Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[I:10]I>[OH-].[Na+]>[I:10][C:5]1[C:6]([OH:8])=[N:7][C:2]([CH3:1])=[N:3][C:4]=1[CH3:9]
Reactant: Cc1cc(O)nc(C)n1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(C)c(I)c(O)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
The crude compound 326-1 (25.6 g) was dissolved in a 1.25 N sodium hydroxide aqueous solution (140 ml). Iodine (19.9 g) was added to the solution, and the obtained mixture was then stirred at 120° C. for 2 hours. The temperature of the reaction solution was returned to room temperature, and the reaction solution was then extracted with chloroform. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure, so as to obtain the title compound (14.5 g).
Reaction SMILES: CCO.CC(O)C.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][N:18](C(OCC2C=CC=CC=2)=O)[C:19]([NH:21]C(OCC2C=CC=CC=2)=O)=[NH:20])[CH2:11][CH2:10]1.[H][H]>[Pd].O>[CH3:8][N:9]1[CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[NH:20])[CH2:13][CH2:14]1
Reactant: CN1CCC(CCCN(C(=N)NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Solvent: CCO
Solvent: O
Product: CN1CCC(CCCNC(=N)N)CC1
Reaction time: 1.5 h

Procedure:
A 13 gal (50 liter) Hastelloy pressure reactor equipped with a mechanical agitator, cooling/heating jacket, and addition lines was charged with a solution of 95/5 EtOH/IPA (27.00 kg) and N-[3-(1-methylpiperidin-4-yl)-propyl]-N,N′-di-Cbz-guanidine (7.28 kg, 14.97 mol). To the resultant solution, under nitrogen, was then added 10% Pd/C (50% wet, 0.50 kg). The reactor was sealed and sequentially placed under vacuum, nitrogen and vacuum to displace any air in the system. The reaction was stirred at 1000 RPM and 300-350 PSI of hydrogen while keeping the temperature below 35° C. using cooling water on the jacket. The reaction ceased to be exothermic after approximately 1.5 hours and was stirred for an additional hour at 300-350 PSI. The resultant slurry was filtered over Celite® to yield a solution containing the title compound. The solution was stored at 5° C. and used in the next step without further isolation or purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]([OH:17])=O)[C:8]3[N:9]2[N:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1.C(Cl)(C(Cl)=O)=O.N1C=CC=CC=1.[NH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]([NH:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[O:17])[C:8]3[N:9]2[N:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cc2ccc(Cl)cc2n2nnnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1cc2ccc(Cl)cc2n2nnnc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of carboxytetrazole (5, 0.05 g, 0.2 mmol) in CH2Cl2 (5 mL) at 0° C. under N2 was added DMF (4-drops) followed by (COCl)2 (IM CH2Cl2, 0.15 mL, 0.3 mmol) and the reaction was stirred for 1 h. The reaction solvent was removed and the resulting residue of acid chloride was dried under high vacuum. The acid chloride was then suspended in CH2Cl2 (5 mL), cooled to 0° C., to it was added pyridine (0.033 mL, 0.4 mmol) followed by H2N-OTHP (0.035 g, 0.3 mmol), and stirred at room temperature for 24 h. The CH2Cl2 solution was washed with water, dried and solvent was evaporated. The resulting residue was filtered through a pad of silica gel to obtain the requisite oxamic acid ester 6. 1H NMR (CDCl3): δ 11.58 (s, 1H), 8.92 (s, 1H), 8.74 (d, 1H, J=1.8 Hz), 8.10 (d, 1H, J=8.1 Hz), 7.77 (dd, 1H, J=1.8 Hz and 8.7 Hz), 5.26 (m, 1H), 4.15 (m, 1H), 3.76 (m, 1H), 2.10-1.50 (m, 6H); LCMS (ret. time): 21.46 min.; MS (m/z): 347 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.O.[NH2:13][NH2:14]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:13][NH:14]2)=[CH:8][C:9]=1[F:10]
Reactant: NN
Reactant: O=Cc1cc(F)c(Cl)cc1F
Solvent: O
Solvent: CCCCO
Product: Fc1cc2cn[nH]c2cc1Cl
Temperature: 140 °C
Reaction time: 72 h
Yield: 15.7 %

