Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].[Si]([C:15]#[N:16])(C)(C)C.B.C1COCC1.CO>C1COCC1.[Zn+2].[I-].[I-]>[NH2:16][CH2:15][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)[OH:6]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: B
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Solvent: C1CCOC1
Product: NCC(O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 772 %

Procedure:
To a mixture of 3,4-dichlorobenzaldehyde (3.50 g, 20.2 mmol) and ZnI2 (19 mg, 0.06 mmol) at 0° C. was added TMSCN (2.2 g, 2.2 mmol). The reaction mixture was stirred at 0° C. for 10 min and then warmed to rt and stirred for an additional 1 h. The mixture was concentrated to afford an orange-brown colored oil. The oil was dissolved in THF (20 mL) and BH3.THF (1 M in THF; 25 mL, 25 mmol) was added at 0° C. The reaction mixture was warmed to rt and stirred overnight. The mixture was cooled to 0° C. and MeOH (6 mL) was added with continued stirring for 2 h. After being warmed to rt, the mixture was concentrated. The residue was dissolved in MeOH (10 mL) and HCl (2 M in Et2O; 25 mL) was added at 0° C. After 30 min, Et2O (100 mL) was added and the resulting white solid was filtered and washed with Et2O (2×50 mL) to give a white solid (3.5 g, 72%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].[CH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)=[O:18]>O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[O:18])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Temperature: 2.5 °C

Procedure:
4-Isopropyl-piperazine (79.53 g, 0.620 mol), THF (444 g, 5.04 mol), water (36 g, 2 mol) and a 50% solution of sodium hydroxide (130.6 g, 1.63 mol) were charged to a reaction vessel and cooled to 0-5° C. 4-Formyl-benzoyl chloride in THF (110.08 g, 0.630 mol) was added to the 4-isopropyl-piperazine reaction mixture while maintaining the temperature below about 10° C. The resulting white suspension was stirred at room temperature until the reaction was deemed complete. Water was added to the reaction slurry and the resulting hazy solution was filtered over Celite to remove insolubles. The filtered reaction solution was settled and the water layer was removed. The product/THF layer was dried sequentially with magnesium sulfate and molecular sieves. The product solution (KF ≦0.5%) was stored at 5° C. for use without further manipulations.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][N:6]1[C:12](=[O:13])[CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][S:9][CH2:8][CH2:7]1.[ClH:26]>O1CCOCC1>[ClH:26].[NH2:14][CH:11]1[CH2:10][S:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:24]=[C:23]([F:25])[CH:22]=2)[C:12]1=[O:13]
Reactant: CC(C)(C)OC(=O)NC1CSCCN(Cc2cc(F)cc(F)c2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: NC1CSCCN(Cc2cc(F)cc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
230 mg of 33 (1.235 mmol) are taken up in a 25 ml round-bottomed flask and 5 ml of a solution of hydrogen chloride in dioxane (4M) are added. The medium is stirred for 2 hours at room temperature under argon. After evaporating off the solvent, 230 mg of amine 34 are obtained in hydrochloride form, which product is used directly in the following step.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[N:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl>C(O)C>[CH3:21][C:17]1[CH:16]=[C:15]([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[N:13]=[N:12][C:11]([OH:14])=[CH:10][CH:9]=3)[CH2:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(C2(O)CCN(c3ccc(O)nn3)CC2)c1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(C2=CCN(c3ccc(O)nn3)CC2)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of 2.9 parts of 6-[4-hydroxy-4-(3-methylphenyl)-1-piperidinyl]-3-pyridazinol, 30 parts of a hydrochloric acid solution 6N and 24 parts of ethanol was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated. Crushed ice was added and the whole was treated with concentrate ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 2.2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (75%) of 6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-3-pyridazinol; mp. 179.0° C. (compound 270).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[F:20])[C:13](OC)=[O:14]>C1COCC1>[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[F:20])[C:13]([NH:8][CH2:7][CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14]
Reactant: COC(=O)c1ccc(F)c(N)c1
Reactant: CC(C)(C)OCCN
Solvent: C1CCOC1
Product: CC(C)(C)OCCNC(=O)c1ccc(F)c(N)c1
Temperature: 90 °C

