Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:25])[CH2:3][NH:4][C:5]([C:7]1[C:8]([C:21]([F:24])([F:23])[F:22])=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[N:11][CH:12]=1)=[O:6].C(N(CC)CC)C>CS(C)=O.ClCCl>[O:1]=[C:2]([CH3:25])[CH2:3][NH:4][C:5]([C:7]1[C:8]([C:21]([F:22])([F:24])[F:23])=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[N:11][CH:12]=1)=[O:6]
Reactant: CC(O)CNC(=O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CNC(=O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a stirred solution of 2-(3-chloro-phenylamino)-trifluoromethyl-pyrimidine-5-carboxylic acid (2-hydroxy-propyl)-amide (200 mg) in dimethylsulfoxide (6.0 ml) and triethylamine (324 mg) at 0° C. was added a solution of sulphur trioxide-pyridine complex (250 mg) in dimethylsulfoxide (6.0 ml). This was allowed to warm to room temperature and after 2 hours the mixture was diluted with dichloromethane and washed twice with 0.1N hydrochloric acid. The organic layer was dried (Na2SO4) and evaporated. The sample was purified by mass directed auto-purification to afford the title compound (91 mg).
Reaction SMILES: C(=O)([O-])O.[Na+].Br[C:7]1[N:11](CC2C=CC(OC)=CC=2)[N:10]=[C:9]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:8]=1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.Br[C:34]1C(C2C=CN=CC=2)=C(C2SC(Cl)=CC=2)N(CC2C=CC(OC)=CC=2)N=1.CB1OB(C)OB(C)O1>C(COC)OC.O.C(OCC)(=O)C>[Cl:26][C:23]1[S:22][C:21]([C:9]2[NH:10][N:11]=[C:7]([CH3:34])[C:8]=2[C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2nc(Br)c(-c3ccncc3)c2-c2ccc(Cl)s2)cc1
Reactant: COc1ccc(Cn2nc(-c3ccc(Cl)s3)c(-c3ccncc3)c2Br)cc1
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c(-c2ccc(Cl)s2)c1-c1ccncc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a mixture of sodium hydrogen carbonate (2.0 mmol) and PdCl2dppf:CH2Cl2 1:1 (0.03 mmol) under argon, was added a degassed solution of 4-[5-bromo-3-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine and 4-[3-bromo-5-(5-chloro-2-thienyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine (mixture of isomers 2:1, 0.65 mmol) in 10.5 mL dimethoxyethane and 3 mL of water. Trimethylboroxin (50% solution in THF, 1.3 mmol) was then added and the mixture was stirred at 90° C. for 3 h. After cooling to room temperature, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 3 mL of trifluoroacetic acid and stirred at 65° C. for 2 h. Water and ethyl acetate were added. And the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with a saturated solution of sodium hydrogen carbonate, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol 20:1 to 10:1) to afford 57 mg of 4-[5-(5-chloro-2-thienyl)-3-methyl-1H-pyrazol-4-yl]pyridine (30% yield).
Reaction SMILES: [C:1]([CH2:5][C:6](OCC)=[O:7])(=O)[CH2:2][CH3:3].FC(F)(F)C(O)=O.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:28]=[C:27]([CH:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](=[NH:36])[NH2:35])[O:26][N:25]=1.C[O-].[Na+]>C(O)CCC>[CH2:2]([C:1]1[N:35]=[C:34]([N:30]2[CH2:31][CH2:32][CH2:33][CH:29]2[C:27]2[O:26][N:25]=[C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH:28]=2)[N:36]=[C:6]([OH:7])[CH:5]=1)[CH3:3]
Reactant: CCOC(=O)CC(=O)CC
Reactant: N=C(N)N1CCCC1c1cc(-c2ccccn2)no1
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Yield: 44.5 %

Procedure:
A mixture of ethyl propionylacetate (350 mg, 2.4 mmol), 2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidine-1-carboximidamide trifluoroacetate salt (Method 38) (901 mg, 2.43 mmol), sodium methoxide (144 mg, 7.7 mmol), in butanol (10 ml) was heated at 120° C. for 18 hours. The mixture was allowed to cool and poured directly on to an isolute SCX2 ion exchange column. The column was eluted with DCM/methanol (4:1) to remove neutrals and then with 7M methanolic ammonia to elute the product. The solvent was evaporated and the residue purified by chromatography on silica gel eluting with DCM/methanol (98:2 increasing in polarity to 95:5) to give the title compound (360 mg, 46%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH2:28][CH3:29])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NC(=O)OCc3ccccc3)(CC1)CC2
Temperature: 55 °C
Reaction time: 5 h

