Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:3]1.O[N:30]=[C:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[CH3:33][CH:32]([C:31]1[N:35]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:4]3[CH2:5][CH2:6][NH:7][C:2](=[O:1])[CH2:3]3)=[O:9])[CH2:11]2)[O:27][N:30]=1)[CH3:34]
Reactant: O=C1CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCN1
Reactant: CC(C)C(N)=NO
Product: CC(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCNC(=O)C3)C2)n1

Procedure:
250 mg (0.626 mmol) of 1-[(3-oxopiperazin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]-piperidine-3-carboxylic acid (Example 206A) and 70.3 mg (0.689 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 1. Yield: 190 mg (62% of theory).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O1CCCCC1ONC([C@H]([C@@H](CC(C)C)C(NNS(C)(=O)=O)=O)C/C=C/C1C=CC=CC=1)=O.[N+](C1C=CC(CBr)=CC=1)([O-])=O>>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([S:36]([CH3:39])(=[O:37])=[O:38])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(Cc1ccc([N+](=O)[O-])cc1)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: O=[N+]([O-])c1ccc(CBr)cc1
Product: CC(C)C[C@@H](C(=O)NN(Cc1ccc([N+](=O)[O-])cc1)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
The (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-(4-nitrobenzyl)valerohydrazide used as the starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-(2R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide by reaction with 4-nitrobenzyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH2:27])=O)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]#[N:27])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[N:16][CH:15]=[N:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cc3cccc(C(N)=O)n3)c(-c3cncnc3)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3cccc(C#N)n3)c(-c3cncnc3)[nH]c2c1
Yield: 97.8 %

Procedure:
To a suspension of 6-(6-methoxy-2-pyrimidin-5-yl-1H-indol-3-ylmethyl)pyridine-2-carboxamide (351 mg) in N,N-dimethylformamide (9.8 mL) was added phosphoryl chloride (0.133 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 3 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate and water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: methanol-ethyl acetate) to obtain the title compound (326 mg). 1H-NMR (CDCl3) δ ppm: 3.87 (3H, s), 4.40 (2H, s), 6.81 (1H, dd, J=2.3, 8.5 Hz), 6.90-6.95 (1H, m), 7.30-7.39 (2H, m), 7.50-7.57 (1H, m), 7.64-7.72 (1H, m), 8.20 (1H, br s), 9.00 (2H, s), 9.20 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:20]=2[CH3:28])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:56]1[CH2:61][CH2:60][CH:59]([N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)[CH2:58][CH2:57]1.[Li+].[Cl-]>CN(C=O)C.C(Cl)(Cl)Cl.C(O)(C)C>[CH3:28][C:20]1[C:21]([C:25]([N:56]2[CH2:61][CH2:60][CH:59]([N:62]3[CH2:67][CH2:66][O:65][CH2:64][CH2:63]3)[CH2:58][CH2:57]2)=[O:27])=[C:22]([CH3:24])[NH:23][C:19]=1/[CH:18]=[C:10]1\[C:11](=[O:17])[NH:12][C:13]2[C:9]\1=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH:16]=[CH:15][CH:14]=2
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)O
Reactant: C1CC(N2CCOCC2)CCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)N1CCC(N2CCOCC2)CC1
Reaction time: 48 h

Procedure:
5-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1 eq.) and BOP (1.25 eq.) were suspended in DMF (5 mL) at rt and TEA (2.4 eq.) was added. After 15 mina, to the homogenous reaction mixture was added 4-piperidin-4-yl-morpholine (1.25 eq.) all at once. After stirring for 2 days, the reaction was added to a mixture of chloroform-isopropanol (5:1) and 5% aq. LiCl. The organic layer was separated, washed with 5% aq. LiCl (2×), 1M aq. NaOH (3×), brine, dried and concentrated. The residue was purified to give the titled compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([O:7][CH2:8][CH2:9][SH:10])[O:3][CH2:4][CH2:5][SH:6].C(N(CC)CC)C.ClC([SiH2][C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1)Cl.SCCO>CCOCC>[CH3:1][Si:2]([C:11]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1)([O:3][CH2:4][CH2:5][SH:6])[O:7][CH2:8][CH2:9][SH:10]
Reactant: C[Si](C)(OCCS)OCCS
Reactant: ClC(Cl)[SiH2]c1ccccc1
Agent: OCCS
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](OCCS)(OCCS)c1ccccc1