Procedure:
A mixture of 4-chloro-2,5-difluorobenzaldehyde (20.6 g, 105.0 mmol) and hydrazine hydrate (77.2 mL, 1575.2 mmol, 15 eq) in n-butanol (35 mL) was stirred at 140° C. for 3 days. The mixture was cooled to room temperature and poured into ice water (750 mL). The mixture was stirred vigorously for 2 h, and the orange solid was filtered. The filtrate was extracted with EtOAc (3×250 mL), and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was combined with the orange solid and then purified by MPLC (Biotage®, gradient elution 25% EtOAc/hexane) to give 2.81 g (16%) of a white solid. 1H-NMR (300 MHz, DMSO-d6) 13.3 (broad s, 1H), 8.09 (s, 1H), 7.80 to 7.76 (m, 2H); ES-MS m/z 171.2/173.2 [M+H]+, RT (min) 3.02.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH2:12][CH:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][CH2:12][C@@H:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: C1COCCN1
Reactant: N#CC1(NC(=O)C2CCC(S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2CC[C@@H](S(=O)(=O)c3ccc(N4CCOCC4)cc3Cl)C2)CC1

Procedure:
The title compound was synthesized in analogy to Example 80, from Rac-(1S,35)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide and morpholine to afford the desired product as a light yellow oil. MS (EI): 438.2 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:11]1[C@H:14]([CH2:15][C@H:16]([OH:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[O:13][C:12]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCCC.[CH:23]([NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24]>>[CH2:1]([C@@H:11]1[C:12](=[O:22])[O:13][C@H:14]1[CH2:15][C@@H:16]([O:21][C:31](=[O:33])[C@H:26]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:25][CH:23]=[O:24])[CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:12][CH2:11][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)C[C@H](NC=O)C(=O)O
Reactant: C=CCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCCCCCC
Product: CCCCCCC/C=C\CC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(C)C)NC=O

Procedure:
by esterifying (S)-3-decyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone with N-formyl-L-leucine there was obtained
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=3[Cl:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(Cl)cc3Cl)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,4-dichloro-phenyl)-acrylic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[S:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:15]=1[Cl:16])[C:12]([OH:14])=[O:13])(=[O:6])=[O:5])[CH3:2].N1(S(C2C=CC=C(C=2F)C(O)=O)(=O)=[O:26])CCCCC1.C(N(CCC)S(C1C=CC=C(C=1F)C(O)=O)(=O)=O)CC.C1(NS(C2C=CC=C(C=2Br)C(O)=O)(=O)=O)C=CC=CC=1.C[C@H]1C[C@@H](C)CN(S(C2C=CC=C(C=2Br)C(O)=O)(=O)=O)C1.CN(C)S(C1C=CC=C(C=1Br)C(O)=O)(=O)=O.N1(S(C2C=CC=C(C=2Br)C(O)=O)(=O)=O)CCCCC1.CC1CC(C)CCN1S(C1C=CC=C(C=1C)C(O)=O)(=O)=O.CC1(C)CCN(S(C2C=CC=C(C=2C)C(O)=O)(=O)=O)CC1.ClC1C(Cl)=CC=CC=1CNS(C1C=CC=C(C=1C)C(O)=O)(=O)=O.C(N(CCCC)S(C1C=CC=C(C=1C)C(O)=O)(=O)=O)CCC.O1CCN(S(C2C=CC=C(C=2C)C(O)=O)(=O)=O)CC1>>[O:26]1[CH2:2][CH2:1][N:3]([S:4]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:15]=2[Cl:16])[C:12]([OH:14])=[O:13])(=[O:5])=[O:6])[CH2:17][CH2:18]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1F
Reactant: CCN(CC)S(=O)(=O)c1cccc(C(=O)O)c1Cl
Agent: CCCCN(CCCC)S(=O)(=O)c1cccc(C(=O)O)c1C
Agent: CCCN(CCC)S(=O)(=O)c1cccc(C(=O)O)c1F
Agent: CN(C)S(=O)(=O)c1cccc(C(=O)O)c1Br
Product: O=C(O)c1cccc(S(=O)(=O)N2CCOCC2)c1Cl

