Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)O1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:42]2[CH:43]=[C:44]([CH:51]=[CH:52][C:53]=2[F:54])[C:45]([NH:47][CH:48]([CH3:50])[CH3:49])=[O:46])=[N:39][C:40]=1Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:42]2[CH:43]=[C:44]([CH:51]=[CH:52][C:53]=2[F:54])[C:45]([NH:47][CH:48]([CH3:50])[CH3:49])=[O:46])=[N:39][C:40]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][N:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[N:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(B4OC(C)(C)C(C)(C)O4)cc23)C1
Reactant: CC(C)NC(=O)c1ccc(F)c(-c2ccc(N)c(Cl)n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)NC(=O)c1ccc(F)c(-c2ccc(N)c(-c3cc4c(N5CCC[C@H](N)C5)ccnc4cn3)n2)c1
Yield: 21 %

Procedure:
A solution of (S)-tert-butyl 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.), 3-(5-amino-6-chloropyridin-2-yl)-4-fluoro-N-isopropylbenzamide ((1.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.2 equiv.) in 3:1 DME/2M Na2CO3 was heated at 120° C. for 20 hours. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by RP HPLC. Upon lyophilization, the Boc group was deprotected by treatment with 25% TFA/CH2Cl2, concentrated, purified by RP-HPLC and lyophilized to yield (S)-3-(5-amino-6-(4-(3-aminopiperidin-1-yl)-1,7-naphthyridin-6-yl)pyridin-2-yl)-4-fluoro-N-isopropylbenzamide (21%). LC/MS=500.3 (M+H), LC=2.36 min.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([C:10]1[C:11](=[O:25])[NH:12][C:13](=[O:24])[N:14]([CH:23]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)#[CH:9].C(Cl)Cl>N1C=CC=CC=1.C(Cl)Cl.CO>[C:1]([O:18][C@@H:17]1[C@@H:19]([CH2:20][O:21][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[O:22][C@@H:15]([N:14]2[CH:23]=[C:10]([C:8]#[CH:9])[C:11](=[O:25])[NH:12][C:13]2=[O:24])[CH2:16]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#Cc1cn([C@H]2C[C@H](OC(=O)C(C)(C)C)[C@@H](COC(=O)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
Pivaloyl chloride (0.3 ml, 2.56 mmoles) was added to a cooled, stirred solution of 2'-deoxy-5-ethynyluridine (0.5 g, 1.98 mmols) in dry pyridine (5 ml) and stirring was maintained at room temperature for 3 hours. TLC in CH2Cl2 /MeOH (19:1) revealed complete reaction. The mixture was poured onto ice/water, methylene chloride added, the organic layer separated and washed with water, dried with sodium sulphate and evaporated to dryness. The residue was chromatographed on silica gel eluted with CH2Cl2 /MeOH. The first product was triturated with hexane to give 2'-deoxy-3',5'-di-O-pivaloyl-5-ethynyluridine. M.p. 151° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].CN1CCOCC1.[Cl:21][C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1.O>C(OC(C)C)(=O)C>[Cl:21][C:22]1[S:26][C:25]([S:27]([NH:1][C@H:2]([CH2:3][OH:4])[CH:5]([C:6]([F:7])([F:8])[F:9])[C:10]([F:11])([F:12])[F:13])(=[O:29])=[O:28])=[CH:24][CH:23]=1
Reactant: N[C@H](CO)C(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CN1CCOCC1
Solvent: CC(=O)OC(C)C
Solvent: O
Product: O=S(=O)(N[C@H](CO)C(C(F)(F)F)C(F)(F)F)c1ccc(Cl)s1
Temperature: 22.5 °C
Reaction time: 0.12 h
Yield: 67.8 %

