Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>O1CCCC1.CO>[C:36]([N:25]1[CH2:24][CH:23]([C:16]2[C:15]([O:27][CH3:28])=[C:14]([CH:12]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([CH3:11])=[N:9]3)[CH3:13])[CH:21]=[C:20]([Cl:22])[C:17]=2[C:18]#[N:19])[CH2:26]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)=O)C1
Temperature: 20 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (60 mg, 0.15 mmol) in tetrahydrofuran (2 mL) at 0° C. was treated with triethylamine (53 μL, 0.38 mmol) followed by acetyl chloride (13 μL, 0.18 mmol) and stirred at 20° C. overnight. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (39 mg, 59%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.52 (d, J=2.5 Hz, 1H), 7.36 (br s, 2H), 6.26 (q, J=7.0 Hz, 1H), 4.57-4.36 (m, 3H), 4.30-4.21 (m, 1H), 4.18-4.08 (m, 1H), 3.71 (d, J=3.1 Hz, 3H), 2.55 (s, 3H), 1.78-1.71 (m, 6H). LCMS for C21H23ClN7O2 (M+H)+: m/z=440.2; Found: 440.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=1)[NH2:17].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:17][C:16]1[CH:18]=[C:12]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[CH:14][C:15]=1[CH3:19]
Reactant: Cc1ccc(Br)cc1N
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1N
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (3.7 g, 0.003 mol) and 4-chlorophenylboronic acid (20.2 g, 0.13 mol) are added to a solution of 5-bromo-2-methylaniline (20 g, 0.1 mol) in 1,2-dimethoxyethane (200 ml). After stirring the reaction mixture for 15 minutes at 20° C., a solution of 20% aqueous sodium carbonate (300 ml) is added to the mixture, and the resulting mixture is heated at reflux for 24 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and extracted using ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 3-amino-4′-chloro-4-methylbiphenyl (21.0 g).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:27][C:28]1[C:29]([OH:37])=[C:30]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[CH:31]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.C(N(CC)CC)C>[Cl:27][C:28]1[C:29]([OH:37])=[C:30]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[CH2:31][N:12]1[CH2:13][CH2:14][C:9]([CH2:15][N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])([F:8])[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CC1(F)CCNCC1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CC1(F)CCN(Cc2cc(Cl)cc(Cl)c2O)CC1
Reaction time: 0.08 h

Procedure:
Triethylamine (9 ml) was added to a solution of a trifluoroacetic acid salt of 2-(4-fluoro-piperidin-4-ylmethyl)-isoindole-1,3-dione (22.6 g) in dichloromethane (300 ml). The obtained solution was stirred for 5 minutes, and then 3,5-dichloro-2-hydroxy-benzaldehyde (12.4 g) and NaBH(OAc)3 (19 g) were added and the mixture was stirred at room temperature for 3 hours. The obtained solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, the dichloromethane was concentrated out, and the residue was recrystallized from ether to obtain 2-[1-(3,5-dichloro-2-hydroxy-benzyl)-4-fluoro-piperidin-4-ylmethyl]-isoindole-1,3-dione.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]2[CH:15]=[C:14]([Br:23])[CH:13]=[CH:12][C:5]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(N)sc2cc(Br)ccc12
Yield: 67.8 %

