Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][CH2:20][NH:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)C>C(Cl)(Cl)Cl.CCCCCC>[C:22]([NH:21][CH2:20][CH2:19][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: BrCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 41.8 %

Procedure:
To a solution of tert-butyl 2-aminoethylcarbamate (4.81 g) in dehydrated chloroform (10 ml) were added sodium carbonate (1.06 g) and N-(2-bromoethyl)tritylamine (3.66 g), and the mixture was stirred under reflux for 3 hours. To the reaction mixture were added diethyl ether and hexane, and the solution was washed with water. The mixture was extracted with 5% aqueous citric acid solution, and the aqueous layer was washed with diethyl ether. The aqueous layer was then made alkaline with sodium hydrogencarbonate followed by extraction with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 2-{[2-(tritylamino)ethyl]amino}ethylcarbamate (1.86 g) as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:11])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](/[N:8]=[CH:14]/[N:15]([CH3:17])[CH3:16])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc(Br)cc1F
Product: CN(C)/C=N/C(=O)c1ccc(Br)cc1F
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 95.5 %

Procedure:
A suspension of 4-bromo-2-fluorobenzamide (0.929 g, 4.26 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (1.66 mL, 11.7 mmol) in a round bottom flask topped with a short path distillation head was heated to 100-100° C. The resulting solution was allowed to stir at this temperature for 3.5 hours, during which time the MeOH that was formed was collected from the distillation condenser. Heptane (5 mL) was added dropwise and the resulting suspension was cooled to 0-5° C. The solids were collected by vacuum filtration, rinsed with excess heptane, and dried to afford (E)-4-bromo-N-((dimethylamino)methylene)-2-fluorobenzamide (1.111 g, 96%) as an off-white solid which was carried on without further purification.
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([OH:26])=[O:25])=[C:6]([CH2:9][S:10][C:11]3[S:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=4)=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH2:41]([O:43]/[N:44]=[C:45](/[C:49]1[N:50]=[C:51]([NH:54]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:52][CH:53]=1)\[C:46](Cl)=[O:47])[CH3:42].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:45](=[N:44]/[O:43][CH2:41][CH3:42])/[C:46]([NH:1][CH:2]2[C:27](=[O:28])[N:4]3[C:5]([C:24]([OH:26])=[O:25])=[C:6]([CH2:9][S:10][C:11]4[S:15][C:14]([C:16]5[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=5)=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:47])[N:50]=1
Reactant: CCO/N=C(\C(=O)Cl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(-c4ccc(O)c(O)c4)s3)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(-c4ccc(O)c(O)c4)s3)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C
Yield: 7 %