Procedure:
4-Benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (56.0 g) was dissolved in N,N-dimethylformamide (1000 mL). To this solution, sodium bicarbonate (46.6 g) and then ethyl iodide (22.2 mL) were added and the mixture was stirred at 50 to 60° C. for 5 hours. Subsequently, additional sodium bicarbonate (46.6 g) and ethyl iodide (22.2 mL) were added and the mixture was stirred for additional 3 hours. The insoluble materials in the mixture were filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (700 mL) and the solution was washed with water, dried over anhydrous sodium sulfate, and dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1→ethyl acetate) to give ethyl 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylate (56.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.COC[C@@H](O)C>O>[CH3:17][O:13][CH2:14][C@H:15]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)[CH3:16]
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: C1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COC[C@@H](C)Oc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.6 %

Procedure:
To a solution of 2-methylquinolin-8-ol (1.0 g, 6.3 mmol) in tetrahydrofuran (5.2 mL, 6.3 mmol) was added triphenylphosphine (6.9 g, 26 mmol), diethyl azodicarboxylate (1.6 mL, 10 mmol), and (S)-1-methoxypropan-2-ol (0.80 mL, 8.2 mmol) and the resultant mixture allowed to stir at ambient temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by reverse phase chromatography on C18 (0-80% acetonitrile/water) afforded the title compound (0.46 g, 28%).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C(O[C:20](=[O:22])[CH3:21])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:7][CH:6]1[O:8][C@H:9]([CH2:14][O:15][C:20](=[O:22])[CH3:21])[C@@H:10]([O:13][C:9](=[O:8])[CH3:10])[C@H:11]([O:12][C:6](=[O:7])[CH3:5])[C@@H:5]1[NH:4][C:1](=[O:3])[CH3:2])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1C(OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 187.1 %

Procedure:
A solution of N-acetylmannosamine (100 mg, 0.420 mmol) in pyridine (5 mL) was stirred at 0° C. To this solution was added acetic anhydride (5.0 mL, 53 mmol) and a catalytic amount of DMAP. The mixture was stirred overnight and allowed to warm to rt. Concentration and co-evaporation with toluene (6×10 mL) afforded the crude product which was purified via silica gel chromatography eluting with a gradient of 1:4 to 1:1 EtOAc/hexanes, yielding 153 mg (94%) of a viscous oil. IR (thin film): 3368, 2965, 2255, 1750, 1665, 1536 cm−1. 1H NMR (500 MHz, CDCl3): δ 2.05 (app s, 6H), 2.051 (app s, 6H), 2.08 (app s, 9H), 2.08 (s, 3H), 2.085 (s, 3H), 2.09 (s, 3H), 3.79 (ddd, 1H, J=2.5, 5.3, 9.6), 4.02-4.05 (m, 2H), 4.08 (dd, 1H, J=2.4, 12.4), 4.27 (dd, 1H, J=3.8, 5.5), 4.29 (dd, 1H, J=3.2, 5.5), 4.62 (ddd, 1H, J=1.8, 4.5, 9.2), 4.76 (ddd, 1H, J=1.7, 4.0, 9.1), 5.04 (dd, 1H, J=4.0, 9.9), 5.11 (app t, 1H, J=9.7), 5.15 (app t, 1H, J=10.0), 5.32 (dd, 1H, J=4.5, 10.2), 5.84 (d, 1H, J=1.7), 5.92 (d, 1H, J=9.1), 6.00 (d, 1H, J=1.7), 6.01 (d, 1H, J=9.1). 13C NMR (125 MHz, CDCl3): δ 20.5, 20.6, 20.7, 20.8, 23.1, 23.3, 49.3, 49.5, 50.7, 61.9, 62.1, 65.3, 65.5, 68.8, 70.1, 71.3, 73.4, 76.7, 77.0, 77.2, 90.6, 91.7, 169.6, 169.7, 169.9, 170.0, 170.2, 170.5. HRMS (FAB) m/z 412.1227 (MNa+C16H23NNaO10 requires 412.1220).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:17]([NH:25][C:26]([NH:16][C:11]1[CH:12]=[C:13]([Br:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(Br)cc(OCc2ccccc2)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a solution of 3-benzyloxy-5-bromo-phenylamine (23.50 g, 84.40 mmol) in acetone (550.0 mL) was added benzoyl isothiocyanate (18.50 mL, 93.13 mmol) and the reaction mixture was stirred at room temperature for 30 min. After the completion of the reaction (TLC monitoring), the solvent was evaporated and the residue thus obtained was washed with hexane to get the desired product (33.0 g, 89%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:23])([CH3:22])[C:18]([O:20]C)=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:23])[C:18]([OH:20])=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:2][CH2:3]1
Reactant: COC(=O)C(C)(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a solution of methyl 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoate (Step G, 1.07 g, 2.64 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 2N sodium hydroxide aqueous solution (5 mL) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was made acidic with 2N hydrochloric acid (pH ˜4) and concentrated under reduced pressure. The residue was dissolved in water (50 mL) and dichloromethane (50 mL). The aqueous layer was separated and extracted with dichloromethane (50 mL×2). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (920 mg, 89%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](F)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([S:16]([C:13]2[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:20]=[C:2]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:3]=[CH:4][C:5]=3[N+:21]([O-:23])=[O:22])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(S(=O)(=O)F)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Product: O=C(Nc1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]

