Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:25]O)[C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:13][C:12]=2[CH:24]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:25]=[CH2:1])[C:11]2[O:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[CH:13][C:12]=2[CH:24]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CO)c3o2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(OC)cc2cc(-c3ccc(OC)cc3)oc12
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
Methyl triphenylphosphonium bromide (0.122 g, 0.334 mmole) was dissolved in 5 mL THF and placed in an acetone/dry ice bath at −78° C. n-Butyl lithium (0.131 mL, 0.328 mmole) was added and the mixture was allowed to stir for 30 minutes. To this solution was added aldehyde 3 (0.078 g, 0.278 mmole) in 3 mL THF. After stirring at room temperature for 4 hours, the reaction mixture was placed in an oil bath and allowed to stir overnight at 65° C. The solvent was evaporated and the residue was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 95:5) to afford 0.055 g (71%) of 28 as a white solid: Mp=182-184° C.; 1H NMR (DMSO-d6) δ 7.87 (d, 2 H, J=8.4 Hz), 7.22 (s, 1 H), 7.08 (m, 3 H), 6.98 (m, 1 H), 6.96 (d, 1 H, J=2.3 Hz), 6.30 (d, 1 H, J=17.8 Hz), 5.59 (d, 1 H, J=11.4 Hz), 3.82 (s, 3 H), 3.80 (s, 3 H); MS 281 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[C:26]([O:30][NH2:31])([CH3:29])([CH3:28])[CH3:27].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:31][O:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)ON
Reactant: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a solution of 200 mg of the N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide prepared in Step 3 in Synthetic Example 10 and 199 mg of O-(tert-butyl)hydroxylamine hydrochloride in 2.6 ml of ethanol, 167 mg of pyridine was added, and the mixture was stirred at 70° C. for 18 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 2 ml of water and extracted with ethyl acetate (2 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 207 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH2:13][N:34]2[CH2:35][CH2:36][CH:31]([C:27]3[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:30]=[CH:29][CH:28]=3)[CH2:32][CH2:33]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Oc2cccc(C=O)c2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4ccc(C(C)(C)C)cc4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(4-tert-butylphenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>C(#N)C>[O:20]1[CH2:19][CH:18]1[CH2:16][O:1][C:2]1[C:3]([O:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ncccc1OCC1CO1

Procedure:
A mixture of 15.4 g of 3-hydroxy-2-methoxy-pyridine, 16 g of potassium carbonate, 25 ml of epichlorohydrin and 150 ml of acetonitrile is refluxed for 7 hours. Cooling and filtering the mixture and evaporating the filtrate yields crude 3-(2,3-epoxy-propoxy)-2-methoxypyridine, which is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([Br:9])=[C:7]([C:10](=[O:12])N)[S:6][N:5]=1)[CH3:2].N([O-])=[O:14].[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[C:8]([Br:9])=[C:7]([C:10]([OH:12])=[O:14])[S:6][N:5]=1)[CH3:2]
Reactant: CCOc1nsc(C(N)=O)c1Br
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nsc(C(=O)O)c1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-Ethoxy-4-bromo-5-carbamoylisothiazole (2.51 g, 0.01 mol) was dissolved in 20 ml of trifluoroacetic acid and the solution cooled to 0° to 5° C. Sodium nitrite (2.76 o, 0.04 mol) was added in small portions to the stirred solution over a five minute period. Stirring was continued for 10 minutes at the same temperature and the reaction mixture poured into 150 ml of ice water. The title compound separated as a white solid (2.2 g, 88%, mp 151°-152.5° C.) and was filtered, washed with ice water and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][OH:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:21][CH:22]([F:39])[O:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][CH:22]([F:39])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][OH:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: O=C(O)C(CO)c1ccc(Nc2ncc(Br)cn2)cc1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Temperature: 150 °C

