Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:32]1[CH:31]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([F:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:35]=[C:34]([CH3:36])[N:33]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(F)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-fluoro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M220) (291 mg, 0.533 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (169 mg, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Br:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24](O)=[O:25].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.[Cl-].[Na+].O>[Br:13][C:12]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:24](=[O:25])[CH2:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][CH3:15])[CH:7]=[CH:6][CH:5]=2)=[N:9][N:10]([CH3:14])[CH:11]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccccc1CC(=O)Nc1cccc(-c2nn(C)cc2Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.5 %

Procedure:
A mixture of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (30 mg, 0.12 mmol), 2-methoxyphenylacetic acid (20 mg, 0.12 mmol), 1-hydroxybenzotriazole hydrate (16 mg, 0.12 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) were dissolved in chloroform (1.5 ml). N,N-Diisopropylethylamine (0.02 ml, 0.13 mmol) was added and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured into brine and the organic layer washed with further brine, dried over magnesium sulphate and then concentrated in vacuo. The crude product was purified by column chromatography (chloroform-methanol, 99:1), giving the title compound (18 mg, 38%) as a colourless solid. Rf 0.65 (chloroform-methanol, 98:2).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([C@H:13]([NH:15]C(=O)C)[CH3:14])=[CH:8][C:7]=1[O:19][CH3:20])(=O)C>CCO>[ClH:12].[NH2:15][C@@H:13]([C:9]1[C:10]([Cl:12])=[CH:11][C:6]([OH:5])=[C:7]([O:19][CH3:20])[CH:8]=1)[CH3:14]
Reactant: COc1cc([C@@H](C)NC(C)=O)c(Cl)cc1OC(C)=O
Agent: Cl
Solvent: CCO
Product: COc1cc([C@@H](C)N)c(Cl)cc1O
Temperature: 25 °C
Yield: 121 %

Procedure:
37% Hydrochloric acid (20 ml) was added to a solution of (R)-4-(1-acetamidoethyl)-5-chloro-2-methoxyphenyl acetate (2.40 g, 8.4 mmol) in EtOH (80 ml) and the mixture was refluxed for 48 hours. The reaction mixture was cooled to room temperature, washed with DCM 3 times, and the aqueous layer was evaporated under reduced pressure. The residue was dissolved in diisopropyl ether and the precipitate was collected by filtration. The solid was washed with DCM and dried in vacuo to give the title compound (1.21 g, 60%) as white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.49 (3H, d, J=6.6 Hz), 3.82 (3H, s), 4.55 (1H, m), 6.91 (1H, s), 7.54 (1H, s), 8.76 (3H, br. s), 9.87 (1H, br. s). MS (ESI) m/z not observed M+ peak.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:44][C@@H:45]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]([F:68])([F:67])[F:66])[CH2:46][N:47]1[C:55](=[O:56])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]1=[O:57]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:44][C@@H:45]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:66])[F:67])[CH2:46][N:47]2[C:55](=[O:56])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]2=[O:57])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1ccc(Br)cn1
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-pyridinecarboxylic acid (97 mg, 2.6 mmol), PyBrOP (269 mg, 0.578 mmol) and diisopropylethyl amine (419 uL, 2.41 mmol) in DCM (5 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (168 mg, 0.481 mmol)[prepared in preparation 3]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fraction were dried (Na2SO4), concentrated and used directly without further purification: LC-MS (ES) m/z=435 (M+H)+.
Reaction SMILES: BrC1C=CC([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[N:10]=2)=CC=1.[CH3:24][Mg]Br>O1CCCC1>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([CH3:23])=[C:16]([C:11]2[N:12]=[C:13]([CH3:24])[N:14]=[C:9]([NH2:8])[N:10]=2)[CH:21]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(Br)cc2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(Cl)ccc2C)n1
Yield: 53.9 %