Procedure:
20.00 g (0.56 mol) of 4-(5-chloro-2-nitro-benzoylamino)-benzenesulfonyl fluoride in 48.5 g (0.557 mol) of morpholine were heated under reflux for 1 h. Subsequently the mixture was cooled, poured onto ice/hydrochloric acid and filtered with suction. 26.0 g (98%) of the title compound having a melting point of 252° C. were obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH:9]=1.[Cl:40][C:41]1[N:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:44]3[CH:45]=[N:46][C:41]([Cl:40])=[CH:42][CH:43]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a 10-20 mL microwave flask was added ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (Int-5l, 1.41 g, 2.05 mmol), 6-chloropyridine-3-boronic acid pinacol ester (514 mg, 2.15 mmol), K3PO4 (1.31 g, 6.15 mmol), PdCl2(dppf).CH2O2 (167 mg, 0.21 mmol) and 9:1 1,4-dioxane:H2O (10 mL). The flask was flushed with argon and sealed. The reaction was stirred overnight at 100° C. After 18 hours, the reaction was diluted with DCM and washed with H2O. The aqueous was extracted with DCM (x2) and the combined organic layers were dried over Na2SO4. The solvent was reduced in vacuo and the title compound was purified via silica gel chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]([CH3:15])=[C:5]([N+:16]([O-])=O)[C:4]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:19])[CH2:3]1.CO>C(O)(=O)C.[Fe]>[NH2:16][C:5]1[C:4]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:19])[CH2:3][C:2]([CH3:1])([CH3:28])[CH:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]=1[CH3:15]
Reactant: CC1=C([N+](=O)[O-])C(C)(NCc2ccccc2)CC(C)(C)C1Nc1ccccn1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC1=C(N)C(C)(NCc2ccccc2)CC(C)(C)C1Nc1ccccn1
Temperature: 70 °C

Procedure:
Add iron powder (7.0 g) to a solution of 6-methyl-3-nitro-4-[benzylamino](2-pyridyl)(2,4,6-trimethylphenyl)amine (8.75 g, 23.2 mmol) in acetic acid (14 mL) an14 MeOH (70 mL). Heat the resulting mixture at 70° C. for 1 h, cool to ambient temperature and filter through a pad of celite. Evaporate the filtrate to dryness under reduced pressure. Treat he residue with 1N aq NaOH and extract with EtOAc. Wash the EtOAc extract with water and saturate aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate to obtain the title compound as a brown solid which is used without further purification.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]([CH3:12])([CH2:10][CH3:11])[C:7](O)=[O:8].[NH2:13][C:14]1[S:15][C:16]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[N:17][N:18]=1.O>CN(C)C(=O)C>[C:21]1([C:19]([C:16]2[S:15][C:14]([NH:13][C:7](=[O:8])[C:6]([OH:5])([CH3:12])[CH2:10][CH3:11])=[N:18][N:17]=2)=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1nnc(C(=O)c2ccccc2)s1
Reactant: CCC(C)(O)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCC(C)(O)C(=O)Nc1nnc(C(=O)c2ccccc2)s1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (60 μl, 0.82 mmol) is added to 2-hydroxy-methylbutyric acid (96.0 mg, 0.813 mmol) in 5.0 ml of N,N-dimethylacetamide at -20°/-15° C. and the mixture is stirred at -15°/-10° C. for one hour. After adding 2-amino-5-(phenylcarbonyl)-1,3,4-thiadiazole (102.3 mg, 0.499 mmol) and equilibrating the reaction mixture to room temperature, it is stirred overnight. The reaction mixture is poured into 100 ml of water and subjected to extraction with 3×25 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and filtered and the solvent is distilled off. The oil which remains is purified by flash chromatography (eluent: 33% v/v ethyl acetate in petroleum ether (40/60)).
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[C:15]([C:19]1[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].[NH2-].[Li+]>CCCCCCC>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:10][CH:7]2[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4][C:3]([CH2:1][CH3:2])([CH3:14])[CH:8]2[CH3:9])=[O:24])=[CH:27][CH:28]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCCC
Product: CCC1(C)CC(OC(=O)c2ccc(C(C)(C)C)cc2)C(C)C(C)(CC)N1
Yield: 104.2 %

