Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Nc3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(S(=O)(=O)Nc2ccccc2)c1
Yield: 31.6 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(3-(N-phenylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (130 mg, 0.29 mmol) in methanol/tetrahydrofuran (5 mL/5 mL) was added 1N sodium hydroxide (4.33 mL). The resultant mixture was heated to reflux for 2.5 h. Organic solvent was removed and the residue was dissolved in water. The aqueous layer was acidified to pH=4. The precipitates were filtered, and dissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate. anhydrous magnesium sulfate was removed, and after evaporation, the residue was purified on preparative Thin layer chromatography to afford 80 mg of crude product, which was recrystallized from dichloromethane and ether to afford 40 mg of 3,3-dimethyl-2-(3-(N-phenylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. (Yield: 32%). MS (ESI+APCI) M+1=437.1.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[N:27]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:25][C:26]2[CH:30]=[CH:29][N:28]([CH2:31][C:32]([OH:34])([CH3:33])[CH3:35])[N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccnc2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccnc3)cc2=O)n1
Yield: 53 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(pyridin-3-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 54) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(pyridin-3-yloxy)-6H-pyridazin-1-yl]-propionamide as an off-white solid (0.78 g, 53%); ES+-HRMS m/e calcd for C24H30N6O4 [M+H+] 467.2402 found 467.2399. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.11 (m, 1H), 1.26-1.75 (m, 8H), 1.92 (m, 1H), 2.29 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.48 (dd, J=4.4, J=11.0 Hz, 1H), 5.88 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.3 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.57 (dd, Jo=8.4, 4.7 Hz, 1H), 7.83 (ddd, Jo=8.4 Hz, Jm=2.8, 1.2 Hz, H), 8.17 (d, J=2.8 Hz, 1H), 8.58 (dd, Jo=4.7 Hz, Jm=1.2 Hz, 1H), 8.61 (d, Jm=2.8 Hz, H), 10.80 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:28]([CH3:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:4]([NH:6][C@@H:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]([N:10]([CH3:23])[C@@H:11]([CH:20]([CH3:22])[CH3:21])/[CH:12]=[C:13](\[CH3:19])/[C:14]([O:16]CC)=[O:15])=[O:9])=[O:5].CO[C@H](C(C)(C1C=CC=CC=1)C)C(N[C@@H](C(C)(C)C)C(N(C)[C@@H](C(C)C)/C=C(\C)/C(OCC)=O)=O)=O.O.O.[OH-].[Li+]>CO.O1CCCC1>[CH3:1][O:2][C@@H:3]([C:28]([CH3:36])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:29])[C:4]([NH:6][C@H:7]([C:8]([N:10]([CH3:23])[C@@H:11]([CH:20]([CH3:22])[CH3:21])/[CH:12]=[C:13](\[CH3:19])/[C:14]([OH:16])=[O:15])=[O:9])[C:24]([CH3:25])([CH3:26])[CH3:27])=[O:5]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](OC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](OC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
According to General Procedure II, a 1:1 mixture of ethyl (E,4S)-4-[((2S)-2-{[(2S)-2-methoxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate and ethyl (E,4S)-4-[((2S)-2-{[(2R)-2-methoxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (1.0 g, 2.0 mmol, from Reference Example 104) is dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). To this solution is added water (5 mL) and lithium hydroxide monohydrate (0.17 g, 4.0 mmol), and the resulting mixture is stirred at 60° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 2 M aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a white foam. A sample of this crude material (240 mg) is subjected to HPLC purification (Prodigy OS3 column, acetonitrile/water/TFA) to give (E,4S)-4-[{N-[(2S)-2-methoxy-3-methyl-3-phenylbutanoyl]-3-methyl-L-valyl}(methyl)amino]-2,5-dimethyl-2-hexenoic acid as a hard white foam (50 mg). MS (ES+): (M+H)=475.0
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:38])[O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][Si](C(C)(C)C)(C)C)=[CH:18][C:17]=3[O:30][Si](C(C)(C)C)(C)C)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-]>CO>[CH:1]1([NH:7][C:8](=[O:38])[O:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[OH:30])[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](OC(=O)NC3CCCCC3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [F-]
Solvent: CO
Product: O=C(NC1CCCCC1)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl cyclohexylcarbamate (28 mg), methanol (10 ml) and Amberlyst fluoride resin (0.3 g) were stirred at room temperature for 72 hr. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:3 v/v) to give the title compound as a white solid (6 mg, 36%); δH(CD3OD) 1.10-2.12 (18H, m), 2.70-2.82 (1H, m), 4.46-4.60 (1H, m), 6.18-6.30 (2H, m), 6.80-6.92 (1H, m); m/z (ES+) 334 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=O)[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[NH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([N:27]2[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:20][S:19]3)[CH2:2][CH2:3]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)N2CCCc3ccccc32)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (100 mg, 0.269 mmol) with 1,2,3,4-tetrahydroquinoline (39 μL, 0.296 mmol) in the presence of triethylamine (68 mg, 0.674 mmol) in dichloromethane (5 mL) gave 79 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.21-0.22 (m, 2H), 0.45-0.47 (m, 2H), 1.09-1.11 (m, 1H), 1.97-2.00 (m, 2H), 2.85-2.87 (m, 2H), 3.66 (d, J=6.6 Hz, 2H), 3.76 (s, 3H), 3.83-3.85 (m, 2H), 6.75 (d, J=16.2 Hz, 1H), 6.85-6.93 (m, 4H), 6.98-7.03 (m, 2H), 7.13-7.15 (m, 1H), 7.26 (d, J=4.2 Hz, 1H), 7.56 (s, 1H), 7.61-7.64 (m, 1H); ESI-MS (m/z) 486.45 (MH)+.
