Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[CH2:12]([O:14]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:13].Cl>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:12](=[O:14])[CH3:13])[CH:3]=2)[O:8][CH2:9][CH2:10]1
Reactant: Brc1cnc2c(c1)OCCO2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Under an argon atmosphere, 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (65 mg, 0.30 mmol) was dissolved in toluene (1.5 mL), added tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) and 1-ethoxyethenyl tri n-butyl tin (112 ΞL, 0.33 mmol), and the mixture was stirred at 100° C. overnight. The reaction solution was reverted to room temperature, and added 1N hydrochloric acid. The reaction solution was filtered through a pad of celite. The reaction solution was added ethyl acetate for extraction. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by preparative thin-layer chromatography (n-hexane/ethyl acetate=1/1). The title compound (37 mg (yield 69%)) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15]C(O)=CC=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CI.[CH3:23]C(=O)OCC.O.[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[C:1]([N:8]([CH3:23])[C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:31]=[CH:30][C:34]([O:33][CH3:32])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Solvent: O
Solvent: CI
Product: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 25 h
Yield: 95 %

Procedure:
6.0 g of NaH suspension were washed by decantation 3 times with PE, 50 ml of THF were poured on, and the mixture was cooled to 0° C. Then 32 mmol of BOC-L-tyrosine dissolved in 110 ml of THF were slowly added dropwise, and subsequently 16 ml of methyl iodide were added. The suspension was stirred at RT with exclusion of light for 25 h, 50 ml of EA were added, and the mixture was cautiously hydrolyzed with water. It was concentrated under reduced pressure to a small volume, EA was added, and the mixture was acidified with 2N KHSO4. After extraction with EA, the organic phases were washed with 10% strength sodium thiosulfate solution, dried (MgSO4) and evaporated under reduced pressure. Yield: 95%.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH:39]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25]>COC(C)(C)C.O1CCCC1>[CH3:2][O:3][CH:4]=[CH:39][CH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 22.2 g of methoxymethyl-triphenylphosphonium chloride in 150 ml of t-butyl methyl ether was treated with 7.4 g of solid potassium t-butylate at 0° C. within 3 minutes while gassing with argon in a sulphonation flask provided with a mechanical stirrer. The orange suspension was stirred at 0° C. for 1 hour and then treated dropwise within 10 minutes with a solution of 9.8 g of 2-[trans-4-(p-cyanophenyl)cyclohexyl]acetaldehyde in 100 ml of tetrahydrofuran. Subsequently, the suspension was left to warm slowly to room temperature while stirring. After 15 hours, the suspension was partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated. In order to separate triphenylphosphine oxide, the residue was dissolved in ethyl acetate and the solution was diluted with petroleum ether, filtered and evaporated. Chromatographic separation of the resulting, yellowish oil (13.7 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 10.5 g (96%) of p-[trans-4-(3-methoxy-2-propenyl)cyclohexyl]benzonitrile as a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.[C:28]([O-:31])([O-])=[O:29].[Na+].[Na+].[CH3:34][C:35]#[N:36]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:36][C@@H:35]([CH2:34][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=2)=[CH:16][CH:15]=1)[C:28]([OH:31])=[O:29]
Reactant: CC#N
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Product: Cc1cccc(-c2ccccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)c1

Procedure:
4-Chloro-6-(2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethoxy)pyrimidin-2-amine (0.16 g, 0.406 mmol), L-p-boronophenylalanine (10 mg, 0.487 mmol), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol), Na2CO3 (95 mg, 0.894 mmol), MeCN (2.5 ml) and water (2.5 ml) were heated at 150° C. for 5 minutes in a microwave. The mixture was concentrated and purified via prep HPLC to give 105 mg of the title compound. M+1=523; 1H NMR (CD3OD) δ 7.85 (d, 2H), 7.70 (d, 1H), 7.44 (m, 4H), 7.31 (t, 1H), 7.21 (m, 2H), 7.10 (m, 2H), 6.87 (q, 1H), 6.84 (s, 1H), 4.25 (t, 1H), 3.30 (m, 1H), 3.18 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:17]([OH:19])=[O:18].[CH3:20]O>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Reactant: CO
Product: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 30 °C

Procedure:
A mixture of 3-methyl-5[4-(trifluoromethyl)phenyl]thiophene-2-carboxylic acid (intermediate 130, 8.1 g) in methanol (300 ml) was heated at 30° C. and hydrogen chloride gas bubbled through the mixture. The reaction mixture was then stirred at reflux for 21 hours; cooled and treated with further hydrogen chloride gas. The reaction mixture was stirred at reflux for a further 6 hours, cooled and concentrated. The resulting precipitate was filtered and washed with cyclohexane to give the title compound as a solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17].[CH2:18]([O:20][C:21](=[O:26])[CH:22]=[C:23](Cl)[CH3:24])[CH3:19]>O1CCCC1>[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[C:23](/[O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[O:8][CH3:7])\[CH3:24])[CH3:19]
Reactant: COc1cccc(O)c1OC
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(OC)c1OC
Temperature: 23 °C
Yield: 46.4 %

