Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH:21]=O.[BH3-]C#N.[Na+].CC(O)=O>CO>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][NH:11][C:10]1[CH:9]=[CH:8][NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=Cc1nc2ccccc2[nH]1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]ccc1NCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A reaction mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.77 g, 4.99 mmol), 1H-benzoimidazole-2-carboxaldehyde (0.88 g, 5.99 mmol), NaCNBH3 (0.31 g, 4.99 mmol) and HOAc (0.57 mL, 9.99 mmol) in methanol (15 mL) was stirred at r.t. overnight. The mixture was then heated at 50° C. for 5 h. Cooled to r.t. and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate (1:0 to 0:1), obtaining 1.15 g (81%) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[Cl:26][C:27]1[S:28][C:29]([S:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)(=[O:35])=[O:34])=[CH:30][C:31]=1[NH2:32]>>[Cl:26][C:27]1[S:28][C:29]([S:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)(=[O:34])=[O:35])=[CH:30][C:31]=1[NH:32][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN1CCN(S(=O)(=O)c2cc(N)c(Cl)s2)CC1
Product: CN1CCN(S(=O)(=O)c2cc(NC(=O)c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)c(Cl)s2)CC1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-ylamine (example B.22) according to general procedure II.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]1[N:12]=[N:13][C:14]([Cl:20])=[CH:15][C:16]=1[C:17]([OH:19])=[O:18].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[Cl:20][C:14]1[N:13]=[N:12][C:11]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=2[F:1])=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=1
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution of 2-fluoro-4-iodoaniline (9.21 g, 38.86 mmol) and 3,6-Dichloro-pyridazine-4-carboxylic acid (10.84 g, 64.77 mmol) in THF (80 mL) at −78° C., was added LiHMDS (5 g, 25.91 mmol). The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture as diluted with ethyl acetate and washed with H2O and brine. The organic layer was dried with solid Na2SO4 and was concentrated. The resulting residue was purified by flash chromatography in silica (25% ethyl acetate-hexane) to give pure product. LC/MS [4.52 min; 394 (M+1)].
Reaction SMILES: [H-].[Na+].[C:3]([OH:7])(=[O:6])[CH2:4][OH:5].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:3]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:4][OH:5]
Reactant: O=C(O)CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CO)OCc1ccccc1
Temperature: 25 °C
Yield: 54 %

Procedure:
Alternatively, to a cold (0° C.) suspension of NaH (3.8 g of a 60% weight dispersion in mineral oil, 95.0 mmol) in THF (50 mL) was added a solution of glycolic acid (7.2 g, 95 mmol) in THF (50 mL) dropwise via cannula. The resulting solution was warmed to 25° C. and concentrated in vacuo. The resulting salt was suspended in DMF (100 mL) and treated with KI (1.57 g, 0.1 eq) and benzyl bromide (12.3 mL, 1.1 eq). The mixture was heated at 100° C. for 23 hours under argon and the DMF was evaporated. The residue was dissolved in ether and washed with water, saturated Na2S2O3, and brine, and dried over MgSO4. Distillation afforded benzyl glycolate (8.5 g, 54%) as a colorless oil, b.p. 85°-87° C. (0.5 Torr).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[C:4]([F:11])[CH:3]=1
Reactant: CCNCC
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCN(CC)Cc1c(F)cc(Br)cc1F
Yield: 86 %

Procedure:
According to procedure for the synthesis of Example A211A, by using 4-bromo-2,6-difluorobenzaldehyde (610 mg, 2.76 mmol), sodium triacetoxyborohydride (883.35 mg, 4.15 mmol) and diethylamine (425.21 mL, 4.15 mmol) to give the title compound as a colorless oil (660 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J=6.4 Hz, 2H), 3.61 (s, 2H), 2.55-2.50 (m, 4H), 1.07 (t, J=6.8 Hz, 6H); MS ESI 279.9 [M+H]+, calcd for [C11H14BrF2N+H]+ 278.03.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:15]([NH:16][C:17](=O)[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:20])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C1(C)C(C)=CC=CC=1>[C:24]([O:23][C:21]([N:19]([CH2:18][C:17]1[NH:16][C:15]2[CH:14]=[CH:13][CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]=2[N:5]=1)[CH3:20])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cccc(NC(=O)CN(C)C(=O)OC(C)(C)C)c1N
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: COC(=O)c1cccc2[nH]c(CN(C)C(=O)OC(C)(C)C)nc12
Yield: 90 %