Procedure:
A mixture comprising 2-tert-butoxyethanamine (1.2 g, 5.12 mmol, 50% w/w) and methyl 3-amino-4-fluorobenzoate (0.866 g, 5.12 mmol) in THF (10 ml) was treated with TBD (0.713 g, 5.12 mmol) and heated at 90° C. for 16 hrs. After cooling to RT, the solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic portion was separated and washed with 10% aq citric acid (×2), NaHCO3 (sat. aq), brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a clear oil;
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:19])[NH:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1)[CH3:2].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.O>CN(C)C=O.C(OCC)(=O)C>[Si:20]([O:19][C:11]1[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[C:14]([C:15]([F:17])([F:18])[F:16])[NH:13][N:12]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1ccc(Cc2c(O[Si](C)(C)C(C)(C)C)n[nH]c2C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
1,2-Dihydro-4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-3H-pyrazol-3-one (4) (prepared by the method described in J. Med. Chem 1996, 39, 3920-3928) (15.0 g; 55.6 mmol) was dissolved in dimethylformamide (150 ml) and cooled to 0° C. t-Butyldimethylsilyl chloride (9.3 g; 61.1 mmol) was added in portions, and then, imidazole (4.2 g; 61.1 mmol) was added in portions. Then, the resulting mixture was back to ambient temperature, then the mixture was stirred for 3 hours. Water was added to the reaction solution, for extraction twice with ethyl acetate. The organic phase was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated, to give the desired compound (21.4 g; 55.6 mmol). (100%)
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[N:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:14]=2[CH:31]=1.[OH-].[Li+]>>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([N:15]2[C:14]3[CH:31]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])[CH:11]=[CH:12][C:13]=3[N:17]=[C:16]2[S:18]([CH2:21][CH2:22][CH3:23])(=[O:19])=[O:20])=[CH:25][CH:26]=1
Reactant: CCCS(=O)(=O)c1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Product: CCCS(=O)(=O)c1nc2ccc(OCCCCCC(=O)O)cc2n1-c1ccc(C)cc1

Procedure:
147 mg of 6-[[1-(4-methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with lithium hydroxide according to general operating instructions 3. 71 mg was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[CH:7]=[CH:6][C:5]=2[C:4]=1[C:23]([C:25]1[N:29](COCC[Si](C)(C)C)[C:28]2[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:27]=2[N:26]=1)=[O:24])[CH3:2].C(C1C=C(C)C2N(S(C3C=CC(C)=CC=3)(=O)=O)C=CC=2C=1C(C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1)=O)C.C[Si](C)(C)[C:89]([F:92])([F:91])[F:90].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN>C1COCC1.CCOC(C)=O>[CH2:1]([C:3]1[C:4]([C:23]([C:25]2[NH:29][C:28]3[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:27]=3[N:26]=2)([OH:24])[C:89]([F:92])([F:91])[F:90])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(=O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(=O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: [F-]
Solvent: NCCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(C)c2[nH]ccc2c1C(O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a mixture of 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 0.653 mmol) and trimethyl(trifluoromethyl)silane (0.204 mL, 1.30 mmol) in THF (1 mL) was added dropwise TBAF in THF (1M, 1.95 mL, 1.95 mmol) at 0° C., and then the mixture was stirred at room temperature for 0.5 hr. To the mixture were added ethylenediamine (0.441 mL, 6.53 mmol) and TBAF in THF (1M, 6.53 mL, 6.53 mmol), and then the mixture was stirred at 60° C. for 77 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc and successively washed by 5% aq. NaHCO3, H2O and brine, dried over Na2SO4, and filtered. After concentration the residue was purified by silica gel flash chromatography [heptanes/(30% EtOAc in CH2Cl2)=44/55] to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 9.25 (br. s., 1H), 8.10 (s, 1H), 7.67 (d, J=8.30 Hz, 1H), 7.61 (dd, J=1.30, 8.30 Hz, 1H), 7.04 (t, J=3.00 Hz, 1H), 6.97 (s, 1H), 6.02 (br. s., 1H), 5.32 (br. s., 1H), 2.92-3.04 (m, 1H), 2.51-2.59 (m, 1H), 2.50 (d, J=0.76 Hz, 3H), 1.12 (t, J=7.33 Hz, 3H). HRMS calcd. for C21H17F3N4O (M+H)+ 399.1427. found 399.1420.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[CH:16][C:9]=12>C(O)(C)C>[C:17]1([N:14]2[C:10]3=[N:11][CH:12]=[N:13][C:8]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[C:9]3[CH:16]=[N:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C1CNCCN1
Reactant: Clc1ncnc2c1cnn2-c1ccccc1
Solvent: CC(C)O
Product: c1ccc(-n2ncc3c(N4CCNCC4)ncnc32)cc1
Yield: 88 %

