Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C)C=O.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1>O>[Cl:1][C:19]1[C:20]([CH3:22])=[CH:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=1
Reactant: COc1cc(C)ccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(Cl)cn1
Reaction time: 18 h
Yield: 83 %

Procedure:
9.2 g (69 mmol) of N-chlorosuccinimide was charged to a N,N-dimethylformamide (DMF) 15 ml solution of 8.0 g (65 mmol) of 2-methoxy-4-methylpyridine, followed by stirring for 18 hours. Water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 8.5 g (yield: 82%) of 5-chloro-2-methoxy-4-methylpyridine (melting point 32 to 33° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.C1(O[C:32]#[N:33])C=CC=CC=1.O>O1CCCC1.CCCCCC>[CH2:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:32]#[N:33])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Reactant: N#COc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#CC#N)cc2)CC1
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.2 g of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene (prepared according to Example 3) in 50 ml of absolute tetrahydrofuran was placed at -40° C. in a sulphonation flask under argon gasification and treated with 4.72 ml of a 1.2N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at -40° C. for a further 15 minutes, subsequently treated at -78° C. with 1.07 ml of phenyl cyanate and stirred at -78° C. for a further 45 minutes. The mixture was then poured into 50 ml of water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the crystalline residue on silica gel with 3% ethyl acetate/petroleum ether gave 1.20 g (91%) of p-(trans-4-pentylcyclohexyl)phenylpropiolonitrile as colourless crystals (purity 99.6%). A single crystallization from 50 ml of methanol yielded 687 mg of the product with m.p. (C-N) 49.7° C. and cl.p. (N-I) 128.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(OC(=O)C)(=[O:17])C.FC(F)F.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:13][OH:17])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(Cl)c[n+]([O-])c1C
Agent: Cl
Agent: FC(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Cl)cnc1CO
Reaction time: 72 h
Yield: 20 %

Procedure:
To a solution of ethyl 5-chloro-2-methylnicotinate 1-oxide (step 3, 4.1 g, 19 mmol) in dichloromethane (100 ml) was added trifluoromethane acetic acid anhydride (4 ml) at room temperature and the reaction mixture was stirred for 3 days. The reaction mixture was added 2 N hydrochloric acid solution (30 ml) with stirring. After 30 min, the whole mixture was extracted with dichloromethane. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20/1 to 4/1) to afford 840 mg (20%) of the title compound:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@H:8]([C:9](=[O:39])[NH:10][C@@H:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:12](=[O:34])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][C@H:24]2[C@@H:31]3[C@@H:27]([NH:28][C:29](=[O:32])[NH:30]3)[CH2:26][S:25]2)[O:7]1)=[O:5])C.[Li+].[OH-]>CO.O>[CH3:37][CH:36]([CH3:38])[CH2:35][C@H:11]([NH:10][C:9]([C@H:8]1[O:7][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:39])[C:12](=[O:34])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][C@H:24]1[C@@H:31]2[C@@H:27]([NH:28][C:29](=[O:32])[NH:30]2)[CH2:26][S:25]1
Reactant: CCOC(=O)[C@H]1O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H]1O[C@@H]1C(=O)O)C(=O)NCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Yield: 24.6 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 17h (155 mg, 0.3 mmol): LiOH (14 mg, 0.58 mmol); MeOH/H2O (1.5 mL: 0.5 mL: 0.5 mL); yielded 27 as a white solid (40 mg, 27.1%). 1H NMR (DMSO-d6, 400 MHz): 8.56 (d, 1H); 8.06 (t, 1H); 7.76 (t, 1H); 6.41 (s, 1H), 6.35 (s, 1H); 4.57 (m, 2H); 4.31 (m, 1H); 3.66 (d, 1H); 3.31 (d, 1H); 3.08 (m, 1H); 3.01 (m, 3H); 2.80 (dd, 1H); 2.56 (d, 1H); 2.04 (t, 2H); 1.53 (m, 6H); 1.43 (m, 3H); 1.36 (m, 2H); 0.89 (d, 3H); 0.84 (d, 3H). 13C NMR (DMSO-d6, 100 MHz): 171.80, 171.06, 568.78, 164.85, 162.68, 61.00, 59.16, 55.36, 52.65, 51.19, 41.14, 35.17, 28.17, 27.98, 26.59, 26.45, 25.28, 24.24, 22.87, 21.61. ESI-HRMS (m/z): no ionization, mass not seen. HPLC Method 1: Rt=14.8 min, purity=95.6%.
Reaction SMILES: [Na].[CH3:2][N:3]([CH2:5][CH2:6][OH:7])[CH3:4].[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>C1(C)C=CC=CC=1>[CH3:2][N:3]([CH3:4])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCBr
Reactant: CN(C)CCO
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCOCCN(C)C