Procedure:
To a solution of 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)-3-hydroxypropanoic acid 25 (0.5 mmol) in 1,4-dioxane (2 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.5 mmol), Na2CO3 (1.5 mmol of a 3.0 M aq. solution) and Pd(PPh3)4 (0.025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 150° C. for 10 min. The reaction mixture is diluted with water (10 mL). The aqueous layer is washed with DCM (2×50 mL) and acidified to pH 5 using aqueous HCl (1 N). The resulting mixture is extracted with DCM (2×50 mL). The organic layer is separated, dried over Na2SO4 and concentrated to yield a crude 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-3-hydroxypropanoic acid 26 which is used without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.65 (s, 1H), 8.79 (s, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.30 (s, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 3.60-3.70 (m, 2H), 3.50-3.58 (m, 2H), 3.20-3.26 (m, 2H). MS (m/z) (M+1)+: 402.1.
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]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17](Cl)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1.[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[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]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17]([N:45]3[CH2:46][CH2:47][CH:42]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH2:43][CH2:44]3)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Reactant: C1CC(N2CCOCC2)CCN1
Product: Cc1ccccc1-c1cc(N2CCC(N3CCOCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Yield: 12.8 %

Procedure:
In a similar manner to Example 1, 4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (51.5 mg) was reacted with 4-(morpholine-4-yl)piperidine (51.1 mg) to obtain 4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-[4-(morpholine-4-yl)piperidine-1-yl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (8.3 mg, 13%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C@H:4]([N+:17]([O-])=O)[CH2:3]1.C(O)(=O)C>CO.[Zn]>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:14])([F:15])[F:16])[C@H:4]([NH2:17])[CH2:3]1
Reactant: CN1C[C@@H]([N+](=O)[O-])[C@H](c2ccccc2C(F)(F)F)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CN1C[C@@H](N)[C@H](c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Racemic (3R,4S) and (3S,4R)-1-Methyl-3-nitro-4-(2-(trifluoromethyl)phenyl)-pyrrolidine (296.8 mg, 1.082 mmol) was dissolved in MeOH (5 mL) and Acetic Acid (5 mL) then zinc (354 mg, 5.41 mmol) was added at 0° C. The reaction mixture was warmed to room temperature and stirred under nitrogen overnight. The suspension was filtered over celite and washed with methanol. The filtrate was concentrated in vacuo and the residue was suspended in ethyl acetate, cooled in an ice bath, and basified with conc. NH4OH. The organic phase was separated and washed with brine. The organic layers were combined and dried over sodium sulfate, filtered, and concentrated in vacuo to give racemic (3R,4S) and (3S,4R)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-amine (230.9 mg, 0.945 mmol, 87%), which was carried onto the next step without further purification. MS ESI calc'd. For C12H15F3N2 [M+1]+ 245, found 245.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:27])[C:3]1=[O:28].[F:29][C:30]1[CH:37]=[CH:36][C:33](CBr)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:1][N:2]2[C:10]3[C:5](=[CH:6][C:7]([S:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@H:15]4[CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:12])=[O:13])=[CH:8][CH:9]=3)[C:4](=[O:27])[C:3]2=[O:28])=[CH:32][CH:31]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc21
Yield: 79 %

