvent: CC#N
Product: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Temperature: 84 °C
Yield: 88.4 %

Procedure:
5-Iodouracil (0.10 g, 0.42 mmol) was suspended in dry MeCN (2.1 mL) and N,O-bis(trimethylsilyl)acetamide (0.25 mL, 1.05 mmol) was added under nitrogen atmosphere. When the reaction mixture turned clear, bromodiphenyl methane (0.15 g, 0.63 mmol) and a catalytic amount of I2 were added and the reaction mixture was heated at 84° C. for 4 hrs. After cooling to room temperature, the mixture was concentrated under reduced pressure, diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc (3×15 mL), the combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 60:40) to afford the title compound (0.15 g, 87%) as white solid. 1H NMR (400 MHz, CDCl3): δ 7.02 (s, 1H), 7.14-7.18 (m, 4H), 7.38-7.45 (m, 6H), 7.46 (s, 1H), 8.58 (s, 1H). MS (ESI) in/Z: 405 [M-H]+.
Reaction SMILES: Cl.[CH:2]12[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])=[CH:22]2>C(#N)C>[CH:2]12[CH2:7][CH:6]1[CH2:5][CH2:4][N:3]2[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])=[CH:22]2
Reactant: O=C(c1cc2cc(OCCCCl)ccc2[nH]1)N1CCOCC1
Reactant: C1CC2CC2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1cc2cc(OCCCN3CCC4CC43)ccc2[nH]1)N1CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
A mixture of 2-aza-bicyclo[3.1.0]hexane hydrochloride (example 4 step 7, 49 mg, 1.2 eq.) and potassium carbonate (118 mg, 2.5 eq.) in acetonitrile was stirred 1 h at 60° C. The reaction mixture was cooled to 30° C. and [5-(3-chloro-propoxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (example 4, step 3, 110 mg, 1.0 eq.) was added. The resulting mixture was stirred 24 h at 80° C. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with an aqueous solution of sodium hydrogencarbonate and water and dried over sodium sulphate and evaporated in vacuo. The residue was purified on silica, eluting with a 98:2 to 9:1 gradient of dichloromethane/methanol, to yield 12 mg (8%) of the desired product as light yellow solid. MS (m/e): 370.4 (MH+, 100%).
Reaction SMILES: C(OC([NH:8][NH:9][C:10](=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[O:25])[CH2:20][CH2:19]2)=[CH:13][CH:12]=1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[CH:32]([N:29]1[CH2:30][CH2:31][N:26]([C:24]([C@H:21]2[CH2:22][CH2:23][C@H:18]([O:17][C:14]3[CH:13]=[CH:12][C:11]([C:10]([NH:9][NH2:8])=[O:35])=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[O:25])[CH2:27][CH2:28]1)([CH3:34])[CH3:33]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NNC(=O)OC(C)(C)C)cc3)CC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NN)cc3)CC2)CC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 440 mg (0.90 mmol) of trans-N′-{4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoyl}-hydrazinecarboxylic acid tert-butyl ester, 1.53 ml (6.12 mmol) of 4M hydrochloric acid in 1,4-dioxane solution and 4 ml of methanol was stirred for 4 h at 40° C. The mixture was evaporated to dryness to yield 0.44 g of the title compound. MS (m/e): 389.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:15]3[CH2:21][C:20]4[CH:22]=[C:23]([C:26]5[N:31]=[C:30]([NH2:32])[C:29]([NH2:33])=[CH:28][CH:27]=5)[CH:24]=[CH:25][C:19]=4[O:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]([NH:38][C:39](=NC(OC)=O)SC)=[O:37]>C(O)(=O)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:15]3[CH2:21][C:20]4[CH:22]=[C:23]([C:26]5[N:31]=[C:30]6[NH:32][C:39]([NH:38][C:36](=[O:37])[O:35][CH3:34])=[N:33][C:29]6=[CH:28][CH:27]=5)[CH:24]=[CH:25][C:19]=4[O:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2ccc3c(c2)CN(c2ncncc2Cc2ccc(F)cc2)CCO3)nc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)Nc1nc2ccc(-c3ccc4c(c3)CN(c3ncncc3Cc3ccc(F)cc3)CCO4)nc2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 304.1 %