Procedure:
5.8 g (0.25 mol) sodium was added to a solution of 22 g (0.25 mol) N,N-dimethylaminoethanol in 350 ml dry toluene. After all the sodium had reacted, 35 g (0.25 mol) butyl bromide was added and the reaction mixture was subsequently refluxed for 2 hours. The reaction mixture was then cooled and washed with water. The toluene layer was extracted with dilute hydrochloric acid. The aqueous layer was subsequently rendered basic with respect to phenolphthalein and extracted with ether. The ether layer was dried and ether evaporated off. The residue was distilled. The dimethyl(2-butoxyethyl)amine obtained had a boiling point of 163°-164° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[Br:12])C>C1(C)C=CC=CC=1>[Br:12][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:6][CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CCc1ccsc1Br
Solvent: Cc1ccccc1
Product: OCCCc1ccsc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A −78° C. solution of the ester of Example 23(e) (3.896 g, 14.8 mmol) in dry toluene (30 mL, Aldrich) was treated with Dibal (21 mL, 31.5 mmol, 1.5 M/toluene, Aldrich). After 1 h, the mixture was allowed to warm to 0° C. and after a further 1 h, the reaction was quenched by addition of 6 M HCl (30 mL). The mixture was stirred for 15 min. and then was extracted with ether (50 mL). The ether solution was washed with 1 M HCl (2×30 mL) and brine (30 mL) and then was dried (MgSO4), filtered, evaporated and purified by flash chromatography (20% ethyl acetate/hexanes→30%) to give 3-(2-Bromo-thiophen-3-yl)-propan-1-ol (3.224 g, 14.6 mmol, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: N#Cc1cccc(O)c1
Product: N#Cc1cccc(Oc2ccc(C=O)cc2F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3-hydroxybenzonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:33])[CH2:29][C:30](O)=[O:31])[CH:4]=[N:3]1.[NH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].CCN=C=NCCCN(C)C.Cl.O>O1CCCC1.ClCCl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:5]([NH:27][C:28](=[O:33])[CH2:29][C:30]([NH:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:31])[CH:4]=[N:3]1
Reactant: Cn1ncc(NC(=O)CC(=O)O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cn1ncc(NC(=O)CC(=O)NCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a suspension of 3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropanoic acid (600 mg) and tert-butyl (2-aminoethyl)carbamate (240 mg) in tetrahydrofuran (12 ml) and dichloromethane (6 ml) was added WSCD HCl (522 mg), and the whole mixture was stirred at room temperature overnight. To the reaction mixture was added water (3 ml), and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over magnesium sulfate. The evaporation of the solvent gave a crude residue, which was triturated with diisopropyl ether-ethyl acetate (2:1) to give tert-butyl {2-[(3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropanoyl)amino]ethyl}carbamate (537 mg).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1([CH3:45])[CH2:18][CH2:17][N:16]([C:19]2[C:20]3[O:44][CH:43]=[CH:42][C:21]=3[N:22]=[C:23]([NH:25][C:26]3[CH:34]=[C:33]4[C:29]([CH:30]=[N:31][N:32]4C(OC(C)(C)C)=O)=[CH:28][CH:27]=3)[N:24]=2)[CH2:15][CH2:14]1)=O)C1C=CC=CC=1.ClC1N=C(Cl)C2OC=CC=2N=1.CC1(CNC(=O)OCC2C=CC=CC=2)CCNCC1.NC1C=C2C(C=NN2C(OC(C)(C)C)=O)=CC=1.Br>CC(O)=O.O>[NH2:11][CH2:12][C:13]1([CH3:45])[CH2:18][CH2:17][N:16]([C:19]2[C:20]3[O:44][CH:43]=[CH:42][C:21]=3[N:22]=[C:23]([NH:25][C:26]3[CH:34]=[C:33]4[C:29]([CH:30]=[N:31][NH:32]4)=[CH:28][CH:27]=3)[N:24]=2)[CH2:15][CH2:14]1
Reactant: CC1(CNC(=O)OCc2ccccc2)CCN(c2nc(Nc3ccc4cnn(C(=O)OC(C)(C)C)c4c3)nc3ccoc23)CC1
Agent: Br
Agent: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Agent: CC1(CNC(=O)OCc2ccccc2)CCNCC1
Solvent: O
Solvent: CC(=O)O
Product: CC1(CN)CCN(c2nc(Nc3ccc4cn[nH]c4c3)nc3ccoc23)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a mixture of tert-butyl 6-(4-(4-((benzyloxycarbonylamino)methyl)-4-methylpiperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-1H-indazole-1-carboxylate (0.13 g, 0.213 mmol, (prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] with benzyl (4-methylpiperidin-4-yl)methylcarbamate [U.S. Pat. No. 6,140,333 example 3 step 5]), B with tert-butyl 6-amino-1H-indazole-1-carboxylate [Frontier] and C) in AcOH (3 mL) was added HBr (1 mL). The mixture was stirred at about 40° C. for about 8 h. Water (30 mL) was added and the mixture was extracted with DCM (4×20 mL). The mixture was concentrated in vacuo to give 4-(4-(aminomethyl)-4-methylpiperidin-1-yl)-N-(1H-indazol-6-yl)furo[3,2-d]pyrimidin-2-amine (0.015 g, 19%): LC/MS (Table 2, Method h) Rt=1.72 min; MS m/z: 378 (M+H)+. Syk IC50=A
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[C:23](=[O:25])[CH3:24].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:24]/[C:23]([C:16]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][CH3:13])=[O:25])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: COc1ccc(OC)c(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cc(OC)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
To a stirred solution of 4-propoxybenzaldehyde (1 g, 6.1 mmol) and 2′,5′-dimethoxyacetophenone (1.1 g, 6.1 mmol) in methanol (15 ml) was added 50% w/v solution of aqueous sodium hydroxide (9.7 ml, 0.122 mol). The reaction mixture was stirred at room temperature for 18 h. A precipitate was isolated by filtration and subsequently recrystallised from ethanol to afford 0.97 g (49%) of pale yellow crystals. 1H-NMR (CDCl3) δ 1.0 (t, 3H), 1.8 (m, 2H), 3.7 (s, 3H), 3.8 (s, 3H), 3.9 (t, 2H), 6.9 (m, 3H), 6.9 (d, 1H) 7.15 (d, 1H), 7.25 (d, 1H), 7.5 (m, 3H), 13C-NMR (CDCl3) δ 192.59, 160.86,161.11, 153.59, 152.34, 130.07, 127.56, 22.47. Mass Spectrum m/e (M+1) 327. Anal. Calcd. for C20H2O4: C, 73.62; H, 6.75. Found C, 73.55; H, 6.88.
Reaction SMILES: S(N)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=O)=O.C[C:13]([OH:15])=[O:14]>[Zn]>[C:4]12([C:13]([OH:15])=[O:14])[CH2:8][CH:7]([CH2:9][CH2:10]1)[CH:6]=[CH:5]2
Reactant: CC(=O)O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [Zn]
Product: O=C(O)C12C=CC(CC1)C2
Yield: 96.8 %