Procedure:
15.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidinol (Compound 1) and 16.0 g of methyl p-t-butylbenzoate were dissolved in 500 ml of heptane. 1.5 g of lithium amide were then added to the solution and the mixture was refluxed by heating in a flask equipped with a Dean-Stark separator. 1.5 g of methanol were first removed and this was followed by 200 ml of heptane, which distilled off over a period of 3 hours. After cooling the reaction mixture, it was washed with water and dried over magnesium sulphate; the solvent was then removed by evaporation under reduced pressure. The residue was distilled under reduced pressure, giving 28.2 g of the title compound as a colourless liquid (bp 176° - 178° C/0.008 mmHg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>ClCCl.O>[C:18]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3-nitroaniline (5.95 g) and triethylamine (6.0 ml) in dichloromethane (40 ml) was added dropwise a solution of benzoyl chloride (5.0 ml) in dichloromethane (20 ml). The mixture was stirred at room temperature for 15 minutes, then poured into a mixture of ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 1-benzoylamino-3-nitrobenzene (9.05 g).
Reaction SMILES: [H][H].[Br:3][C:4]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>C(OCC)(=O)C.[Pt]>[Br:3][C:4]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1Br
Yield: 98.9 %

Procedure:
Hydrogen gas was passed through a solution of methyl 2-bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3% sulfided platinum on carbon in 25 mL ethyl acetate for 24 hours at room temperature. The catalyst was removed by filtration through CELITE. Concentration of the filtrate afforded 0.175 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil. 1H NMR (CDCl3) δ 7.15 (t, 1H, J=8 Hz), 7.1 (dd, 1H, J=1 and 8 Hz), 6.8 (dd, 1H, J=1 and 8 Hz), and 3.95 (s, 3H). IR (CHCl3, cm−1) 3550, 3380, 2980, 2900, 1729, 1613, 1465, 1451, 1434, 1324, 1266, and 1025. MS (FD) m/e 230, 232.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]=[CH:11][CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4].Cl[C:23]([F:28])([F:27])C([O-])=O.[Na+]>COCCOCCOC>[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]3[C:23]([F:28])([F:27])[CH:11]3[CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC=C2
Agent: [Na+]
Solvent: COCCOCCOC
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC1C2C1(F)F
Temperature: 160 °C
Yield: 56.3 %

Procedure:
Methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (Intermediate 45, 1.0 g) was dissolved in diglyme (30 mL) and the solution was heated to 160° C. Sodium chlorodifluoroacetate (4.27 g) was added in portions over 15 minutes with the final portion being washed in with diglyme (15 mL). On completion of the addition the mixture was heated at 180° C. for 15 minutes. After cooling, the mixture was poured into water and extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 2.5-15% to give methyl (1aRS,7bSR)-5-(2,2-dimethylpropionylamino)-1,1-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.66 g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([CH:6]=[CH:7][C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:23])[NH:10][N:9]=2)=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[C:17]([NH:1][C:2]1[CH:25]=[CH:24][C:5]([CH:6]=[CH:7][C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:23])[N:10]([C:16](=[O:21])[CH3:15])[N:9]=2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: COc1cc2c(cc1OC)C(C=Cc1ccc(N)cc1)=NNC(C)C2
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC)C(C=Cc1ccc(NC(C)=O)cc1)=NN(C(C)=O)C(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 142.8 %

Procedure:
1.2 g (3.56,mmoles) of 1-(4-aminostyryl)-4-methyl-7,8-dimethoxy-3,4-dihydro-5H-2,3-benzodiazepine prepared according to Example 33 is suspended in 6 ml of acetic anhydride. The suspension is stirred for 1 hour at room temperature. In the meantime the starting compound gets dissolved, the end-product begins to separate and the reaction mixture gets thick. The separated product is filtered off, washed three times with 15 ml each of diethyl ether and dried at a temperature between 80° C. and 100° C. Thus 1.07 g (71.3%) of the desired compound is obtained.
Reaction SMILES: [ClH:1].[Cl-].[CH3:3][N+:4]([CH2:17][CH2:18][N:19]([CH2:26][CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:11][CH2:12][CH2:13][NH:14]C=O)[CH2:5][CH2:6][CH2:7][NH:8]C=O>>[Cl-:1].[CH3:3][N+:4]([CH2:17][CH2:18][N:19]([CH2:26][CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:5][CH2:6][CH2:7][NH2:8])[CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CCN(CC[N+](C)(CCCNC=O)CCCNC=O)c1ccccc1
Reactant: Cl
Agent: [Cl-]
Product: CCN(CC[N+](C)(CCCN)CCCN)c1ccccc1

Procedure:
Dilute hydrochloric acid hydrolysis of N-methyl-N-2-(N'-ethylanilino)ethyl-N,N-bis(3-formamidopropyl)ammonium chloride following a procedure similar to that of B-4 above gave N-methyl-N-2-(N'-ethylanilino)ethyl-N,N-bis(3-aminopropyl)ammonium chloride.