Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26](/[CH:27]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)cc2)c(O)c([N+](=O)[O-])c1
Yield: 75.5 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (100 mg, 0.51 mmol) and 4-benzyloxybenzaldehyde (100 mg, 0.47 mol) were reacted according to the same procedure as Preparation 1 to give 150 mg (Yield 75%) of the title compound.
Reaction SMILES: [C:1]([CH2:3][CH:4]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:5]([O:7][CH3:8])=[O:6])#[N:2].C([Sn]([N:33]=[N+:34]=[N-:35])(CCCC)CCCC)CCC>C1COCC1>[NH:33]1[C:1]([CH2:3][CH:4]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:5]([O:7][CH3:8])=[O:6])=[N:2][N:35]=[N:34]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COC(=O)C(CC#N)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1nnn[nH]1)NC(=O)OCc1ccccc1
Yield: 85.8 %

Procedure:
2.5 g (9.54 mmol, 1 equiv.) of the compound of Example 51 (3-cyano-2-benzyloxymethanamidopropionic acid, methyl ester) was dissolved in 10 mL of dry THF and 3.0 g (9.54 mmol, 1 equiv.) of tri-n-butyltin azide was added. The reaction was refluxed for 72 hours followed by concentration in vacuo. 50 mL of 1M NaOH was added and the aqueous solution was extracted with ethyl acetate (3×50 mL). The aqueous solution was acidified to pH=1 with 4M HCl and extracted with ethyl acetate (4×60 mL). After drying over sodium sulfate, the organics were decanted and concentrated an vacuo to yield 2.5 g of the title compound. 1H-NMR (CDCl3): 7.3 p.p.m (m, 5H); 6.1 p.p.m. (m, 1H); 5.1 p.p.m. (s, 2H); 4.8 p.p.m. (m, 1H); 3.8 p.p.m. (s, 3H); 3.5 p.p.m. (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:29]=1[N:37]=[C:38]=[O:39])([CH3:27])[CH3:26]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)[C:38]([NH:37][C:29]2[C:28]([CH:25]([CH3:26])[CH3:27])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:34]([CH3:36])[CH3:35])=[O:39])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2ccc(C#N)cc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccc(C#N)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 8.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-cyanophenylmethyl)(4-octylphenyl)amine (3.65 g) and 2,6-diisopropylphenyl isocyanate (2.55 g) as starting materials, N-(4-cyanophenylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-octylphenyl)urea (0.49 g) was obtained.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15]([Br:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=3[OH:20])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]12([C:11]3[C:12]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:13][C:14]([O:18][CH3:19])=[C:15]([Br:17])[CH:16]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: BrCc1ccccc1
Reactant: COc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Yield: 76.2 %

Procedure:
To a stirred solution of 2-(1-adamantyl)-4-bromo-5-methoxyphenol (2.59 g, 7.68 mmol) in acetone (26 mL) was added benzyl bromide (1.31 g, 7.68 mmol) followed by K2CO3 (1.33 g, 9.60 mmol). The mixture was stirred and heated at reflux for 17.25 h under argon. Acetone was removed at reduced pressure before 1 N HCl (40 mL) was added. The mixture was extracted with EtOAc (100 mL), and the organic layer was washed with H2O and brine and dried. After removal of solvent at reduced pressure, the residue was purified on silica gel (0% to 4% EtOAc/hexane) to give 2.50 g (76%) of 5-(1-adamantyl)-4-benzyloxy-2-methoxyphenyl bromide as a white solid, mp 124-126° C. IR 2902, 2847, 1498, 1161 cm−1; 1H NMR (CDCl3) δ 1.71 (bs, 6H, AdCH2), 2.02 (bs, 311, AdCH), 2.08 (bs, 6H, AdCH2), 3.82 (s, 3H, OCH3), 5.12 (s, 2H, C6H5CH2), 6.53 (s, 1H, 3-ArH), 7.34 (s, 1H, 6-ArH), 7.31-7.50 ppm (m, 5H, C6H5).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([NH:26][C:27]2[N:32]=[C:31]([C:33]3[CH:34]=[N:35][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=34)[CH:30]=[CH:29][N:28]=2)=[CH:20][C:19]=1[NH2:42].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)[C:19]([NH2:42])=[CH:20][C:21]=1[NH:26][C:27]1[N:32]=[C:31]([C:33]2[CH:34]=[N:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=23)[CH:30]=[CH:29][N:28]=1
Reactant: COc1cc(Br)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.7 mg, 0.03 mmol) was added to a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 137, 215 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was then heated at 100° C. for 1 h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc and this solution was washed three times with water, then with brine. The solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (160 mg, 72%) as a tan solid after trituration with diethyl ether; 1H NMR: 1.79-1.87 (2H, m), 1.96-2.03 (2H, m), 2.29 (3H, s), 2.34-2.40 (2H, m), 2.58 (2H, t), 2.98-3.02 (2H, m), 3.15 (2H, t), 3.75 (3H, s), 4.12 (2H, t), 4.32 (2H, br s), 5.67-5.71 (1H, m), 6.60 (1H, s), 7.01 (1H, d), 7.58 (1H, s), 7.69 (1H, s), 8.09 (1H, s), 8.32 (1H, d); m/z: ES+ MH+ 432.72.
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:58])[C@H:12]([CH3:57])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:56])[CH2:22][C@@H:23]([O:54][CH3:55])[C@@H:24]([N:29]([CH3:53])[C:30](=[O:52])[C@@H:31]([NH:35][C:36]([C@@:38]2([CH3:51])[CH2:43][CH2:42][CH2:41][CH2:40][N:39]2C(OC(C)(C)C)=O)=[O:37])[CH:32]([CH3:34])[CH3:33])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[ClH:59]>O1CCOCC1>[ClH:59].[CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:58])[C@H:12]([CH3:57])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:56])[CH2:22][C@@H:23]([O:54][CH3:55])[C@@H:24]([N:29]([CH3:53])[C:30](=[O:52])[C@@H:31]([NH:35][C:36]([C@@:38]2([CH3:51])[CH2:43][CH2:42][CH2:41][CH2:40][NH:39]2)=[O:37])[CH:32]([CH3:34])[CH3:33])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCCN1)C(C)C
Yield: 83 %