Procedure:
Potassium t-butoxide (7.54 g, 0.067 mol) was added to a stirred solution of 2,3-dimethoxy-phenol (5.20 g, 0.034 mol) in tetrahydrofuran (30 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2,3-dimethoxy-phenoxy)-but-2-enoic acid ethyl ester (4.20 g, 47%) as a yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38]CCO)=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].[CH3:45][C:46]([NH:51]S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)([CH3:50])[C:47]([NH2:49])=[O:48].[N+]([C:67]1C=CC=C[C:68]=1S(NCC(N)=O)(=O)=O)([O-])=O>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:67][CH2:68][NH:51][C:46]([C:47](=[O:48])[NH2:49])([CH3:45])[CH3:50])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:43])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: NC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCNC(C)(C)C(N)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Example 39 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-methyl-2-(2-nitrobenzenesulfonylamino)propionamide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-(2-nitrobenzenesulfonylamino)acetoamide, respectively.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31]C(OC)=O)=[CH:26][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1.[OH-].[Na+].O.[ClH:39]>CO>[ClH:39].[F:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCCc4ccncc4)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline (300 mg, 0.63 mmol) and 2M aqueous sodium hydroxide (0.38 ml, 0.76 mmol) in methanol (6 ml) was stirred at ambient temperature for 2 hours. Water was added and the mixture adjusted to pH7 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried under vacuum. The solid was dissolved in methylene chloride/methanol and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The mixture was diluted with isopropanol, and the methylene chloride and methanol solvents were removed by evaporation. The resulting precipitate was collected by filtration, washed with methylene chloride and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline hydrochloride (270 mg, 94%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14]CCCCCC=CCCC.CI>C1C=CC=CC=1>[CH3:14][O:12][C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:9]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCCC=CCCCCCC
Solvent: c1ccccc1
Solvent: CI
Product: COC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo 5.4.0!-undec-7-ene (DBU; 40.19 g, 0.264 mol) in one portion. To the above clear solution added 74.94 g (0.528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring and then cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, a saturated sodium bicarbonate solution, and then brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4%) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1.[OH2:43].C(OCC)(=O)C>ClCCl.CO>[CH2:1]([S:3]([C:4]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:7]2=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)(=[O:40])=[O:43])[CH3:2]
Reactant: O
Reactant: CCSc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCS(=O)(=O)c1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
6.4 g (15 retool) of 2-ethylthio-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H- imidazo[4.5-b]pyridine was dispersed in 150 ml of dichloromethane. 150 ml of a dichloromethane solution of 3.94 g (23 mmol) of meta-chloro-perbenzoic acid was added dropwise to the solution over 40 minutes, while agitated and cooled with water and ice. The mixture was stirred at room temperature for 20 minutes. The reaction product mixture was washed separately with 10% aqueous solution of sodium bisulfate, a saturated aqueous solution of sodium bicarbonate and a saturated saline. The dichloromethane phase was separated and taken, then dried with aqueous magnesium sulfate. The solvent was distilled out at a reduced pressure and the residue was treated chromatographically with silicagel to obtain 5.93 g of the above named compound from the eluate of ethyl acetate and methanol (9:1 v/v).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:15]=[CH:14]3)=[CH:5][CH:4]=1>COC(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:15]=[CH:14]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(C=Cc2ccc3c(=O)n(CCCN(C)C)ncc3c2)cc1
Agent: [Pd]
Agent: COC(C)O
Product: COc1ccc(CCc2ccc3c(=O)n(CCCN(C)C)ncc3c2)cc1
Reaction time: 2 h