Procedure:
1 equivalent of 7-amino-3-[2-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-5-ylthiomethyl]ceph-3-em-4-carboxylic acid was silylated with 4 equivalents of bistrimethylsilylacetamide in anhydrous dichloromethane at room temperature for three hours. To this solution, cooled to 0° C. under argon, was added 1 equivalent of 2-[(Z)-ethoxyimino-2-(tritylaminothiazol-4-yl) acetic acid chloride (prepared from the corresponding acid (1 equivalent), 1 equivalent PCl5 and 1 equivalent TEA in dichloromethane at 0° C. for 2 hours followed by evaporation of the solvent and all POCl3, and redissolution in dichloromethane). After a few minutes at 0° C., the solvent was evaporated, and all the protecting groups removed by treating the crude reaction mixture with TFA/water for 1 hour at room temperature. The solvents were evaporated and the crude product dissolved in MeOH and precipitated in ether. Further purification was achieved by MPLC, to yield the title compound (7%), NMR (DMSOd6, AcOD, TFA): 1.25 (t,3H); 3.7 (m,2H); 4.2 and 4.25 (2d,2H); 4.4 (q,2H); 5.15 (d,1H); 5.75 (d,1H); 6.85 (d,1H); 7 (s,1H); 7.15 (d,1H); 7.3 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:24][C:25]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1)[CH3:23]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:25]3([O:24][CH2:22][CH3:23])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCOC1=CCCCCCC1
Product: CCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCCC1
Yield: 46.4 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1-ethoxycyclooctene (1.61 g, 10 mmol) in the same manner as the example 20 to give the compound 31 (232 mg, 46%). Rf 0.54 (Al2O3 hexane-EtOAc 4:1) PMR (CDCl3 -0.1% d5 -Py): δH1.06 (3 H, d, J 7 Hz), 1.37-1.80 (14 H, m), 3.00 (2 H, t, J 6 Hz, CH2 -Im), 3.00 (2 H, t, J 6 Hz, CH2 -Im), 3.07 (2 H, q, J 7 Hz, OCH2), 3.10 (1 H, s, J 7 Hz, (CH3)2CH), 3.51 (3 H, s, NCH.3), 3.68 (2 H, t, J 6.2 Hz, OCH2), 6.82 (2 H, d, J 1.8 Hz, arom-H), 7.11 (1 H, t-like, arom-H) Elementary analysis (for C25H36N2O2Cl2S) Calcd. : C, 60.11% H, 7.26% N, 5.61% S, 6.42% Cl, 14.19% Found: C, 59.91% H, 7.36% N, 5.74% S, 6.23% Cl, 13.88%
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=O)[N:7]=1.[NH2:11][C@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@H:12]([NH:11][C:8]([C:6]3[N:7]=[C:3]([NH:2][CH3:1])[S:4][CH:5]=3)=[O:10])[CH3:28])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: CNc1nc(C(=O)O)cs1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CNc1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 9.08 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(methylamino)thiazole-4-carboxylic acid (0.34 g, 2.149 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.467 g, 1.791 mmol). The product was purified by Flash-chromatography. Yield 9.08%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 2.85 (d, 3H), 4.30-4.42 (m, 3H), 6.96 (d, 1H), 7.18 (d, 1H), 7.59 (d, 1H), 7.84 (d, 1H), 7.91 (d, 1H), 7.95-7.96 (m, 2H), 8.08 (dd, 1H).
Reaction SMILES: N=C=N.[CH3:4][N:5]([C:9]1[S:10][C:11]([CH3:14])=[CH:12][N:13]=1)[CH2:6][CH2:7][NH2:8].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=1.CN(C1SC=CN=1)CCNC(=O)C#CC1C=CC=C(Cl)C=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24]([NH:8][CH2:7][CH2:6][N:5]([CH3:4])[C:9]2[S:10][C:11]([CH3:14])=[CH:12][N:13]=2)=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)C#Cc1cccc(Cl)c1
Reactant: Cc1cnc(N(C)CCN)s1
Agent: CN(CCNC(=O)C#Cc1cccc(Cl)c1)c1nccs1
Agent: N=C=N
Solvent: ClCCl
Product: Cc1cnc(N(C)CCNC(=O)C#Cc2cccc(Cl)c2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.19 g (˜2.6 mmol) of PS carbodiimide were added to a solution of 232 mg (1.35 mmol) of N1-methyl-N1-(5-methylthiazol-2-yl)ethane-1,2-diamine and 367 mg (2.03 mmol) of (3-chlorophenyl)propiolic acid in DCM (40 ml). The mixture was then shaken for 16 h at RT, after which the resin was filtered out and rinsed with DCM and EtOH. The filtrate was evaporated under a vacuum and CC (DCE/EtOH 5:1) was carried out with the residue, 169 mg (0.51 mmol, 37%) of N-(2-(methyl(thiazol-2-yl)amino)ethyl)-3-(3-chlorophenyl)-propiolamide being obtained. MS [MH+] 334.1
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]1[NH:56][N:57]=[C:58]([C:60](O)=[O:61])[CH:59]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:58]2[N:57]=[N:56][NH:55][CH:59]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(O)c1cn[nH]n1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2c[nH]nn2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 48 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2H-1,2,3-triazole-4-carboxylic acid as starting materials in 48% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.12 (s, 1H), 9.41 (m, 2H), 9.15 (s, 1H), 8.32 (m, 2H), 8.21 (m, 2H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.52 (m, 2H), 3.19 (m, 2H), 2.99 (m, 4H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C27H28ClN10O2 (M+H)+: m/z=559.2.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@@H:11]2[CH2:16][C@H:15]([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13][C@@H:12]2[N:21]2[CH2:26][CH2:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)=[CH:23][C:22]2=[O:37])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:40]([BH3-])#N.[Na+].O>CO>[C:1]1([S:7]([CH2:10][C@@H:11]2[CH2:16][C@H:15]([N:17]([CH:18]([CH3:20])[CH3:19])[CH3:40])[CH2:14][CH2:13][C@@H:12]2[N:21]2[CH2:26][CH2:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[CH:23][C:22]2=[O:37])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.75 h
Yield: 99.4 %