Procedure:
To an isopropanol solution (10 mL) of piperazine (3.74 g, 43.4 mmol), 4-chloro-1-phenylpyrazolo[3,4-d]pyrimidine (100 g, 4.34 mmol) described in J. Org. Chem., 21: 1240-1256 (1956) was added, followed by heating under reflux for 6 hours. The reaction solution was concentrated, saturated brine was added thereto, the mixture was extracted with chloroform, the extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated to give the target compound (1.07 g, 3.82 mmol).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:16][CH:15]([CH2:17]I)[O:14][C:13]2=[O:19])[CH:9]=[CH:8][C:7]=1[N:20]1[CH2:28][CH:27]2[CH:22]([O:23][CH2:24][CH2:25][N:26]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:21]1>CN(C)C=O>[N:1]([CH2:17][CH:15]1[O:14][C:13](=[O:19])[N:12]([C:10]2[CH:9]=[CH:8][C:7]([N:20]3[CH2:28][CH:27]4[CH:22]([O:23][CH2:24][CH2:25][N:26]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:21]3)=[C:6]([F:5])[CH:11]=2)[CH2:16]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCOC2CN(c3ccc(N4CC(CI)OC4=O)cc3F)CC21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC2CN(c3ccc(N4CC(CN=[N+]=[N-])OC4=O)cc3F)CC21
Temperature: 60 °C
Reaction time: 3 h
Yield: 124.3 %

Procedure:
Sodium azide (1.21 g) was added to the compound tertbutyl 6-{2-fluoro-4-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate (2 g) obtained from example 02 above in dimethyl formamide (30 mL) and the reaction mixture was stirred at 60° C. for 3 hrs. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (2.1 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CC1C2C(=CC=CC=2)C=CC=1ON1CCCCC1.Br[CH2:38][CH2:39][CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[OH:41].ClCCCC(C1C=CC(F)=CC=1)=O>>[C:42]1([CH:40]([OH:41])[CH2:39][CH2:38][N:16]2[CH2:15][CH2:14][CH:13]([O:12][C:7]3[C:8]4[C:3](=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=4)[CH:4]=[CH:5][CH:6]=3)[CH2:18][CH2:17]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Fc1cccc2c(OC3CCNCC3)cccc12
Reactant: OC(CCBr)c1ccccc1
Agent: Cc1c(ON2CCCCC2)ccc2ccccc12
Agent: O=C(CCCCl)c1ccc(F)cc1
Product: OC(CCN1CCC(Oc2cccc3c(F)cccc23)CC1)c1ccccc1

Procedure:
When in the procedure of Example 18, 4-(5-fluoro-1-naphthalenyloxy)piperidine is substituted for (1-methyl-2-naphthalenyloxy)piperidine and 3-bromo-1-phenylpropanol substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, α-phenyl-4-(5-fluoro-1-naphthalenyloxy)-1-piperidinepropanol is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH2:10].[Cl:11][CH2:12][C:13](Cl)=[O:14]>ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:11][CH2:12][C:13]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][C:13](=[O:14])[CH2:12][Cl:11])=[O:14]
Reactant: O=C(Cl)CCl
Reactant: NCCOCCOCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)NCCOCCOCCNC(=O)CCl
Reaction time: 0.17 h

