Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:5]([CH:19]=1)=[CH:6][C:7]1[C:8]([CH3:18])([CH3:17])[C:9]3[C:14]([C:15]=1[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3.C([Li])CCC.C(N)(C)(C)C.[C:30]([NH:34][Si:35](C1C2C(=CC3C(C)(C)C4C(C=3C=2)=CC=CC=4)C=C1C)([CH3:37])[CH3:36])([CH3:33])([CH3:32])[CH3:31]>C(OCC)C>[C:30]([NH:34][Si:35]([CH:19]1[C:5]2=[CH:6][C:7]3[C:8]([CH3:18])([CH3:17])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH:3]=[C:2]1[CH3:1])=[CH:13][CH:12]=[CH:11][CH:10]=4)([CH3:37])[CH3:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC(C)(C)C)-c1ccccc1C3(C)C
Reactant: CC1=Cc2cc3c(cc2C1)-c1ccccc1C3(C)C
Agent: [Li]CCCC
Solvent: CC(C)(C)N
Solvent: CCOCC
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC(C)(C)C)C(C)(C)c1ccccc1-3
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
In a 500 mL round flask, 2,9,9-trimethyl-3,9-dihydrocyclopenta[b]fluorene (15.0 g, 60.9 mmol) was dissolved in 300 mL of diethyl ether, and then the temperature was lowered to −78° C. Then, n-butyllithium (2.5M hexane solution, 24.8 mL) was slowly injected thereto, followed by stirring at room temperature for 12 hours. After volatile materials were removed by vacuum, 350 mL of n-hexane was added to the mixture to lower the reactor temperature to −78° C., followed by addition of dichlorodimethylsilane (23 g). The temperature was again raised to room temperature, followed by stirring for 24 hours, and then salts were removed through filtering. Then, volatile materials were removed by vacuum. The product was again inputted to a 500 mL round flask, and dissolved in 320 mL of diethyl ether. The temperature was lowered to −78° C., and tert-butylamine (16.1 g, 152.2 mmol) was added thereto. The temperature was raised to room temperature, followed by stirring for 12 hours, and then volatile materials were completely removed by vacuum. Then, 200 mL of toluene was added to dissolve the resultant material, and salts were removed through filtering. The solvent was removed, to thereby obtain 21.0 g of a mixture of N-tert-butyl-1-(2,9,9-trimethyl-3,9-dihydrocyclopenta[b]fluoren-3-yl)-1,1- dimethylsilanamine and N-tert-butyl-1-(2,9,9-trimethyl-1,9-dihydrocyclopenta[b]fluoren-1-yl)-1,1-dimethylsilanamine (yield: 91.8%), as a viscous material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:46][NH:47][CH2:48][C:49]1[S:50][CH:51]=[C:52]([CH2:54][N:55]2[CH2:59][CH2:58][CH2:57][CH2:56]2)[N:53]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]([CH3:46])[CH2:48][C:49]3[S:50][CH:51]=[C:52]([CH2:54][N:55]4[CH2:59][CH2:58][CH2:57][CH2:56]4)[N:53]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1nc(CN2CCCC2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3nc(CN4CCCC4)cs3)co2)c(C)c1
Reaction time: 0.75 h

Procedure:
5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (30 mg, 0.085 mmol) was dissolved in DCM (10 mL) and EDCI (30 mg, 0.15 mmol) and HOBt (21 mg, 0.15 mmol) were added. The resulting solution was stirred for 45 min prior to the addition of a solution of N-methyl-1-[4-(pyrrolidin-1-ylmethyl)-1,3-thiazol-2-yl]methanamine (26 mg, 0.12 mmol) in DCM (2 mL). The reaction was stirred at ambient temperature for 5 h, saturated aqueous NaHCO3 (15 mL) was added and the mixture was extracted with DCM (3×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by FCC eluting with 3% MeOH in DCM. A portion of the resulting product was purified by prep method B to afford the title compound.