Procedure:
5-diethylaminosulfonyl-6-chlorobenzoic acid; 5-(2-p-chlorophenethylaminosulfonyl)-6-chlorobenzoic acid; 5-hexamethyleneiminosulfonyl-6-fluorobenzoic acid; 5-piperidinosulfonyl-6-fluorobenzoic acid; 5-di-n-propylaminosulfonyl-6-fluorobenzoic acid; 5-(2-p-bromophenethylaminosulfonyl)-6-fluorobenzoic acid; 5-phenylaminosulfonyl-6-bromobenzoic acid; 5-(cis-3,5-dimethylpiperidinosulfonyl)-6-bromobenzoic acid; 5-dimethylaminosulfonyl-6-bromobenzoic acid; 5-hexamethyleneiminosulfonyl-6-bromobenzoic acid; 5-piperidinosulfonyl-6-bromobenzoic acid; 5-(2,4-dimethylpiperidinosulfonyl)-6-methylbenzoic acid; 5-(4,4-dimethylpiperidinosulfonyl)-6-methylbenzoic acid; 5-(2-p-chlorophenethylaminosulfonyl)-6-methylbenzoic acid; 5-(2,3-dichlorobenzylaminosulfonyl)-6- methylbenzoic acid; 5-di-n-butylaminosulfonyl-6-methylbenzoic acid; and 5-morpholinosulfonyl-6-methylbenzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][N:19]=[N+]=[N-])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1
Agent: [Pd]
Product: NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1
Yield: 76 %

Procedure:
Treatment of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (4.3 g, 10.37 mmol) with sodium azide (3.03 g, 46.68 mmol) generally according to the procedure described for Intermediate 98 gave 2.91 g (98%) of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.29 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 2.3 g (76%) of (±)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 222-224° C.; Anal calcd. for C15H13F2NOHCl: C, 60.51; H, 4.74; N, 4.7. Found C, 60.65; H, 4.76; N, 4.51.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(C1(N[C:34]([CH:36](NC(N2CCOCC2)=O)CC(C)(C)C)=[O:35])CC(C2C=CC=CC=2)NC(C2C=CC=CC=2)C1)#N>C(O)(=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:34](=[O:35])[CH3:36])=[CH:12][CH:11]=1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNC(C)=O)cc1

Procedure:
Methyl-4-(acetylamino-methyl)-benzoate was prepared from acetic acid and methyl 4-(aminomethyl)benzoate using a method analogous to that of Example 1-part (d). The crude N-acyl ester was saponified using a method analogous to that of Example 1-part (c). The crude product was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[S:20][C:21]([C:25](=[O:35])[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[CH:27]=3)=[C:22]([NH2:24])[N:23]=2)=[CH:14][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:24][C:22]1[N:23]=[C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][NH2:7])=[CH:13][CH:14]=2)[S:20][C:21]=1[C:25]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[CH:27]=1)=[O:35]
Reactant: COc1ccc(C(=O)c2sc(Nc3ccc(OCCCNC(=O)OC(C)(C)C)cc3)nc2N)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)c2sc(Nc3ccc(OCCCN)cc3)nc2N)cc1F
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of (3-[4-[4-Amino-5-(3-fluoro-4-methoxy-benzoyl)-thiazol-2-ylamino]-phenoxy]-propyl)-carbamic acid tert-butyl ester (254 mg) (from Step A above) in dichloromethane (6 mL) at 0° C. was added trifluoroacetic acid (3 mL). After stirring for 1 hour, the mixture was concentrated and the residue was purified on HPLC to give [4-Amino-2-[4-(3-aminopropoxy)-phenylamino]-thiazol-5-yl]-(3-fluoro-4-methoxy-phenyl)-methanone (180.9 mg, 88% yield) as a light yellow solid. HRMS, Observed: 417.1394; Calcd for M+H+: 417.1391.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.CS(C)=O.O.[NH2:25][NH2:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:25][NH2:26])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: NN
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 24 h