Procedure:
Acetic acid (45 ml) was added to a solution of methyl 2-amino-3-(2-(tert-butoxycarbonyl(methyl)amino)acetamido)benzoate (19.28 mmol, 1.0 eq.) in xylene (130 ml) and the reaction mixture was heated under reflux for 1 h. When the reaction was complete (checking by TLC), the solvent was evaporated to dryness, the residue was dissolved in ethyl acetate and the solution was washed with water and NaCl solution. The organic phase was concentrated to dryness in vacuo in order to obtain the desired product, which was employed in the next stage without further purification. Yield: 90%
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)=[CH:10][C:9]=1[F:19])(=[O:5])=[O:4])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[C:31]([CH2:32][NH2:33])=[CH:30][C:29]([C:34]([F:37])([F:36])[F:35])=[N:28]2)[CH:24]=[CH:25][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>O1CCOCC1>[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[C:31]([CH2:32][NH:33][C:15](=[O:17])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[C:9]([F:19])[CH:10]=3)[CH3:18])=[CH:30][C:29]([C:34]([F:35])([F:36])[F:37])=[N:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCS(=O)(=O)NCc1ccc(C(C)C(=O)O)cc1F
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CCS(=O)(=O)NCc1ccc(C(C)C(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Reaction time: 8 h

Procedure:
2-(4-(ethyl-sulfonamidomethyl)-3-fluorophenyl)propanoic acid (60 mg, 0.207 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (63 mg, 0.228 mmol) were dissolved and mixed in 1,4-dioxane followed by addition of HOBt (42 mg, 0.310 mmol) and EDC (60 mg, 0.313 mmol) and TEA (0.07 mL, 0.518 mmol). The reaction mixture was stirred for overnight and then quenched by water and extracted with EtOAc. Drying (MgSO4) and evaporation of the ethyl acetate followed and the residue was purified by CC (EtOAc/n-hexane) to give the example B17 in pure form (104 mg, 92%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[CH2:23]([CH:30]1[CH2:33][C:32](=O)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([C@H:30]1[CH2:31][C@H:32]([N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH2:33]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CC(Cc2ccccc2)C1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN([C@H]2C[C@H](Cc3ccccc3)C2)C1

Procedure:
The title compound, MS: m/e=372.3 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and 3-benzyl-cyclobutanone.
Reaction SMILES: [NH2:1][C@@:2]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[CH2:6][O:5][C@H:4]([CH3:7])[C@H:3]1[CH2:8][OH:9].[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C@@:2]1([NH:1][C:27]([NH:26][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[S:28])[C@H:3]([CH2:8][OH:9])[C@@H:4]([CH3:7])[O:5][CH2:6]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C[C@H]1OC[C@@](N)(c2ccc(F)cc2F)[C@@H]1CO
Solvent: ClCCl
Product: C[C@H]1OC[C@@](NC(=S)NC(=O)c2ccccc2)(c2ccc(F)cc2F)[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
((2R*,3R*,4S*)-4-Amino-4-(2,4-difluorophenyl)-2-methyltetrahydrofuran-3-yl)methanol (120 mg, 0.49 mmol) was dissolved in DCM (2 mL). Benzoyl isothiocyanate (66 μl, 0.49 mmol) was added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and purified by column chromatography, eluting with 0-30% EtOAc in n-hexane to leave the title compound as a yellow oil (165 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 11.81 (s, 1H), 8.89 (s, 1H), 7.84-7.91 (m, 2H), 7.62-7.75 (m, 2H), 7.49-7.58 (m, 2H), 6.91 (dt, J=1.71, 8.38 Hz, 1H), 6.80 (ddd, J=2.63, 8.80, 11.80 Hz, 1H), 4.69 (d, J=10.15 Hz, 1H), 4.39 (dd, J=1.71, 10.15 Hz, 1H), 3.91-4.08 (m, 3H), 2.85 (dd, J=4.58, 6.79 Hz, 1H), 2.59 (dt, J=3.73, 8.10 Hz, 1H), 1.37 (d, J=5.99 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:5])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NC(C)(C)C
Reaction time: 0.5 h

