Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18](Cl)[C:17]=1[Cl:27])[OH:15].C(N(CC)CC)C>[C].[Pd].CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[CH:18][C:17]=1[Cl:27])[OH:15]
Reactant: COc1cc(C)c(C(O)c2c(C(F)(F)F)cnc(Cl)c2Cl)c(OC)c1OC
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(C)c(C(O)c2c(Cl)cncc2C(F)(F)F)c(OC)c1OC
Reaction time: 4 h
Yield: 69.9 %

Procedure:
2.1 g of 5% palladium carbon was added to a methanol 200 ml solution of 24.8 g (58.1 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(2,3-dichloro-5-trifluoromethyl-4-pyridyl)methanol obtained in Step (a) and 9.50 ml (68.2 mmol) of triethylamine, followed by stirring under hydrogen atmosphere for 4 hours. The mixture was subjected to filtration, 50 ml of water was added, and methanol was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 15.9 g (yield: 70%) of (2,3,4-trimethoxy-6-methylphenyl)(3-chloro-5-trifluoromethyl-4-pyridyl)methanol (melting point: 102 to 105° C.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]1[N:16]([CH3:38])[C:17](=[O:37])[C:18]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:20]=1)(C)(C)C>Cl.CCOC(C)=O>[NH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]1[N:16]([CH3:38])[C:17](=[O:37])[C:18]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[C:19]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:20]=1
Reactant: Cn1c(C2CCCN2CCNC(=O)OC(C)(C)C)cc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1c(C2CCCN2CCN)cc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of {2-[2-(1-methyl-5-naphthalen-2-yl-6-oxo-1,6-dihydro-[4,4′]bipyridinyl-2-yl)-pyrrolidin-1-yl]-ethyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol) in sat. HCl in EtOAc was stirred at RT for 4 h. Then the title compound was isolated by filtration and washed with dry EtOAc. MS (ES+): 425 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH:22]([CH3:24])[CH3:23])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(Cl)c3nn2C(C)C)cc1
Yield: 10.6 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.016 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]23[CH2:24][N:21]([CH2:22][CH2:23]2)[CH2:20][CH2:19][CH2:18]3)=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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][N:2]1[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]34[CH2:24][N:21]([CH2:22][CH2:23]3)[CH2:20][CH2:19][CH2:18]4)=[CH:13][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(B(O)O)cn1
Reactant: Brc1ccc(C23CCCN(CC2)C3)cn1
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: CCO
Solvent: Cc1ccccc1
Product: Cn1cc(-c2ccc(C34CCCN(CC3)C4)cn2)cn1
Temperature: 105 °C
Yield: 93.2 %

Procedure:
0.162 g (0.78 mmol) of 1-methyl-4-pyrazolylboronic acid, 0.160 g (0.6 mmol) of (−)-5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane (obtained by reacting 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane (−)-hydrobromide (1:1), prepared in step 1.2, with saturated aqueous sodium carbonate solution) are successively introduced into a 10 ml three-necked round-bottomed flask, as a solution in 3 ml of toluene and 0.3 ml of ethanol. 0.035 g (0.03 mmol) of tetrakis(triphenylphosphine)palladium and 0.6 ml of aqueous 2M sodium carbonate solution are then added and the mixture is heated at 105° C. for 18 hours. It is cooled to room temperature, the solvent is evaporated off under reduced pressure and the residue is taken up in 10 ml of chloroform and filtered through diatomaceous earth. The solvent is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 95/5/0.5 proportions. 0.15 g of (−)-5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane is obtained, and is dissolved in 2 ml of isopropyl alcohol to add 0.196 ml of a 5.7N solution of hydrobromic acid in acetic acid. The crystals obtained are collected by filtration and dried under vacuum. 0.163 g of product is obtained.
Reaction SMILES: C(N[C:5](=[O:12])[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=O)(=O)C.[NH2:13][NH:14][C:15]([NH:17][NH2:18])=[S:16]>C(O)C.Cl>[NH2:13][N:14]1[C:5](=[O:12])[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:18][N:17]=[C:15]1[SH:16]
Reactant: NNC(=S)NN
Reactant: CC(=O)NC(=O)C(=O)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1nnc(S)n(N)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
5.1 g (0.03 mole) of trimethylpyruvic acid N-acetylamide in 20 ml of ethanol were added dropwise to 3.2 g (0.03 mole) of thiocarbohydrazide in 50 ml of 1 N HCl and the reaction mixture was subsequently stirred at room temperature for 5 hours. The product which had precipitated was filtered off, washed with water and dried. 5.7 g of the above product of formula (V) of melting point 210° C. were obtained with a content, determined by gas chromatography, of >99%, which corresponded to a yield of 95% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[OH:11][CH2:12][CH:13]([CH2:15]O)[OH:14]>>[OH:14][CH:13]1[CH2:12][O:11][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[O:6][CH2:15]1
Reactant: OCC(O)CO
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C1OCC(O)CO1