Procedure:
Compound 4 (27.0 g; 0,062 mole) and Zn° (16.2 g; 0,249 mol) were combined in HOAc (100 ml) and heated to reflux for one half hour. The reaction mixture was cooled and filtered through Celite®. The filtrate was concentrated and the residue suspended in H2O, whereupon the oil crystallized. The solid was filtered, washed with H2O and suction dried to yield 18.4 g (96.8%) of Compound 5 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.N1C=CC=CC=1.[CH:39]1[C:51]2[CH:50]([CH2:52][O:53][C:54](Cl)=[O:55])[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]=2[CH:42]=[CH:41][CH:40]=1.Cl>C(Cl)Cl.O>[CH:39]1[C:51]2[CH:50]([CH2:52][O:53][C:54]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([S:8][C:9]4[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=4[N+:18]([O-:20])=[O:19])=[CH:6][CH:7]=3)=[O:55])[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]=2[CH:42]=[CH:41][CH:40]=1
Reactant: Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A suspension of the product of Example 52A (1.00 g, 3.445 mmol) in anhydrous methylene chloride (40 mL) was treated with N,O-bis(trimethylsilyl)acetamide (1.77 mL, 7.234 mmol) dropwise, and the resulting orange-colored solution was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Anhydrous pyridine (0.557 mL, 6.89 mmol) was then added, followed by solid 9-fluorenylmethoxycarbonyl chloride (1.114 g, 4.306 mmol) in three portions. The reaction was stirred for 30 minutes, then poured into water (75 mL) and adjusted the pH to 1 with 1N aqueous hydrochloric acid. After stirring for 15 minutes at room temperature, the mixture was transferred to a separatory funnel and extracted with ethyl acetate (500 mL, followed by 2×150 mL). The combined organic extracts were washed with water (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Trituration with methylene chloride provided the title compound as a yellow solid (1.29 g, 73%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][CH2:54][CH3:55])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][CH2:54][CH3:55])[CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOc1cccc(OB([O-])[O-])c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOc1cccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-propoxyphenyl borate (125 mg) and potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 8 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(3-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 109) (282 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6]C(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:45]=[C:46]([C:50]2[C:51]([C:56](O)=[O:57])=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:47]=[CH:48][CH:49]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:56]([C:51]1[C:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:45]=2)=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:57]
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: O=C(O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccccc1-c1cccc(CSCCOc2ccccc2)c1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.95 g, 2.61 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.43 g, 2.66 mmol, 1.02 eq.) and 3-(dimethylamino)propylamine (0.32 g, 3.13 mmol, 1.2 eq.) as described. When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.[CH3:27][C:28](O)([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:9][C:10]([O:12][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:11])=[CH:5][CH:6]=1
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 62 h
Yield: 38 %

