Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11](C)[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21](=[O:39])[C@@H:22]([NH2:38])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:39])[CH:22]([NH:38][C:12](=[O:14])[CH2:11][NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Product: CC(C)(C)OC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CNC(=O)N1CCCCCC1
Yield: 46.3 %

Procedure:
A solution of the product from Example AE ((S)-2-[(azepane-1-carbonyl)-amino]-propanoic acid) (0.50 g, 2.38 mmol) and the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.76 g, 2.33 mmol) were coupled according to the procedure described in Example AH. The reaction mixture was purified by chromatography (silica gel, 1:1 EtOAc/heptane) to give the title compound as a white foam (0.55 g, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH:15]=[CH:14][CH2:13][O:12]1)[C:5]([OH:7])=O.[Cl:17][C:18]1[CH:29]=[CH:28][C:21]2[NH:22][C:23]([C@@H:25]([NH2:27])[CH3:26])=[N:24][C:20]=2[CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH:15]=[CH:14][CH2:13][O:12]1)[C:5]([NH:27][C@H:25]([C:23]1[NH:22][C:21]2[CH:28]=[CH:29][C:18]([Cl:17])=[CH:19][C:20]=2[N:24]=1)[CH3:26])=[O:7]
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(N2CC=CCO2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)c1ccc(N2CC=CCO2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.[CH3:14]I>C1COCC1>[CH3:14][S:1][C:2]1[CH2:3][CH2:4][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=S)N1
Reactant: CI
Solvent: C1CCOC1
Product: CSC1=N[C@H](C(=O)OC(C)(C)C)CC1
Reaction time: 3.5 h
Yield: 90.5 %

Procedure:
To a solution of thiolactam 1b (10.50 g, 52.2 mmol) in 200 mL THF at rt, was added MeI (13.0 mL, 208.7 mmol). The mixture was stirred for 3.5 h, then concentrated. The residue was partitioned between CH2Cl2 and sat. NaHCO3 and the aqueous phase was extracted with CH2Cl2 (3×). The combined organic extract was dried (Na2SO4) and concentrated to afford 10.17 g (91%) of the title compound, 1c, as a brown oil. 1H NMR (300 MHz, CDCl3) δ4.60 (dd, J=6.2, 7.3, 1H), 2.83-2.58 (m, 2H), 2.49 (s, 3H), 2.37-2.22 (m, 1H), 2.17-2.03 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C@H:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3](O)=[O:4].Cl.[O:21]=[C:22]1[CH2:27][CH2:26][C:25]([NH2:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.CCCC(C)C.CCO>>[CH3:1][C@H:2]([C:6]1[CH:7]=[C:8]([C:16]([F:17])([F:19])[F:18])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[C:3]([NH:34][C:25]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23][C:22](=[O:21])[CH2:27][CH2:26]1)=[O:4]
Reactant: C[C@@H](C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Solvent: CCO
Solvent: CCCC(C)C
Product: C[C@@H](C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (R)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 41) and 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 18) according to the method of Example 50. 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.72 (2H, s), 7.29 (5H, m), 5.71 (1H, s), 3.70 (1H, q, J 7.0 Hz), 2.81 (1H, m), 2.64 (1H, m), 2.47–2.04 (5H, m), 1.60 (1H, m), and 1.52 (3H, d, J 7.0 Hz). e.e. [Determined by chiral HPLC (Chiralcel OD-H 250×4.6 mm i.d.; isohexane/EtOH (96:4); 1 mL/min; 210 nm]>99%.
Reaction SMILES: [Mg].II.Br[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].[CH3:14][O:15][B:16](OC)[O:17][CH3:18]>C1COCC1.CCOCC>[CH3:14][O:15][B:16]([O:17][CH3:18])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13]
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: COB(OC)OC
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COB(OC)c1c(C)cc(C)cc1C
Temperature: -15 °C
Reaction time: 3 h

