Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:34]1([CH2:38][O:39][C:40]2[N:45]=[C:44]([C:46]([OH:48])=O)[CH:43]=[N:42][C:41]=2[N:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:37][CH2:36][CH2:35]1.[CH3:54][CH:55]([CH3:59])[CH2:56][CH2:57][NH2:58].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:54][CH:55]([CH3:59])[CH2:56][CH2:57][NH:58][C:46]([C:44]1[CH:43]=[N:42][C:41]([N:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)=[C:40]([O:39][CH2:38][CH:34]2[CH2:35][CH2:36][CH2:37]2)[N:45]=1)=[O:48]
Reactant: CC(C)CCN
Reactant: O=C(O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Reaction time: 0.33 h
Yield: 51.7 %

Procedure:
A solution of PyBOP (156.1 mg, 0.3 mmol) in N,N-dimethylformamide (0.5 mL) was added to a solution of the 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (62.7 mg, 0.2 mmol) in N,N-dimethylformamide (1 mL) and the reaction mixture was left to stand for 20 minutes. 3-methyl butylamine (34.9 mg, 0.4 mmol) and N-ethyldiisopropylamine (103.4 mg, 0.8 mmol) were added and the reaction mixture was shaken for 16 hours. The solvent was removed in vacuo and the crude product was purified by preparative HPLC to afford 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (3-methyl-butyl)-amide as a solid 35.8 mg (52% yield) LC@215 nm; Rt 2.63: 100%, m/z (ES+): 347 (M+H).
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]([OH:28])=O)=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CCN(CC)CC.[NH2:37][CH2:38][CH2:39][S:40]([CH3:43])(=[O:42])=[O:41].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:43][S:40]([CH2:39][CH2:38][NH:37][C:26]([C:24]1[S:25][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:29])=[O:28])(=[O:42])=[O:41]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)O)s1
Reactant: CS(=O)(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)NCCS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a mixture of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (0.6344 g, 1.52 mmol) and CH2Cl2 (10 mL) is added Et3N (0.85 mL, 6.07 mmol), followed by hydrochloride salt of 2-aminoethylmethylsulfone (0.2416 g, 1.52 mmol), EDCl (0.320 g, 1.67 mmol), and HOBT (0.226 g, 1.67 mmol). The resulting solution is stirred at RT overnight, diluted with CH2C2 (30 mL), washed with 1.0 M HCl (3×20 mL), brine (20 mL), dried over MgSO4, and concentrated. The resulting residue is purified by chromatography (50% EtOAc/Hex) to give the titled compound (0.4042 g, 0.77 mmol, 51%). 1H NMR (CDC3), δ 0.71 (t, J=7.3 Hz, 6H), 1.03 (s, 9H), 2.09 (q, J=7.3 Hz, 4H), 2.21 (s, 3H), 2.42 (d, J=3.0 Hz, 1H), 2.46 (s, 3H), 2.98 (s, 3H), 3.32 (t, J=6.4 Hz, 2H), 3.71 (dt, J=8.9, 2.9 Hz, 1H), 3.84-3.94 (m, 3H), 4.10 (dd, J=9.3, 2.5 Hz, 1H), 6.44 (t, J=5.8 Hz, 1H), 6.59 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H), 7.03 (dd, J=8.7, 2.5 Hz, 1H). LC/MS (m/z): calcd for C27H42NO5S2 (M+H)+:524.8; found: 524.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:32]=1[C:33](Cl)=[O:34]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:33](=[O:34])[C:32]3[C:36]([F:40])=[CH:37][CH:38]=[CH:39][C:31]=3[Cl:30])[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CC1CC(Oc2cccc(N)n2)CCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1CC(Oc2cccc(NC(=O)c3c(F)cccc3Cl)n2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Combine 4-(6-Amino-pyridin-2-yloxy)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (preparation 63, 0.286 g, 0.93 mmol), 1,4-dioxane (10 mL), triethylamine (0.16 mL, 1.12 mmol) and 2-chloro-6-fluorobenzoyl chloride (0.215 g, 1.12 mmol) with stirring at ambient temperature. After 2 hr., partition between water (50 mL) and 4:1 hexane:ethyl acetate (100 mL). Separate aqueous layer and wash with 4:1 hexane:ethyl acetate (50 mL). Combine organic layers, dry over sodium sulfate, filter and concentrate to obtain the title compound (0.53 g>100%). Mass spectrum (electrospray): m/z=462.3 (M−1); 1H NMR (CDCl3): 7.9 (m, 2H), 7.65 (dd, 1H), 7.4 (m, 1H), 7.25 (m, 1H), 7.1 (dd, 1H), 6.5 (d, 1H), 5.25 (m, 1H), 4.35 (m, 1H), 3.9 (m, 1H), 3.25 (m, 1H), 1.9 (m, 3H), 1.7 (m, 1H), 1.45 (s, 9H), 1.3 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[CH:29])=[CH:23][CH:22]=1>>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]2[C:3]([CH2:29][C:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=3)=[N:1]2)=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: C[C@]1(c2cc(N)c(I)cc2F)N=C(N)OCC1(F)F
Reactant: C#CCc1ccc(C)cc1
Product: Cc1ccc(CC2=Nc3cc([C@@]4(C)N=C(N)OCC4(F)F)c(F)cc3C2)cc1
Yield: 73 %