Procedure:
Using the method of Example 5e, 40.8 g 2-methoxybenzaldehyde and 27.6 g glycerol were reacted to form 5-hydroxy-2-(2-methoxyphenyl)-1,3-dioxane, crude b.p. 150°-155° C/10-5 mm.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+]>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([OH:14])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 65 °C
Yield: 52 %

Procedure:
70 g (0.39 mol) of 4-fluoro-3-trifluoromethylaniline, prepared according to G.C. Finger and colleagues, Journal of Med. Chem., 7, (1964), 572, are added a little at a time, while stirring, to 500 ml of a 2.5 N solution of sulphuric acid heated to a temperature of 65° C. The solution obtained is cooled to 0° C and 27 g of sodium nitrite dissolved in 45 ml of water are added whilst continuing the stirring and ensuring that the temperature does not exceed +5° C. After the end of the addition, the mixture is stirred for a further hour, during which it becomes perfectly clear. Thereafter, whilst carrying out a steam distillation, the cold solution of the diazonium salt is introduced dropwise into a mixture of 56g of copper sulphate, 21 g of urea, 70 ml of water and 2 ml of concentrated sulphuric acid. The speed of addition is regulated so that the phenol formed is immediately carried away. The distillate is cooled and is extracted repeatedly with ether. The ether solutions are combined and dried, the solvent is driven off and the residue is rectified. 37 g (yield: 52%) of 4-fluoro-3-trifluoromethyl-phenol, distilling at 84° C under 15 mm, are obtained.
Reaction SMILES: [Na].Cl.[C:3]([NH2:11])(=[NH:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>CC(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:10][C:3](=[NH:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCCCC(=N)NC(=O)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 3.9 g. sodium in 300 ml. dry acetone, 24.6 g. heptanamidine hydrochloride, and 23 g. 4-chlorophenyl isocyanate in 100 ml. dry acetone, there was obtained after recrystallization from acetonitrile 29.8 g. of the hydrochloride of 1-(4-chlorophenyl)-3-(heptanimidoyl)urea; m.p. 168°-169°C.
Reaction SMILES: C[O-].[Na+].[F:4][CH:5]([F:8])[C:6]#[N:7].Cl.[CH3:10][O:11][C:12](=[O:17])[CH:13]([CH2:15][OH:16])N>CO>[F:4][CH:5]([F:8])[C:6]1[O:16][CH2:15][CH:13]([C:12]([O:11][CH3:10])=[O:17])[N:7]=1
Reactant: N#CC(F)F
Reactant: COC(=O)C(N)CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1COC(C(F)F)=N1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a cooled (0° C.) solution of sodium methoxide (25 wt % solution in methanol; 0.230 mL, 1.032 mmol) and MeOH (20 mL) was added dropwise difluoroacetonitrile (0.690 mL, 10.03 mmol) while maintaining an internal temperature of <1° C. After 20 min DL-serine methyl ester hydrochloride (1.55 g, 9.96 mmol) was added followed by MeOH (20 mL) and the reaction was allowed to warm to rt overnight. Subsequently, the reaction was heated to 55° C. for 5 h. The reaction was cooled to rt and partitioned between DCM/water. The aqueous layer was extracted with DCM (3×) and the combined organic layers were washed with water and dried over MgSO4. The filtrate was concentrated in vacuo to give 1.59 g (89%) of a light-brown oil. MS m/z=180 [M+H]+. Calculated for C6H7F2NO3:179.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(O[C@H:14]1[O:26][C@@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]1[O:16][C:17](=[O:19])[CH3:18])(=O)C.FC(F)(F)S(O)(=O)=O.[N+](C1C=CC(OP([O-])(OC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1)([O-])=O>>[C:17]([O:16][C@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:26][C@@H:14]1[N:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: COC(=O)c1nc[nH]n1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Product: COC(=O)c1ncn([C@H]2O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1