Reaction SMILES: [CH2:1]([N:10]1[CH2:15][C:14]2[C:16]3[C:29]([OH:30])=[CH:28][C:27]([CH2:31][CH:32]4[CH2:34][CH2:33]4)=[CH:26][C:17]=3[O:18][C:19]([CH2:23][CH2:24][CH3:25])([CH2:20][CH2:21][CH3:22])[C:13]=2[CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:35].[N:36]1([CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[CH2:40][CH2:39][CH2:38][CH2:37]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:35].[CH2:1]([N:10]1[CH2:15][C:14]2[C:16]3[C:29]([O:30][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:28][C:27]([CH2:31][CH:32]4[CH2:34][CH2:33]4)=[CH:26][C:17]=3[O:18][C:19]([CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH3:25])[C:13]=2[CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCC1(CCC)Oc2cc(CC3CC3)cc(O)c2C2=C1CCN(CC=Cc1ccccc1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCC1(CCC)Oc2cc(CC3CC3)cc(OC(=O)CCCN3CCCC3)c2C2=C1CCN(CC=Cc1ccccc1)C2

Procedure:
2-Cinnamyl-8-cyclopropylmethyl-5,5-di(1-propyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-pyrrolidinobutyric acid hydrochloride and dicyclohexyl-carbodiimide are reacted in equimolar amounts according to Example 1 to form the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]([CH3:15])[CH:9]=[C:10]([CH2:11][C:12]([OH:14])=O)[C:6]=2[C:5](=[O:16])[N:4]([CH3:17])[C:3]1=[O:18].[CH3:19][C:20]([CH3:38])([CH3:37])[CH2:21][O:22][C:23]1[C:28]([F:29])=[CH:27][C:26]([C:30]2[N:31]=[C:32]([NH2:35])[S:33][CH:34]=2)=[CH:25][C:24]=1[F:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.ClCCCl>[F:36][C:24]1[CH:25]=[C:26]([C:30]2[N:31]=[C:32]([NH:35][C:12](=[O:14])[CH2:11][C:10]3[C:6]4[C:5](=[O:16])[N:4]([CH3:17])[C:3](=[O:18])[N:2]([CH3:1])[C:7]=4[N:8]([CH3:15])[CH:9]=3)[S:33][CH:34]=2)[CH:27]=[C:28]([F:29])[C:23]=1[O:22][CH2:21][C:20]([CH3:38])([CH3:37])[CH3:19]
Reactant: Cn1c(=O)c2c(CC(=O)O)cn(C)c2n(C)c1=O
Reactant: CC(C)(C)COc1c(F)cc(-c2csc(N)n2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4cc(F)c(OCC(C)(C)C)c(F)c4)cs3)cn(C)c2n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7 (100 mg, 0.398 mmol) with 4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-amine (118 mg, 0.398 mmol) in the presence of EDCI hydrochloride (91 mg, 0.475 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (4 mg, 0.032 mmol) in 1,2-dichloroethane (5 mL) to give 40 mg of the product as an off white solid; 1H-NMR (δ ppm, DMSO-d6, 300 MHz) 1.01 (s, 9H), 3.21 (s, 3H), 3.73 (s, 3H), 3.80 (s, 5H), 3.93 (s, 2H), 6.35 (s, 1H), 7.64 (d, J=9.6 Hz, 2H), 7.67 (s, 1H), 12.53 (br s, 1H, exchangeable with D2O); ESI-MS (m/z) 532.24 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].C[O-].[Na+].[I-].[K+].Br[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]>CO.C1C=CC=CC=1.O>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1ccc2c(c1)CCCC2)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 3.70 g of 5,6,7,8-tetrahydro-2-naphthol, 1.19 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 40 ml of benzene. The mixture is maintained at reflux overnight and then poured into 100 ml of water. The mixture is then extracted with 2 × 75 ml of ether. The combined extracts are washed with 2 × 50 ml of 5% NaOH, 50 ml of water, 50 ml of saturated brine and dried (MgSO4). Evaporation of the solvent yields a yellow oil. Chromatography on 100 g of silica gel yields a yellow oil.