Procedure:
A solution of 1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one (41 mg, 0.077 mmol) in methanol (1 mL) was treated with aqueous formaldehyde (37%, 0.029 mL, 0.383 mmol) and the mixture was stirred for 45 min. Sodium cyanoborohydride (7 mg, 0.115 mmol) was added, and the mixture stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum to provide the title product (42 mg) as a white glassy solid. MS found: (M+H)+=548.67.
Reaction SMILES: [C:1]([NH:8][C@H](C(O)=O)CC)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=O.[CH2:23]1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:23][C@@H:20]([CH:19]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH3:17])[C:21]([NH2:16])=[O:22]
Reactant: O=C1CCC(=O)N1O
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)[C@H](C)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
BOC-homoalanine (Podlech, J.; Seebach, D. (1995) Liebigs Ann. 1217) (0.44 g, 2.17 mmol) was dissolved in 5 mL methylene chloride. HOSu (376.4 mg, 3.27 mmol) was added and the solution cooled to 0° C. After addition of DCC (587.8 mg, 2.85 mmol) the solution was stirred 1 hour at 0° C., warmed to room temperature and stirred for an additional 2 hours. A stream of methylamine was bubbled through the suspension for 10 minutes, and stirring was continued overnight. The white precipitate was filtered off by suction filtration and the filtrate concentrated to give a pale yellow solid that was purified by chromatography (silica gel, CHCl3/MeOH 19:1) to yield 0.41 g (1.90 mmol, 88%) Of BOC-homoalanine methylamide (18) as a white solid. 1H-NMR (300 MHz, CDCl3) δ 6.11 (b, NH), 5.23 (b, NH), 3.92 (m, 1H), 2.75 (d, J=4.8 Hz, 3H), 2.35 (m, 2H), 1.39 (s, 9H), 1.17 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[NH:22][CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=3)[N:25]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[OH-].[K+]>CS(C)=O.C(Cl)Cl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[N:22]([CH2:3][CH2:4][N:5]([CH3:7])[CH3:6])[CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=3)[N:25]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)c[nH]2)CC1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
Add (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.10 equiv; 579 μmol; 83 mg) in one portion to a mixture of 4-[4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1 equiv; 526 μmol; 200 mg) and powdered KOH (2.5 equiv; 1.316 mmol; 73.8 mg) in DMSO (3 mL). Warm to 50° C. and stir for 2 h. Dilute with DCM, wash with water, brine, dry over MgSO4, filter, evaporate and purify on 40 g silica gel with 10% methanol/ACN to provide the title compound (194 mg; 0.43 mmol; 82%). MS (ES+): m/z=451 (M+H).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:19][C:20]([NH:23][C:24]([CH2:26][O:27]C(=O)C)=[O:25])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:43][Si](C)(C)[N-][Si](C)(C)C.[K+].CI.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([C:17]2[CH:22]=[N:21][C:20]([N:23]([C:24](=[O:25])[CH2:26][OH:27])[CH3:43])=[CH:19][C:18]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH3:38])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)OCC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N(C)C(=O)CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of 70 mg (0.12 mmol) acetic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-ylcarbamoyl)-methyl ester in 4 ml tetrahydrofuran at room temperature under argon were added dropwise 0.13 ml (0.12 mmol) of a 1 M solution of potassium hexamethyldisilazide in tetrahydrofuran. Stirring was continued for 1 h at room temperature and 17 mg (0.12 mmol) methyl iodide were added. After stirring overnight, saturated ammonium chloride solution was added and the aqueous layer was extracted with diethyl ether. The diethyl ether layer was dried with sodium sulfate, evaporated, and the residue was purified by flash-chromatography to give 12 mg (18%) of the title compound as a white solid.
Reaction SMILES: [OH-].C([N+](CC)(CC)CC)C.[O:11]1[CH:17]2[CH:12]1CC(CC[Si](OC)(OC)OC)[CH2:15][CH2:16]2.C(O[Si](OCC)(OCC)[O:31][CH2:32][CH3:33])C.C1([Si](OC)(OC)[O:47]C)C=CC=CC=1>C(OCC)(=O)C.O.C(O)C>[C:32]([O:47][CH:16]([CH3:15])[CH2:17][O:11][CH3:12])(=[O:31])[CH3:33]
Reactant: CO[Si](OC)(OC)c1ccccc1
Reactant: CO[Si](CCC1CCC2OC2C1)(OC)OC
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCC(C)OC(C)=O
Temperature: 40 °C
Yield: 100 %