Procedure:
Methyl 1,2,4-triazole-3-carboxylate and 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose are heated under reduced pressure in the presence of trifluoromethanesulfonic acid or bis(p-nitrophenyl)-phosphate. The residue is recrystallized from ethanol or methanol to obtain methyl 1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxylate. Subsequently, the obtained methyl 1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxylate is treated with ammonia in a methanol solvent, and the resultant mixture is then recrystallized from ethanol to obtain a crude product of 1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxamide. The obtained compound is further recrystallized from an ethanol aqueous solution, so as to obtain high-purity 1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxamide.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[CH2:4]1.[OH-].[Na+].O>CC(C)=O.CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C@H:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@H:3]([NH:2][CH3:1])[CH2:4]2)=[CH:13]1
Reactant: CN[C@@H]1C[C@@H](c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: CN[C@@H]1C[C@@H](c2c[nH]c3ccccc23)c2ccccc21
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
Dimethylbromoborane (1.77 mL, 1.05 equiv) (Synthesized according to Nöth, H., Vahrenkamp, H. Journal of Organometallic Chemistry 11(1968), 399-405) was added to 3-((1R,3R)-3-azido-indan-1-yl)-1-(toluene-4-sulfonyl)-1H-indole (17.3 mmol ) in 100 mL 1,2-dichloro-ethane under argon at 0° C. The reaction mixture was warmed to room temperature and stirred 2.5 hours. 1 mL Ethanol was added. The reaction mixture was extracted with ethyl acetate and 0.5N aqueous NaOH. The organic phase was washed with brine, dried over MgSO4, concentrated in vacuo to give methyl-{(1R,3R)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-indan-1-yl}-amine after flash chromatography (ethyl acetate, methanol, triethylamine, silica gel). Methyl-{(1R,3R)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-indan-1-yl}-amine was dissolved in 8 mL acetone and 20 mL methanol. 8 mL 28% Aqueous NaOH was added and the reaction mixture was stirred in two portions at 120° C. for 10 minutes under microwave irradiation using the Emry Optimizer™ instrument. The reaction mixture was poured into 250 mL water and a precipitate was formed. Recrystallization gave 2.15 g [(1R,3R)-3-(1H-indol-3-yl)-indan-1-yl]-methyl-amine.
Reaction SMILES: BrBr.CCOCC.[Cl:8][C:9]1[CH:10]=[C:11]([C:14](=O)[CH3:15])[S:12][CH:13]=1.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[NH2:20][C:18]1[S:19][CH:15]=[C:14]([C:11]2[S:12][CH:13]=[C:9]([Cl:8])[CH:10]=2)[N:17]=1
Reactant: CC(=O)c1cc(Cl)cs1
Reactant: NC(N)=S
Agent: BrBr
Solvent: CCOCC
Solvent: CCO
Product: Nc1nc(-c2cc(Cl)cs2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine was added to an ether solution of 4-chloro-2-acetylthiophene under ice cooling, and the mixture was stirred at room temperature for 2 hours to obtain a brominated compound. Thiourea was added to an EtOH solution of the brominated compound at room temperature, and the mixture was stirred overnight at 80° C. to obtain 2-amino-4-(4-chlorothiophen-2-yl)thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][C:8](=O)[CH:7]([CH3:13])[C:6]=2[CH:14]=1.B.O1CCCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: CC1C(=O)NCCc2ccc(Cl)cc21
Agent: B
Solvent: C1CCOC1
Product: CC1CNCCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapin-2-one (150 mg, 0.716 mmol, purified by HPLC or recrystallization) was added to a 50 mL round bottom flask with 2M borane-tetrahydrofuran solution (2 mL, 2.15 mmol). The mixture was stirred 10 hours at room temperature under an argon balloon. LC/MS showed the desired product as the major peak with approximately 5% of starting material still present. The reaction mixture was quenched with 5 mL methanol and the solvents were removed on the rotary evaporator. This procedure was repeated with methanol addition and evaporation. The mixture was evaporated on the rotary evaporator followed by 2 hours in vacuo to give the product as a white solid (117 mg, 70 % yield). 1H NMR (CDCl3): δ 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3H), 1.5 (d, 3H, J=7 Hz). LC/MS: 1.41 minute, 196.1 M+H+ and 139 major fragment.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:17]([O:21][C:22](=[O:23])[NH:24][CH2:25][C:26](=[O:27])[NH:16][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of 7.9 mmol C-(4-chloro-phenyl)-C-phenyl-methylamine hydrochloride (CA [5267-39-0]) in 100 ml acetonitrile was treated successively with 7.9 mmol N-tert.butyloxycarbonyl glycine, 39 mmol DIPEA and 8.7 mmol TBTU. After stirring for 1 hour at room temperature, the mixture was concentrated. Chromatography (SiO2; ethyl acetate/cyclohexane) yielded the title compound as a colorless solid. Yield=84%.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:10]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=2)[C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:14][CH:13]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(CN(Cc2ccc(Br)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 4-bromobenzylbromide (550 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.153 g (32.5%); MS m/z: 472.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.63 (s, 4H); 6.66-6.67 (m, 1H); 6.71 (dd, 1H, 4J=2.4 Hz, 3J=8.9 Hz); 7.22-7.24 (m, 4H); 7.34 (d, 1H, 3J=8.9 Hz); 7.48-7.50 (m, 4H); 7.93 (s, 1H); 11.99 (br s, 1H; HPLC (METHOD [A]): rt 18.49 min (98.4%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]([NH:20][CH2:21][CH2:22]F)=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.C(CN)[OH:25]>>[F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]([NH:20][CH2:21][CH2:22][OH:25])=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: NCCO
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Product: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C