Reaction SMILES: [NH:1]([C:15]([CH3:17])=[O:16])[C@H:2]([C:10]([O:12]CC)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:18][C@H:19]([C:21]([NH2:23])=[O:22])[CH3:20].C(#N)C.C(O)(C(F)(F)F)=O>O1CCOCC1.O>[NH:1]([C:15]([CH3:17])=[O:16])[C@H:2]([C:10]([NH:18][C@H:19]([C:21]([NH2:23])=[O:22])[CH3:20])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](N)C(N)=O
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(C)=O
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](C)C(N)=O
Reaction time: 12 h

Procedure:
An equimolar solution of AcPhe-OEt (acceptor) and Ala-NH2 (donor) was dissolved in dioxane containing 5 vol % tertiary amine and approximately 1 vol % water at 23° C. The solution was shaken at 25 oscillations/min and approximately 10 units of poly(2-N-methacrylamido-2-deoxy-D-glucose) α-chymotrypsin conjugate was added. The reaction was monitored using HPLC analysis on a C18 column using 25% acetonitrile aqueous solution with 0.1% TFA as the eluent. After 12 hours, HPLC analysis found a quantitative yield of AcPheAla-NH2. The solution was then filtered, the dioxane reduced in vacuo and the product purified by recrystallization obtaining a 97% yield of AcPheAla-NH2. Additional examples of the use of protease-polymer conjugates for the formation of peptide bonds are contained in Table 2. Note that despite the presence of organic solvent, peptide bond formation can be accomplished at elevated temperatures. The use of protease-polymer conjugates for the synthesis of peptide bonds is important, not only for the preparation of peptides and proteins, but also because the chemistry demonstrates the stability of protein-polymer conjugates in organic solvents. Under the same conditions and at the same activity levels used for the preparation of peptide bonds using protease-polymer conjugates, the native enzymes gave less than 5% of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1.Cl[CH2:18][CH2:19][CH2:20][CH2:21][P:22]([O:27][CH2:28][CH3:29])(=[O:26])[O:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][P:22](=[O:26])([O:27][CH2:28][CH3:29])[O:23][CH2:24][CH3:25])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1
Reactant: COCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCOP(=O)(CCCCCl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2CCOC)n(C)c1=O)OCC
Temperature: 70 °C

Procedure:
9 g (0.04 mol) of 7-methoxyethyl-3-methylxanthine were suspended in 100 ml of DMF, treated with 11 g (0.048 mol) of diethyl 4-chlorobutane-phosphonate and 10 g (0.064 mol) of activated potassium carbonate and heated at 70° C. for 4 hours. The solid was filtered off, the filtrate was concentrated under reduced pressure and the oily residue which remained was taken up in ethyl acetate, filtered again and crystallized from diisopropyl ether.
Reaction SMILES: [F:1][C:2]1[C:3]([I:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=O)[O:7][CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:28][O:29][NH:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[C:3]([I:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([N:30]([O:29][CH3:28])[CH3:31])=[O:14])[O:7][CH2:6][CH2:5]2
Reactant: O=C(O)C1OCCc2c1ccc(F)c2I
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1OCCc2c1ccc(F)c2I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-fluoro-5-iodo-3,4-dihydro-1H-isochromene-1-carboxylic acid (1.32 g, 4 mmol) and CDI (690 mg, 4.9 mmol) in 50 mL of dry DCM was stirred at r.t. for 3 hrs and then O,N-dimethyl-hydroxylamine (500 mg, 5.1 mmol) was added. The result mixture was stirred oversight. The solvents were removed under vacuum, and the residue was purified via column chromatograph to afford 6-fluoro-5-iodo-N-methoxy-N-methyl-3,4-dihydro-1H-isochromene-1-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[Cl:12][CH2:13][C:14](O)=O>Cl>[Cl:12][CH2:13][C:14]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=C(O)CCl
Agent: Cl
Product: O=C(O)c1ccc2[nH]c(CCl)nc2c1
Yield: 76.4 %

Procedure:
3,4-Diaminobenzoic acid (6.09 g, 40 mmol) and chloroacetic acid (4.35 g, 46 mmol) were refluxed in 5 N HCl (30 ml) for 5 h. The reaction mixture was cooled, the gray precipitate obtained was separated by filtration and subsequently washed with acetone (100 ml) and ether (100 ml) to obtain 6.44 g of product 4 (76%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3ccc(C(F)(F)F)cc3)ccnc12
Yield: 62.3 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-11, step-3 using 4-chloro-8-nitroquinoline (Intermediate-11, step-2, 200 mg, 0.96 mmol), 4-(trifluoromethyl)phenol (233 mg, 1.43 mmol), K2CO3 (264 mg, 1.91 mmol) in CH3CN (5 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.85 (d, J=4.8 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.36 (d, J=7.2 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.82 (t, J=8.1 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 6.98 (d, J=5.4 Hz, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:14][N:15]=[C:16]=[S:17])[CH:10]=[CH:11][CH:12]=1>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[C:16]([SH:17])=[N:15][CH2:14][CH:13]2[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(C(CN=C=S)c2cccc(Cl)c2)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C2CN=C(S)c3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.75 ml of concentrated sulfuric acid were added to 0.4 g (1.255 mmol) of 2-(3-chlorophenyl)-2-(4-nitrophenyl)ethyl isothiocyanate with external ice cooling and internal stirring. Stirring at RT for a further 4 hours was followed by addition of ice-water and extraction with dichloromethane.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]>CN(C)C=O.C(OCC)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][CH:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
Sodium hydride (7.2 g, 180.4 mmol) was slowly added at 0° C. to a solution of 4-fluorophenol (17.11 g, 152.6 mmol) in 200 ml of N,N-dimethylformamide and then the reaction mixture was stirred for 30 minutes at room temperature. 4-Chloro-3-nitropyridine (22.0 g, 138.8 mmol) prepared in Step 1 of Preparation 1 was added at 0° C. to the reaction mixture, which was stirred for 1 hour at room temperature, diluted with 200 ml of ethyl acetate, and then washed with 200 ml of water three times. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give the titled compound as a pale yellow solid (25.2 g, 76.8%).
