Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5]C(S(O[C@H](C#C)C)(=O)=O)=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C[C@H](O)C#C.[NH2:32][OH:33].Cl.[O:35]([C:37]#[N:38])[K]>CO.O.C(N(CC)CC)C>[OH:33][N:32]([C@@H:1]([C:6]#[CH:5])[CH3:15])[C:37]([NH2:38])=[O:35]
Reactant: N#CO[K]
Reactant: NO
Reactant: C#C[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Agent: C#C[C@H](C)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: C#C[C@@H](C)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 46047.3 %

Procedure:
To a solution of (S)-O-p-toluenesulfonyl-3-butyn-2-ol (11.2 g, 50.0 mmol), prepared by addition of p-toluenesulfonyl chloride and triethylamine to (S)-3-butyn-2-ol, in methanol (100 mL), was added 55% aqueous hydroxylamine (30 mL, 0.50 mol) and the reaction mixture was stirred at ambient temperature for 40 hours. The reaction mixture was cooled to 10° C. and concentrated HCl (50 mL) was added dropwise. The reaction mixture was concentrated in vacuo and the residue was partitioned between H2O (50 mL) and ethyl acetate (200 mL). The 2-phase mixture was cooled to 10° C. and taken to pH 8 with 50% aqueous NaOH solution (60 mL). After stirring for 15 min the layers were separated and the aqueous phase was extracted twice with 200 mL of ethyl acetate. The combined ethyl acetate extracts were cooled to 10° C. and a solution of KOCN (8.1 g, 0.10 mmol) in H2O (30 mL) was added, followed by dropwise addition of 11 mL of concentrated HCl, and the reaction mixture was stirred for 30 min. The ethyl acetate layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 5.9 g (92% yield) of (R)-N-hydroxy-N-(3-butyn-2-yl)urea. mp 129° C. [α]D24 =+53.3° (c=0.58, CH3OH). 1H NMR (DMSO-d6, 300 MHz) δ1.25 (d, 3H, J=7 Hz), 3.05 (d, 1H, J=2.5 Hz), 4.85 (dq, 1H, J=2.5, 7 Hz), 6.50 (br s, 2H), 9.24 (s, 1H). 13CNMR (DMSO-d6, 75 MHz) d 18.43, 45.14, 72.81, 83.87, 161.51. IR (KBr) 3455, 3330, 3290, 3215, 1658, 1637, 1585 cm-1. MS (DCI/NH3) m/e 146 (M+NH4)+, 163 (M+NH4.NH3)+. Anal. Calc for C5H8N2O2 : C, 46.87; H, 6.29; N, 21.86. Found: C, 46.78; H, 6.34; N, 21.72.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.[Br:12]P(Br)Br>CN(C)C=O>[Br:12][CH2:8][C:6]1[O:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(C(F)(F)F)no1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CBr)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of (3-(trifluoromethyl)isoxazol-5-yl)methanol (2.5 g, 15 mmol) in dimethylformamide (25 mL) was added drop wise tribromophosphine (4.64 g 17.1 mmol, 1.15 eq) and the mixture was stirred at 0° C. for 15 min and at ambient temperature for 2 h. The reaction mixture was partitioned between 10% sodium bicarbonate and dichloromethane. The phases were separated and the organic phase was washed with water and passed over a plug of silica eluting with dichloromethane. The UV active product fractions were collected and evaporated to yield the title compound as colorless oil (2.04 g 59.3%), MS 229 and 231 (M.)+.
Reaction SMILES: CS[C:3]1[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[N:6]=[CH:7][N:8]=1.[NH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>C(O)C>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH:13]1[NH:12][C:3]1[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnc2cscc12
Reactant: NC1Cc2ccccc2C1
Solvent: CCO
Product: c1ccc2c(c1)CC(Nc1ncnc3cscc13)C2
Yield: 22 %