Procedure:
(S)-1-(4-Fluorobenzyl)-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (11c) was prepared according to the same procedure for compound 11a, except using 4-fluorobenzyl bromide, and purified with hexanes-ether (1:2) to afford 196 mg (79%) of 11c as an orange solid, mp 74.5-75.4° C. 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.95 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.34-7.19 (m, 4H), 7.06 (t, J=8.7 Hz, 2H), 6.92 (t, J=7.2 Hz, 1H), 6.87-6.79 (m, 3H), 4.89 (s, 2H), 4.13 (m, 1H), 3.93 (m, 2H), 3.47 (m, 1H), 3.23 (m, 1H), 2.01 (m, 2H), 1.78 (m, 2H). Anal. Calcd for C26H23FN2O5S: C, 63.15, H, 4.69; N, 5.66. Found: C, 63.05, H, 4.69; N, 5.60.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@H: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.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C@H: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)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H](COS(C)(=O)=O)C1
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (0.48 mL) was added to a solution of (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (1.10 g) and triethylamine (1.42 mL) in DCM (20 mL) at 0° C. under nitrogen. The reaction was stirred for 2 h before being partitioned between DCM (200 mL) and water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle product (1.20 g) as a yellow oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:19][CH:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][N:6]2[C:5]1=[O:20])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([N:4]1[CH2:19][CH:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:20])([CH3:3])[CH3:2]
Reactant: CC(C)N1CC2CN(C(=O)OC(C)(C)C)CCN2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CC2CNCCN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (compound 104-C-1) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. After the reaction mixture was stirred at rt for 1 hour, the solvent was removed in vacuum to give the crude product 104-C, which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH3:13][CH2:14][CH:15]([NH:19][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(N)CC
Reactant: COc1ccc(C(=O)O)cc1C
Product: CCCC(CC)NC(=O)c1ccc(OC)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and hexan-3-amine (example 28a). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 6H); 1.41 (m, 4H); 1.46 (m, 1H); 1.64 (m, 1H); 2.24 (s, 3H); 3.87 (s, 3H); 4.08 (m, 1H); 5.69 (d, 1H); 6.83 (d, 1H); 7.54 (s, 1H); 7.62 (d, 1H). MS (M+H, 250).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[C:10]1([CH2:16][C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>[OH-].[Na+]>[C:10]1([CH2:16][C:17]([NH:1][CH:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)C(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(NC(=O)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of DL-tert-leucine (2 g, 15.3 mol) in aqueous sodium hydroxide (2 M, 25 ml) was added dropwise phenylacetyl chloride (646 mg, 20.8 mmol), simultaneously with sodium hydroxide (2 M, 25 ml), at 0° C. over a period of 5 min. The solution was allowed to warm to room temperature and stirred for an additional 60 min until complete dissolution occurred. The reaction was then cooled to 0° C., acidified to pH 4 with conc. HCl, and stirred for 30 min. The resulting precipitate was collected by filtration, dried, and recrystallised from ethanol/water (1:1 v/v) to yield the product as a white solid (2.06 g, 54%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[CH3:21][O:22][C:23]1[CH:37]=[CH:36][C:26]([CH2:27][N:28]2[C:32]([CH2:33][NH:34][CH3:35])=[N:31][CH:30]=[N:29]2)=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:34]([CH3:35])[CH2:33][C:32]1[N:28]([CH2:27][C:26]3[CH:36]=[CH:37][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[N:29]=[CH:30][N:31]=1)=[N:6]2
Reactant: CNCc1ncnn1Cc1ccc(OC)cc1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2ncnc2CN(C)c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)cc1

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol), N-[[2-(4-methoxybenzyl)-2H-[1,2,4]triazol-3-yl]methyl]methylamine (I-163) (0.18 g, 0.77 mmol) and diisopropylethylamine (0.13 ml, 0.76 mmol) were dissolved in dichloromethane (10 ml), followed by heating under reflux for 3 hours. This was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[ClH:11].[NH3:12]>CO.C(O)C>[ClH:11].[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]([NH2:12])=[NH:6]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: N
Agent: Cl
Solvent: CCO
Solvent: CO
Product: N=C(N)c1ccc(F)c(F)c1