Procedure:
The reaction of the title compound of Example 20 (200 mg, 0.49 mmol) with methyl magnesium bromide (3 M in diethyl ether, 1 ml, 3 mmol) in tetrahydrofuran (4 ml) using the method described in Example 22 provided the title compound (62 mg, 32% yield). 1H NMR (DMSO-d6) 10.37 (s, 1H), 7.85 (s, 1H), 7.71 (m, 2H), 7.47-7.54 (m, 3H), 7.38 (m, 1H), 2.53 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH2:16][CH2:17][C:18](O)=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49].N12CCCN=C1CCCCC2.Cl>O1CCCC1.O.C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH2:16][CH2:17][C:18]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c(OCC(C)C)c1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(CCC(=O)NS(C)(=O)=O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
In 10 ml of tetrahydrofuran is dissolved 1.00 g of 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]-propanoic acid, to which is added 0.52 g of 1,1′-carbonyldiimidazole at ambient temperature. The mixture thus obtained is heated under reflux for one hour with stirring. To the reaction mixture cooled to ambient temperature are added 0.22 g of methane-sulfonamide and 0.4 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, and the mixture thus obtained is stirred for 30 minutes at ambient temperature. The reaction mixture is added to a mixture of chloroform and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to obtain 1.10 g of N-{3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]propanoyl}methanesulfonamide as a white-colored foaming product.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[CH2:13][C:14]#[N:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1(CC2CCCCN2CCN)CCCC1>>[CH2:2]([N:1]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[CH2:13][CH2:14][NH2:15])[CH2:5][CH3:4])[CH3:3]
Reactant: N#CCN1CCCCC1CN1CCCC1
Agent: NCCN1CCCCC1CN1CCCC1
Product: CCN(CC)CC1CCCCN1CCN

Procedure:
from 2-[2-[(pyrrolidin-1-yl)methyl]-piperidin-1-yl]acetonitrile in a yield of 64% of theory, 2-[2-[(pyrrolidin-1-yl)methyl]-piperidin-1-yl]ethanamine, B.p.20 mm Hg 156°-158° C.;
Reaction SMILES: [OH:1][C:2]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].O.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:16][C:15]1[C:2]([OH:1])=[C:3]([CH:12]=[CH:13][CH:14]=1)[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5])(=[O:20])[CH3:19]
Reactant: COC(=O)CCC(=O)c1cccc(O)c1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)CCC(=O)c1cccc(OC(C)=O)c1O
Reaction time: 2 h

Procedure:
Methyl 3-(2,3-dihydroxybenzoyl)propionate was treated with boroacetic anhydride in acetic anhydride on a steam bath for 20 minutes and the mixture was poured into water and stirred for 2 hours to give methyl 3-(3-acetoxy-2-hydroxybenzoyl)-propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:27])[CH:22]([N:24]=[C:25]=[O:26])[CH3:23].C(N(C(C)C)CC)(C)C>>[CH3:19][O:20][C:21](=[O:27])[C@@H:22]([NH:24][C:25]([N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:14][CH2:15]1)=[O:26])[CH3:23]
Reactant: COC(=O)C(C)N=C=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)NC(=O)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, 2-isocyanato-propanic acid-methyl ester, and diisopropylethyl amine, are reacted to give the product as a white solid. LC-MS: 392 (M++1). 1H NMR (DMSO-d6) δ 1.30 (d, 3H), 2.96 (br.s, 4H), 3.55 (m, 4H), 3.61 (s, 3H), 4.16 (m, 1H), 6.26 (s, 1H), 6.45 (br.s, 2H), 6.90 (d, 1H), 7.10 (dd, 1H), 7.38 (d, 1H), 7.75 (d, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:76][N:77]([CH3:81])[CH2:78][CH2:79][NH2:80]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:80][CH2:79][CH2:78][N:77]([CH3:81])[CH3:76])=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCN
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.047 g (0.359 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0120 g (0.134 mmole) of N,N-dimethylethylenediamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0359 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-ethyl-benzamide (I-198) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[OH-].[Na+].Cl.[CH:21](Cl)(Cl)[Cl:22]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:22][C:21]1[C:2]([CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[N:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: c1ccc2[nH]c(CCC3CCNCC3)cc2c1
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: Clc1cc2ccccc2nc1CCC1CCNCC1