Procedure:
To a suspension of (2S)-2-amino-4,4,4-tri-fluoro-3-(trifluoromethyl)butan-1-ol (2 g, 8.1 mmol) in isopropyl acetate (10 mL), 4-methyl morpholine (2.7 mL, 24.6 mmol) was added. The mixture was stirred at 20 to 25° C. for 5 to 10 minutes and then 5-chlorothiophene-2-sulfonyl chloride (2.0 g, 9.2 mmol) was added. The reaction mixture was stirred at 20 to 25° C. for 6 to 18 hours. Water (10 mL) was added to the reaction mixture and the solid dissolved. The two layers were separated, the organic layer was washed with 10% NaHCO3 (10 mL) and 10% NaCl (10 mL), and heptane (10 mL) was added to the isopropyl acetate layer (about 10 mL). The mixture was reduced in volume by about half by distillation under atmospheric conditions. While the solution remained at 80 to 90° C., heptane (10 mL) was added over 5 to 10 minutes. A solid began to form during heptane addition. After addition, the mixture was cooled to 20 to 25° C., the solution was stirred for 1 to 2 hours, and then further cooled to 5 to 10° C. for 1 hour. The solid was collected by filtration, washed with heptane (5 mL), and oven-dried to give 2.15 g (67%) of an off-white solid. 98% area HPLC purity and >99% chiral purity by HPLC.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[O:21]=[C:9]1[N:8]2[C:4]([CH2:3][NH:2][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:5][N:6]=[C:7]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: O=C(O)c1ccccc1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CN)nnc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CNC(=O)c3ccccc3)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
The mixture of 3-(aminomethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one hydrochloride (160 mg, 0.51 mmol), [B] benzoic Acid (0.069 g, 0.56 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.25 g, 0.56 mmol) and triethylamine (0.21 mL, 1.5 mmol) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was purified by preparative LCMS to yield the desired product (150 mg, 77%). LCMS calculated for C19H22N7O2(M+H): 380.2; found: 380.2.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:19]=[CH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:5].[OH-].[Na+]>CO.C1COCC1>[CH3:29][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:19]=[CH:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:8])([CH3:5])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C=CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(NC(=O)c1ccc2ccccc2c1C=CCCc1ccccc1)C(=O)O

Procedure:
80 mg of a mixture of the (E)- and (Z)-isomers of 2-methyl-2-{[1-(4-phenyl-but-1-enyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester were reacted with 0.5 ml of 2 M sodium hydroxide in 1 ml methanol and 2 ml THF for 15 min at 60° C. The organic solvents were removed in vacuo, the mixture was acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated to yield 75 mg of a mixture of the (E)- and (Z)-isomers of 2-methyl-2-{[1-(4-phenyl-but-1-enyl)-naphthalene-2-carbonyl]-amino}-propionic acid.
Reaction SMILES: C([NH:8][C:9](=[O:12])[CH2:10][NH2:11])C1C=CC=CC=1.O=[CH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:22]1([CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:28]([N:11]1[CH2:10][C:9](=[O:12])[NH:8][CH:14]1[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)CCC=O
Reactant: NCC(=O)NCc1ccccc1
Product: CCOC(=O)CCC1NC(=O)CN1Cc1ccccc1

Procedure:
A suspension of N-benzylglycinamide (35.5 g, 0.22 mol) and ethyl 4-oxobutanoate (31 g, 0.24 mol) in toluene (370 ml) was refluxed for 6 hours in a Dean-Stark apparatus. After cooling, the mixture was extracted twice with 10% sulphuric acid (200+100 ml); the aqueous extracts were neutralized with sodium hydrogen carbonate and extracted twice with toluene (250 ml each time). The organic solution was washed with water (100 ml), dried (MgSO4) and evaporated under vacuum to afford an oil which was triturated with a mixture of diethyl ether-light petroleum (1:2) to give 45 g (75%), of the title compound as a yellow solid, m.p. 60°-62° C. NMR (CDCl3): deltaH =7.5 (bs, 1H, NH); 7.30 (bs, 5H, PhH); 4.5-4.25 (ABX, 1H, CH-M); 4.13 (q, J=6.9 Hz, 2H, OCH2); 4.00 and 3.53 (ABq, J=12.4 Hz, 2H, PhCH2); 3.37 and 3.02 (ABX, J=14.9 Hz, 2H, NCH2CO); 2.65-2.30 (c.a., 2H, CH2CH2CO); 2.20-1.15 (c.a., 2H, CH2CH2CO); 1.24 (t, J=6.9 Hz, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=276 (M+), 231 (M-OEt)+, 185 (M-PhCH2)+, 175 (M-C5H9O2)+, 91 (PhCH2)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4].[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])nn1CC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)nn1CC(=O)OC(C)(C)C
Yield: 97.6 %