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC([O:19]C)=CC=3OCC)=NC2CCC)=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[N:38]([C:39]([N:41]3[CH2:46][CH2:45][N:44](C)[CH2:43][CH2:42]3)=[O:40])[C:37]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=3[O:56][CH2:57][CH3:58])=[N:36][CH:35]2[CH2:59][CH:60]2CCC[CH2:61]2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[N:38]([C:39]([N:41]3[CH2:46][CH2:45][NH:44][C:43](=[O:19])[CH2:42]3)=[O:40])[C:37]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=3[O:56][CH2:57][CH3:58])=[N:36][CH:35]2[CH2:59][CH2:60][CH3:61])=[CH:30][CH:29]=1
Reactant: CCCC1N=C(c2ccc(OC)cc2OCC)NC1c1ccc(Cl)cc1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Product: CCCC1N=C(c2ccc(OC)cc2OCC)N(C(=O)N2CCNC(=O)C2)C1c1ccc(Cl)cc1

Procedure:
4-[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-propyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-propyl-4,5-dihydro-1H-imidazole (Example 18) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 499.2113, calculated for C26H32N4O4Cl [(M+H)+]499.2107.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[S:43])[NH:24][C@H:25]([CH2:33][N:34](C)[C:35](OC(C)(C)C)=O)[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[S:43])[NH:24][C@H:25]([CH2:33][NH:34][CH3:35])[CH2:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=S)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@H](CC1CCCCC1)NC(=S)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(tert-butoxycarbonyl)amino)propan-2-ylcarbamothioyl)piperidin-3-yl)methoxy)ethylcarbamate (640 mg, 0.1 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 1 h, a solution of saturated sodium bicarbonate was added dropwise to adjust the pH to 7-8. The resulting mixture was extracted with CH2Cl2 (3×15 mL), washed with brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by preparative HPLC to afford methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamothioyl)piperidin-3-yl)methoxy)ethylcarbamate (10 mg, 19%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][CH:8]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[O:1]([CH2:2][C:3]1[CH:4]=[N:5][C:6]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cnc(Nc2ccccc2)nc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
5-Hydroxymethyl-2-(phenylamino)pyrimidine (280 mg, 1.39 mmol) obtained in Step 3 was dissolved in DMF (10 mL), and imidazole (190 mg, 2.76 mmol) and tert-butyldimethylsilylchloride (420 mg, 2.79 mmol) were added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 5-(tert-butyldimethylsiloxymethyl)-2-(phenylamino)pyrimidine (423 mg, 82%).
Reaction SMILES: C[O:2][C:3](=[O:72])[C@H:4]([CH2:60][CH2:61][CH2:62][CH:63]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[NH2:64])[NH:5][NH:6][C:7]([C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([NH:23][C:24]([C:26]2[N:30]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:29]=[C:28]([NH:40][C:41]([C:43]3[N:47]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=4)[N:46]=[C:45]([N+:57]([O-:59])=[O:58])[CH:44]=3)=[O:42])[CH:27]=2)=[O:25])[CH:10]=1)=[O:8].[OH-].[Li+]>CO.C1COCC1.O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:13]2[C:9]([C:7]([NH:6][NH:5][C@H:4]([C:3]([OH:72])=[O:2])[CH2:60][CH2:61][CH2:62][CH:63]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[NH2:64])=[O:8])=[CH:10][C:11]([NH:23][C:24]([C:26]3[N:30]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[N:29]=[C:28]([NH:40][C:41]([C:43]4[N:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=5)[N:46]=[C:45]([N+:57]([O-:59])=[O:58])[CH:44]=4)=[O:42])[CH:27]=3)=[O:25])=[N:12]2)=[CH:16][CH:17]=1
Reactant: COC(=O)[C@H](CCCC(N)C(=O)OC(C)(C)C)NNC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])nn3Cc3ccc(OC)cc3)nn2Cc2ccc(OC)cc2)nn1Cc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2nc(NC(=O)c3cc(NC(=O)c4cc([N+](=O)[O-])nn4Cc4ccc(OC)cc4)nn3Cc3ccc(OC)cc3)cc2C(=O)NN[C@@H](CCCC(N)C(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
A 143 mg (146 μmol, 1.00 equiv) amount of 2-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido-6-(tert-butoxycarbonyl)-lysine methyl ester and 9 mg lithium hydroxide (376 μmol, 2.57 equiv) were stirred in a mixture of methanol/THF/water (5:5:1) for 16 h at 65° C. Workup and purification were conducted according to general procedure A to yield the free carboxylic acid as a colorless solid. Yield: 111 mg (115 μmol, 79%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.C(#N)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:6]2[C:2](=[O:1])[CH2:3][CH2:4][C@H:5]2[C:7]([OH:9])=[O:8])=[CH:16][CH:15]=1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: CC#N