Procedure:
To a stirred solution of activated magnesium flakes (3.11 g, 0.128 mol) and a crystal of iodine, 2-bromomesitylene (23.40 g, 0.118 mol) in THF (80 cm3) was added dropwise at room temperature. The reaction was allowed to reflux for 3 hours. After the reaction mixture was cooled, it was added dropwise to an ether solution (80 cm3) of trimethoxyborane (26 cm3, 0.229 mol) at −15° C. The reaction stirred at −15° C. for 3 hours and then was warmed up to room temperature and left to stir overnight. The solution was then filtered under argon and the precipitated salts were washed with dry pentane (20 cm3). The filtrates were combined, concentrated and distilled under vacuum to give the desired dimethoxymesitylborane. 1H NMR (200 MHz, CDCl3) δ 2.28 (s, 6H), 2.30 (s, 3H), 3.58 (s, 6H), 6.84 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1.CN(C)C=O>O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=2)[CH:8]=1)=[O:6]
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1F
Reactant: FC(F)(F)c1cccc(CBr)n1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ccccc3c2=O)cc1F
Yield: 85 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 150 mg (0.505 mmol) of 3-(3-Fluoro-4-methoxy-benzoyl)-1H-quinolin-4-one, 145.3 mg (0.605 mmol) of 2-bromomethyl-6-trifluoromethyl-pyridine, 24.2 mg (0.605 mmol, 60% dispersion in oil), and 1 mL of N,N dimethylformamide. Water was added and the solid was collected by filtration. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane to yield 195.9 mg of 3-(3-Fluoro-4-methoxy-benzoyl)-1-(6-trifluoromethyl-pyridin-2-ylmethyl)-1H-quinolin-4-one. LC-MSD, m/z for C24H16F4N2O3 [M+H]: 457.11 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.5 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=O)O[C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18].O>C(Cl)Cl>[CH3:19][C:16]([N:15]1[CH2:11][C:6]2[C:7](=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:8]1)([CH3:20])[CH2:17][OH:18]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(N)CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(CO)N1Cc2ccc([N+](=O)[O-])cc2C1

Procedure:
20 g of 4-Nitro-phthalic anhydride and 8.94 g of 2-amino-2-methylpropanol were heated to 170° C. for 30 min. After cooling, water and CH2Cl2 were added, and the organic phase separated, concentrated and purified by chromatography on silica (eluent CH2Cl2/MeOH 97/3).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[CH3:10].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.O>CN(C=O)C.CCOC(C)=O>[Cl:12][C:13]1[CH:18]=[C:17]([O:11][C:6]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([CH3:3])[CH:5]=2)[N:16]=[CH:15][N:14]=1
Reactant: Cc1ccc(O)cc1C
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2cc(Cl)ncn2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
218 mg (5.00 mmol) sodium hydride (55%, suspension in mineral oil) were added to 617 mg (5.00 mmol) 3,4-dimethylphenol in 10 ml DMF and the mixture was stirred for 10 min at RT. Then 768 mg (5.00 mmol) 4,6-dichloropyrimidine were added and the mixture was stirred for 48 h at RT. Water and EtOAc were added to the reaction mixture, the organic phase was separated off, dried on sodium sulphate, filtered and evaporated down. The residue was dried i. vac.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[O:10])[C:6](OC)=[O:7])[CH3:2].O.[NH2:12][NH2:13]>C(O)C>[CH2:1]([O:3][NH:4][C:5](=[O:10])[C:6]([NH:12][NH2:13])=[O:7])[CH3:2]
Reactant: CCONC(=O)C(=O)OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCONC(=O)C(=O)NN
Temperature: 65 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A solution of 234 g (1.59 mol) of methyl (ethoxyamino)-oxoacetate in 450 ml of ethanol was added to a solution of 92.8 g (1.855 mol) of hydrazine hydrate in 300 ml of ethanol and the mixture was stirred for 2 hours at 65° C. The mixture was cooled to +10° C., the precipitate was suction filtered, washed with a small amount of cold ethanol, and dried. There was obtained 150 g (64.2% of theory) of 1-(ethoxyamino)-2-(hydrazino)-ethane-1,2-dione as white crystals of m.p. 182° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.S1C=CC=C1.N.[H][H]>CO.[Pd]>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(CNc2ccccc2[N+](=O)[O-])o1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: c1ccsc1
Product: Cc1ccc(CNc2ccccc2N)o1
Yield: 95 %