Procedure:
Method as described for 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-fluoroethyl)urea (intermediate 31) using ethanolamine as starting material.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([CH:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.1 %

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (496 mg, 3.72 mmol), 1,1-dimethylethyl 4-formylhexahydro-1H-azepine-1-carboxylate (871 mg, 3.83 mmol) and AcOH (l μL, 0.017 mmol) in chloroform (5 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (950 mg, 4.48 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-40% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 40 g column) to afford the desired product (168 mg, 12%) as a pale yellow oil LC-MS (ES) m/z=345 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([C:28]#[N:29])=[C:25]([F:27])[CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(N(C(C)C)CC)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>CO.Cl[Ni]Cl>[F:27][C:25]1[CH:26]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C@H:11]3[O:10][C:9]([CH3:31])([CH3:30])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:12]3[CH2:13][F:14])=[CH:20][CH:19]=2)[CH:22]=[N:23][C:24]=1[CH2:28][NH:29][S:44]([CH3:43])(=[O:46])=[O:45]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cnc(C#N)c(F)c3)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cnc(CNS(C)(=O)=O)c(F)c3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4S,5R)-tert-butyl-5-(4-(6-cyano-5-fluoropyridin-3-yl)phenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (1440 mg, 3.4 mmol) in methanol (25 mL) at 5° C. is treated with NiCl2 (80 mg, 0.34 mmol) and then sodium borohydride (380 mg, 10 mmol) is added in portions. The mixture is stirred for 1 hour at room temperature, concentrated to remove the methanol, quenched with aqueous sodium bicarbonate and extracted with ethyl acetate. The organics are dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil is dissolved in dichloromethane (5 mL), cooled to 5° C. and treated with diisopropylethylamine (0.88 mL, 5.0 mmol) and methanesulfonyl chloride (0.30 mL, 3.7 mmol) and stirred for 2 hours at room temperature. The mixture is concentrated and chromatographed on silica eluting with ethyl acetate in heptane to give the title compound. 1H NMR (400 MHz, CDCl3) 1.53 (s, 9H), 1.63 (s, 3H), 1.75 (s, 3H), 3.80-4.00 (m, 1H), 4.40-4.50 (m, 0.5H), 4.55-4.65 (m, 2.5H), 5.22 (d, 1H, J=7.33 Hz), 5.72 (bs, 1H), 7.60-7.70 (m, 5H), 8.63 (s, 1H). m/z (Cl) M+H 512.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]#[N:8].[C:9]([N:17]=[C:18]=[O:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[C:7]([C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[NH:1][C:18]([NH:17][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:19])#[N:8]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#CC1=C(N)CCC1
Solvent: C1COCCO1
Product: N#CC1=C(NC(=O)NC(=O)c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of 2-aminocyclopent-1-enecarbonitrile (400 mg, 3.7 mmol) in 1.4-dioxane (20 mL) was added benzoyl isocyanate (545 g, 3.7 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitate was collected by filtration, washed with 1.4-dioxane, and dried to give N-(2-cyanocyclopent-1-enylcarbamoyl)benzamide (720 mg, 76%) as a white solid. 1H NMR (400 MHz, CDCl3) δ11.33 (s, 1H), 11.22 (brs, 1H), 7.99-7.97 (m, 2H), 7.67-7.63 (m, 1H), 7.54-7.51 (m, 2H), 3.04-3.0 (m, 2H), 2.51-2.47 (m, 2H) 1.95-1.90 (m, 2H). MS 256 (MH+).