Procedure:
Ethyl 2-amino-1-benzothiophene-3-carboxylate (10.4 g, 44.7 mmol) was dissolved in chloroform (100 mL) and treated with NBS (7.95 g, 44.7 mmol). Upon completion of the reaction, a light tan solid precipitated from the mixture. The slurry was concentrated to ˜30% of the original volume on a rotavap and then filtered. The solid was slurried in EtOAc (300 mL) and treated with satd NaHCO3 (200 mL) to obtain two clear phases. The organic phase was washed further with satd NaHCO3 (4X˜200 mL) and water (200 mL). The organic layer was collected, dried with sodium sulfate, filtered, and concentrated to yield an off-white solid (9.1 g, 68%). 1H NMR (DMSO-d6) δ 8.00 (s, 2H), 7.85 (s, 1H), 7.83 (d, 1H), 7.36 (d, 1H), 4.28 (q, 2H), 1.33 (t, 3H).
Reaction SMILES: [N:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br>C(OCC)C>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[C:10]1=[O:15]
Reactant: BrBr
Reactant: O=C1CCCCC1C(=O)N1CCCCC1
Solvent: CCOCC
Product: O=C1C(Br)CCCC1C(=O)N1CCCCC1
Temperature: 0 °C
Yield: 107 %

Procedure:
2-(piperidine-1-carbonyl)-cyclohexanone (19) (4.0 g, 19 mmol) was dissolved in diethyl ether (5 mL) and cooled to 0° C. under N2. Bromine (5.9 g, 19 mmol, 1.0 mL) was added dropwise over 15 min and the reaction mixture was allowed to warm to room temperature over 90 min. The solid was collected by filtration to give 5.86 g (quantitative) of 2-bromo-6-(piperidine-1-carbonyl)-cyclohexanone (20) as a white solid which was used in the next step without purification. The structure, was confirmed by 13C NMR (75 MHz, DMSO-d6) δC 17.3, 24.2, 25.3, 25.8, 32.5, 44.0, 51.6, 108.3, 145.5, 167.8.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:17])([C:14](O)=[O:15])[O:13][C:9]=2[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[O:22][Si:23]([CH3:26])([CH3:25])[CH3:24])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:29](CC)[CH2:30][CH3:31])[CH3:28].N1CCCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[C:1]([C:5]1[C:10]2[CH2:11][C:12]([CH3:17])([C:14]([N:29]3[CH2:30][CH2:31][CH2:28][CH2:27]3)=[O:15])[O:13][C:9]=2[CH:8]=[C:7]([C:18]([CH3:20])([CH3:19])[CH3:21])[C:6]=1[O:22][Si:23]([CH3:25])([CH3:26])[CH3:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC1(C(=O)O)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC1(C(=O)N2CCCC2)Cc2c(cc(C(C)(C)C)c(O[Si](C)(C)C)c2C(C)(C)C)O1
Reaction time: 4 h
Yield: 92 %

Procedure:
In 3 ml of dichloromethane were dissolved 0.20 g of 4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carboxylic acid, 0.20 ml of triethylamine and 0.06 ml of pyrrolidine at room temperature, and 0.35 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate was added and the mixture was stirred for 4 hours. The mixture was extracted with water and diethyl ether, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography eluting with n-hexane containing 33% ethyl acetate to give 0.21 g of 1-(4,6-di-t-butyl-2-methyl-5-trimethylsilyloxy-2,3-dihydrobenzofuran-2-carbonyl)pyrrolidine as a colorless solid (yield 92%).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH3:43])=[O:41]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH3:43])=[O:41])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC)cc1)n2C)c1ccccc1
Yield: 41 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and methyl chloroformate. Yield: 41% of theory, C30H32N6O5 (556.6) Rf value: 0.85 (silica gel; dichloromethane/ethanol=4:1) ##EQU62##
Reaction SMILES: OC1O[C@H](C)[C@H](O)C[C@H]1O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)#[N:12].C([O-])([O-])=O.[K+].[K+].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br>CC(C)=O>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: Fc1cccc(CBr)c1
Agent: C[C@H]1OC(O)[C@H](O)C[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 87.2 %