Procedure:
A solution of 2-tert-Butoxycarbonylmethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (3 gm) in ethyl acetate (60 ml) and acetic acid (4.5 ml) was hydrogenated at 50 psi hydrogen in the presence of 1.5 gm of 10% palladium/carbon for 3 hours. The mixture was then filtered and evaporated to obtain 2.62 gm of pure title product. ESI M+1=256.
Reaction SMILES: N1C=CN=C1.C(N(CC)CC)C.[CH:13](O)=[O:14].C(Cl)(=O)C(Cl)=O.[O:22]=[C:23]1[NH:28][C:27]([CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[N:26][C:25]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[C:24]1[C:41]#[N:42]>ClCCl>[CH:13]([N:38]1[CH2:37][CH2:36][N:35]([C:25]2[N:26]=[C:27]([CH2:29][C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[NH:28][C:23](=[O:22])[C:24]=2[C:41]#[N:42])[CH2:40][CH2:39]1)=[O:14]
Reactant: N#Cc1c(N2CCNCC2)nc(Cc2ccsc2)[nH]c1=O
Reactant: O=CO
Agent: O=C(Cl)C(=O)Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1c(N2CCN(C=O)CC2)nc(Cc2ccsc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11.3 mg (0.17 mmol) of imidazole are introduced together with 33.6 mg (0.33 mmol) of triethylamine and 7.64 mg (0.17 mmol) of formic acid into 5 ml of dichloromethane under an argon atmosphere and cooled to 0° C. Then a solution of 21.1 mg (0.17 mmol) of oxalyl chloride in dichloromethane is added dropwise, and the mixture is then stirred for 15 min. 50 mg (0.17 mmol) of 6-oxo-4-(piperazin-1-yl)-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are added, and the mixture is stirred at RT overnight. It is then washed with 1 N potassium bisulphate solution, the dichloromethane phase is dried over sodium sulphate and concentrated, and the residue is flash-chromatographed on silica gel (mobile phase: dichloromethane/methanol 100:1, 80:1, 60:1). 16 mg (29% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:14][C:13]=2[Cl:26])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[Cl:26][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][CH2:28][OH:32])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:27])=[O:11]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl
Reactant: C#CCCO
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 462 (0.23 mmol) and but-3-yn-1-ol (0.28 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 6:1 as the eluent to afford the title compound as light yellow foam. 13C NMR (CDCl3) δ 194.9, 147.7, 146.3, 141.4, 140.7, 138.3, 135.4, 135.3, 134.8, 133.8, 132.6, 130.7, 128.7, 123.8, 122.4, 120.9, 120.7, 120.0, 118.8, 117.1, 113.6, 61.6, 28.7, 20.0
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:33][CH2:32][CH2:31][CH:30]5[CH3:34])[CH2:25]4)=[CH:20][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>O1CCOCC1.CO.C(Cl)Cl>[ClH:37].[CH3:34][CH:30]1[CH2:31][CH2:32][CH2:33][N:29]1[CH:26]1[CH2:27][CH2:28][CH:24]([C:21]2[CH:22]=[CH:23][C:18]([N:15]3[CH2:14][CH2:13][CH2:12][C:11]4([CH2:35][CH2:36][NH:8][CH2:9][CH2:10]4)[C:16]3=[O:17])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1CCCN1C1CCC(c2ccc(N3CCCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CC1CCCN1C1CCC(c2ccc(N3CCCC4(CCNCC4)C3=O)cc2)C1
Yield: 105.2 %