Procedure:
To a solution of 2.9 parts of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione in a mixture of 2.5 parts by volume of dimethylsulfoxide and 100 parts by volume of ethanol is added 5 parts by volume of 80% hydrazine hydrate, and the mixture is allowed to stand for 24 hours. After evaporation of the solvent under reduced pressure, the residue is diluted with water, followed by extraction with methylene chloride. The methylene chloride layer is dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with benzene gives 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine. Recrystallization from a mixture of methylene chloride and benzene gives crystals melting at 205° C to 207° C (decomposition) which are confirmed to be identical with the product prepared in Examples 1 and 9.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]([F:38])([F:37])[C:5]1[CH:36]=[CH:35][C:8]([O:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([CH3:34])([CH3:33])[CH2:16][CH2:17][C:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]#[N:20])[CH2:11]2)=[CH:7][CH:6]=1>CC(O)(CC)CC>[F:38][C:4]([F:37])([F:3])[C:5]1[CH:6]=[CH:7][C:8]([O:9][C@@H:10]2[CH2:14][CH2:13][N:12]([C:15]([CH3:34])([CH3:33])[CH2:16][CH2:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:19]([NH2:20])=[O:1])[CH2:11]2)=[CH:35][CH:36]=1
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@@H](Oc2ccc(C(F)(F)F)cc2)C1
Reactant: [OH-]
Agent: CCC(C)(O)CC
Agent: [K+]
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC[C@@H](Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Yield: 68 %

Procedure:
Potassium hydroxide (23 mg, 0.406 mmol) was added to a solution of example 25 (10 mg, 0.0203 mmol) in 3-methyl-3-pentanol (2 mL) and the mixture was heated under reflux for 16 hours. The solution was cooled to 25° C. and potassium hydroxide (23 mg, 0.406 mmol) was added and the solution was heated under reflux for an additional 24 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:methanol:0.88 ammonia, 95:5:0.5. to afford the title compound as a colourless gum in 68% yield, 7 mg.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:22](=O)[C@H:23]4[CH2:27][CH2:26][CH2:25][N:24]4[CH3:28])[CH2:18][C:17]4[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1.Cl>C1COCC1.CO.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:35]([O:37][CH3:38])=[O:36])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][C@H:23]4[CH2:27][CH2:26][CH2:25][N:24]4[CH3:28])[CH2:18][C:17]4[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)[C@H]1CCCN1C)Cc1cc(F)ccc1-3
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C[C@H]1CCCN1C)Cc1cc(F)ccc1-3
Temperature: 25 °C

Procedure:
To a solution of methyl 14-cyclohexyl-3-fluoro-6-(1-methyl-D-prolyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate in THF (0.02 M), 3×5 eq of BH3.THF (1 M solution in THF) were added sequentially over a period of 48 h. The solution was allowed to stir at RT and monitored until no starting material was visible by RP-LC-MS. MeOH (0.02 M) and a 1.25 M solution of HCl in MeOH (0.24 M) were added carefully and the mixture heated at reflux for 2 h. The volume of the solution was reduced in vacuo, before diluting with EtOAc. The organic phase was washed with aqueous NaHCO3 solution and brine, before being dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound. The crude was used in the next step without further purification (quant); MS (ES+) m/z 504 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[F:20])=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=1)=O>C(O)(=O)C>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:5]1[CH:4]=[C:3]2[N:21]=[C:22]([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[NH:1][C:2]2=[N:7][C:6]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cn1cncc1C(=O)Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Solvent: CC(=O)O
Product: Cn1cncc1-c1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Yield: 57.5 %