Procedure:
55.8 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.2 mol.) are dissolved in 300 ml. of alcohol and 25 g. of triethylamine. At reflux temperature, 14.6 g. of tert. butylamine are slowly added dropwise and the mixture is heated with stirring for an additional 30 minutes. The solvent is distilled off in vacuo and the residue is dissolved in benzene. The precipitated triethylamine hydrochloride is filtered off and the benzene layer is evaporated to dryness. The remaining oil, 6-chloro-4-[(1,1-dimethylethyl)amino]-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester crystallizes with methanol, yield 38.4 g. (61%), m.p. 40°-43°.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([N:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([O:32]CC1C=CC=CC=1)=[O:31])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:26]([N:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([OH:32])=[O:31])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Reaction time: 3 h

Procedure:
H-Glu(OtBu)-Val-Val-Pro-OH was prepared by dissolving Z-Glu(OtBu)-Val-Val-Pro-OBzl (2.90 g, 3.89 mmol) in 100 mL methanol containing 1% acetic acid. Pearlman's catalyst, Pd(OH)2, (100 mg) was added and the flask was placed on the Parr hydrogenation apparatus with an initial H2 pressure of 34 psi. After three hours, the catalyst was removed by filtration through a celite pad and the filtrate was evaporated in vacuo to yield a yellow oil (1.30 g, 2.61 mmol, 67%). ESI/MS calculated for C24H42N4O7+H: 499.3 Found: 499.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C[O-].[Na+].Cl.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28]>CCOCC>[CH3:26][N:27]([CH3:28])[CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2nc3ncccc3o2)c1
Reactant: CN(C)CCCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)CCOc1cccc(-c2nc3ncccc3o2)c1
Temperature: 25 °C

Procedure:
To a solution of 1.1 g. (0.005 mole) of 2-(3-hydroxyphenyl)oxazolo[4,5-b]pyridine in 15 ml. dried dimethylformamide is added 0.6 g. (0.011 mole) of sodium methoxide in portions over about 10 min. To the reddish-orange solution cooled in an ice-bath is added 0.72 g. (0.005 mole) of N,N-dimethyl-2-chloroethylamine hydrochloride in portions over 15 minutes. The resultant mixture is then stirred 10 minutes, set in an oil-bath at 75° C., and kept at 75-90° C. (bath) for 20 hours. After cooling to room temperature, 15 ml. of dried ether is added with stirring, and the resultant mixture is filtered. The filtrate is then stripped of solvent, and the residue distributed between methylene chloride and water. The organic layer is dried over sodium sulfate, filtered, and concentrated in vacuo to yield 2-[3-(2-dimethylaminoethoxy)phenyl]oxazolo[4,5-b]pyridine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].CO>O1CCCC1>[Cl:7][C:8]1[C:9]([CH2:10][OH:11])=[CH:13][CH:14]=[C:15]([Cl:17])[N:16]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(Cl)nc1Cl

Procedure:
Lithium aluminum hydride (1.78 g) was suspended in dry tetrahydrofuran (10 ml), and 2,6-dichloronicotinic acid was added under ice-cooling at an inside temperature of not more than 10° C. The mixture was stirred under ice-cooling for 1 hr and 28% aqueous amonia was added dropwise to the reaction mixture until foams disappeared. Methanol was added and the mixture was stirred at room temperature for 3 hr, and filtered through celite. The mother liquor was concentrated and the residue was applied to flash silica gel column chromatography (silica gel, 200 ml) and eluted with chloroform:ethyl acetate=8:1 to give 2,6-dichloro-3-hydroxymethylpyridine as colorless crystals (2.89 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:6]1[CH2:10][CH2:11][O:12][CH:5]1[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: OCCO
Reactant: O=Cc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1cccc(C2OCCO2)c1
Yield: 64.4 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (91.6 g, 0.75 mol) in 500 ml toluene is added ethylene glycol (333.0 g, 5.3 mol) and p-toluenesulfonic acid (0.19 g, 0.001 mol). The flask is equipped with a Dean-Stark trap and the mixture is refluxed for 2 days, extracted with saturated sodium bicarbonate solution and the organic phase separated and dried (MgSO4). Filtration and evaporation of solvent gives the title product as an oil (80.3 g, 64% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:5].C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[OH:3][NH:2][C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[NH:5]
Reactant: N#CN1CCCCC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(NO)N1CCCCC1