Reaction SMILES: Br[C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:14](#[N:17])[CH:15]=[CH2:16].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOCC.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[CH3:12][C:6]12[CH2:7][CH:8]3[CH2:10][C:4]([CH3:13])([CH2:3][C:2]([CH2:16][CH2:15][C:14]#[N:17])([CH2:9]3)[CH2:11]1)[CH2:5]2
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reactant: C=CC#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC12CC3CC(C)(C1)CC(CCC#N)(C3)C2
Yield: 86.3 %

Procedure:
A solution of 1-bromo-3,5-dimethyladamantane (1.0 g, 4.11 mmol), acrylonitrile (436 mg, 8.22 mmol) and 1,1′-azobis(cyclohexanecarbonitrile) (50 mg, 0.21 mmol) in dry toluene (12 mL) was treated with tri-n-butyltin hydride (1.44 g, 4.93 mmol) at room temperature, refluxed for 3.5 h, cooled, diluted with ether (30 mL), washed with 0.2-M NH4OH (30 mL), water (10 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography [SiO2, CH2Cl2-hexane (0:100 to 100:0)] to give the product (771 mg, 86%) as a colourless oil: IR νmax (liquid film)/cm−1 2899, 2841, 2247, 1545 and 1359; NMR δH (400 MHz, CDCl3) 0.81 (6H, s), 1.0-1.2 (6H, m), 1.25-1.35 (6H, m), 1.53 (2H, t, J 4.2 Hz), 2.05-2.10 (1H, m) and 2.27 (2H, tJ 4.2 Hz).
Reaction SMILES: Cl.O.[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([Cl:14])[CH:13]=1)[O:10][CH2:9][CH2:8][C:7]2=O>[Zn].C1(C)C=CC=CC=1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([Cl:14])[CH:13]=1)[O:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=C1CCOc2c(Cl)cc(Br)cc21
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cc(Br)cc2c1OCCC2
Yield: 50.3 %

Procedure:
To the amalgam of zinc--prepared from 1280 g (19.7 gram-atoms) of zinc, 128 g (5.4×10-1M) of mercurous chloride, 64 cm3 of concentrated hydrochloric acid and 1900 cm3 of water--are added, in order, 1000 cm3 water, 1500 cm3 of concentrated hydrochloric acid, 3500 cm3 of toluene and 640 g (2.45M) of 6-bromo-8-chloro-4-chromanone (III2). The mixture is refluxed for 1 hour and, after cooling and decantation, it is extracted with ether and washed in water up to neutrality. 305 g (yield=50%) of expected product are thus isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH:20]([CH3:22])[CH3:21])[NH:11][C:10]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br-].[Br-].[Br-].C1([N+](CC)(CC)CC)C=CC=CC=1.C1([N+](CC)(CC)CC)C=CC=CC=1.C1([N+](CC)(CC)CC)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:23])[NH:11][N:12]([CH:20]([CH3:21])[CH3:22])[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)N1NC(=O)C(c2ccc(Cl)c(Cl)c2)C1c1ccncc1
Agent: CC[N+](CC)(CC)c1ccccc1
Agent: [Br-]
Solvent: ClCCl
Product: CC(C)n1[nH]c(=O)c(-c2ccc(Cl)c(Cl)c2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The solution of 4-(3,4-Dichloro-phenyl)-1-isopropyl-5-pyridin-4-yl-pyrazolidin-3-one 90 mg in dichloromethane 10 mL was treated with phenyltriethylammonium tribromide 0.1 g at room temperature, The reaction mixture was stirred at room temperature for 15 h. The reaction was quenched with sat. Na2SO3 25 mL at 0° C. The reaction mixture was extracted with dichloromethane, 3×50 mL. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as light yellow solid 45 mg. MS (ES+): 348 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C@@H:10]([CH3:13])[O:11][CH3:12])=O)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[CH3:18][N:16]([CH3:17])[C:14](=[O:15])[C@H:9]([C@@H:10]([CH3:13])[O:11][CH3:12])[NH2:8]
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CO[C@H](C)[C@H](N)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To a solution of N2-(tert-butoxycarbonyl)-N,N,O-trimethyl-L-threoninamide (2.02 g) in ethyl acetate (10 mL) was added 4N hydrogen chloride/ethyl acetate solution (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hr, and the reaction mixture was concentrated under reduced pressure. To the reaction mixture was added methanol (10 mL). To the reaction mixture was added AMBERLYST (registered trademark) A21 (1.00 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hr, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.20 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br:10]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][C:7]=1[Br:10]
Reactant: BrBr
Reactant: N#Cc1ccc(N)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#Cc1ccc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