Procedure:
In a manner analogous to that described in Example 39, the coupling and cyclisation reaction of (R)-4-(5-amino-2-fluoro-4-iodo-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate B6.1) with 1-methyl-4-prop-2-ynyl-benzene yielded the title compound (73% yield) as a light green foam. MS (ISP): m/z=388.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CS(O)(=O)=O>C(O)CCCCC>[CH2:23]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:2]([NH:1][CH2:4][CH2:3][CH2:2][CH2:10][CH2:9][CH3:8])[CH:3]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCBr
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCCCCCO
Product: CCCCCCNc1cc(C(=O)OCCCCCC)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulphamyl-benzoic acid (4.62 g), 1-bromo-n-hexane (5 g), methanesulphonic acid (0.05 ml), and n-hexanol (40 ml) was refluxed for 60 hours. After cooling, the precipitated n-hexyl-3-n-hexylamino-4-phenoxy-5-sulphamyl-benzoate was collected and recrystallized from hexanol. The melting point was 137°-138°C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:33]#[N:34])[CH2:24][C:23](=[O:35])[NH:22][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4cccc(F)c4F)cc3NC(=O)C2)c1
Yield: 88 %

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′,3′-difluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K8) (35 mg, 0.07 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a grey solid (23 mg).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[C:32]#[CH:33])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>ClCCl.CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[C:32]#[C:33][C:2]3[CH:16]=[CH:15][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC1CCN(Cc2ccc(I)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: COC1CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)-4-methoxypiperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 25 mg (13% of theory); melting point: 145° C.-146° C.; C28H27ClN2O2 (M=458.99); calc.: molecular ion peak (M+H)+: 459/461; found: molecular ion peak (M+H)+: 459/461; Rf value: 0.4 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)[CH:17]=[CH:18][CH:19]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[Br:26][C:23]1[CH:22]=[CH:21][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:5]3[CH:4]=[C:3]([OH:2])[N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:6]=3)[CH:15]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3ccc(Br)cc3)c2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2cccc(-c3ccc(Br)cc3)c2)nn1-c1ccccn1
Yield: 84 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 36 of Example C-10 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.[OH:26][C:27]1C=CC(C=O)=C[CH:28]=1>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([O:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([O:26][CH2:27][CH3:28])=[O:24])=[CH:21][CH:22]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: O=Cc1ccc(O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Oc3ccc(C=O)cc3)ccc21
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
4-Formylphenyl 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthoate-Using 4-hydroxybenzaldehyde, the title compound was synthesized as a white solid. PMR (CDCl3): δ 1.32 (6H, d), 1.34 (6H, s), 1.73 (4H, s), 7.39 (2H, d, J~9.0 Hz), 7.45 (1H, d, J~8.4 Hz), 7.92-7.98 (3H, m), 8.16 (1H, d, J~1.8 Hz), 9.99 (1H, s).
Reaction SMILES: [CH:1]1([PH:7](=[O:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]=[O:15]>>[CH:1]1([P:7]([CH2:14][OH:15])(=[O:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCO[PH](=O)C1CCCCC1
Reactant: C=O
Product: CCCCOP(=O)(CO)C1CCCCC1

Procedure:
The title compound was prepared from cyclohexylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31. Purification by chromatography, eluting with dichloromethane containing 5% methanol, gave an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]([N+:12]([O-])=O)[C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:12][C:9]1[C:5]2[N:6]([CH:2]([CH2:10][CH3:9])[CH2:3][CH3:4])[N:7]=[N:8][C:4]=2[CH:3]=[C:2]([CH3:1])[C:10]=1[CH3:11]
Reactant: Cc1cc2nn[nH]c2c([N+](=O)[O-])c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)n1nnc2cc(C)c(C)c(N)c21
Yield: 137.9 %