Procedure:
The operation is as in Example 1, but starting from 8.3 g of 4-[2-(2-indolyl)-ethyl]-piperidine and 0.18 g of triethylbenzylammonium chloride in 90 ml of chloroform, and 11 g of sodium hydroxide in solution in 22 ml of water. 1.45 g of 3-chloro-2-[2-(4-piperidyl)-ethyl]-quinoline are obtained the monohydrochloride of which melts at 162° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1.C(=O)([O-])O.[Na+].[C:18](Cl)([CH:20]=[CH2:21])=[O:19]>O>[C:18]([NH:3][C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)(=[O:19])[CH:20]=[CH2:21]
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: C=CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CC(=O)Nc1ccc2[nH]nnc2c1
Reaction time: 1 h
Yield: 58.5 %

Procedure:
20.7 g of 5-aminobenzotriazole dihydrochloride and 30 g of sodium hydrogen carbonate were dissolved in 300 ml of water, and 10 g of acryl chloride was added dropwise at a temperature of lower than 10° C. over 20 minutes. After being stirred for 1 hour, the formed white precipitate was filtered off. Yield: 13.8 g. It was dissolved in 100 ml of DMF, and 500 ml of hot water at about 70° C. was added. It was immediately filtered under atmospheric pressure. The filtrate was allowed to cool, and the separated crystals were filtered out, washed with water and dried to obtain 11 g of the desired product which melted at 248°-253° C. The structure was confirmed by IR, NMR and elementary analysis.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([CH2:23][C:24]([OH:26])=[O:25])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=3)[S:12][C:13]=2[CH2:23][C:24]([OH:26])=[O:25])=[CH:21][CH:20]=1
Reactant: CC(=O)Oc1ccc(-c2nc(-c3ccc(Cl)cc3)c(CC(=O)O)s2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1sc(-c2ccc(O)cc2)nc1-c1ccc(Cl)cc1

Procedure:
2-(4-Acetoxyphenyl)-4-(4-chlorophenyl)-thiazole-5-acetic acid (prepared according to Example 3) is hydrolysed using 2 N sodium hydroxide to give the title compound.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].Cl.[O:37]1CCOCC1.O>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([OH:37])[N:11]=1)=[O:9]
Reactant: C1COCCO1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1
Agent: Cl
Solvent: O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(O)ncc1-c1ccccc1
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 0.3 g (0.58 mmol) 2-methanesulfonyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml dioxan/H2O 5 ml 2N NaOH solution was added. The reaction mixture was stirred for 3 hrs. The pH of the reaction solution was than adjusted to 4 with 25% HCl. The aqueous layer was extracted three times with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/methanol 9:1) to give 0.20 g (75%) 2-hydroxy-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a off-white solid, m.p. 218.5-219.5°.
Reaction SMILES: [CH:1]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:9]1[C:22]2[C:21]3([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([N:31]=[C:32]=[O:33])[CH2:27][CH2:26]4)[CH2:23][CH:14]([C:15]4[C:20]3=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13]=2[CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH:19]1[C:20]2[C:21]3([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([NH:31][C:32]([NH:7][CH2:6][CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:33])[CH2:27][CH2:26]4)[CH2:23][CH:14]([C:13]4[C:22]3=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=C=NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: NCC1CCCC1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCC1CCCC1)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a cold (ice bath) stirred solution of cyclopentylmethylamine (664 mg, 6.70 mmol) in methylene chloride (5 mL) was added [(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidyl]isocyanate hydrochloride (221 mg, 0.67 mmol). After stirring the resulting mixture for 0.5 h, at 0° C., the cooling bath was removed and the reaction was allowed to reach ambient temperature. After stirring for 18 h, the reaction mixture was treated with 1N sodium hydroxide and extracted with methylene chloride (2×50 mL). The combined extracts was washed with 1N sodium hydroxide (2×50 mL) and brine (50 mL), dried (sodium sulfate), and concentrated to give a tan syrup. Chromatography of this material over silica gel (eluant: 98:2 methylene chloride:methanol) affords a white foam. This was triturated with hot ether to provide the title compound as a white solid (101 mg, 35%), mp 197.0°-8.0° C.; MS(CI): 430 (M+H); NMR (300 MHz,DMSO-d6): 1.05-1.35 (m, 4H), 1.38-1.78(m, 8H), 1.89(quinlet, 1H, J=7.3 Hz), 2.20-2.36(m, 2H), 2.45(s, 2H), 2.78-2.95(m, 4H), 3.26-3.42(m, submerged, 3H), 4.30(s, 1H), 5.66(d, 1H, J=7.5 Hz), 5.73(t, 1H, J=5.5 Hz), 6.84-6.99(m, 4H), 71.8(d, 2H, J=6.4 Hz), 7.26(d, 2H, J=6.9 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:23])([CH3:22])[S:20](=[O:25])(=[O:24])[CH2:19][C@:18]([C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=2[F:36])([CH3:26])[N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:47](Br)[CH:48]=[CH2:49].[NH4+].[Cl-]>C1COCC1>[CH2:49]([CH:19]1[C@:18]([C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=2[F:36])([CH3:26])[N:17]=[C:16]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[C:21]([CH3:23])([CH3:22])[S:20]1(=[O:25])=[O:24])[CH:48]=[CH2:47]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.3 %