Procedure:
According to the general procedure C, from #179 (162 mg, 0.199 mmol, 1 eq.) and 4M solution of hydrochloric acid in dioxane (2.0 mL) was synthesized the desired material as a gum (155 mg). A portion of this gum (25 mg) was azeotroped with a 1/1 mixture of methanol/acetonitrile to afford #180 (20 mg, 83%) as a solid. 1H NMR (400 MHz, DMSO-d6), δ 9.02-9.13 (m), 8.83-8.93 (m), 8.39-8.46 (m), 8.00-8.06 (m), 7.78 (t), 7.24-7.30 (m), 7.16-7.21 (m), 6.54-6.65 (m), 6.09-6.19 (m), 5.11-5.18 (m), 4.69-4.78 (m), 4.59-4.68 (m), 4.46-4.56 (m), 4.08-4.13 (m), 3.95-4.03 (m), 3.77-3.85 (m), 3.54-3.73 (m), 3.43-3.53 (m), 3.37-3.42 (m), 3.24-3.33 (m), 3.16-3.22 (m), 3.03-3.15 (m), 2.99-3.02 (m), 2.89-2.98 (m), 2.65-2.76 (m), 2.41-2.54 (m), 2.15-2.39 (m), 2.07-2.15 (m), 1.51-1.94 (m), 1.49 (d), 1.38 (t), 1.20-1.32 (m), 1.02-1.09 (m), 0.84-0.97 (m), 0.73-0.81 (m). LC-MS (Protocol Q1): m/z 714.6 [M+H+], retention time=0.76 HPLC (Protocol U): m/z 714.4 [M+H+], retention time=7.409 minutes (purity=90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 100 °C
Yield: 68.2 %

Procedure:
To a solution of 3.9 mL (35 mmol) of 3,4-difluoronitrobenzene in 60 mL of dimethyl sulfoxide were added 9.7 mL (87.5 mmol) of N-methylpiperazine and 12.1 g (87.5 mmol) of potassium carbonate, and the mixture was refluxed for 5 hours at 100° C. The reaction mixture was cooled to room temperature and poured into 500 mL of ice water, and the resulting precipitates were collected. The collected precipitates were dissolved in 2M-HCl aqueous solution and washed with ether. The aqueous layer was neutralized with 4M-NaOH aqueous solution to give the precipitates. The precipitates were collected to give 5.71 g (68%) of the title compound.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([NH:31][C@H:32]([C:37](O)=[O:38])[CH2:33][C:34](=[O:36])[NH2:35])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:37]([C@@H:32]([NH:31][C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:30])[CH2:33][C:34]([NH2:35])=[O:36])=[O:38])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC(N)=O)NC(=O)C(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using Nα-pivaloyl-L-asparagine (65 mg, 0.3 mmol) which was prepared in step A this example. The final product was purified by preparative HPLC to yield 21 mg (12%) of the desired material.
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].[CH2:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10](Cl)=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]1=[O:24])[CH3:6]>O>[CH2:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10]([O:4][CH2:2][CH3:3])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]1=[O:24])[CH3:6]
Reactant: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(CC)c1=O
Reactant: CCO
Agent: [Na]
Solvent: O
Product: CCOC(=O)c1c(OCC)c2ccc(C)nc2n(CC)c1=O