Procedure:
In a 1 liter Paar hydrogenator is added 3.0 grams of 5,6-dimethyl-7-nitrobenzotriazole in 250 milliliters of absolute ethanol along with 0.5 gram of 5% Pd/C. Hydrogen is introduced at about 40 psi and the reduction is accomplished without heating. The catalyst is removed by filtration and on evaporation of the solvent, 2.5 grams (94%) of the product is isolated, m.p. 114°-117° C. The analytical sample is recrystallized from n-hexane, m.p. 116°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[N+:19]([CH2:22][CH3:23])([O-:21])=[O:20].C(N)CCC>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](/[CH:13]=[C:22](/[N+:19]([O-:21])=[O:20])\[CH3:23])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Solvent: CC(=O)O
Solvent: CCCCN
Product: C/C(=C\c1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1)[N+](=O)[O-]
Temperature: 80 °C

Procedure:
5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-carbaldehyde (4.00 g, 14.5 mmol), nitroethane (3.00 ml, 40.7 mmol), n-butylamine (1.7 ml, 17.5 mmol) and acetic acid (7.5 ml) were mixed and heated up to 80° C. for 2 h. After cooling to RT the mixture was filtered. The precipitate was crystallized from ethanol affording 2.58 g of the title product. 1H-NMR (400 MHz; d6-DMSO): δ 2.62 (s, 3H), 7.39 (d, 1H), 7.57 (d, 1H), 7.87 (m, 1H), 8.00 (s, 1H), 8.11 (m, 1H), 8.22 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3([CH2:21][C:22]([O:24]C)=[O:23])[CH2:20][CH2:19]3)=[C:8]2[CH3:26])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.CCOCC.CCCCCC>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19]3)=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC(=O)CC1(c2c(C)n(Cc3ccc(Br)cc3)c3ccc(OC)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc2c(c1)c(C1(CC(=O)O)CC1)c(C)n2Cc1ccc(Br)cc1
Yield: 78 %

Procedure:
To the methyl ester from Step 7 (1.63 g, 3.68 mmol) in 20 mL of methanol was added 5 mL of 2N NaOH, and the mixture was heated to reflux for 2 h then cooled. The reaction mixture was partitioned between ethyl acetate and 1M HCl. The organic layer was washed with brine, dried over MgSO4 and evaporated to give a solid. This material was swished twice in 15% ether/hexane to provide 1.23 g of the title compound.
Reaction SMILES: C([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([O:56][CH3:57])=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.[ClH:58]>C(OC)(=O)C.O1CCOCC1>[ClH:58].[NH2:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([O:56][CH3:57])=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1
Reactant: CCCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(C(=O)OC)C3
Agent: Cl
Solvent: COC(C)=O
Solvent: C1COCCO1
Product: CCCC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(C(=O)OC)C3
Reaction time: 1 h

Procedure:
To a solution of 0.896 g of methyl Boc-L-tyrosyl-D-norleucyl-glycyl-phenylalanyl-3-amino-1-adamantanecarboxylate in 10 ml of methyl acetate is added 10 ml of a 6 M solution of hydrogen chloride in dioxane. The reaction mixture is allowed to stand for one hour at room temperature, then the solvent is removed under vacuum. The residue is extracted with ethyl acetate. Removal of the solvent gives methyl L-tyrosyl-D-norleucyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride which is represented by the formula ##STR54##
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C:14]([CH3:26])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15](OC)=[O:16].[Cl-].[NH4+]>C1COCC1>[CH3:13][C:14]([CH3:26])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C(C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)(C)Cc1ccccc1)OC
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of dimethyl methylphosphonate (2.4 ml, 21.8 mmol) in 100 ml of anhydrous THF was added dropwise n-butyl lithium (1.49N, 14.7 ml, 21.8 mmol) at -78° C. under argon atmosphere. After the mixture was stirred for 30 minutes, methyl 2,2-dimethyl-3-phenylpropionate (1.75 g, 10.0 mmol) was added dropwise and the mixture was stirred at -78° C. for 20 minutes and then at room temperature overnight. To this reaction mixture was added an aqueous saturated solution of ammonium chloride, and the mixture was extracted with ethyl acetate (50 ml×4). Then, the combined ethyl acetate layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (silica gel, ethyl acetate) yielded a pure product of dimethyl 3,3-dimethyl-2-oxo-4-phenylbutylphosphonate (2.3144 g, 8.14 mmol, 89.5%). This compound was assigned the structure by the following data: m.p. 39° -46° C. (colorless needle-like crystal)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:31]([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH3:31])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 100 %