Product: O=C(O)[C@@H]1CCC(=O)N1c1ccc(Cl)cc1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of (S)-5-oxo-pyrrolidine-2-carboxylic acid (775 mg, 6 mmol) in acetonitrile (10 mL) 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (1.8 mL, 12 mmol) is added at room temperature. After 10 min di-μ-hydroxy-bis[N,N,N′,N′-tetramethylenediamine)-copper (II) chloride (Cu-TMEDA) (300 mg, 0.65 mmol) is added to the clear solution. The bluish green colored mixture is stirred for 10 min and 4-chlorophenylboronic acid (1 g, 6.4 mmol) is added. After 20 h acetonitrile is evaporated in vacuo, the concentrate taken up in ammonium chloride (150 mL) and the aqueous layer is washed with ethyl acetate (3×100 mL). The aqueous layer is cooled in an ice-bath, treated with 1 N sulfuric acid to pH 2 and extracted with ethyl acetate (3×100 mL). Combined organic extracts washed with brine (2×50 mL), dried over anhydrous Na2SO4 and solvent removed in vacuo to give the title compound as an off-white solid. ESI m/z 240 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[N:14]1[CH:13]=[CH:12][C:11]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=2)=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccc(Nc2ccncc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(Nc2ccncc2)c1
Reaction time: 2 h
Yield: 87 %

Procedure:
A suspension of compound A3 (7.26 g, 33.7 mmol) and 10% Pd/C in MeOH was hydrogenated for 2 h, filtered through a pad of Celite, and solvent evaporated. The residue was recrystallized from MeOH/H2O to give A4 as a pale yellow powder (5.43 g, 83%): mp. (MeOH/H2O) 170-171° C. 1H NMR [(CD3)2SO] δ 8.48 (bs, 1H, NH), 8.14-8.12 (m, 2H, H-2′&6′), 6.96 (t, J=7.9 Hz, 1H, H-5), 6.86-6.84 (m, 2H, H-3′ & 6′), 6.43 (t, J=2.0 Hz, 1H, H-2), 6.32 (dd, J=7.8, 1.3H, 1H, H-6), 6.26 (dd, J=7.8, 1.5 Hz, 1H, H-4) 5.07 (br s, 2H, NH2); HRMS (EI+) calc. for C11H11N3 (M+) m/z 185.0953, found 185.0945; Anal. calc. for C11H11N3.0.125 H2O: C, 70.5; H, 6.1; N, 22.5; found, C, 70.6; H, 6.0; N, 22.7%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[C:17]([O:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:26]([O:25][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:24])[C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NOC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)c1ccccc1)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
tert-Butyl {[2-(methylsulfonyl)phenyl]sulfonyl}[(phenylcarbonyl)oxy]carbamate (47) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino benzoate according to Scheme 2. (1.7 g, 91%), 1H NMR (250 MHz, DMSO-d6) δ ppm 8.25-8.45 (2H, m), 8.03-8.20 (4H, m), 7.77-7.93 (1H, m), 7.59-7.73 (2H, m), 3.48 (3H, s), 1.29 (9H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:5]=1[C:6]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:8])[CH3:2]
Reactant: CCOc1ccc(OCC(F)(F)F)cc1C(=O)O
Reactant: NCc1ccccn1
Product: CCOc1ccc(OCC(F)(F)F)cc1C(=O)NCc1ccccn1

Procedure:
Using the general method of Example XXIII Part D, 15.4 g (0.058 mole) of 2-ethoxy-5-(2,2,2-trifluoroethoxy)benzoic acid was converted to the acid chloride and then reacted with 2-aminomethylpyridine to provide 14.1 g of crystalline 2-ethoxy-5-(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide, m.p. 110°-111° C. Analysis: Calculated for C17H17F3N2O3 : %C, 57.6; %H, 4.85; %N, 7.9; Found: %C, 57.1; %H, 4.8; %N, 7.8.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]([F:13])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+]>CCO>[F:13][CH:4]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:14])=[O:2]
Reactant: COC(=O)C(F)CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(F)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
(RS)-2-Fluoro-4-phenyl-butyric acid methyl ester (0.39 g, 2 mmol) was added to a solution of KOH (0.56 g, 10 mmol) in EtOH (5 ml). After 1 hour stirring at room temperature. the reaction mixture was concentrated, diluted with H2O (5 ml), acidified to pH 1 with 2N HCl and extracted with CH2Cl2 (3 times). The combined organic phases were dried over Na2SO4, filtered and concentrated to provide (RS)-2-fluoro-4-phenyl-butyric acid (0.343 g, 92%) as a colorless oil MS: m/e=182.1 (M+).