Procedure:
3,4-difluorobenzonitrile (4) is reacted with dried HCl gas in anhydrous methanol, followed by reacting the resulting crystals with dried ammonia gas in anhydrous ethanol to obtain 3,4-difluorobenzamidine hydrochloride (5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].Cl[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[Si:13]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a magnetically stirred solution of 2-amino-5-nitrophenol (5.62 g, 36.5 mmol) and chloro-t-butyldimethylsilane (5.00 g, 33.2 mmol) in dry dichloromethane (66 mL) was added triethylamine (5.55 mL, 39.8 mmol) at 25° C. The reaction mixture was stirred at ambient temperature for 4 hours and partitioned between diethyl ether (200 mL) and saturated ammonium chloride. The aqueous layer was separated and the ether layer washed (saturated ammonium chloride, 1x; water, 1x; brine, 1x), dried (MgSO4), filtered, and evaporated in vacuo. Crystallization from ethyl acetate/hexanes gave 7.5 g (84%) of O-t-butyldimethylsilyl-2-amino-5-nitrophenol
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:24][CH2:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][CH2:8]1.CCN(CC)CC>>[CH3:1][S:2]([O:6][CH:7]1[CH2:8][CH2:9][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH2:23][CH2:24]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(OS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
Methanesulfonyl chloride (0.98 ml, 12.27 mmol, 1.5 eq.) was added to a solution of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (2.20 g, 8.18 mmol, 1.0 eq.) (see step-6 product of AMN-38) and Et3N (2.84 ml, 20.45 mmol, 2.5 eq.) in MC (20 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 14 h. The reaction mixture was diluted with MC (50 ml) and washed with sat. NH4Cl solution (2×25 ml) and brine (2×25 ml) and then dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel; 10% ethyl acetate/hexanes) to give the desired compound as a light orange solid. Yield: 88% (2.84 g, 8.18 mmol).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1(=O)[C:19]2=[C:20]3[C:15](=[CH:16][CH:17]=[CH:18]2)[CH:14]=[CH:13][CH:12]=[C:11]3[C:10]1=O>O>[CH:12]1[C:11]2[C:10]3[C:9]([C:19]4[C:20]=2[C:15]([CH:16]=[CH:17][CH:18]=4)=[CH:14][CH:13]=1)=[N:8][C:1]1[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=1)[N:7]=3
Reactant: O=C1C(=O)c2cccc3cccc1c23
Reactant: Nc1ccccc1N
Solvent: O
Product: c1cc2c3c(cccc3c1)-c1nc3ccccc3nc1-2

Procedure:
To a reaction vessel equipped with a stirrer, 5-liter of glacial acetic acid and 490 g of purified acenaphthenequinone were added and stirred for 15 minutes under nitrogen bubbling to obtain an acenathphenequinone solution. Similarly, to another reaction vessel equipped with a stirrer, 7.5-liter of glacial acetic acid and 275 g of o-phenylenediamine were added and stirred for 15 minutes under nitrogen bubbling to obtain an o-phenylenediamine solution. Thereafter, while stirring under nitrogen atmosphere, the o-phenylenediamine solution was added to the acenaphthenequinone solution gradually over one hour, and then allowed to react by continuing to stir for 3 hours. After ion exchange water was added to the obtained reaction liquid, the precipitate was filtrated to obtain a crude product. This crude product was recrystallized with a heated glacial acetic acid for purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2ccccc2[N+](=O)[O-])c1
Temperature: 110 °C

Procedure:
3-Methoxyphenyl boronic acid (7.4 g, 48.71 mmol), 1-bromonitrobenzene (10.25 g, 40.59 mmol) and K2CO3 (28.05 g, 202.9 mmol) were dissolved in H2O (85 mL) and ethylene glycol dimethyl ether (170 mL). The solution was degassed, Pd(PPh3)4 (1.7 g, 1.50 mmol) was added and the vessel was heated to 110° C. under argon for 5 hours. The reaction was cooled, diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from EtOAc/Hex. The mother liquor was concentrated in vacuo and chromatographed on silica gel, eluting with a gradient of 1 to 10% EtOAc in hexanes, to yield the above-titled compound.
Reaction SMILES: [I:1]I.[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.C([O-])([O-])=O.[K+].[K+].Cl>O>[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:1])[N:5]=1
Reactant: II
Reactant: Oc1cccnc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1ccc(I)nc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add I2 (21.0 g, 82.7 mmol) in solid form, a little at a time, in the space of 5 min, to a solution of 2-bromo-3-pyridinol (14.0 g, 80.8 mmol) and of K2CO3 (22.3 g, 161 mmol) in H2O (180 mL). Stir the reaction medium at room temperature for 2 h, then cool it (ice/H2O) to 0-5° C. and neutralize it to pH 6 by adding 2N HCl. A precipitate forms, which is filtered, washed with H2O and dried under vacuum at 70° C. to give 2 (19.48, 80.7%) in solid form, of an ivory color: 1H NMR (CDCl3) δ 7.54 (d, 1H, J=8.1 Hz), 6.98 (d, 1H, J=8.1 Hz), 5.55 (s broad, 1H); m/z obs.=299.4 (M+1).