Procedure:
A 3-necked RBF equipped with a mechanical stirrer, Claisen adapter with thermocouple and a nitrogen inlet was charged with tert-butyl N-tert-butoxycarbonyl-N-[(3R)-3-(2-fluoro-5-nitro-phenyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (8.8 g, 16.62 mmol) and THF (80 mL). The yellow solution was cooled to Tinternal−72+/−1° C. using a dry ice/IPA bath. KHMDS, 1M in THF (24.93 mL, 24.93 mmol) was added dropwise via cannula over ˜15 min keeping Tinternal<−72+/−1° C. The reaction mixture became dark brown, and was stirred at Tinternal˜−72+/−1° C. for 45 min. Allyl bromide (2.157 mL, 24.93 mmol) was added via syringe over 3 min, and stirring was continued at Tinternal<−75° C. for 75 min. 10 mL saturated aq. NH4Cl was added, the cooling bath was removed, and the reaction mixture was allowed to warm to RT. Water was added until all solids were dissolved, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel chromatography (heptane/EtOAc: 100/0 to 40/60+5% DCM isocratic) to provide tert-butyl N-[(3R)-2-allyl-3-(2-fluoro-5-nitro-phenyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (8.93 g, 2.85:1 ratio of diastereomers) as an off-white solid. LC/MS (ESI+) m/z=592.2 (M+Na).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br[C:6]1[CH:7]=[C:8]([C:12]2([CH:22]3[CH2:24][CH2:23]3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:21])=[N:13]2)[CH:9]=[CH:10][CH:11]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:21][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:8]2[CH:7]=[C:6]([C:33]3[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:34]=3)[CH:11]=[CH:10][CH:9]=2)([CH:22]2[CH2:23][CH2:24]2)[N:13]=1
Reactant: NC1=NC(c2cccc(Br)c2)(C2CC2)c2ccccc21
Reactant: COc1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Solvent: CC(=O)O
Product: COc1ccc(C#N)c(-c2cccc(C3(C4CC4)N=C(N)c4ccccc43)c2)c1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield as described for Example 78 (Scheme #14, N) starting from 1-(3-bromophenyl)-1-cyclopropyl-1H-isoindol-3-amine acetate (Scheme #15, O) and 4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile: 1H NMR (DMSO-d6) δ 7.89-7.84 (m, 2 H), 7.75-7.68 (m, 1 H), 7.68-7.63 (m, 1 H), 7.56-7.51 (m, 1 H), 7.43-7.35 (m, 4 H), 7.12 (dd, J=8.66, 2.64 Hz, 1 H), 7.06 (d, J=2.51 Hz, 1 H), 3.89 (s, 3 H), 1.92-1.83 (m, 4 H), 0.49-0.38 (m, 2 H), 0.25-0.16 (m, 1 H), −0.04-0.03 (m, 1 H): MS (ES) m/z 380 [M+1]+.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:13]=[CH:12][CH:11]=1)(=O)C.Cl>CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([NH:9][C:5]3[NH:6][CH2:7][CH2:8][N:4]=3)=[CH:11][CH:12]=[N:13]2)=[CH:20][CH:19]=1
Reactant: CC(=O)N1CCN=C1Nc1ccnn1-c1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: Fc1ccc(-n2nccc2NC2=NCCN2)cc1

Procedure:
1-Acetyl-2[1-(4-fluorophenyl)-5-pyrazolyl] amino-2-imidazoline (17.13 g.) was treated with HCl in methanol as described in Example II to give 12.06 g. product. mp 195°-197°