Procedure:
A mixture of 62 parts of 5-methyl-N-(2-nitrophenyl)-2-furanmethanamine, 2 parts of a solution of thiophene in methanol 4% and 400 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 50.5 parts (95%) of N1 -[(5-methyl-2-furanyl)methyl]-1,2-benzenediamine as a residue (intermediate 8).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)(=O)[CH3:2]>O=P(Cl)(Cl)Cl>[ClH:20].[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]3=[C:18]([CH:17]=1)[C:1]([CH3:2])=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]3[CH2:12][CH2:13]2
Reactant: CC(=O)Nc1ccccc1N1CCc2cc(Cl)ccc21
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=Nc2ccccc2N2CCc3cc(Cl)cc1c32
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 286.8 g of 1-(2-acetamidophenyl)-5-chloro-indoline and 1250 ml POCl3 is stirred for 1 hour at room temperature and then slowly heated to reflux. After 20 hours, the resulting solution is permitted to cool and the POCl3 is distilled off at reduced pressure. The residue is then cautiously triturated with absolute ethanol (spontaneous vigorous boiling) and then boiled for 0.5 hour. After cooling to room temperature, the resulting solid is filtered, washed with ethanol and then with ether and dried at 60° C. under vacuum to give 4-chloro-1,2-dihydro-6-methylindolo[1,7-ab][1,5]benzodiazepine hydrochloride, m.p. 251°-254° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31](O)(=[O:33])=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([NH:35][S:31]([C:5]2[C:6](=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=2)/[CH:7]=[CH:8]/[C:9]2[N:17]([CH3:18])[C:16]3[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=3[N:10]=2)(=[O:32])=[O:33])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)Nc3ccccc3)n2C)n(CCC)c1=O
Yield: 23.5 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (1.96 mmol) of Compound 1 obtained in Example 1 and 1.85 ml (20.3 mmol) of aniline. The resulting crude crystals were recrystallized from toluene to give 261 mg (yield 23%) of Compound 10 as a pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28]>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>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:3]=2)=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc(-c2cccc(-n3cnc4cc(C(=O)NCc5cccnc5)ccc43)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22 %