Procedure:
In a 3000 ml glass flask, 1400 g of ethanol, 700 g of pure water, and 50 g of 25% tetraethylammonium hydroxide were placed, and stirred. To this mixture was added dropwise a mixture of 79 g of 2-(3,4-epoxycyclohexyl) ethyl trimethoxy silane, 70 g of tetraethoxy silane, and 14 g of phenyl trimethoxy silane at a liquid temperature of 40 degrees C. After that, the solution was stirred for 2 hours at 40 degrees C. After the reaction finished, the reaction was quenched by adding 35 g of acetic acid, and ethanol was removed under a reduced pressure. To thus-obtained solution was added 2000 ml of ethyl acetate, and a water layer was separated. An organic layer was washed twice with ultrapure water. To this contents was added 600 g of propylene glycol monomethyl ether acetate (PGMEA), and the contents were heated up to a liquid temperature of 40 degrees C. under a reduced pressure to remove ethyl acetate and to give a PGMEA solution of a polymer.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[C:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]=1[OH:32])([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC=CC=1.CCCCCC>C1(C)C(C)=CC=CC=1>[C:28]([C:24]1[CH:25]=[C:26]([CH:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[CH:27]=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:23]=1[OH:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C1CCNCC1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(C(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N2CCCCC2)cc1

Procedure:
To 30.4 g (0.2 mol) of 4-dimethylaminobenzaldehyde in 100 ml of xylene, 39.1 g (0.46 mol) of piperidine is added dropwise over a period of six minutes. The mixture is heated at reflux using a Dean-Stark trap until the separation of water is complete. To the cooled reaction mixture 40.3 (0.2 mol) of 2,6-di-tert-butylphenol in 70 ml of xylene is added rapidly. The mixture is then heated at reflux for five hours. The title compound is isolated as an almost white solid by evaporation of the solvent and recrystallization from toluene-hexane. The yield is 66.3 g of the title compound, melting at 184°-185° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:18][C:14]1[CH:13]=[C:12]([CH2:11][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)[CH:17]=[CH:16][CH:15]=1.[F:18][C:14]1[CH:13]=[C:12]([CH2:11][N:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1]2)[CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(Cn2nc3ccccc3n2)c1
Product: Fc1cccc(Cn2nnc3ccccc32)c1