Procedure:
The compound (625.7 mg) obtained in Example 115-1 was dissolved in methanol (25.0 ml) and added with a 36% formaldehyde aqueous solution (0.246 ml) and sodium cyanoborohydride (220.9 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 27 hours. The reaction solution was concentrated under reduced pressure and the residue was added with a 1 mol/l sodium hydroxide aqueous solution, followed by separation/extraction with chloroform. After having been washed with saturated saline solution, the extract was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (648.1 mg) as a colorless oily substance.
Reaction SMILES: C1C=CC=CC=1.[OH:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=2[N:10]=[N:9]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)(=O)C.O>[CH3:25][S:26]([O:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=2[N:10]=[N:9]1)(=[O:28])=[O:27]
Reactant: On1nnc2c(Cl)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CS(=O)(=O)On1nnc2c(Cl)cccc21
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To benzene (14 ml) are added 1-hydroxy-4-chloro-1,2,3-benzotriazole (3.4 g) and further triethylamine (2.8 ml). To the solution is added methanesulfonyl chloride (2.3 g) with stirring under ice-cooling and the mixture is stirred at the same temperature for 20 minutes and further at room temperature for 1.5 hours. After allowing to stand overnight, to the reaction mixture are added water (20 ml) and ethyl acetate (30 ml) and the ethyl acetate layer is separated. The water layer is again extracted with ethyl acetate (20 ml). The ethyl acetate extracts are combined, washed with a small amount of a saturated aqueous sodium hydrogen carbonate and water in order, dried over anhydrous sodium sulfate and the solvent is distilled off under a reduced pressure. The residue is washed with petroleum ether (10 ml) to give faint yellow crystals of 1-methanesulfonyloxy-4-chloro-1,2,3-benzotriazole (3.89 g; 79%), melting point: 71°-74° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:14](I)=[CH:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]1([NH:7][C:8]([C:10]2[C:14]([C:1]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:25][OH:28])[CH:2]=3)=[CH:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Cn2cc(I)c(C(=O)Nc3ccccc3)n2)cc1
Reactant: O=C([O-])[O-]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2cc(-c3cccc(CO)c3)c(C(=O)Nc3ccccc3)n2)cc1
Temperature: 120 °C
Yield: 263.8 %

Procedure:
A mixture of 4-iodo-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide (50 mg; 0.11 mmol), bis(tri-tert-butylphosphine)palladium (12 mg), potassium carbonate (100 mg; 0.66 mmol) and 3-(hydroxmethyl)benzene boronic acid (21 mg; 0.14 mmol) in ethanol/toluene/water (4 ml:1 ml:1 ml) was heated at 120° C. (50 W) for 15 minutes in a CEM Discover microwave synthesiser. The reaction was evaporated and the residue partitioned between ethyl acetate and brine. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated and the crude material purified by flash column chromatography eluting with 1:2 then 2:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 60 mg of 4-(3-hydroxymethyl-phenyl)-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide.
Reaction SMILES: [CH:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[C:3]([C:14]([C@:16]2([CH3:36])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[C:23]=4[NH2:25])[N:18]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:17]2=[O:35])=[O:15])[N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.CI.[C:39](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[CH3:39][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:4]=[C:3]([C:14]([C@:16]3([CH3:36])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[C:23]=4[NH2:25])[N:18]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:17]3=[O:35])=[O:15])[N:2]=[CH:1][C:6]1=2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(c1N)[C@@](C)(C(=O)c1cc3c(cn1)[nH]c1ccccc13)C(=O)N2c1ccc(F)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1N)[C@@](C)(C(=O)c1cc3c4ccccc4n(C)c3cn1)C(=O)N2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
A mixture of 0.55 g of (S)-3-{9H-pyrido[3,4-b]-indol-3-yl-carbonyl}-amino-3-methyl-1-(4-fluorophenyl)-5-methoxy-2-indolinone, 0.2 ml of methyl iodide, 0.78 g of potassium carbonate and 10 ml of dimethylformamide was stirred at room temperature for 3 hours, and water and ethyl acetate were added to the mixture. The organic layer was separated, washed, dried, and evaporated under reduced pressure. The residue was crystallized from a mixed solvent of hexane and ethyl acetate to afford 0.403 g of the title compound as pale yellow crystals. Melting point: 232° to 233° C., [α]D20 : 0° (c=0.214, CHCl3)