Procedure:
(Nakamoto, Kazutaka; Tsukada, Itaru; Tanaka, Keigo; Matsukura, Masayuki; Haneda, Toru; Inoue, Satoshi; Ueda, Norihiro; Abe, Shinya; Hata, Katsura; Watanabe, Naoaki, WO 2005033079 (2005)). A mixture of 4-cyanophenol (11.91 g, 100.0 mmol), K2CO3 (55.20 g, 400.0 mmol), and 3-fluorobenzylbromide (22.68 g, 120.0 mmol) were heated in acetone (400 mL) at reflux (5 h). The volatiles were evaporated and the residue was diluted in CH2Cl2 (300 mL), and then washed with H2O (500 mL), dried (MgSO4), and concentrated in vacuo to give white needles (19.81 g, 87%): Rf=0.45 (hexanes/EtOAc 9/1); mp 104-105° C.; 1H NMR (CDCl3) δ 5.11 (s, CH2O), 6.98-7.20 (m, 5 ArH), 7.33-7.41 (m, 1 ArH), 7.59 (d, J=8.7 Hz, 2 ArH); HRMS (M+Na+) (ESI+) 250.0641 [M+Na+] (calcd for C14H10NONa+250.0641).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8]1.O>C1(C)C=CC=CC=1>[Br:2][CH2:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8]1
Reactant: BrP(Br)Br
Reactant: CC1(C)CC(CO)Sc2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CC(CBr)Sc2ccccc21
Reaction time: 1 h
Yield: 88 %

Procedure:
Phosphorus tribromide (1 ml, 10.7 mmol) is added drop by drop with a syringe at between 20 and 25° C. to a solution of the previous 6-(hydroxymethyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyrane (1.85 g, 8.9 mmol) in 6.2 ml of anhydrous toluene. The mixture was left to agitate for 1 hour and then hydrolysed at 0° C. by ice and then by water. This was then extracted with ethyl ether, dried over MgSO4, filtered and the solvents evaporated. 2.14 g of 6-(bromomethyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyrane is obtained (gross yield=88%).
Reaction SMILES: [CH3:1][C:2]1([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[N+:26]([O-])=O)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:29](OC)(OC)OC>>[CH3:1][C:2]1([N:15]2[C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=3[N:26]=[CH:29]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(OC)OC
Reactant: CC1(Nc2ccc(S(C)(=O)=O)cc2[N+](=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(C)(n2cnc3cc(S(C)(=O)=O)ccc32)CC1

Procedure:
Using tert-butyl 4-methyl-4-{[4-(methylsulfonyl)-2-nitrophenyl]amino}piperidine-1-carboxylate as starting material and following the procedure outlined in Method C, Step 2 but replacing trimethyl orthoacetate with trimethyl orthoformate, there is obtained tert-butyl 4-methyl-4-[5-(methylsulfonyl)-1H-benzimidazol-1-yl]piperidine-1-carboxylate.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH:42]=[C:41]2[C:54]1[CH:59]=[N:58][CH:57]=[C:56]([N:60]2[CH2:65][CH2:64][CH:63]([NH:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:62][CH2:61]2)[N:55]=1>C(Cl)Cl>[C:70]([O:69][C:67]([NH:66][CH:63]1[CH2:62][CH2:61][N:60]([C:56]2[N:55]=[C:54]([C:41]3[C:40]4[C:44](=[CH:45][CH:46]=[C:38]([NH:37][C:1](=[O:4])[CH2:2][CH3:3])[CH:39]=4)[N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH:42]=3)[CH:59]=[N:58][CH:57]=2)[CH2:65][CH2:64]1)=[O:68])([CH3:73])([CH3:72])[CH3:71]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(N)cc34)n2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc2c(c1)c(-c1cncc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To solution of propionyl chloride (52.5 mg, 0.708 mmol) in DCM (7 mL) at 0° C. was added Et3N (0.2 mL, 1.47 mmol), HBTU (292 mg, 0.75 mmol), tert-butyl 5-amino-3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-1H-indole-1-carboxylate (300 mg, 0.59 mmol) The resulting reaction mixture was stirred at RT for 3 h. The reaction mixture was extracted with DCM (14 mL), washed with brine, dried over Na2SO4, and concentrated to dryness. The crude product was purified by column chromatography to obtain the title compound (150 mg, 45%) as an off white solid. MS (ESI, pos. ion) m/z: 565.2 (M+1).
Reaction SMILES: C([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[C:8]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[CH:23]=2)[CH:7]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:22]2[CH:23]=[C:18]([C:8]3[CH:7]=[C:6]([NH2:5])[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[CH:9]=3)[CH:19]=[N:20][CH:21]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(-c2cncc(-c3cc(NC(C)(C)C)nc(-c4ccccn4)c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(-c2cncc(-c3cc(N)nc(-c4ccccn4)c3)c2)c1
Temperature: 70 °C

