Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]([Si:13]([CH3:29])([CH3:28])[O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[NH:21]2)=[CH:17][CH:16]=1)([CH3:12])[CH3:11]>CN(C=O)C>[Br:8][C:19]1[C:18]2[C:22](=[CH:23][C:15]([O:14][Si:13]([C:10]([CH3:9])([CH3:11])[CH3:12])([CH3:28])[CH3:29])=[CH:16][CH:17]=2)[NH:21][C:20]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2ccc(O[Si](C)(C)C(C)(C)C)cc2[nH]1
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2cc(O[Si](C)(C)C(C)(C)C)ccc2c1Br
Reaction time: 8 h
Yield: 17 %

Procedure:
NBS (0.670 g, 3.77 mmol) was added to a solution of methyl 6-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1H-indole-2-carboxylate (1.15 g, 3.77 mmol) in DMF (6 mL) and stirred overnight. The reaction was partitioned between EtOAc and water. The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was adsorbed onto silica gel and purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to afford the title compound (0.246 g, 17%). 1H NMR (400 MHz, CDCl3): δ ppm 9.31 (br. s., 1H), 7.48 (d, 1H), 6.76-6.84 (m, 2H), 3.98 (s, 3H), 0.99 (s, 9H), 0.21 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:41][O:42][C:43](=[O:48])[CH2:44][CH2:45][CH2:46]I>CN(C=O)C.CS(C)=O>[CH3:41][O:42][C:43](=[O:48])[CH2:44][CH2:45][CH2:46][NH:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)CCCI
Reactant: NC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCNC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of N4-(4-amino-cyclohexylmethyl)-5-nitro-N2-(2-trifluoromethoxy-benzyl)-pyrimidine-2,4-diamine (80 mg, 0.182 mmol) in 2:1 DMF/DMSO (0.6 mL) was added N,N-diisopropylethylamine (32 μL, 0.272 mmol) followed by methyl-4-iodobutyrate (19 μL, 0.136 mmol). The mixture was stirred at room temperature overnight then partitioned with EtOAc (15 mL) and water (10 mL). The layers were separated and the organics dried over Na2SO4. After concentration in vacuo, the residue was purified by column chromatography using a 12 g ISCO combi-flash cartridge (silica gel, 100:0 to 90:10 DCM/MeOH) to afford 4-(4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexylamino)-butyric acid methyl ester (39 mg, 53%) as a white solid: m/z 541 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:39])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[NH:17][CH:16]2[C:36]([OH:38])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[C:43]([CH3:50])([CH3:49])[O:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:45][C@H:44]([C:43]([OH:42])([CH3:50])[CH3:49])[CH2:46][CH2:47][NH:48][C:36]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:39])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:35])[CH2:32][OH:33])[NH:17]1)=[O:38]
Reactant: CC1(C)O[C@@H](CCN)C(C)(C)O1
Reactant: CC(C)(CO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CO)CC1NC(C(=O)NCC[C@H](O)C(C)(C)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 64.6 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (0.82 g, 1.37 mmol) was reacted with 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethylamine prepared in Example 131a (0.5 g, 2.88 mmol), HATU (0.94 g, 2.5 mmol) and iPr2NEt (1.2 mL, 6.9 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide as a white solid (0.53 g, 70%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10](=O)[CH2:9][CH:8]1[CH2:19][CH3:20])=[O:6])([CH3:3])[CH3:2].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26][NH2:27].[BH4-].[Na+].[OH-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(OCC)(=O)C.CO>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[CH:10]([NH:27][CH2:26][C:25]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=2)[CH2:9][CH:8]1[CH2:19][CH3:20])=[O:6])([CH3:3])[CH3:2]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCC1CC(=O)c2ccc(C)nc2N1C(=O)OC(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(C)nc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
Inject titanium(IV)isopropoxide (0.0870 ml, 0.299 mmol) to a mixture of 2-ethyl-7-methyl-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid isopropyl ester (0.055 g, 0.199 mmol), and 3,5-bis(trifluoromethyl)benzylamine (0.0500 g, 0.199 mmol), and then stir at room temperature for 6 h. Add methanol (2 ml) followed by NaBH4 (0.0380 g, 0.995 mmol) and stir at room temperature overnight. Treat the mixture with 1 N sodium hydroxide (2 ml) and ethyl acetate (5 ml), and then filter through a Celite® pad. Wash the filtered residue thoroughly with ethyl acetate (30 ml). Separate the organic layer, wash with brine (3×50 ml), dry over sodium sulfate, filter, and concentrate to provide crude 4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-7-methyl-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid isopropyl ester (0.0900 g) which was elaborated without further purification. MS (ES+): 504 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C:10](OCC)=[O:11])=[CH:6][N:5]=[C:4](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[NH3:23].CO>>[C:17]1(/[CH:16]=[CH:15]/[CH:4]2[NH:3][C:2]3[NH:23][C:10](=[O:11])[CH2:9][CH2:8][C:7]=3[CH:6]=[N:5]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N
Reactant: CCOC(=O)CCc1cnc(/C=C/c2ccccc2)nc1Cl
Solvent: CO
Product: O=C1CCC2=C(N1)NC(/C=C/c1ccccc1)N=C2
Temperature: 110 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a 320 mL sealed flask at room temperature was added ethyl 3-{4-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanoate (6.6 g, 20.83 mmol) and ammonia in MeOH (59.5 mL, 417 mmol, 7M solution). The flask was sealed and the reaction was heated at 110° C. for 7 h. After 3 h a solid precipitated. The reaction was then stirred at room temperature overnight, followed by heating for an additional 5 h. The reaction mixture was filtered through a Buchner funnel and the resulting solid was washed with ethanol and dried. Obtained solid (2 g, 36.3%). LCMS (ES+) m/z 252 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[C:7]([Br:16])[CH:6]=1)[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[CH:8]=[C:7]([Br:16])[CH:6]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(Br)cc(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)c1cc(Br)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 3-Bromo-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH3:5].[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]>>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([N:4]([CH2:3][CH2:2][OH:1])[CH3:5])[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CNCCO
Product: CN(CCO)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using (2-hydroxy-ethyl)-N-methylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 441 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][F:23])[CH2:17][CH2:16]1)=O)(C)(C)C.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FCCN1CCNCC1