Procedure:
A flask containing a mixture of 1-(3-bromophenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide (prepared according to the general procedures described above, 80 mg, 0.20 mmol) and 4-cyanophenylboronic acid (57 mg, 0.39 mmol) was evacuated and refilled with N2 (2×). To this was added Pd(PPh3)4 (34 mg, 0.029 mmol) in one portion with minimum exposure to air. The flask was again evacuated and refilled with N2 (3×). Degassed solutions of DME-EtOH (4:1 v/v, 2 mL) and aq Na2CO3 (2M, 0.6 mL) were added via syringe and the solution was stirred under N2 for 10 min at rt and then at 85° C. for 19 h. The reaction was then cooled to rt, filtered, and purified using the Waters mass-directed HPLC purification system. Further recrystallization from acetonitrile yielded 1-(4′-cyano-1,1′-biphenyl-3-yl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as a white solid (18.5 mg, 22% yield). MS (ES+): m/z430 (100) [MH+]. 1H NMR (400 MHz, CD3OD): δ=8.66 (s, 1H), 8.61 (d, J=2.4Hz, 1H), 8.45 (dd, J=4.8 Hz, 1.2 Hz, 1H), 8.34 (dd, J=1.0 Hz, 0.4 Hz, 1H), 7.99 (t, J=1.6 Hz, 1H), 7.88-7.86 (m, 3H), 7.86-7.82 (m, 4H), 7.80 (t, J=8.0 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.43 (dd, J=8.4 Hz, 5.2 Hz, 1H), 7.67 (s, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9](O)=[O:10])=[C:7]([F:12])[C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([F:21])[CH:4]=1.Cl.[CH3:23][NH:24][CH3:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:2][C:3]1[C:8]([C:9]([N:24]([CH3:25])[CH3:23])=[O:10])=[C:7]([F:12])[C:6]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([F:21])[CH:4]=1
Reactant: CNC
Reactant: Nc1cc(F)c(OCc2ccccc2)c(F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1c(N)cc(F)c(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
To a solution of 6-amino-3-benzyloxy-2,4-difluorobenzenecarboxylic acid hydrochloride (2.07 g) in DMF (30 mL) were added dimethylamine hydrochloride (1.07 g), 1-hydroxybenzotriazole (1.51 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.89 g) and triethylamine (2.0 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate and purified by column chromatography (hexane:ethyl acetate=1:2) on silica gel to give 6-amino-3-benzyloxy-2,4-difluoro-N,N-dimethylbenzamide (1.19 g).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:5]=1[CH:6]([OH:15])[C:7]([O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])([O-:3])=[O:2].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C1(NC2CCCCC2)CCCCC1>CC(C)=O>[S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)([O:15][CH:6]([C:7]([O:9][CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:8])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:19][CH:18]=[CH:17][C:16]=1[N+:20]([O-:22])=[O:21])(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)COC(=O)C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)OC(C(=O)OCC(C)(C)C)c2c([N+](=O)[O-])cccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Neopentyl 2,6-dinitromandelate (1.50 g, 4.80 mmol) and p-toluenesulfonyl chloride (1.00 g, 5.28 mmol) were mixed in dry acetone (50 mL) under argon. Dicyclohexylamine (0.957 g, 5.28 mmol) was added slowly to the reaction at 0° C. The mixture was stirred at room temperature for 2 hours at which time the reaction was shown to be complete by thin-layer chromatography (tlc). The acetone was then removed by evaporation under vacuum. The residue was put through a silica gel (60-200 mesh) column using methylene chloride/hexane (1:1) as the eluant. Recrystallization from CHCl3 /petroleum ether gave a yield of 2 g (89%).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](C)=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=[CH:24]1>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH3:24])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Reactant: CNC(=O)CC(c1ccccc1)c1ccc2[nH]c(C)cc2c1
Product: CNCCC(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Yield: 68 %

Procedure:
Methyl-[3-(3-methyl-1H-indol-5-yl)-3-phenyl-propyl]-amine LXXIV (221 mg, 68% yield) was prepared from N-methyl-3-(2-methyl-1H-indol-5-yl)-3-phenyl-propionamide using the procedure described above for [3-(1H-indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (see Example 4). MS (M+H)=279.
Reaction SMILES: NO[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].NOC[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].[C:18](=[N:31][OH:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na]>CN1CCCC1=O>[C:6]1(=[O:7])[O:8][CH2:3][CH2:4][CH2:5]1.[C:19]1([C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:31][O:32][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NOCCCC(=O)O
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: NOCCCCC(=O)O
Agent: [Na]
Solvent: CN1CCCC1=O
Product: O=C(O)CCCON=C(c1ccccc1)c1ccccc1
Product: O=C1CCCO1