Procedure:
The 2-[methyl-phenyl-(2-sulfanylethoxy)silyl]oxyethanethiol (4) composition was synthesized according to the same procedure as 2-[dimethyl(2-sulfanylethoxy)silyl]oxyethanethiol (1), using triethylamine (5.02 g, 0.050 mol), dichloromethylphenylsilane (4.74 g, 0.025 mol), and 2-mercaptoethanol (3.88 g, 0.050 mol) in ether (500 mL). The 2-[methyl-phenyl-(2-sulfanylethoxy)silyl]oxyethanethiol (4) composition was obtained as a clear, colorless, foul-smelling liquid (6.30 g, 92.6%). The product was purified by distillation under reduced pressure and obtained as a clear, colorless, foul-smelling liquid (3.70 g, 54.4%), Bp=140-142° C. at 0.50 mmHg.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]3)[CH2:13][CH2:14]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccc(F)cc1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(F)cc1
Yield: 74 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-fluoro-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 74% of theory; Mass spectrum (ESI+): m/z=366 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].[N+:23]([O-])([N+]([O-])=O)=[O:24]>>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 62.3 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-mannopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(D-mannopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: Cl.Cl.Cl.Cl.[C@H:5]12[CH2:11][C@H:8]([CH2:9][CH2:10]1)[C@@H:7]([C:12]1[NH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[CH:29]=[C:28]([C:33]4[NH:37][C:36]([C@@H:38]6[CH2:44][C:41]7([CH2:43][CH2:42]7)[CH2:40][N:39]6[C:45](=[O:55])[C@@H:46]([NH:50][C:51](=[O:54])[O:52][CH3:53])[CH:47]([CH3:49])[CH3:48])=[N:35][CH:34]=4)[CH:27]=[CH:26]5)=[CH:19][CH:18]=3)=[CH:15][N:16]=1)[NH:6]2.[F:56][CH:57]([F:70])[O:58][CH2:59][CH2:60][C@H:61]([NH:65][C:66]([O:68][CH3:69])=[O:67])[C:62](O)=[O:63].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.CN1CCOCC1>CN(C)C=O>[CH3:53][O:52][C:51](=[O:54])[NH:50][C@@H:46]([CH:47]([CH3:49])[CH3:48])[C:45]([N:39]1[C@H:38]([C:36]2[NH:37][C:33]([C:28]3[CH:27]=[CH:26][C:25]4[C:30](=[CH:31][CH:32]=[C:23]([C:20]5[CH:19]=[CH:18][C:17]([C:14]6[NH:13][C:12]([C@@H:7]7[C@@H:8]8[CH2:11][C@@H:5]([CH2:10][CH2:9]8)[N:6]7[C:62](=[O:63])[C@@H:61]([NH:65][C:66]([O:68][CH3:69])=[O:67])[CH2:60][CH2:59][O:58][CH:57]([F:70])[F:56])=[N:16][CH:15]=6)=[CH:22][CH:21]=5)[CH:24]=4)[CH:29]=3)=[CH:34][N:35]=2)[CH2:44][C:41]2([CH2:42][CH2:43]2)[CH2:40]1)=[O:55]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CC2)C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@H]6N[C@@H]7CC[C@H]6C7)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](CCOC(F)F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)N[C@@H](CCOC(F)F)C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CC7(CC7)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl (S)-1-((S)-6-(5-(6-(4-(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate tetrahydrochloride (66 mg, 0.096 mmol), (S)-4-(difluoromethoxy)-2-(methoxycarbonylamino)butanoic acid (20 mg, 0.088 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (24 mg, and hydroxybenzotriazole hydrate (HOBt)(17 mg, 0.125 mmol) were all weighed out in a flask and anhydrous N,N-dimethylformamide (1 mL) was added. The mixture was cooled down in an ice bath to 0° C. and N-methylmorpholine (NMM) (58 mg, 0.576 mmol) was added from a syringe to the mixture. The reaction content was stirred for 4 hours at room temperature. The resulting mixture was then directly purified on reverse phase prep. HPLC. 37 mg, (43%). 1H-NMR: 400 MHz, (CD3OD) δ 8.08 (s, 1H), 8.01 (d, J=16 Hz, 1H), 7.86-7.66 (m, 10H), 7.38 (s, 1H), 7.27 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.58 (t, J=75.6 Hz, 1H), 5.32 (t, J=7.2 Hz, 1H), 4.70 (s, 1H), 6.66-6.25 (m, 1H), 4.51 (s, 1H), 4.14 (m, 1H), 3.98-3.78 (m, 4H), 3.63 (s, 6H), 3.50-3.46 (m, 1H), 2.70 (brs, 1H), 2.39-1.78 (m, 7H), 1.71-1.40 (m, 2H), 0.99-0.90 (m, 5H), 0.82-0.60 (m, 4H). MS (ESI) m/z 894.16 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([CH2:7][C:8]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[CH2:10][CH2:9]1)([OH:6])CO.I([O-])(=O)(=O)=O.[Na+]>CO>[F:21][C:2]([F:1])([F:20])[C:3](=[O:6])[CH2:7][C:8]1([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])[CH2:9][CH2:10]1
Reactant: COc1ccc(F)cc1C1(CC(O)(CO)C(F)(F)F)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: COc1ccc(F)cc1C1(CC(=O)C(F)(F)F)CC1
Reaction time: 7 h
Yield: 71.7 %