Procedure:
To a solution of 6-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridine-2,3-diamine (0.200 g, 0.438 mmol) in glacial acetic acid (3 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.117 g, 0.570 mmol). The reaction mixture was stirred at 80° C. for 2 h and then concentrated. Ethyl acetate (100 mL) was added to the residue, and the solution was washed with saturated sodium bicarbonate (50 mL) then dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue that was taken up in diethyl ether (10 mL) and the resulting precipitate was collected by filtration to give methyl [5-(4-{5-[(4-fluorophenyl)methyl]pyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-3H-imidazo[4,5-b]pyridine-2-yl]carbamate (0.70 g, 30% yield) as a brown solid. MS (EI) for C26H25FN6O: 457 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33]C(C1N(C)C(C(S(C2C=CC=CC=2)(=O)=O)N)=CC(=O)C=1OCC1C=CC=CC=1)=O>>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)cc1
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccc(C)cc2)n1C
Yield: 54.34 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-06) (280.0 mg, 54.34%) was synthesized as an off white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-06) (500.0 mg, 1.13 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyoxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-01).
Reaction SMILES: [CH:1]([N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)([CH2:3][CH3:4])[CH3:2].[C:10]1([OH:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>>[C:10]1([O:20][CH2:6][CH:7]([OH:9])[CH2:8][NH:5][CH:1]([CH2:3][CH3:4])[CH3:2])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc2ccccc12
Reactant: CCC(C)N1CC(O)C1
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)NCC(O)COc1cccc2ccccc12
Temperature: 160 °C
Yield: 57 %

Procedure:
To a mixture of 14.2 parts of 1-(sec.-butyl-3-azetidinol and 14.4 parts of α-naphthol 0.2 part of sodium hydroxide was added and the mixture was heated under nitrogen gas at 160° C. for 22 hours. The reaction mixture was cooled and then extracted with ether. The extract was washed with 2N-NaOH aqueous solution and then with water. The liquid was dried over anhydrous sodium sulfate and the solvent was distilled off. Recrystallization of the residue gave 15.5 parts of 1-(α-naphthoxy)-3-(sec.-butylamino)-2-propanol melting at 57°-59° C. The yield was 57%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[CH3:12][S-:13].[Na+].C(I)C.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:13][CH3:12])=[CH:4][C:3]=1[O:9][CH2:10][CH3:11]
Reactant: CCOc1cc(F)ccc1Br
Reactant: C[S-]
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(SC)ccc1Br
Temperature: 65 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a stirred solution of 1-bromo-2-ethoxy-4-fluorobenzene (2.0 g) in DMF (20 mL) was added sodium methanethiolate (1.66 g). The mixture was stirred for 2 h at 65° C. The mixture was cooled to room temperature and ethyl iodide (1.3 mL) was added. The mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.65 g of the title compound.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=O)[NH:2]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C12CC(C=C1)CN2.[N:22]1[O:23][N:24]=[C:25]2[CH:30]=[C:29]([C:31](Cl)=[O:32])[CH:28]=[CH:27][C:26]=12>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][N:2]2[C:31]([C:29]1[CH:28]=[CH:27][C:26]2=[N:22][O:23][N:24]=[C:25]2[CH:30]=1)=[O:32]
Reactant: O=C1NC2C=CC1C2
Reactant: O=C(Cl)c1ccc2nonc2c1
Agent: C1=CC2CC1CN2
Agent: [Al+3]
Agent: [H-]
Product: O=C(c1ccc2nonc2c1)N1CC2C=CC1C2