Procedure:
In a procedure as in Example 2 but using 1H-benzotriazole (20.6 g, 0.173 mol), 1-(chloromethyl)-3-fluorobenzene (25.0 g, 0.173 mol), K2CO3 (35.9 g) and CH3CN (150 mL) for 1 h gave the title compound and (3-fluorophenyl)methyl-2H-benzotriazole. Similar workup and recrystallization gave the pure 1H-isomer (73%): mp 103°-104° C. (cyclohexane); 1H NMR (270 MHz, CDCl3) δ 5.87 (s, 2H, CH2), 6.97-7.08 (m, 3H), 7.29-7.49 (m, 4H), 8.10 (d, J=8.0 Hz, 1H); Anal. Calcd for C13H10N3F (227.24): C, 68.71; H, 4.44; Found: C, 68.40; H, 4.67.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:27]([C:29]1[C:30]([C:43]([F:46])([F:45])[F:44])=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39](=[NH:42])[NH:40]O)[CH:33]=[CH:32]2)#[N:28]>CC#N>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:42]=[C:39]([CH2:38][N:34]3[C:35]4[C:31](=[C:30]([C:43]([F:46])([F:44])[F:45])[C:29]([C:27]#[N:28])=[CH:37][CH:36]=4)[CH:32]=[CH:33]3)[N:40]=2)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
4-Chloro-3-(trifluoromethyl)benzoic acid (0.016 g, 0.071 mmol) and CDI (0.012 g, 0.071 mmol) were combined in CH3CN (3 mL). 2-[5-Cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.020 g, 0.071 mmol) was added after 5 min. After stirring at rt for 1 h, the reaction was heated at 150° C. in a microwave for 10 min. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.022 g): MS (ESI): m/z 471 (M+1).
Reaction SMILES: [CH2:1]1[C:7]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:3](=[O:4])[CH2:2]1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]2[C:7]=1[CH2:1][CH2:2][C:3](=[O:4])[NH:5]2
Reactant: ClCC1CO1
Reactant: O=C1CCc2c(O)cccc2N1
Product: O=C1CCc2c(cccc2OCC2CO2)N1

Procedure:
5-Hydroxy-3,4-dihydro-2-quinoline (prepared in three steps from cyclohexane-1,3-dione and acrylonitrile) is allowed to react with epichlorohydrin to give 5-(2,3-epoxypropoxy)-3,4-dihydro-2-quinolinone [J. Med. Chem. 17,529 (1974)].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH:29][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: NCCN1CCOCC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCN1CCOCC1)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 75 °C

Procedure:
A mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (300 mg, 1.29 mmol, 1.0 equiv) and thionyl chloride (2.0 ml) was heated at 75° C. for 1 h. The solvent was removed in vacuo and the residue taken up in CH2Cl2 (5.0 ml). To the solution was added 2-morpholinoethanamine (185 mg, 1.42 mmol, 1.1 equiv) and triethylamine (0.54 ml, 3.86 mmol, 3.0 equiv). After the reaction was complete, the solution was diluted with CH2Cl2 (ca. 10 ml) and washed with water and brine. After drying with Na2SO4 and concentration in vacuo, the resulting N-(2-morpholinoethyl)-3-nitro-5-(trifluoromethyl)benzamide was advanced without further purification. MS m/z: 348 (M+H+); Calculated for C14H16F3N3O4: 347.1
Reaction SMILES: ClC(C[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)C=O.[NH2:12]C(N)=S.[CH2:16]([OH:18])C>>[CH3:16][O:18][C:7]1[C:6]([NH2:12])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: NC(N)=S
Reactant: O=CC(Cl)Cc1cccnc1
Reactant: CCO
Product: COc1ncccc1N

Procedure:
A mixture of 2-chloro-3-pyridin-3-yl-propionaldehyde (crude from above) and thiourea (14.8 g, 0.194 mol) in ethanol (200 mL) was heated to reflux overnight. The solvent was removed and the residue was diluted with dichoromethane (1.2 L) and then washed with sodium hydroxide (10% aqueous solution, 400 mL) and water (200 mL). The organic layer was extracted three times with hydrochloric acid (5% aqueous solution, 400 mL) and the combined aqueous layer was brought to between pH 9 and 10 with sodium hydroxide (10% aqueous solution). The resulting precipitate was filtered to give the crude product, which was recrystallized, from ethyl acetate and hexanes to give the pure product (5.1 g, 0.023 mol, 5.6% from 2-methoxy-pyridin-3-ylamine). ESI-MS m/z calc. 221.1. found 222.2 (M+1)+.