Procedure:
Amidine (e) is readily produced from nitrites. More specifically, hydroxylamine hydrochloride dissolved in a suitable solvent, such as water, is reacted with cyanopiperidine (g) in the presence of a base such as sodium carbonate in a suitable solvent, such as in methanol and exposed to heat to provide the hydroxycarbamimidoyl-piperidine (h). The hydroxycarbamimidoylpiperidine (h) in a suitable solvent, such as acetic acid, is then hydrogenated via palladium catalyst in the presence of acetic acid anhydride under pressure to provide amidine (e).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([CH2:2][CH2:3][CH2:4][CH3:5])[C:22](=[O:26])[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCn1ccc(OCc2ccccc2)cc1=O
Yield: 97.9 %

Procedure:
1-Bromobutane (3.75 g, 27.33 mmol) and potassium carbonate (10.3 g, 74.52 mmol) were added to a solution of 4-benzyloxy-1H-pyridin-2-one (5.0 g, 24.84 mmol) in acetonitrile (200 ml) and the mixture was heated at reflux for 16 hours. The reaction mixture was filtered through diatomaceous earth and concentrated in vacuo. The crude residue was then triturated with diethylether to yield pure D4 (6.26 g, 98%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([NH:22][CH3:23])=[O:21]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:18][C@@H:19]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([NH:22][CH3:23])=[O:21])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=374.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[O:4][CH:5](O)[C:6]=1[Br:7].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[Br:1][C:2]1[C:3](=[O:9])[O:4][CH:5]([C:13]2[CH:14]=[CH:15][C:10]([CH3:16])=[CH:11][CH:12]=2)[C:6]=1[Br:7]
Reactant: Cc1ccccc1
Reactant: O=C1OC(O)C(Br)=C1Br
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C2OC(=O)C(Br)=C2Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3,4-dibromo-5-hydroxyfuran-2(5H)-one (0.5 g, 1.939 mmol) in toluene (5 mL, 1.939 mmol) was added AlCl3 (0.310 g, 2.327 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc (3×20 mL), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound without further purification. LCMS m/z=332.8 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4cc(C)ccc4nc3OC)CC2)cc(OC)c1OC
Yield: 94 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 94%). 1H NMR (300 MHz, CDCl3): δ 2.44-2.49 (m, 3H), 3.18-3.25 (m, 4H), 3.80-3.86 (m, 12H), 4.04-4.13 (m, 4H), 6.20 (s, 2H), 7.02-7.20 (m, 1H), 7.31-7.40 (m, 1H), 7.46-7.63 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([CH:23]([CH2:26][CH3:27])[CH2:24][NH2:25])[CH3:22]>>[CH2:21]([CH:23]([CH2:26][CH3:27])[CH2:24][NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:22]
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: CCC(CC)CN
Product: CCC(CC)CNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 68.4 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-ethylbutylamine (0.0186 g, 0.184 mmol) gives the title compound (0.0450 g, 68.6%): TOF MS ES+ 358.2 (M+H)+. HRMS calcd for C20H28N3O3 358.2131 (M+H)+, found 358.2127, time 0.41 ml; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.6 min, 98.8% purity.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[CH:20]=[CH:19][S:18][C:12]=2[NH:13][C:14](=O)[CH2:15][N:16]=1)([O-:3])=[O:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[CH:20]=[CH:19][S:18][C:12]=2[NH:13][C:14](=[S:22])[CH2:15][N:16]=1)([O-:3])=[O:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccc2[N+](=O)[O-])c2ccsc2N1
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1C1=NCC(=S)Nc2sccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
15.7 g (0.055 mol) of 1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepin-2-one are warmed to 60° C. in 40 ml of absolute pyridine and there are added with vigorous stirring 15.7 g of finely powdered phosphorus pentasulphide. The mixture is stirred for a further 1.5 hours at this temperature, subsequently poured on to 500 g of ice and 500 ml of water with vigorous stirring and stirred for 2 hours. The resulting precipitate is filtered under a vacuum and washed with a large amount of water. The precipitate is suspended in water and shaken out thoroughly with 500 ml of methylene chloride each time. After drying, the organic phase is evaporated under reduced pressure and the residue refluxed with a small amount of chloroform. After completion of the crystallization in a refrigerator, there is obtained 1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepine-2-thione which, after recrystallization from absolute methanol, melts at 207°-209° C.