Procedure:
Prepared from 2-azabicyclo[2.2.1]hept-5-en-3-one by reducing with LiAlH4 and then coupling the resultant 2-azabicyclo[2.2.1]hept-5-ene with [2,1,3]-benzoxadiazole-5-carbonylchloride as described for Example 7. The title product was isolated as a white solid after crystallization from MTBE/hexane: mp=106-108° C., LC-MS, MH+=242.25; 1H NMR (300 MHz, CDCl3, rotamers) δ 7.98-7.86 (m, 2H), 7.58-7.53 (m, 1H), 6.60-6.50 (m, 1H), 6.36-6.32 (m, 1H), 5.25 and 4.57 (s, total 1H), 3.67-3.62 (m, 1H), 3.39 and 3.32 (s, total 1H), 3.03 and 2.70 (both d, J=10.2 and 8.7 Hz respectively, total 1H), 1.75 ppm (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[CH:9])[N:3]=1.[CH3:10][Si:11]([CH2:14][N:15]=[N+:16]=[N-:17])([CH3:13])[CH3:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:17]=[N:16][N:15]([CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:9]=2)[N:3]=1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#Cc1cccc(Br)n1
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[Si](C)(C)Cn1cc(-c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-ethynylpyridine (Example 465, Step 1) (350 mg, 1.92 mmol) and trimethylsilylmethyl azide (323 mg, 2.50 mmol) were combined in t-BuOH (4.0 mL) and water (3.0 mL). CuSO4.5H2O (24 mg, 0.096 mmol) in water (0.50 mL) was added, followed by sodium ascorbate (76 mg, 0.39 mmol) in water (0.50 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to a yellow residue that was purified by flash chromatography (0-50% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([Br:17])=[C:10]([CH3:18])[CH:9]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:20][Si:2]([CH3:1])([CH3:21])[CH2:3][CH2:4][O:5][C:6](=[O:19])[NH:7][C:8]1[CH:9]=[C:10]([CH3:18])[C:11]([Br:17])=[C:12]([NH2:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OCC[Si](C)(C)C)cc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(NC(=O)OCC[Si](C)(C)C)cc(N)c1Br
Temperature: 85 °C
Yield: 86.1 %

Procedure:
Iron powder (6.1 g, 109 mmol) was added to a suspension of (4-bromo-3-methyl-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (Example 294: step c (4.1 g, 10.9 mmol)) and NH4Cl (5.84 g, 109 mmol) in EtOH (27 mL) and water (54 mL). The reaction was heated at 85° C. for 14 h. The cooled mixture was filtered through celite and the solids were washed with 1:1 EtOAc/MeOH (200 mL). The filtrate was concentrated in vacuo and the residue was partitioned between EtOAc (100 mL) and H2O (30 mL). The organic solution was washed with water (30 mL), and brine (50 mL). Drying and concentration of the solution yielded the title compound (3.24 g, 86%) as a brown solid which was used without further purification. 1H NMR (CDCl3) δ 6.96 (s, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 4.26 (m, 2H), 4.16 (s, 2H), 2.35 (s, 3H), 1.06 (m, 2H), 0.08 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[OH-].[NH4+].[CH:13](O)=O>Cl>[Cl:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]2[N:9]=[CH:13][NH:8][C:6]=2[CH:7]=1
Reactant: Cc1cc(N)c(N)cc1Cl
Reactant: O=CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc2nc[nH]c2cc1Cl
Temperature: 50 °C

Procedure:
A solution of 5-chloro-4-methyl-1,2-phenylenediamine (7.8 g) in a mixture of formic acid (35 mL) and hydrochloric acid (300 mL) was heated at 50° C. for 3 hours then treated with ammonium hydroxide solution until the solution was basic. The reaction mixture was then extracted with dichloromethane. The extracts were evaporated to give 6-chloro-5-methyl-1H-benzoimidazole (7 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([C:25]([F:28])([F:27])[F:26])[O:17][C:15]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:41])C(=O)C1>C(#N)C>[C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:9][O:10][C:11]1[C:12]([Cl:41])=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([C:25]([F:28])([F:26])[F:27])[O:17][C:15]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)OC(C(F)(F)F)c1cnccc1-2)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)C[C@@H](COc1cc2c(cc1Cl)-c1ccncc1C(C(F)(F)F)O2)NC(=O)OC(C)(C)C
Yield: 86 %

Procedure:
A stirred solution of tert-butyl((2S)-4-methyl-1-((5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate (50 mg, 0.107 mmol) and NCS (14.31 mg, 0.107 mmol) in acetonitrile (12 mL) was heated to 60° C. under nitrogen atmosphere for 12 h. The solvent was removed under reduced pressure. The residue was partitioned between water (15 mL) and DCM (15 mL). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to yield tert-butyl((2S)-1-((9-chloro-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (51 mg, 0.092 mmol, 86% yield) as a yellow solid. LCMS (ESI) m/e 501.2 [(M+H)+, calcd for C24H29ClF3N2O4 501.2]; LC/MS retention time (Method D): tR=2.02 min.