Procedure:
To a solution of 310 mg (1.01 mmol) of 3,3,3-trifluoro-2-[1-(5-fluoro-2-methoxyphenyl)cyclopropylmethyl]propane-1,2-diol in 15 mL of MeOH was added 1.5 g (7.01 mmol) of sodium periodate. After 7 hours, the mixture was concentrated and the residue diluted with hexanes and filtered through diatomaceous earth. The crude residue was chromatographed on silica gel using hexanes to load the sample and then eluting with EtOAc-hexanes (0:100, then 0.25:99.75, then 0.5:99.5, then 1:99) to afford 200 mg of the title compound as a clear oil. The following trifluoromethyl ketones were also prepared by the method of Example 25:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([F:12])=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)cc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)c(F)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
5-Bromo-4-fluoro-2-hydroxybenzoic acid (I-227) (34.39 g, 0.146 mol) was dissolved in concentrated sulfuric acid (260 ml), and cooled at 0° C. At the same temperature, fuming nitric acid (d=1.52) (6.67 ml, 0.161 mol) was dropwise added with keeping the inner temperature at 0° C. or lower (about 20 minutes). After the addition, the disappearance of the starting material was confirmed by TLC, then the reaction liquid was gradually poured into ice. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and the solvent was evaporated away. N-hexane was added to the residue, the crystal was ground, the suspension was stirred at room temperature for 1 hour (optionally with sonication). The crystal was washed with n-hexane, followed by filtration and drying to obtain the entitled compound (33.82 g, 83%) as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:35]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
Combine 4-(2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (100 g, 231 mmol), ammonium acetate (178.3 g; 2.31 mol, 10 eq), and methanol (1000 mL). The reactor used for this transformation is a coiled 1/16″ I.D. stainless steel tube (total internal volume of tubing in oven is 541 mol). Heat the reactor in an oven to 140° C. Control the back pressure in this tube at 250 psig by a regulator to allow super-heating of the solution above its normal boiling point. Pump the solution prepared above continuously through the heated tube under pressure at 6.01 mL/min (affording a total residence time in the heated tube of 90 minutes). As the solution exits the oven, cool it back to 20° C. in a tube-in-tube heat exchanger. Once the entire solution process through the reactor (8 hours total processing time), concentrate the resulting orange solution under vacuum at 30° C. to a total volume of 600 mL. Add ACN (200 mL) and heat the solution to 50° C. Add water (700 mL) drop wise with seeding over 2 hours to crystallize the product. Cool the resulting slurry to 20° C. and filter the solid, then wash with 20% MeOH in water (2×200 mL). Dry the resulting solid under vacuum at 50° C. Re-slurry the solid in ACN (200 mL) at 50° C. Cool the slurry to ambient temperature, filter the solid and wash with ACN (100 mL) to afford 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (54.43 g, 132 mmol, 57%) as an off white solid. 1H NMR (300 MHz, DMSO): 12.01 (s, 1H), 8.08-8.04 (m, 2H), 7.70 (d, J=1.4 Hz, 1H), 7.49-7.43 (m, 1H), 3.99 (d, J=12.6 Hz, 2H), 2.92-2.85 (m, 3H), 1.91-1.87 (m, 2H), 1.64-1.51 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([CH3:10])[N:3]=1>CCO.O.[Pd]>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]([NH2:9])=[CH:6][N:7]=1
Reactant: Cc1nc(Cl)nc(Cl)c1N
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1nc(Cl)ncc1N
Reaction time: 8 h
Yield: 19.8 %

Procedure:
2,4-Dichloro-6-methylpyrimidin-5-amine (1.0 g, 5.62 mmol) was dissolved in anhydrous EtOH (3.5 mL) and H2O (7.0 mL). MgO (1.40 g, 34.74 mmol) and 10% Pd/C (35 mg) were added to the reaction mixture which was hydrogenated at 1 atm, at room temperature, overnight. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH/CH2Cl2 gradient, 0-15% MeOH) to afford 2-chloro-4-methylpyrimidin-5-amine as light pink solid (0.16 g, 20%).
Reaction SMILES: C(N1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)CC1)(C)C.[CH3:26][O:27][CH2:28][CH2:29]Br.[H-].[Na+]>>[CH2:7]([O:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]3[CH2:20][CH2:21][CH2:22][N:23]([CH2:29][CH2:28][O:27][CH3:26])[C:24](=[O:25])[C:15]3=[CH:14][C:13]=2[CH:12]=1)[C:8]1[CH:9]=[CH:13][CH:12]=[CH:11][CH:19]=1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCNC2=O)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCN1CCCn2c(cc3cc(OCc4ccccc4)ccc32)C1=O