Procedure:
Tert-Butyl-[5″-(3-methoxy-phenyl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (1 eq, 0.073 mmol, 0.030 g) is dissolved in TFA (6 ml)/DCM (1 ml) and the reaction mixture is heated at 70° C. for 5 hours. The reaction mixture is cooled down and reduced in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 355.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:37])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([N:29]3[CH2:34][C@@H:33]([CH3:35])[NH:32][CH2:31][C@@H:30]3[CH3:36])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:16]=2)[CH2:9][CH2:8]1)[CH3:2].[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH:43]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:37])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([N:29]3[CH2:34][C@@H:33]([CH3:35])[N:32]([CH2:43][C:42]4[CH:45]=[CH:46][CH:47]=[C:40]([F:39])[CH:41]=4)[CH2:31][C@@H:30]3[CH3:36])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:16]=2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)CCN1CCCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)CCN1CCCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 3-(4-{3-[(R)-((2S,5R)-2,5-Dimethyl-piperazin-1-yl)-(3-hydroxy-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid ethyl ester (288 mg; Example 11), 3-fluorobenzaldehyde (137 mg) and acetic acid (66 mg) in DMF (3 mL) was stirred under nitrogen at room temperature for 20 minutes, followed by the addition of Na(OAc)3BH (292 mg). The reaction was stirred under nitrogen at room temperature for overnight. The reaction was quenched by the addition of H2O (4 mL). The solution was neutralized by sat. NaHCO3 solution to pH≅7. The solution was extracted by EtOAc (5 mL×3). The combined organic layer was washed by water (5 mL×2) and brine (5 mL×1), dried by Na2SO4 and concentrated to give crude product (300 mg), which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 3-(4-{3-[(R)-[(2S,5R)-4-(3-Fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxy-phenyl)-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid ethyl ester as white solid (120 mg; 35%). 1H NMR (300 MHz, CDCl3) δ 7.59-7.48 (m, 1H), 7.40-7.22 (m, 4H), 7.16-7.04 (m, 3H), 6.92 (m, 1H), 6.72 (m, 3H), 5.04 (bs, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.92 (m, 1H), 3.77 (m, 1H), 3.71 (m, 1H), 3.43 (m, 1H), 3.35 (m, 1H), 3.24 (m, 1H), 2.94-2.81 (m, 3H), 2.72-2.44 (m, 9H), 2.05 (m, 2H), 1.96 (m, 1H), 1.75 (bs, 1H), 1.26 (t, J=7.0 Hz, 3H), 1.06 (m, 6H).
Reaction SMILES: CC(CC(O)=O)=O.[CH3:8][CH:9]([O:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19][OH:20])=[CH:15][CH:14]=1)[CH2:10][CH3:11].[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24].CCOCC>CN(C=O)C.O>[CH2:23]([NH:25][C:26](=[O:27])[O:20][CH2:19][CH2:18][O:17][C:16]1[CH:21]=[CH:22][C:13]([O:12][CH:9]([CH3:8])[CH2:10][CH3:11])=[CH:14][CH:15]=1)[CH3:24]
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Reactant: CCN=C=O
Agent: CC(=O)CC(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)OCCOc1ccc(OC(C)CC)cc1
Temperature: 25 °C