Procedure:
Trifluoroacetic acid (20 ml) was added to a mixture of 4-(tert-butoxycarbonyl)-1-(2-fluoroethyl)piperazine (3.7 g), triethylsilane. (8 ml) and methylene chloride (100 ml) and the resultant mixture was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was isolated, washed with diethyl ether and dried to give 1-(2-fluoroethyl)piperazine trifluoroacetic acid salt (6.0 g) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)C>C(O)C.[OH-].[Na+]>[C:16]12([C:10]3[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:26])=[O:3])[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][CH:20]([CH2:21]3)[CH2:25]1)[CH2:17]2
Reactant: CCOC(=O)CCCOc1cc(C)ccc1C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C23CC4CC(CC(C4)C2)C3)c(OCCCC(=O)O)c1
Reaction time: 60 h

Procedure:
A solution of 7.9 g of 4-[2-(1-adamantyl)-5-methylphenoxy]-butyric acid ethyl ester in 80 ml of ethanol and 80 ml of 1 N sodium hydroxide solution is left to stand for 60 hours at about 25°C. It is then evaporated to dryness in vacuo and the evaporation residue is partitioned between 100 ml of 2 N hydrochloric acid and twice 200 ml of ether. The organic phases are washed until neutral, treated with active charcoal, dried over sodium sulphate and evaporated in vacuo. Crystallising the evaporation residue twice from ether-petroleum ether gives 4-[2-(1-adamantyl)-5-methylphenoxy]-butyric acid of melting point 147°-150°C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.[F:26][C:27]1[CH:32]=[C:31](Br)[CH:30]=[CH:29][N:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([F:26])[CH:32]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Reactant: Fc1cc(Br)ccn1
Product: Cc1cc(-c2ccnc(F)c2)cc(C(=O)Nc2nc(C)cs2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 2-Fluoro-4-bromopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=329.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].[F:80][C:81]1[CH:89]=[CH:88][CH:87]=[C:86]([F:90])[C:82]=1[C:83]([NH2:85])=[O:84]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:80][C:81]1[CH:89]=[CH:88][CH:87]=[C:86]([F:90])[C:82]=1[C:83]([NH:85][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:84]
Reactant: Fc1cccc(Nc2ncc(F)c(-c3c(-c4cccc(Br)c4)nn4ccccc34)n2)c1
Reactant: NC(=O)c1c(F)cccc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2nc(Nc3cccc(F)c3)ncc2F)c1)c1c(F)cccc1F
Temperature: 160 °C
Yield: 20.4 %