Procedure:
The title compound was synthesized in analogy to example 17, from 9-benzyloxy-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (example 15, intermediate b)), 2-bromoethyl methyl ether and sodium hydride, to give the compound as a white solid (77%).
Reaction SMILES: C(NC([C:8]1[CH:25]=[CH:24][C:11]2[NH:12][C:13]([C:15]3[C:23]4[C:18](=CC=CC=4)[NH:17][N:16]=3)=[N:14][C:10]=2[CH:9]=1)=O)C(C)C.C1(N)C=CC=CC=1N.S(=O)(O)[O-].[Na+]>CN(C)C=O>[NH:17]1[CH:18]=[CH:23][C:15]([C:13]2[NH:12][C:11]3[CH:24]=[CH:25][CH:8]=[CH:9][C:10]=3[N:14]=2)=[N:16]1
Reactant: CC(C)CNC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Agent: Nc1ccccc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(-c3cc[nH]n3)nc2c1
Temperature: 25 °C
Yield: 121.5 %

Procedure:
A mixture of 1H-pyrazole-3-carbaldehyde (0.961 g, Reference Example 10), o-phenylenediamine (0.973 g), sodium bisulfite (1.898 g) and dry dimethylformamide (10 mL) was stirred at reflux for 2 hours, then cooled to room temperature and then poured onto cracked ice (35 g). The mixture was filtered and the solid was washed with aqueous sodium bicarbonate and then with water. The solid was vacuum dried at 70° C. and then recrystallised from ethanol to give 2-(1H-pyrazol-3yl)-1H-benzoimidazole (0.645 g) as a pale yellowish solid, mp 335-338° C. [Elemental analysis: C, 62.56%; H, 4.04%; N, 29.14%. Calculated for C10H8N4: C, 65.19%; H, 4.39%; N, 30.42%]. (b) 3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-5-methoxy-1H-indazole
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([N:14]([CH2:17][CH3:18])[C:12]1[C:11]([C:19]#[N:20])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)c1cc2c(cc1C#N)NC(=O)CC(c1cccc(-c3cc(C)no3)c1)=N2

Procedure:
The title compound was prepared from (4-cyano-5-diethylamino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M94) (0.35 g, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (209 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@@H:24]3[C@H:29]([C:30]([OH:32])=O)[CH2:28][CH:27]=[CH:26][CH2:25]3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:33][N:34]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C)C=O>[OH:33][NH:34][C:30]([C@H:29]1[C@@H:24]([NH:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:19][CH:18]=2)(=[O:21])=[O:22])[CH2:25][CH:26]=[CH:27][CH2:28]1)=[O:32]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CC=CC[C@H]3C(=O)O)cc2)c2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CC=CC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.4 %

Procedure:
To a solution of 181.0 mg (0.4 mmol) of cis-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylic acid and 162.2 mg (1.2 mmol) of 1-hydroxybenzotriazole in 3 mL of N,N-dimethylformamide at 0° C. was added 230.0 mg (1.2 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 1.5 h. To the reaction mixture at 0° C. was added 0.2 mL of 50% hydroxylamine solution. The resulting reaction mixture was stirred at room temperature for 18 h. The volatile materials were removed under reduced pressure, below 40° C. The residue was dissolved in 80 mL of ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution (5×30 mL) and a saturated sodium chloride solution (2×30 mL) and dried over sodium sulfate. After removal of the ethyl acetate, the residue was triturated with a 7:3 mixture of hexane:ethyl acetate to give 71.9 mg of cis-N-hydroxy-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxamide as a solid in 38% yield. MS: 468.1 (M+H)+
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C)C=O.S(Cl)([Cl:73])=O>ClCCl>[CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23][Cl:73])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
Under an argon atmosphere, 3,4,5-tris(octadecyloxy)benzyl alcohol (10.0 g, 11.0 mmol) was dissolved in dichloromethane (100 mL), N,N-dimethylformamide (84.0 μL, 1.10 mmol) and thionyl chloride (1.20 ml, 16.4 mmol) were added, and the mixture was stirred at 30° C. for 90 min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, acetonitrile was added, and the precipitated solid was filtered. The obtained solid was dried under reduced pressure to give the title compound (10.0 g, 98.2%) as a white solid.