Procedure:
2-{4-[3-(2-Methyl-pyrrolidin-1-yl)-cyclopentyl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxyl ic acid tert-butyl ester (example 3) (22 mg, 0.044 mmol) was treated with 4 M HCl (0.5 mL, 2 mmol, excess) in dioxane and methanol (0.5 mL) at rt for 4 h when TLC (10% MeOH in DCM) showed the reaction was complete. The volatiles were removed in vacuo and the residue was dried under high vacuum for 2 h to obtain 20 mg (100% yield) of the title compound as a gummy solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](Cl)=[O:33].C(N(CC)CC)C>ClCCl>[CH:23]1[CH:22]=[CH:21][N:13]2[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])=[N:7][CH:6]=3)=[O:9])[CH2:11][C:12]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Reactant: Cc1ccccc1CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.0 mmol of 10, 11-dihydro-10-(6-amino-3-pyridinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 2.1 mmol of 2-methylbenzeneacetyl chloride and 5 mmol of triethylamine in 10 ml of dichloromethane is stirred under argon at room temperature for 16 hours. The solvent is removed under vacuum and the residue partitioned between 50 ml of ethyl acetate and 25 ml of water. The organic layer is separated, washed with H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: C[O:2][C:3](=[O:49])/[C:4](/[CH2:39][C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)=[C:5](/[C:21]1[N:25]([O:26][CH2:27][O:28][CH:29]([Si:31]([CH3:34])([CH3:33])[CH3:32])[CH3:30])[C:24]([CH2:35][CH2:36][CH2:37][CH3:38])=[N:23][CH:22]=1)\[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[O:14][CH2:15][C:16]([O:18]CC)=[O:17]>[OH-].[Na+].C(O)(C)C>[CH2:35]([C:24]1[N:25]([O:26][CH2:27][O:28][CH:29]([Si:31]([CH3:32])([CH3:33])[CH3:34])[CH3:30])[C:21](/[C:5](/[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[O:14][CH2:15][C:16]([OH:18])=[O:17])=[C:4](\[CH2:39][C:40]2[CH:45]=[CH:44][C:43]3[O:46][CH2:47][O:48][C:42]=3[CH:41]=2)/[C:3]([OH:49])=[O:2])=[CH:22][N:23]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCc1ncc(/C(=C(\Cc2ccc3c(c2)OCO3)C(=O)OC)c2ccc(OC)cc2OCC(=O)OCC)n1OCOC(C)[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCCc1ncc(/C(=C(\Cc2ccc3c(c2)OCO3)C(=O)O)c2ccc(OC)cc2OCC(=O)O)n1OCOC(C)[Si](C)(C)C

Procedure:
Methyl-(2E)-3(2-n-Butyl-1-trimethylsilylethyloxymethoxy-1H-imidazol-5-yl)-3-(2-ethoxycarbonylmethoxy-4-methoxyphenyl)-2-(3,4-methylenedioxybenzyl)prop-2-enoate (123 mg, 0.181 mmol) in 2.5N NaOH (2.0 ml) and isopropanol (2.0 ml) was heated under argon at 95° for 18 h. The solvent (i-PrOH) was removed under reduced pressure and the residue was diluted with H2O and washed with EtOAc. The pH of the aqueous layer was lowered to 3.5-4.5 with 1M HCl and the resultant precipitate was collected and air-dried (101 mg, 88%). The crude solid was recrystallized from i-propanol to afford the hydrochloride salt of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][OH:9].[Br:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[CH:17]=1.O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:21]=1
Reactant: COc1ccc(CO)cc1OC
Reactant: Fc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(F)cc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
Sodium hydride (80% disp. in oil; 933 mg, 31.1 mmol) was added, all at once, to 3,4-dimethoxybenzyl alcohol (3.48 g, 20.7 mmol) in DMF (40 mL) at 0° C. and under Ar. After 5 min., the mixture was allowed to warm to r.t. After 1 h, 1-bromo-3,5-difluorobenzene (4 g, 20.7 mmol) in DMF (5 mL) was added dropwise at r.t. The resulting mixture was kept at this temperature for 16 h and slowly poured into H2O (500 mL). It was extracted with EtOAc (3×) and the combined organics were washed with 25% NH4OAc buffer (1×), H2O (2×) and brine. The solution was dried (MgSO4) and concentrated to give a pale yellow solid that was purified by column chromatography on silica gel (EtOAc:hexane, 10:90-15:85) to afford the title compound as a white solid (5.85 g, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:12]([CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19]C)=[O:18])=[S:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:35]([O:34][C:32]([NH:31][CH2:30][CH2:29][N:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:12]([CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:17]([OH:19])=[O:18])=[S:13])=[O:33])([CH3:36])([CH3:37])[CH3:38]
Reactant: COC(=O)[C@H](CCC(=S)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=S)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To the solution of the ester XV (290 mg, 0.51 mmol) in MeOH (10 mL) was added 4 M NaOH dropwise until pH=13. The mixture was stirred overnight at r.t. before evaporating the MeOH under reduced pressure. The residue was mixed with water and washed with ether. After acidifying to pH˜3 with 2 M HCl, the product was extracted with DCM, dried over MgSO4 and concentrated under vacuum to give (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamothioyl]-2-{[(tert-butoxy)carbonyl]amino}butanoic acid XVI (250 mg, 0.45 mmol, 88% yield). ESIMS found for C24H44N4O8S m/z 549 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:39])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[C:31]([F:38])[CH:30]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:39])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:37])=[C:31]([F:38])[CH:30]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COC(=O)COc1ccc(N=C=O)c(F)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with (3-fluoro-4-isocyanato-phenoxy)-acetic acid methyl ester (example 24.1) in 1,2-dichloroethane in the presence of Et3N (2.2 eq.) for 3 days under reflux conditions to give the title compound as brown gum. MS: m/e=551.3 [M+H+].
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[NH2:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]=1[C:16]#[N:17])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: N#Cc1c(N)nc2ccccc2c1-c1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC1=C(N)Nc2ccccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 1.42 h
Yield: 39.7 %