5-Aminopyridine-2-carbonitrile (2.38 g, 20 mmol) was dissolved in 6 mL of glacial acetic acid. A solution of bromine (1 mL, 20 mmol) in 2.5 mL of glacial acetic acid was added dropwise over a period of 30 minutes while the room temperature was maintained with a water bath. The resulting slurry was stirred for 1 hour at room temperature, treated with 50 mL of aqueous 20% sodium hydroxide solution and extracted with three 160 mL portions of dichloromethane. The combined organic layers were dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by crystallization from ethyl acetate-hexanes to give 5-amino-6-bromopyridine-2-carbonitrile (1.42 g, 35% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14].N1([CH2:35][OH:36])C2C=CC=CC=2N=N1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[C:13]([C:15]1([CH2:35][OH:36])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: OCn1nnc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C#N)(CO)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of N-isopropylpropan-2-amine (11.54 mL) in THF (50 mL) was added dropwise a solution of n-butyllithium in hexane (1.6 M, 51.45 mL) at −78° C. The reaction mixture was warmed to 0° C. and then stirred for 30 minutes. The reaction mixture was cooled to −78° C. again, and then a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (5.0 g) in THF (30 mL) was added dropwise, followed by stirring at −78° C. for 1 hour. To the reaction mixture was added dropwise a solution of 1H-benzotriazol-1-yl-methanol (8.19 g) in THF (20 mL) at −78° C., followed by stirring at −78° C. for 3 hours. To the reaction mixture was added a saturated aqueous NH4Cl solution (100 mL), followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 50:50) to obtain tert-butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate (5.68 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([CH:14]([F:16])[F:15])=[CH:12][N:11]([CH:17]([CH3:34])[C:18]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][CH:22]=3)=[O:19])[C:10](=[O:35])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]#[N:37])=[C:6]([C:8]2[C:13]([CH:14]([F:16])[F:15])=[CH:12][N:11]([CH:17]([CH3:34])[C:18]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[O:19])[C:10](=[O:35])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(C(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
64 mg (0.12 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 19.1F) were hydrolysed with TFA according to General Method 2. Yield: 46 mg (80% of theory)
Reaction SMILES: [CH:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:5](=[O:8])[CH2:6]Br)([CH3:3])[CH3:2].[C:17]1(N)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:5](=[O:8])[CH2:6][NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2ccccc2)C(C)C)cc1
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of N-Isopropyl-N-(4-methoxy-phenyl)bromoacetamide (257.6 g 924 mmol), 1,2-phenylene diamine (100 g, 924 mmol) and potassium carbonate (128 g, 924 mmol) in DMF (1200 ml) was stirred at 0° for 2 h and then allowed to stir at rt for 20 h. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo The resultant residue was dissolved in EtOAc (1200 ml), washed with water (3×200 ml), brine (200 ml), dried (MgSO4) and concentrated in vacuo. After removal of about 70% of the solvent a precipitate formed which was removed by filtration and washed with cold EtOAc and dried to afford the title compound (67.1 g) as a beige solid. The combined filtrates were concentrated in vacuo to afford a dark oil (88 g). Two Recrystallisations from ethanol afforded a second batch of the title compound as a beige solid (29.6 g).1H NMR (300 MHz, DMSO-d6). s 7.22 (m, 2H), 7.05(m, 2H), 6.47 (m, 1H), 6.34 (m, 2H), 5.95 (m, 1H), 4.81 (sept., 1H, J=6.8 ), 4.59 (dt, 1H, J=27.2, 6.1), 4.4 (s, 2H), 3.77 (s, 3H), 3.30 (s, 2H), 0.96 (d, 6H, J =6.8).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:14][C:15](OC)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:14][CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N(CCO)Cc2ccc(Cl)cc2)C1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[(4-chloro-benzyl)-methoxycarbonylmethyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.44 g, 1.15 mmol) in methanol cooled to 0° C. was added sodium borohydride (0.13 g, 3.45 mmol) and the resulting mixture was heated to 65° C. for 16 h. Additional sodium borohydride (0.26 g, 6.90 mmol) was added to the reaction mixture and stirred further at 65° C. for 18 h. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (50%) to ethyl acetate (100%). ESI-MS m/z: 355 (M+1), UV retention time: 1.27 min.