Procedure:
Dibutylin diacetate (0.004 ml) is added to a solution of the above alcohol (0.42 g, 2.0 mmol) in 1.5 ml of DMF and the mixture is chilled in an ice bath. Ethyl isocyanate (0.18 ml, 2.2 mmol) is then added and the mixture is allowed to warm slowly to RT. The mixture is then poured into ether and water containing 10% potassium dihydrogen phosphate. The aqueous phase is extracted with ether, and the combined organic phases are washed with water and with brine, dried, filtered and the solvent is removed in vacuo to give O-2-[4-(1-methylpropoxy)phenoxy]ethyl N-ethylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][CH3:18])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[C:40]([CH2:42][NH2:43])[CH:39]=[C:38]([C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([F:54])([F:53])[F:52])=[CH:46][CH:45]=3)[N:37]=2)[CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:17][CH3:18])[C:12](=[CH2:16])[C:13]([NH:43][CH2:42][C:40]2[CH:39]=[C:38]([C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([F:54])([F:52])[F:53])=[CH:46][CH:45]=3)[N:37]=[C:36]([N:33]3[CH2:32][CH2:31][O:30][CH2:35][CH2:34]3)[CH:41]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)c1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)c1)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
Acid 4D (289.74 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 27D (1.1 equiv., 388 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded 140 mg of a pale yellow solid. Yield=22% 1HNMR (DMSO, 400 MHz) δ 1.15 (3H, t), 3.38 (2H, q), 3.50 (4H, m), 3.70 (4H, m), 4.40 (2H, d), 5.20 (1H, s), 6.18 (1H, s), 6.80 (1H, s), 7.20 (1H, s), 7.42 (2H, d), 7.76 (2H, d), 7.82 (2H, d), 8.18 (2H, d), 8.89 (1H, bt) [M+1] 626.9 (C28H28ClF3N4O5S requires 625.06).
Reaction SMILES: [CH:1]1([C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:29]([OH:31])=O)[CH2:26][CH2:27][CH3:28])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[SH:44][CH2:45][CH2:46][C:47]([NH:49][C:50]([CH3:55])([CH3:54])[C:51]([OH:53])=[O:52])=[O:48].C(N1CCOCC1)C>CN(C)C=O>[CH:1]1([C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:29]([S:44][CH2:45][CH2:46][C:47]([NH:49][C:50]([CH3:55])([CH3:54])[C:51]([OH:53])=[O:52])=[O:48])=[O:31])[CH2:26][CH2:27][CH3:28])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(NC(=O)CCS)C(=O)O
Reactant: CCC[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)C1CCCC1)C(=O)O
Agent: CCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)C1CCCC1)C(=O)SCCC(=O)NC(C)(C)C(=O)O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 10 mmoles of Nα -(Nα -cyclopentanecarbonyl-Nε -tert-butyloxycarbonyl-L-lysyl-norvaline in redistilled dimethylformamide (DMF) is cooled in an ice-dry ice-acetone bath at -20° C. To this solution is added a cold solution of 10 mmoles of 1,1'-carbonyldiimidazole in DMF. The solution is stirred at -10° C. for two hours and then mixed with a cold solution of 10 mmoles of 2-[(3-mercaptopropanoyl)amino]-2-methylpropanoic acid (from Example 46) in DMF which is neutralized with N-ethyl morpholine. The reaction mixture is storred at -10° C. for an additional hour and then slowly warmed to room temperature. The solvent is removed under reduced pressure at 40° C. and ethyl acetate is added to the residue. The mixture is cooled in an ice water bath and washed with 1N citric acid and then three times with saturated NaCl solution. The solvent is removed with a rotary evaporator after drying over anhydrous MgSO4. The product is purified by LH-20 column chromatography using a 1.2 cm by 95 cm column and eluted with THF:isopropanol, 3:7 (parts by volume). The peak fractions are pooled and the solvent is removed under reduced pressure yielding the named product.