Procedure:
A solution of N-(6′-amino-3″-fluoro-3,2′:3′,4″-terpyridin-5′-yl)-1-methyl-1H-imidazole-5-carboxamide (0.040 g, 0.103 mmol) in acetic acid (1 mL) was heated in a sealed tube at 118° C. for 16 h. The solvent was evaporated and 4% sodium bicarbonate aqueous solution was added and extracted with ethyl acetate. The organic layer was dried and evaporated to give the title compound (0.022 g, 58% of yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:7]=1[O:18]CC1C=CC=CC=1)=[O:4]>CO.[Pd]>[NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:7]=1[OH:18])=[O:4]
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of (S)-2-amino-N-(2-(benzyloxy)-5-(pyridin-4-yl)phenyl)-3-phenylpropanamide 13.F (200 mg, 0.473 mmol) in methanol (2 mL) was added 10% Pd on carbon by weight (50 mg). The air was evacuated from the reaction flask and was replaced with hydrogen. The resulting slurry was stirred overnight at room temperature. The reaction mixture was filtered and the mother liquor condensed. The crude material was purified by reverse phase preparative HPLC to afford (S)-2-amino-N-(2-hydroxy-5-(pyridin-4-yl)phenyl)-3-phenylpropanamide 13.G (100 mg, 63% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH:22]1([CH2:25][NH:26][CH3:27])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:22]1([CH2:25][N:26]([CH3:27])[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:24][CH2:23]1
Reactant: CNCC1CC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1CC1)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 1-cyclopropyl-N-methylmethanamine hydrochloride (77335-18-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=352.4 [MH+].
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.CN(C)CCN(C)C.C([Li])(C)(C)C.[F:26][C:27]1([F:34])[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1>C1COCC1>[F:26][C:27]1([F:34])[CH2:32][CH2:31][C:30]([C:2]2[CH:3]=[N:4][N:5]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[CH:6]=2)([OH:33])[CH2:29][CH2:28]1
Reactant: Ic1cnn(C2CCCCO2)c1
Reactant: O=C1CCC(F)(F)CC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OC1(c2cnn(C3CCCCO3)c2)CCC(F)(F)CC1
Yield: 10.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (J. Org. Chem., 2007, 72 (9), 3589-3591; 10.0 g, 35.9 mmol), N,N,N′,N′-tetramethylethylenediamine (5.38 mL, 35.9 mmol), t-butyl lithium (1.60 M solution in pentane; 26.2 mL, 43.2 mmol), 4,4-difluorocyclohexanone (4.82 g, 35.9 mmol) and THF (100 mL), to yield the title compound (1.10 g, 11%) as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C>C(O)=O>[O:26]([C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]([OH:33])=[O:5])(=[O:19])=[O:18])=[CH:25][CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Solvent: O=CO
Product: O=C(O)CN(CC(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 4a (1.02 g, 2.14 mmol) was dissolved in formic acid (10 mL) and stirred overnight at room temperature. The solid was filtered off, the filtrate was evaporated in vacuo, and co-evaporated with toluene (6×20 mL). The pure product obtained was dried overnight in high vacuum. Yield: 0.71 g, 1.95 mmol, 91% (off-white solid). 1H-NMR (DMSO-d6): δ 7.91 (d, 2H, 3JHH=9.0 Hz, ArH), 7.20 (d, 2H, 3JHH=9.0 Hz, ArH), 7.28 (d, 2H, 3JHH=9.0 Hz, ArH), 7.00 (d, 1H, 3JHH=9.0 Hz, ArH), 6.87 (d, 2H, 3JHH=9.0 Hz, ArH), 4.07 (s, 4H, 2×CH2CO2H).
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:20])[NH:14][O:15][CH2:16][C:17]([OH:19])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]([CH2:45][C:46]([NH:48][C:49]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C:23]([N:25]([CH2:35][C:36]1[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[S:39][CH:40]=1)[C@@H:26]([CH3:34])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:24]>>[S:39]1[CH:40]=[C:36]([CH2:35][N:25]([C@@H:26]([CH3:34])[CH:27]([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])[C:23](=[O:24])[C@@H:22]([NH:21][C:17](=[O:19])[CH2:16][O:15][NH:14][C:13]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:20])[CH2:45][C:46](=[O:47])[NH:48][C:49]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CONC(=O)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetic acid (Compound VI-12) 63 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxy-propan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.