Procedure:
A solution 4-[2-(3-bromophenyl)pyrazolo[1,5-a]pyridin-3-yl]-5-fluoro-N-(3-fluorophenyl)-2-pyrimidinamine (40 mg, 84 mmol), Pd2(dba)3 (15.3 mg, 0.016 mmol), xantphos (14.5 mg, 0.025 mmol), Cs2CO3 (95 mg, 0.29 mmol), and 2,6-difluorobenzamide (39 mg, 0.25 mmol) in anhydrous 1,4-dioxane, that had been previously degassed with nitrogen, was heated at 160° C. in the microwave for 15 min. At this time, the crude reaction was adsorbed to silica gel and purified by LC (DCM to 5% MeOH/DCM) to afford the product (28.3 mg, 61%) as a white solid. ESIMS (M+H)+=555. 1H NMR (400 MHz, DMSO-d6) δ 6.63-6.67 (m, 1H), 7.09-7.24 (m, 4H), 7.29-7.49 (m, 3H), 7.54-7.61 (m, 1H), 7.68-7.72 (m, 1H), 7.81 (s, 1H), 7.90-7.94 (m, 1H), 8.04 (m, 1H), 8.09 (m, 1H), 8.53-8.54 (m, 1H), 8.87-8.89 (m, 1H), 9.91 (s, 1H), 10.84 (s, 1H); ESIMS (M+H)+=555.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:12])[CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1>ClCCl>[C:1]([O:5][C:6]([N:8]([CH3:12])[CH2:9][CH2:10][NH:11][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Product: CN(CCNC(=O)CCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a well stirred solution of N-(tert-Butoxycarbonyl)-N-methyl-ethylenediamine 101 (5.5 g, 0.032 mol) in dichloromethane (CH2Cl2, 30 mL) was added succinic anhydride 102 (3.2 g, 0.032 mol) in one portion. After stirring the reaction mixture for 1 hour at room temperature, a slurry resulted. This slurry was used in Step 2 without further work-up.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([OH:25])[CH:19]=2)=[O:15])=[O:6])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34]O)[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH2:34][CH2:33][N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)[CH:19]=2)=[O:15])=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1CCCCC1NC(=O)c1cc2ccc(O)cc2[nH]1
Reactant: CN1CCN(CCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCN(CCOc2ccc3cc(C(=O)NC4CCCCC4C(=O)NCC#N)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To 85 mg (0.25 mM) 6-Hydroxy-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide in 5 ml dichloromethane at 0° C. was added 144 mg (1 mM) 2-(4-Methyl-piperazin-1-yl)-ethanol, 262 mg (1 mM) triphenylphosphine and 131 mg (0.75 mM) DEAD. After several hours the mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was purified directly on a preparative TLC plate and eluted with 10% methanol/dichloromethane. The product was then partitioned between 1 M HCl and ethyl acetate, the aqueous layer was neutralized and extracted with ethyl acetate, dried over magnesium sulfate and stripped to give 18.9 mg 6-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 10C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H), 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.02 (d, J=1.3 Hz, 1H), 7.96-8.01 (m, 1H), 7.88-7.92 (m, 1H), 7.09-7.21 (m, 3H), 3.80-3.83 (m, 4H), 3.73 (s, 2H), 3.08-3.10 (m, 4H); MS (APCI+) M/Z 401 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:21][F:22])([CH3:20])[CH:4]([OH:19])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:19][CH:4]([C:3]([CH2:21][F:22])([CH2:2][F:1])[CH3:20])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)(=[O:25])[CH3:24]
Reactant: CC(CF)(CF)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC(C(Oc1ccc(Cl)cc1)n1cncn1)C(C)(CF)CF
Temperature: 100 °C
Reaction time: 16 h