Procedure:
1,2-bis[2-(2-chloroacetamido)ethoxy]ethane was prepared as follows. To a mixture of 1,2-bis(2-aminoethoxy)ethane (1.5 g, 10 mmol) in dichloromethane (100 mL) and 1 M Na2CO3 (50 mL) cooled in an ice bath was added chloroacetyl chloride (2.6mL, 33 mmol) dropwise. After stirring for 10 minutes, the organic layer was separated and evaporated to give the title compound (2.6 g, eual to 92% yield). HLPC analysis revealed a single peak using ultraviolet (220 nm) absorbtion spectrometry.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]([NH2:9])[C:7](=[O:10])[CH:6]=[C:5]([CH3:11])[N:4]=1.[F:12][C:13]([F:21])([CH2:19][CH3:20])[C:14](OCC)=O.Cl>O1CCOCC1.C(O)C>[F:12][C:13]([C:14]1[N:2]=[C:3]2[N:4]=[C:5]([CH3:11])[CH:6]=[C:7]([OH:10])[N:8]2[N:9]=1)([F:21])[CH2:19][CH3:20]
Reactant: Cc1cc(=O)n(N)c(N)n1
Reactant: CCOC(=O)C(F)(F)CC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: C1COCCO1
Product: CCC(F)(F)c1nc2nc(C)cc(O)n2n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of NaEtO prepared from sodium (FLUKA, 0.152 g, 6.62 mmol) and ethanol (25 mL), Intermediate 1 (0.773 g, 5.52 mmol) was added, and the mixture was heated at 80° C. for 30 min. Then, the reaction was cooled down to room temperature and ethyl 2,2-difluorobutanoate (FLUOROCHEM, 1007 mg, 6.62 mmol) was added and the reaction mixture was stirred at 80° C. for 3 h. A solution of HCl (1.655 mL, 6.62 mmol) in dioxane was added and a white solid was formed. The residue was purified (silica gel column, eluting with DCM:MeOH mixtures from 100:0 to 90:10%) to obtain Intermediate 6 as a white solid.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH3:11]>C(O)C>[NH2:11][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: N
Solvent: CCO
Product: Cc1ccc(C#N)c(N)n1
Yield: 82 %

Procedure:
2-Chloro-6-methyl-nicotinonitrile (25 g, 0.164 mol) and liquid ammonia (250 mL) in 500 mL of ethanol were reacted in a sealed high-pressure vessel at 130° C. for 20 hours. The reaction mixture was concentrated under vacuum and the residue washed with water (2×50 mL) then dried in a vacuum oven for 24 hours to provide the title compound as a light yellow solid (18 g, 82%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.30 (s, 3H), 6.52 (d, J=7.7 Hz, 1H), 6.78 (s, 2H), 7.73 (d, J=7.7 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:12])([CH3:11])[CH2:4][C@H:5]([NH2:10])[CH2:6][N:7]([CH3:9])[CH3:8].C(N(CC)CC)C.[CH3:20][C@@H:21]1[C@@H:26]([NH:27][C:28]([CH:30]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[N:31]2[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]=O)[CH:39]=2)=[O:29])[CH2:25][C@H:24]2[CH2:46][C@@H:22]1[C:23]2([CH3:48])[CH3:47].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:20][C@@H:21]1[C@@H:26]([NH:27][C:28]([CH:30]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[N:31]2[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][NH:10][C@H:5]([CH2:6][N:7]([CH3:9])[CH3:8])[CH2:4][C:3]([CH3:12])([CH3:11])[CH3:2])[CH:39]=2)=[O:29])[CH2:25][C@H:24]2[CH2:46][C@@H:22]1[C:23]2([CH3:47])[CH3:48]
Reactant: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(C=O)c2)C[C@H]2C[C@@H]1C2(C)C
Reactant: CN(C)C[C@@H](N)CC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(CN[C@H](CN(C)C)CC(C)(C)C)c2)C[C@H]2C[C@@H]1C2(C)C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
To a stirred solution of (S)-4,4,N1,N1-tetramethyl-pentane-1,2-diamine hydrochloride salt (Intermediate 2, 0.100 g, 0.43 mmol) in methanol (5 mL) at 0° C. was added triethylamine (0.12 g, 0.16 ml, 1.2 mmol). After 10 min of stirring at the same temperature, a solution of 2-(3-formyl-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.181 g, 0.43 mmol) in methanol (1 mL) was added and stirring was continued for an additional 15 min at room temperature. The reaction mixture was again brought into 0° C. and sodium cyanoborohydride (0.022 g, 0.35 mmol) and acetic acid (0.2 mL) were added simultaneously into the reaction mixture. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (5 mL), washed with water (3 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude 2-{3-[((S)-1-dimethylaminomethyl-3,3-dimethyl-butylamino)methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (0.216 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16]COC)[CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COCOc1cccc(COc2cccnc2N)c1
Agent: O=S(=O)(O)O
Product: Nc1ncccc1OCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
A mixture of 2-amino-3-(3-methoxymethoxybenzyloxy)pyridine (7.6 g) and 10% sulfuric acid (150 ml) was stirred at room temperature for 4 hours and the resulting precipitates were collected by filtration. The obtained sulfate was treated with an aqueous solution of sodium bicarbonate and the precipitates were collected by filtration, washed with water, and air-dried to give 2-amino-3-(3-hydroxybenzyloxy)pyridine (4.88 g).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C[O-].[Na+].[C:12](O)(=[O:14])C>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1](=[NH:8])[O:14][CH3:12])[CH:3]=1
Reactant: N#Cc1cccnc1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cccnc1
Reaction time: 18 h