Procedure:
6-[2-(4-methoxyphenyl)ethenyl]-2-[3-(dimethylamino)propyl]phthalazin-1(2H)-one (9 gm) was dissolved in 200 ml methoxyethanol and reduced on a Parr hydrogenator using 1 gm of 10% palladium on carbon as catalyst. Reduction was complete within 2 hours. The catalyst was filtered off, the solvent removed on a rotary evaporator and the residue recrystallized from 500 ml of isoproanol. The product weighed 8.3 gm and melted at 201°-203° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH3:15])[C:12]2[CH:16]=[CH:17][C:18]([N:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH3:21])=[CH:19][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][NH:30][S:31]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)(=[O:33])=[O:32]>>[ClH:28].[CH3:29][NH:30][S:31]([CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:24]2[N:23]=[C:22]([N:20]([C:18]3[CH:17]=[CH:16][C:12]4[N:13]([CH2:14][CH3:15])[C:9]([NH:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:10][C:11]=4[CH:19]=3)[CH3:21])[CH:27]=[CH:26][N:25]=2)=[CH:40][CH:41]=1)(=[O:32])=[O:33]
Reactant: CCn1c(NCc2ccccc2)nc2cc(N(C)c3ccnc(Cl)n3)ccc21
Reactant: CNS(=O)(=O)CCc1ccc(N)cc1
Product: CCn1c(NCc2ccccc2)nc2cc(N(C)c3ccnc(Nc4ccc(CCS(=O)(=O)NC)cc4)n3)ccc21
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N2-Benzyl-N5-(2-chloro-pyrimidin-4-yl)-1-ethyl-N5-methyl-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 2-(4-amino-phenyl)-ethanesulfonic acid methylamide (54 mg, 0.25 mmol) as a white solid (74 mg, 49%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.04 (s, 1H), 7.75 (d, J=6.0 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.23-7.42 (m, 7H), 7.07-7.12 (m, 3H), 6.94 (q, J=5.1 Hz, 1H), 6.83 (dd, J=8.4 and 2.1 Hz, 1H), 5.63 (d, J=5.7 Hz, 1H), 4.61 (d, J=5.7 Hz, 2H), 4.11 (q, J=6.9 Hz, 2H), 3.41 (s, 3H), 3.32 (s, 3H), 3.20-3.25 (M, 2H), 2.83-2.88 (M, 2H), 2.59 (d, J=4.8 Hz, 3H), 1.26 (t, J=6.9 Hz, 3H). MS (ESI) m/z=571 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:28]([O-])([O-])([O-])[O:29][CH2:30][C:31]([F:34])([F:33])[F:32]>>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]2[C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=[C:28]2[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[CH:15][CH:16]=1)#[N:27]
Reactant: [O-]C([O-])([O-])OCC(F)(F)F
Reactant: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Product: COC(=O)c1cccc2nc(OCC(F)(F)F)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 25 %

Procedure:
The title compound was prepared as pale yellow crystals from methyl 3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate and 2,2,2-trifluoroethyl orthocarbonate according to the procedure for Working Example 3. Yield: 25%, m.p. 143-145° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:33][CH2:32][C:27]2([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:14])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)c3ccc(Cc4ccccc4)cc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 56.1 %

Procedure:
4-Benzyl-benzoic acid (21.2 mg, 0.100 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (23.5 g, 0.100 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (41.8 μL, 0.300 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (38.0 mg, 0.100 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (24.1 mg, 0.0561 mmol, 56.1%) ESI-MS m/z calc. 429.2, found 430.4 (M+1)+. Retention time of 3.75 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@@H:17]2[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18]2)[C:13]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])([CH3:38])[CH3:40])[N:32]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@@H]2CCC(F)(F)C2)C(=O)O)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(C[C@@H]2CCC(F)(F)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3,3-difluoro-cyclopentyl)-propionic acid (210 mg, 0.57 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 329 μL, 0.66 mmol) which produced gas evolution and was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to about 2 mL. In another round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 97 mg, 0.63 mmol), 2,6-lutidine (95 μL, 0.86 mmol) and methylene chloride (10 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 mL) dropwise. The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture diluted with methylene chloride (10 mL). The organic layers were then washed with a saturated aqueous sodium bicarbonate solution (10 mL). The aqueous layer was then extracted with methylene chloride (2×10 mL). The organics were combined and then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an Isco flash system (12 g column, 40% ethyl acetate/hexanes to 65% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3,3-difluoro-cyclopentyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (as a mixture of two diastereomers, 207 mg, 72%) as a light yellow foam: ES-HRMS m/e calcd for C22H28N3O4SClF2 (M+H)+ 504.1530, observed 504.1526; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.42 (m, 1H, CH), 1.65-2.29 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.90 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.0 Hz, 1H, Ar), 7.52 (d, J=2.0 Hz, 1H, Ar), 7.60 (d, Jo=8.3 Hz, 1H, Ar), 7.71 (s, 1H, Ar), 8.01 (d, Jo=8.3 Hz, 1H, Ar), 10.85 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([OH:27])=[CH:22][CH:23]=3)[CH:18]2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[ClH:50].[N:51]1([CH2:57][C:58](O)=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.C(N(CC)CC)C>>[ClH:50].[ClH:50].[CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:27][C:58](=[O:59])[CH2:57][N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[CH:22][CH:23]=3)[CH:18]2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccc(O)cc3C2C)c1C
Reactant: O=C(O)CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccc(OC(=O)CN4CCOCC4)cc3C2C)c1C

Procedure:
The same procudures as in Example 167 were repeated using 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), 4-morpholineacetic acid hydrochloride(28.8 mg, 0.158 mmol), and triethylamine(46 μl, 0.330 mmol) to afford the titled compound.