Procedure:
112 g (0.328 mol) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-butan-2-ol (as the diastereomeric mixture of the pure forms A and B) were dissolved in 500 ml of acetic anhydride. The solution was stirred at 100° C. for 16 hours, the excess acetic anhydride was distilled off in vacuo and the residue was taken up in 600 ml of methylene chloride. The organic phase was washed twice with 1.5 liters of water each time, dried over sodium sulphate and concentrated. The oily residue was subjected to fractional crystallization in diisopropyl ether. 48 g (38% of theory) of the A-form (Compound 1a) of 2-acetoxy-3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-butane of melting point 130°-133° C. and 20.5 g (16% of theory) of the B-form (Compound 1b) of 2-acetoxy-3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-butane of melting point 98° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([Mg]Br)[CH:19]=[CH2:20].Cl>O1CCCC1>[CH2:1]([O:8][C:9]([C:11]1[O:12][C:13]([CH:16]([OH:17])[C:19]([CH3:20])=[CH2:18])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC[Mg]Br
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)o1
Agent: Cl
Solvent: C1CCOC1
Product: C=C(C)C(O)c1ccc(C(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
5-Formyl-2-furancarboxylic acid benzyl ester (300 mg, 1.30 mmol) was dissolved in tetrahydrofuran (12 mL), 2-propenylmagnesium bromide (0.5 mol/L tetrahydrofuran solution, 2.6 mL, 1.3 mmol) was added at −78° C., and the mixture was stirred for 15 minutes. 1N Hydrochloric acid was added to the reaction mixture, the mixture was heated to room temperature and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give the title compound (332 mg, 1.23 mmol, 94%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[N:16](COCC[Si](C)(C)C)[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])=[C:8]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:7]=1)(=[O:3])[NH2:2].CCO.C(O)(C(F)(F)F)=O.C(O)CC>C(Cl)Cl>[C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])=[C:8]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:7]=1)(=[O:3])[NH2:2]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CCC(N)=O)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: CCO
Solvent: CCCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(CCC(N)=O)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(2-carbamoyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as prepared in the previous step, 150 mg, 0.304 mmol) in 2 mL of DCM was added 60 μL of EtOH followed by 1 mL of TFA. The resulting solution was stirred at RT for 3 h. The reaction was treated with 20 mL of n-propanol and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (2-5% MeOH/DCM) to afford 86.1 mg (78%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.08 (d, 1H, J=8.3 Hz), 8.00 (s, 1H), 7.14 (dd, 1H, J=8.3, 2.2 Hz), 7.06 (d, 1H, J=2.2 Hz), 5.79 (m, 1H), 2.89 (t, 2H, J=7.7 Hz), 2.50 (t, 2H, J=7.7 Hz), 2.20-2.30 (m, 4H), 1.72-1.88 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H21N5O2, 364.2 (M+H). found 364.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[NH2:24].FC1C=CC(B(O)O)=CC=1>>[NH2:1][C:2]1[C:7]([C:8]2[NH:17][C:18]3[CH:19]=[C:20]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:21]=[CH:22][C:23]=3[N:24]=2)=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Agent: Nc1ncc(-c2ccc(F)cc2)cc1C=O
Agent: OB(O)c1ccc(F)cc1
Product: Nc1ncc(-c2ccc(F)cc2)cc1-c1nc2ccc(S(N)(=O)=O)cc2[nH]1

Procedure:
The title compound was synthesized using the procedure of step (c) in Example 13 except that 2-amino-5-(4-fluorophenyl)pyridin-3-carboxaldehyde and 3,4-diaminobenzene-1-sulfonamide were utilized. The 2-amino-5-(4-fluorophenyl)pyridin-3-carboxaldehyde was synthesized according to step (b) of example 13, using 4-fluorophenylboronic acid.
Reaction SMILES: CS(C)=O.[C:5]([N:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>C(N(CC)CC)C>[O:16]=[C:14]1[CH2:15][N:12]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: 50 °C
Yield: 61.7 %

Procedure:
A DMSO (10 mL) solution of a sulfur trioxide-pyridine complex (2.2 g; Ald) was added to a triethylamine (4 mL) solution of 1-Boc-3-(hydroxy)azetidine (500 mg; CNH) at room temperature and the resulting mixture was stirred 50° C. for 2 and half hours. The resulting mixture was stirred for approx. 10 minutes at room temperature, then the reaction mixture was poured into ice water (40 mL) and extracted with ethyl acetate (40 mL), the organic layer was dried, and the solvent was evaporated under reduced pressure to give the title compound (305 mg).