Procedure:
The synthesis of 4-aminooxybutyric acid and 5-aminooxyvaleric acid are described in Tetrahedron, 23, 4441 (1967). Benzophenone oxime in N-methylpyrrolidone is reacted first with sodium then with γ-butyrolactone to provide N-diphenylmethylidene-4-aminooxybutyric acid which is subsequently hydrolyzed to form 4-aminooxybutyric acid. 5-aminooxyvaleric acid hydrochloric acid salt is prepared similarly by substituting γ-butyrolactone with γ-valerolactone. Aminooxyacetic acid is available as the hemihydrochloride from a commercial source.
Reaction SMILES: O1C2C=CC(N[N:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])=CC=2OC1.[CH2:17]1[O:26][C:25]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=2[O:18]1.C(#N)CC#N.O.[NH2:33][NH2:34]>CC(C)=O>[O:26]1[C:25]2[CH:24]=[CH:23][C:21]([NH:22][N:11]=[C:12]3[C:13]([NH2:14])=[N:34][N:33]=[C:15]3[NH2:16])=[CH:20][C:19]=2[O:18][CH2:17]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccc2c(c1)OCO2
Solvent: N#CCC#N
Solvent: CC(C)=O
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc2c(c1)OCO2

Procedure:
4-(benzo[1,3]dioxol-5-ylhydrazono)-4H-pyrazole-3,5-diamine was prepared using 107 mg (0.5 mmol) of 2-(benzo[1,3]dioxol-5-yl-hydrazono)malononitrile, which was derived from 3,4-methylenedioxyaniline (137 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 minutes after the addition of hydrazine hydrate. The resulting black solid was isolated by filtration, dissolved in acetone, and hexanes was added to precipitate a small amount of black solid. The solid was removed by filtration and the filtrate was concentrated to yield 1.0 mg (1% yield) of the compound as a black solid; 1H NMR (200 MHz, DMSO-d6) δ: 6.0 (br s, 6H), 6.92 (d, 1H), 7.18 (d, 1H), 7.38 (s, 1H), 10.60 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.CCN(C(C)C)C(C)C.[C:18]([C:20]1[CH:21]=[C:22]([CH3:27])[C:23](F)=[N:24][CH:25]=1)#[N:19]>C(O)CCC.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:23]1[C:22]([CH3:27])=[CH:21][C:20]([C:18]#[N:19])=[CH:25][N:24]=1
Reactant: Cc1cc(C#N)cnc1F
Reactant: COCC1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: COCC1CCCN1c1ncc(C#N)cc1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
2-(Methoxymethyl)pyrrolidine (Acb-blocks C5A-0029; 406 mg; 3.53 mmol; 1.2 eq.) and DIEA (1.52 ml; 8.82 mmol; 3 eq.) were added to a solution of 5-cyano-2-fluoro-3-methylpyridine (400 mg; 2.94 mmol; 1 eq.) in 1-butanol (1 mL) and the reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was allowed to return to room temperature then diluted with ethyl acetate, washed with water, dried over magnesium sulphate and concentrated in vacuo to afford the title compound (0.59 g, 87%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21]O)=[CH2:19].[Bi](Br)(Br)[Br:27].C(O)C>ClCCl.ClCCCC>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]2[CH2:19][CH:18]([Br:27])[CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21][O:14]2)=[CH:11][C:10]=1[F:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(CO)CCC
Reactant: O=Cc1ccc(OCc2ccccc2)c(F)c1
Reactant: Br[Bi](Br)Br
Solvent: CCO
Solvent: ClCCl
Solvent: CCCCCl
Product: CCCC1COC(c2ccc(OCc3ccccc3)c(F)c2)CC1Br
Temperature: 25 °C
Reaction time: 19 h

Procedure:
188.0 g (0.79 mol) of 4-benzyloxy-3-fluorobenzaldehyde are initially introduced in 1000 ml of dichloromethane at 0° C. together with 90.0 g (0.79 mol) of 2-vinylpentan-1-ol. 176.0 g (0.39 mol) of bismuth(III) bromide are added in portions, and the mixture is stirred at room temperature for 19 h. Insoluble constituents are separated off, and the mixture is filtered absorptively (SiO2, CH2Cl2). The filtrate is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:MTBE=4:1). The oil obtained is taken up in chlorobutane, and the solution is added dropwise to cold ethanol. The crystals which deposit are collected and recrystallised again from n-heptane. In this way, 2-(4-benzyloxy-3-fluorophenyl)-4-bromo-5-propyltetrahydropyran is obtained as a yellowish solid.