Procedure:
To a solution of 0.11 g. (0.005 g. atoms) of sodium in 20 ml. of ethanol was added 1.47 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester. The mixture was heated under reflux for 4 hours. The mixture was cooled and was diluted with water. The precipitate which formed was collected, air dried and was recrystallized from heptane to give 0.5 g. of the title compound, m.p. 77°-9° C.
Reaction SMILES: FC(F)(F)S([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)(=O)=O.N1[C:44]2C=CC=C[C:43]=2NC=1>CN(C)C=O>[NH:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25]([C:43]#[CH:44])[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: O=C(c1ccc2c(c1)ncn2S(=O)(=O)C(F)(F)F)N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21
Reactant: c1ccc2[nH]cnc2c1
Solvent: CN(C)C=O
Product: C#Cc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A flask charged with a stir bar, trifluoromethanesulfonic acid cis-1-(1-trifluoromethane-sulfonyl-1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment to N-1 or N-3 of the benzimidazole, 0.20 g) and N,N-dimethylformamide (2 mL) is sparged with argon for 5 min. Copper(I) iodide (13 mg), Pd(PPh3)2Cl2 (25 mg), triethylamine (0.31 mL), and trimethylsilylacetylene (0.14 mL) are added in the given order, the vessel is sealed, and the resulting mixture is heated to 60° C. After stirring the mixture at 60° C. overnight, it is cooled to room temperature and aqueous K2CO3 solution is added. The resulting mixture is extracted with ethyl acetate, the combined extract is dried (Na2SO4), and the solvent is evaporated. The residue is chromatographed on silica gel (dichloromethane/methanol 1:09:1) to afford the trimethylsilylated title compound which is taken up in methanol (3 mL) and treated with saturated aqueous K2CO3 solution at room temperature for 2 h. The mixture is then concentrated, water is added to the residue, and the resulting mixture is extracted with ethyl acetate. The combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0→9:1) to afford the title compound. Yield: 0.03 g (26% of theory); LC (method 1): tR=2.65 min; Mass spectrum (ESI+): m/z=342 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:21][NH:22][C:23]1[CH:24]=[N:25][C:26]([N:37]2[CH2:42][CH2:41][S:40][CH2:39][CH2:38]2)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[CH3:36].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14]([N:22]([CH3:21])[C:23]2[CH:24]=[N:25][C:26]([N:37]3[CH2:38][CH2:39][S:40][CH2:41][CH2:42]3)=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[CH3:36])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N2CCSCC2)cc1-c1ccc(F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A solution of 8.5 g (26.6 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 12 ml dichloromethane was added dropwise at room temperature to a solution of 8.0 g (24.2 mmol) methyl-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-amine and 4.7 ml (33.9 mmol) triethylamine in 65 ml dichloromethane. The reaction mixture was stirred for 1 hour and poured onto 50 ml 1 N aqueous sodium hydroxide. After extraction the phases were separated, the aqueous phase was extracted with dichloromethane and the organic phases were washed with water. The combined organic extracts were concentrated under reduced pressure and the solvent was exchanged for 150 ml ethanol. The solution was seeded at 40° C. with some crystals, 30 ml water were slowly added and the system was stirred for 1 hour at room temperature and for 1 hour at 0° C. The precipitate was filtered off, washed with cold ethanol (0° C.) and dried under high vacuum to yield 13.0 g (76% over 3 steps) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[4-(4-fluoro-2-methyl-phenyl)-6-thiomorpholin-4-yl-pyridin-3-yl]-isobutyramide as an off-white powder of
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[CH:4]=1.[C:11](O)(=[O:13])[CH3:12].Br>O>[OH:9][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][C:6]=1[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: COc1cccc(OC)c1
Agent: Br
Solvent: O
Product: CC(=O)c1ccc(O)cc1O
Temperature: 25 °C