Procedure:
4-methylthiothieno[3,4-d]pyrimidine (90 mg, 0.50 mmol) (see J. Heterocyclic Chem., 30, 509 (1993)) and 2-aminoindan (200 mg, 1.5 mmol) in dry ethanol (4 ml) were heated to reflux under an argon atmosphere for 4 hours. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (30 mg, 0.11 mmol) having the following physical properties;
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[NH:5][N:4]=1)[CH3:2].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([O:28]C)=[O:27])=[CH:16][CH:15]=1>>[CH2:1]([C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: CCCCc1nc(CC)n[nH]1
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nc(CC)nn1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 10.1 %

Procedure:
Following General Procedure A, 1.0 g (6.0 mmol) of 3-ethyl-5-butyl-1H-1,2,4-triazole was reacted with 2.41 g (7.9 mmol) of the alkylating reagent prepared in step 1 of Example 1. Hydrolysis of the faster moving isomer provided 220 mg of 4′-[(3-ethyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ 0.85 (t, J=7 Hz, 3H), 1.19 (t, J=7 Hz, 3H), 1.27–1.38 (m, 2H), 1.52–1.63 (m, 2H), 2.59 (q, J=7 Hz, 2H), 2.74 (t, J=7 Hz, 2H), 5.35 (s, 2H), 7.21 (d, J=8 Hz, 2H), 7.31 (d, J=8 Hz, 2H), 7.35 (dd, J=8 and 2 Hz, 1H), 7.48 (dt, J=8 and 2 Hz, 1H), 7.57 (dt, J=8 and 2 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[CH2:25]([NH:31][CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>ClCCl>[CH2:25]([N:31]([CH3:32])[C:9]([C:7]1[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC(=O)c1ccc(C(=O)O)o1
Reactant: CCCCCCNC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCCCN(C)C(=O)c1ccc(C(C)=O)o1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of 4.6 g. (0.03 mole) of 5-acetylfuran-2-carboxylic acid in 150 ml. of dichloromethane was added 3.3 g. (0.033 mole) of N-methylmorpholine. The resulting solution was cooled to -20° C., and 3.6 g. (0.033 mole) of ethyl chloroformate was added dropwise, with stirring. Stirring was continued for 1 hour at -15° C. and then 3.8 g. (0.033 mole) of n-hexylmethylamine was added dropwise at -20° C. The resulting mixture was stirred for 1.5 hours while being allowed to warm to room temperature. The reaction mixture was then washed with water, dried (Na2SO4) and evaporated in vacuo to give 7.5 g. of an oil. This oil was chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate, to give 5.6 g. of the title amide as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([C:9]([Br:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[C:17]([CH3:24])(C)[C:18]([O:20][CH2:21][CH3:22])=[O:19].[I-].[K+].[C:27](=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[Br:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([N+:13]([O-:15])=[O:14])[C:2]([NH:1][CH:24]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:27])=[CH:11][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(Br)ccc(N)c1[N+](=O)[O-]
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Cs+]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC(C)Nc1ccc(Br)c(C(=O)OC)c1[N+](=O)[O-]
Yield: 31 %

Procedure:
A mixture of methyl 3-amino-6-bromo-2-nitrobenzoate (Reference Compound No. 1-(4), 11.6 g, 42.0 mmol), ethyl 2-bromoisobutyrate (60.4 mL, 412 mmol), potassium iodide (7.76 g, 46.2 mmol) and cesium carbonate (56.1 g, 172 mmol) was stirred at 85° C. for 4 days. After cooling down, ethyl acetate (500 mL) and water (500 mL) were added thereto, the mixture was partitioned, and then the water layer was extracted with ethyl acetate (300 mL). The organic layer was combined, washed with water (1 L, twice) and saturated brine (1 L) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (5.08 g) as an orange oil. (Yield 31%)
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][NH:5][C:6]1[C:18]2[C:17](=[O:19])[C:16]3C=CN=C[C:11]=3[C:10]=2[C:9]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:8]=2[N:7]=1.[CH3:27][NH:28][CH2:29][CH2:30]N>>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:9]2[C:10]3[C:11]4[CH:30]=[CH:29][N:28]=[CH:27][C:16]=4[C:17](=[O:19])[C:18]=3[C:6]([NH:5][CH2:4][CH2:3][NH:2][CH3:1])=[N:7][C:8]=2[CH:23]=1
Reactant: COc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1ccncc1-3
Reactant: CNCCN
Product: CNCCNc1nc2cc(OC)ccc2c2c1C(=O)c1cnccc1-2