Procedure:
A solution of nicotinonitrile (11.35 g) and sodium methoxide (1.1 g) in methanol was allowed to stand at ambient temperature under nitrogen for 18 hours, then acetic acid (1.2 ml) was added, and the solvent was removed in vacuo. The residue was triturated with cyclohexane, undissolved solid was removed by filtration, and the solvent was removed in vacuo to leave methyl pyridine-3-carboximidate as an orange oil (10.6 g).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[Cl:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:9]=1[C:10]([NH2:12])=[O:11]>C(Cl)Cl>[Cl:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[C:9]=1[C:10]([N:12]=[C:2]=[O:3])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl

Procedure:
3.5 ml of oxalyl chloride are added dropwise at room temperature over a period of 30 minutes to a suspension of 7.68 g of 2,6-dichloro-3-nitrobenzoic acid amide in 570 ml of methylene chloride. The batch is then heated at reflux temperature for 18 hours and the solvent is subsequently distilled off in vacuo, affording 8.6 g of crude 2,6-dichloro-3-nitrobenzoyl isocyanate which can be used directly in the subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:49]=[CH:48][C:28]([C:29]([NH:31][C@H:32]5[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46]C)=[O:45])[CH2:33]5)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>C1COCC1.CCOC(C)=O>[C:40]([O:39][C:37]([N:35]1[CH2:36][C@@H:32]([NH:31][C:29](=[O:30])[C:28]2[CH:48]=[CH:49][C:25]([NH:24][C:14]3[N:13]=[C:12]([NH:11][C:8]4([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)[CH2:9][CH2:10]4)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:23])[F:22])[N:15]=3)=[CH:26][CH:27]=2)[CH2:33][C@@H:34]1[C:44]([OH:46])=[O:45])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)C[C@@H]1C(=O)O
Reaction time: 2 h
Yield: 100 %

Procedure:
(2S,4R)-1-tert-butyl 2-methyl 4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-1,2-dicarboxylate (500 mg, 0.708 mmol), was dissolved in THF (Ratio: 1.000, Volume: 4 mL) followed by the addition of LiOH (85 mg, 3.54 mmol) and Water (Ratio: 1.000, Volume: 4). The reaction was headed to 65° C. for 2 h. The reaction was diluted with EtOAc and acidified with 1N HCl. The organic layer was collected, washed with brine, dried over sodium sulfate, and concentrated under vacuum to give (2R,4S)-1-(tert-butoxycarbonyl)-4-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pyrrolidine-2-carboxylic acid (490 mg) which was used in the next step without further purification. 1H NMR (400 MHz, MeOD) δ ppm 1.33-1.41 (m, 4H), 1.45 (s, 9H), 2.28-2.49 (m, 2H), 3.40-3.47 (m, 1H), 3.85 (dd, J=10.7, 6.9 Hz, 1H), 4.33-4.47 (m, 1H), 4.60-4.72 (m, 1H), 4.86-4.93 (m, 2H), 7.20-7.32 (m, 4H), 7.59-7.71 (m, 3H), 7.77-7.89 (m, 1H); LC-MS (Condition A), MS m/z (M++H) 692.0.