Procedure:
A solution of 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoic acid (250 mg, 0.703 mmol), tBuOH (0.135 ml, 1.407 mmol), EDCl (270 mg, 1.407 mmol) and 4-dimethylaminopyridine (86.0 mg, 0.704 mmol) in DCM (7 ml) is allowed to stir at room temperature under nitrogen for 62 hours. The reaction is quenched with water, and the organic layer is separated and concentrated. The residue is purified by flash column chromatography on silica gel to give tert-butyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (110 mg); HPLC retention time=1.77 minutes (condition B); MS (ES+)=412.1 (m+1) 300.0 (m-tBux2+3; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (s, 9H) 1.47 (s, 9H) 2.36 (A of ABX, Jab=15.5 Hz, Jax=6.2 Hz, 1H) 2.44 (B of ABX, Jab=15.5 Hz, Jbx=5.6 Hz) 2.82-2.94 (m, 2H) 4.11-4.17 (m, 1H) 5.08-5.10 (m, 1H) 7.25-7.34 (m, 3H) 7.41-7.44 (m, 2H) 7.51-7.58 (m, 4H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.CC(C)([O-])C.[K+].O>C1COCC1.CO>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[N:17]=[C:16]([NH:18][C:24]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:25])[CH:15]=[CH:14][N:13]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccnc(N2CCN(C3CCCC3)CC2)n1
Reactant: O=C(Cl)C1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(Nc1ccnc(N2CCN(C3CCCC3)CC2)n1)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.8 %

Procedure:
A mixture of 10 mg (0.04 mmol) 2-(4-cyclopentyl-piperazin-1-yl)-pyrimidin-4-ylamine, 10.8 mg (0.082 mmol) cyclopentylcarbonyl chloride and 13.5 mg (0.12 mmol) potassium t-butoxide in 0.7 mL THF was shaken at room temperature for 16 h. The mixture was treated with water and methanol and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 3 mg (21%) of the title compound as white solid. MS (m/e): 344.1 (MH+).
Reaction SMILES: [Na+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=[O:20])[CH:18]=[CH2:19])([CH3:15])([CH3:14])[CH3:13].C(O)C.C(O)(=O)C>C(OCC)(=O)C>[C:12]([O:16][C:17](=[O:20])[CH2:18][CH2:19][S:9]([C:6]1[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CCS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of 4-bromophenylsulfinic acid sodium salt (729 mg), 2-propenoic acid t-butyl ester (439 μl), 95% ethanol (4 ml) and acetic acid (372 μl) was stirred for 12 hours at room temperature. Further, 2-propenoic acid t-butyl ester (2.20 ml) was added to the mixture and it was refluxed for 4 hours. The reaction mixture was diluted with ethyl acetate. The mixture was washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (872 mg) having the following physical data.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH2:5][Cl:6].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)([O-])O.[Na+]>O.C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16]([NH:2][C@@H:3]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](=[O:7])[CH2:5][Cl:6])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)CCl
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 83 %

Procedure:
(3S)-3-Amino-1-chloro-4-phenyl-2-butanone hydrochloride (100 mg) was dissolved in water (4.3 ml). A solution (5.3 ml) of benzyl chloroformate (0.794 ml) in toluene was added to the obtained solution. Further, an aqueous solution (1.0 ml) of sodium hydrogencarbonate (71.9 mg) was added dropwise to the obtained mixture. They were stirred at room temperature for 50 minutes to conduct the reaction and then the aqueous layer was separated. The obtained toluene layer was analyzed by HPLC to find that (3S)-3-benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone (118 mg) was obtained in a yield of 83%.