Procedure:
This compound was prepared from the compound of Example 1c-2 and N-methylethylenediamine. The desired product was obtained as a red solid. EI−MS: m/z 334 (M+); 1H-NMR (CDCl3): δ2.51 (3H, s), 2.94 (2H, t, J=6 Hz), 3.82 (2H, d, J=6 Hz), 3.97 (3H, s), 6.98 (1H, dd, J=9 Hz, 2.5 Hz), 7.10 (1H, d, J=2.5 Hz), 7.88 (1H, dd, J=5 Hz, 1 Hz), 8.05 (1H, d, J=9 Hz), 8.84 (1H, d, 5 Hz), 8.87 (1H, d, J=1 Hz).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.O.[NH2:21][NH2:22]>CCO>[NH2:2][C:1]1[NH:22][N:21]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: NN
Reactant: Cc1ccc(N)cc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added p-Toluidine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-(p-tolylamino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(C)(=O)=O)cn2)CC1
Yield: 70.3 %

Procedure:
To a stirred solution of 2-bromo-5-methanesulfonyl-pyridine (0.24 g, 1.0 mmol, 1.0 equiv; prepared as described in EP 1298 116 A1 (Pfizer Products Inc., USA)) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.23 g, 1.1 mmol, 1.1 equiv) in acetonitrile (6.0 mL) was added N-ethyl diisopropylamine (0.87 mL, 0.66 g, 5.0 mmol, 5.0 equiv) drop by drop at rt and the reaction mixture heated to reflux for 19 h. The reaction mixture was poured into crashed ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.25 g (70%) of the title compound as light brown oil. MS (ISP): 356.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[N:14]([CH3:15])[C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1.[CH3:21]I>COCCOC>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[N:14]([CH3:15])[C:13]([CH:16]([CH3:21])[C:17]#[N:18])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: Cn1c(CC#N)ccc1C(=O)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C#N)c1ccc(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (12.2 g. of 50% w/w NaH in mineral oil) in 1,2-dimethoxyethane is added 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile (62.6 g., 0.24 mole) in 1,2-dimethoxyethane over a period of 1/2 hr. at room temperature. After the addition is complete, the mixture is stirred for 1 hour and then 35 g. (0.25 mole) of methyl iodide is added. The reaction mixture is stirred for an additional 3 hours, concentrated under reduced pressure, diluted with water and extracted with chloroform. After drying, the chloroform is removed leaving a brown solid residue which is triturated with cold methanol to give yellow crystals of 5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetonitrile, m.p. 145-148° C. Two recrystallizations from methanol raises the m.p. to 151.5-152.5° C.
Reaction SMILES: CS(C)=O.[C:5]([O:22]C)(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>O1CCCC1>[C:27]1([C:24](=[O:26])[CH2:25][C:5](=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Reactant: CC(=O)c1ccccc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.88 h