Procedure:
1,3-Dimethoxybenzene (8.00 g, 57.4 % mmol) was combined with acetic acid (500 ml) and 48% hydrobromic acid (300 ml). The solution was stirred and heated to reflux for five days. The reaction mixture was allowed to cool to room temperature then poured into water (500 ml). The aqueous solution was extracted with ether (500 ml, 2×) and concentrated in vacuo to a reddish brown oil. Chromatography by HPLC yielded a small amount of the title product uncontaminated by the resorcinol side product:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[NH:26][C:27]([C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=1)=[O:28].C(N(CC)C(C)C)(C)C.I[CH2:46][C:47]([NH2:49])=[O:48]>CN(C)C=O>[NH2:49][C:47](=[O:48])[CH2:46][N:11]1[C:12](=[N:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:4]=2)=[CH:10]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)cn2CC(N)=O)cc1
Yield: 72.6 %

Procedure:
In the same manner as in Reference Example 5 and using N-{2-fluoro-5-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (7.25 g, 14.6 mmol), N,N-diisopropylethylamine (3.31 mL, 19.0 mmol), N,N-dimethylformamide (30 mL) and iodoacetamide (3.51 g, 19.0 mmol) as starting materials, the title compound (5.86 g, 73%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:45]=[CH:44][C:6]2[N:7]([CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[CH:33][C:32]=3[CH:41]3[CH2:43][CH2:42]3)[C:8](=[O:29])[C@@H:9]([NH:21]C(=O)OC(C)(C)C)[C@H:10]([CH3:20])[N:11]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:5]=2[CH:4]=1)#[N:2].[ClH:46]>O1CCOCC1.CCOCC>[ClH:46].[ClH:46].[NH2:21][C@@H:9]1[C:8](=[O:29])[N:7]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][C:32]=2[CH:41]2[CH2:43][CH2:42]2)[C:6]2[CH:44]=[CH:45][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:11]([C:12]([CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[C@H:10]1[CH3:20]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N1C(=O)C1CCOCC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@H]1[C@H](N)C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccc(C#N)cc2N1C(=O)C1CCOCC1
Yield: 91 %

Procedure:
A rt solution of tert-butyl(3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (69 mg, 113 μmol) in 4 M HCl in dioxane (566 μl) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration to provide (3S,4S)-3-amino-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile dihydrochloride (60 mg, 91%) as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:9][C:10](=[O:59])[C@H:11]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[NH:12][C:13]([C:15]1([CH2:20][C@H:21]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:22][NH:23][C:24](=[O:43])[C@H:25]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH3:8].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:7]([O:9][C:10](=[O:59])[C@H:11]([CH2:51][C:52]1[CH:53]=[CH:54][C:55]([O:58][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:56][CH:57]=1)[NH:12][C:13]([C:15]1([CH2:20][C@H:21]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:22][NH:23][C:24](=[O:43])[C@H:25]([CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(C[C@@H](CNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NS(C)(=O)=O)C(=O)OC(C)(C)C)CCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(C[C@H](NC(=O)C2(C[C@@H](CNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NS(C)(=O)=O)C(=O)OC(C)(C)C)CCCC2)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Ethyl chloroformate (0.1093 g, 1.007 mmol) was added to an ice-cooled solution of N-{1-[3-(N2 -methanesulphonyl-N6 -t-butyloxycarbonyl-(S)-lysylamino)-2-(S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbony}-(S)-tyrosine-ethyl ester (0.7041 g, 0.916 mmol), triethylamine (0.2781 g, 2.75 mmol and 4-dimethylaminopyridine (0.0112 g in dry dichloromethane (20 ml). After 30 minutes the ice-cooling was removed and the reaction stirred overnight at room temperature. The solvent was then evaporated under reduced pressure and the residual oil partitioned between ethyl acetate (50 ml) and 2N hydrochloric acid (50 ml). The phases were separated and the organic phase washed with saturated sodium bicarbonate solution (50 ml), then with saturated brine, (50 ml) and was finally dried over magnesium sulphate, before removing the solvent under reduced pressure to give the crude product as an oil. Chromatography over silica gel, eluting with mixtures of dichloromethane and diethyl ether gave the title compound as a white foam (0.367 g, 48%). Found: C,56.68; H,7.36; N,6.65. C39H64N4O13S requires C,56.50; H,7.78; N,6.76%.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([O:1][C:2]2[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][C:5]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[N:20]=1
Reactant: COC(=O)c1nc(N2CCCC2)ccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N2CCCC2)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 0 °C
Yield: 84 %

Procedure:
1.55 g (7 mmol) of methyl 3-hydroxy-6-(1-pyrrolidinyl)picolinate, 1.83 g (8.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.96 g (7 mmol) of potassium carbonate were added to 50 ml of DMF and reacted at 100° C. for 3 hours. After completion of the reaction, the reaction product was poured into ice water, extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off, and the residue was crystallized from diisopropyl ether to obtain the desired product.