Procedure:
Sodium cyanoborohydride (10 mg) was added to 2-amino-4-phenylquinoline-3-carbonitrile (5 mg) in solution in acetic acid (0.25 mL). After stirring 85 min at room temperature, there was no more change in TLC, so sodium cyanoborohydride (15 mg) was further added. The reaction mixture was allowed to stir for another 20 min, then was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried. The crude obtained after removing the solvent was passed through a bond-elute (4:1 to 7:3 hexane-ethyl acetate) yielding 2 mg of 2-amino-3-cyano-4-phenyl-1,4-dihydroquinoline. 1H NMR (CD3OD): 7.22–7.26 (m, 2H), 7.12–7.19 (m, 3H), 7.07 (dt, J=7.8, 1.6 Hz, 1H), 6.92 (finely split doublet, J=7.8 Hz, 1H), 6.82 (dt, J=7.6, 1.2 Hz, 1H), 6.77 (dd, J=8.1, 1.2 Hz, 1H), 4.76 (s, 1H).
Reaction SMILES: [CH2:1]([CH:3]([C:7]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=O)[C:4]([CH3:6])=O)[CH3:2].Cl.O.[NH2:28][NH2:29].[OH-].[Na+]>O.CO.C(O)(=O)C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[C:8]2[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:7]=2[CH:3]([CH2:1][CH3:2])[C:4]([CH3:6])=[N:29][N:28]=1
Reactant: NN
Reactant: CCC(C(C)=O)c1cc(OC)c(OC)cc1C(=O)c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCC1C(C)=NN=C(c2ccccc2Cl)c2cc(OC)c(OC)cc21
Temperature: 95 °C

Procedure:
A mixture of 10.37 g (28.9 mmoles) of 2-(1-ethylacetonyl)-4,5-dimethoxy-2'-chlorobenzophenone, 10.5 ml of glacial acetic acid and 2.65 ml of concentrated hydrochloric acid is heated to 95° C. under stirring. The mixture is cooled to 60° C., and 2.14 ml of 98% hydrazine hydrate are added to the mixture in portions, whereupon the temperature of the mixture raises to 85° C. After 30 minutes a solution of 1.44 g of sodium hydroxide in 4.5 ml of water is added to the mixture, followed by 10 ml of methanol. The resulting solution is poured into 130 ml of water, and the separated 5H-2,3-benzodiazepine derivative is isolated. 9.04 g (88%) of the title compound are obtained; m.p.: 129°-131° C. C20H21ClN2O2 =356.9. The crude product can be recrystallized e.g. from ethanol. The product with the highest purity grade melts at 147°-149° C. The rhodanide salt of the title compound ([C20H22ClN2O2 ]SCN=425.95) melts at 169°-171° C. after recrystallization from isopropanol.