Procedure:
An apparatus as described in Example 1 is charged with 31.7 g of sodium-tert-butylate, 150 g of DMSO and 150 g of tetrahydrofuran (THF) and the mixture is cooled to 0° C. Then a mixture of 89 g of methyl palmitate and 36 g of acetophenone is added dropwise over 45 minutes. The reaction mixture is then stirred for ca. 45-60 minutes at 30° C., the solvent is removed by distillation on a rotary evaporator (bath temperature <60° C.), and the residue is taken up in 1000 ml of water. The aqueous solution is acidified with dilute hydrochloric acid and the precipitate is isolated by filtration, washed with water, and dried.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:29](=O)[CH2:30][CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:29]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:14][C:15]([CH3:21])([CH3:22])[CH2:16][C:17]([CH3:20])([CH3:19])[CH2:18]2)[CH2:6][CH2:5]1)[CH2:30][CH2:31][CH3:32]
Reactant: CC1(C)CC(c2ccc(N3CCOCC3)cc2N2CCNCC2)CC(C)(C)C1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1CCN(c2cc(N3CCOCC3)ccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine (14 mg, 0.0363 mmol) produced in Example (81e), butyraldehyde (0.0097 mL, 0.109 mmol) and tetrahydrofuran (0.5 mL) was added sodium triacetoxyborohydride (23 mg, 0.109 mmol), followed by stirring for 1 hour and 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The solvent was distilled of by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 4-[3-(4-butylpiperazin-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:35][C:36](=[NH:55])[C:37]1[CH:54]=[CH:53][C:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45][C:39]=2[CH:38]=1>CN(C=O)C>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[O:11][N:35]=[C:36]([C:37]3[CH:54]=[CH:53][C:40]4[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[CH2:44][CH2:45][C:39]=4[CH:38]=3)[N:55]=2)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cc2CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.5 %

Procedure:
2-(Trifluoromethyl)-4-biphenylcarboxylic acid (Preparation 40) (284 mg, 1.07 mmol), HOBT (159 mg, 1.18 mmol) and EDC (225 mg, 1.18 mmol) were stirred in DMF (10 ml) under argon for 20 minutes. 1,1-Dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41) (326 mg, 1.07 mmol) was added and the mixture stirred at room temperature for 2.5 h before it was heated to 80° C. for 16 h. The reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml) and the organic layer washed with aqueous sodium bicarbonate and water before it was dried (phase separator) and evaporated. The residue was triturated with methanol to give the title compound as a white solid (370 mg, 0.69 mmol). The filtrate was purified by Biotage Horizon, reverse phase cartridge, eluting with 5-100% acetonitrile in water to give further title compound (70 mg, 0.13 mmol). δH (d6DMSO, 400 MHz): 8.52 (1H, s), 8.50 (1H, d), 7.93 (1H, s), 7.90 (1H, dd), 7.74 (1H, d) 7.56-7.48 (3H, m), 7.41-7.38 (3H, m), 3.55-3.47 (4H, m), 3.02-2.93 (4H, m), 1.41 (9H, s).
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3].[H-].[Na+].C1COCC1.[F:18][C:19]([F:37])([F:36])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([NH:32][CH3:33])=[CH:25][C:24]=1F>CCOC(C)=O>[F:18][C:19]([F:36])([F:37])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([NH:32][CH3:33])=[CH:25][C:24]=1[N:8]1[CH2:9][CH2:10][CH:5]([C:2]([OH:1])([CH3:4])[CH3:3])[CH2:6][CH2:7]1
Reactant: CC(C)(O)C1CCNCC1
Reactant: CNc1cc(F)c(C(=O)NCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1cc(N2CCC(C(C)(C)O)CC2)c(C(=O)NCC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A mixture of 4-(1-hydroxy-1-methyl-ethyl)-piperidine (24 mg, 0.17 mmol), NaH-suspension (50% in mineral oil, 8 mg, ˜0.17 mmol) and THF (1 mL) is stirred for 10 min. Then, N-(2,2,2-trifluoro-ethyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide is added and it is stirred for 1.5 h. The mixture is diluted with EtOAc, washed with water, concentrated, dried and directly used in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([NH2:19])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:12]=[C:11]([NH:19][C:21](=[O:23])[CH3:22])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cc(C(C)(C)C)cc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(C(C)(C)C)cc(OCc2ccccc2)c1C

Procedure:
This is obtained, by acetylating 2-methyl-3-amino-5-tert.-butylphenyl benzyl ether with acetic anhydride in toluene, in the form of colorless crystals; m.p. 170°-172° C.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[CH3:8][CH:9]([CH2:12][CH2:13][CH3:14])[CH:10]=[O:11]>ClCCl>[N:1]([C:10]([CH:9]([CH2:12][CH2:13][CH3:14])[CH3:8])=[O:11])=[N+:2]=[N-:3]
Reactant: CCCC(C)C=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: ClCCl
Product: CCCC(C)C(=O)N=[N+]=[N-]
Temperature: 25 °C

Procedure:
Under Ar, a mixture of azidotrimethylsilane (1.15 g, 9.98 mmol) and chromic anhydride (998 mg, 9.98 mmol) was stirred at room temperature till homogeneous solution. The solution of 2-methylpentanal (500 mg, 4.99 mmol) in 5 mL of dichloromethane was added. The mixture was stirred another 5 hours, and then filtered through silica gel. The filtrate was concentrated to give the crude material. FT-IR 2135.80 cm−1, 2110.9 cm−1.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([I:17])C(=O)C1>>[CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[I:17])[CH3:2]
Reactant: CCc1cccc(N)n1
Reactant: O=C1CCC(=O)N1I
Product: CCc1nc(N)ccc1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 10.0 g (83 mmol) 6-ethyl-pyridin-2-ylamine and 18.4 g (83 mmol) NIS. Yield after precipitation from the reaction mixture: 18.0 g (89%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:15].C(N(CC)CC)C.Cl>CCOC(C)=O>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[F:7]
Reactant: Oc1cccc(F)c1F
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)Oc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Step M (1): Ethyl chloroformate (16.6 g, 153 mmol) was added to a solution of 2,3-difluorophenol (20 g, 153 mmol) and triethylamine (20.7 mL, 146 mmol) in EtOAc (200 mL). The resulting mixture was stirred at rt for 2 h. The crude reaction was poured into 1 N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (5% EtOAc/hexane) to afford 2,3-difluorophenyl ethyl carbonate (20 g, 64% yield).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:20]=[C:21]([S:25]([N:28]2[CH2:32][C@H:31]3[C@H:33]([NH2:36])[CH2:34][CH2:35][C@H:30]3[CH2:29]2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1.[CH2:39](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:40]1[CH:45]=CC=C[CH:41]=1>>[CH2:6]([NH:8][C@H:9]([C:14]([NH:36][C@H:33]1[C@H:31]2[C@H:30]([CH2:29][N:28]([S:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:37])[F:38])[CH:20]=3)(=[O:26])=[O:27])[CH2:32]2)[CH2:35][CH2:34]1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:40]([CH3:45])([CH3:41])[CH3:39]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Product: CC(C)C[C@H](NCC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting (S)-4-methyl-2-(neopentylamino)pentanoic acid from Step A of Example 244 for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step A for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.37-8.38 (bs, 1H), 8.15-8.19 (m, 2H), 7.90-7.92 (m, 1H), 7.71 (t, J=7.8 Hz, 1H), 4.22-4.28 (m, 1H), 3.88 (dd, J=9.9, 2.8 Hz, 1H), 3.23 (dd, J=8.5, 5.7 Hz, 1H), 3.19 (dd, J=9.7, 2.8 Hz, 1H), 3.15 (dd, J=9.9, 7.6 Hz, 1H), 2.96 (dd, J=9.6, 7.2 Hz, 1H), 2.50-2.59 (m, 2H), 2.41-2.44 (m, 1H), 2.32 (d, J=11.2 Hz, 1H), 1.92-2.01 (m, 1H), 1.82-1.92 (m, 2H), 1.60-1.78 (m, 1H), 1.69 (ddd, J=13.5, 7.8, 5.7 Hz, 1H), 1.50-1.59 (m, 2H), 1.32 (ddt, J=9.4, 13.0, 6.5 Hz, 1H), 0.92 (s, 9H), 0.92 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 518 (M+H)+.