Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36](=O)[CH2:37]Br)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:42]([NH2:45])(=[S:44])[CH3:43]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]5[N:45]=[C:42]([CH3:43])[S:44][CH:37]=5)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:16])([F:17])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:40][CH:41]=1)([O-:3])=[O:2]
Reactant: CC(N)=S
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(C(=O)CBr)cc(C#N)nc3c2)nn1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4csc(C)n4)cc(C#N)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of 1-(1-{[4-(bromoacetyl)-2-cyanoquinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (see Example 52, Step 2) (65 mg, 0.1 mmol) and thioacetamide (9 mg, 0.11 mmol) in DMF (1 mL) was stirred at 100° C. overnight. The reaction mixture was diluted in ethyl acetate, washed with water, brine and dried over MgSO4. The crude compound was purified on silica gel (eluting solvent: 3% acetone in dichloromethane) to give the desired product. 1H NMR (acetone-d6): δ 8.85 (d, 1H), 8.52 (s, 1H), 8.42 (d, 2H), 8.30 (d, 2H), 8.17 (d, 2H), 8.05 (s, 1H), 7.75 (d, 1H), 6.05 (s, 2H), 3.05 (m, 1H), 2.85 (s, 3H), 2.85 (m, 1H), 1.15 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:29][C:30]1[C:31]([O:45][CH3:46])=[C:32]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=1>>[C:36]([C:34]1[CH:33]=[C:32]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:31]([O:45][CH3:46])=[C:30]([NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][C:19]([CH2:22][N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:35]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(CN3CCOCC3)nc2)nn1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(CN5CCOCC5)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 13 was prepared by coupling 4-methyl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid (2:1 with 4-methyl-3-[5-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzoic acid) with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. Chromatography separated the triazole isomers. ESI MS m/z 635 [C32H39N7O5S+H]+.
Reaction SMILES: O[N:2]=[CH:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:20])([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[CH3:11])[C:6](=[O:21])[C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[C:3]([C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:20])([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[CH3:11])[C:6](=[O:21])[C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:2]
Reactant: CC(C)(c1cc(Cl)cc(Cl)c1)N1COC(C=NO)=C(c2ccccc2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(c1cc(Cl)cc(Cl)c1)N1COC(C#N)=C(c2ccccc2)C1=O
Yield: 82 %

Procedure:
6-Hydroxyiminomethyl-3-[1-methyl-1-(3,5-dichlorophenyl)ethyl]-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 135, 0.50 g), triphenylphosphine (0.33 g), carbon tetrachloride (0.19 g) and triethylamine (0.13 g) were mixed, and dichloromethane (5 ml) was added thereto. The mixture was refluxed for two and one-half hours. The reaction mixture was rinsed with water and dried with magnesium sulfate, then the solvent was removed by evaporation and the crude product was purified by silica gel chromatography to afford the captioned compound (0.39 g, yield 82%).
Reaction SMILES: C([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])(OC(C)(C)C)=O.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23](F)[CH:24]=1>[OH-].[Na+].C(O)C>[NH2:8][C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:21]1[CH:20]=[C:19]([O:18][CH3:17])[CH:24]=[CH:23][C:22]=1[N+:26]([O-:28])=[O:27])[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NCCC[C@H](N)C(=O)O)c1
Reaction time: 12 h

Procedure:
A solution of 696 mg (3.0 mmol) of Nα -BOC-L-ornithine and 513 mg (3 mmol) of 5-methoxy-2-nitrofluorobenzene in 3 mL of 1N NaOH and 3 mL of ethanol were heated at reflux for 20 hours, then concentrated in vacuo to a yellow oil. The oil was dissolved in 21 mL of 4N HCl in 33% acetic acid and stirred for 12 hours, then suspended in 50 mL of water and washed with 30 mL of dichloromethane and concentrated in vacuo to give a yellow powder. This was recrystallized twice from acetic acid/water to afford the title product as yellow crystals. mp 245°-246°; MS M/Z (DCl/NH3) 284 [M+H]; 1H NMR (300 MHz, D2O/NaOD) δ: 8:1.45 (m, 4H), 2.81 (m, 2H), 3.10 (d, J=1 Hz, 4.2H), 3.52 (d, J=3 Hz, 5.7H), 5.52 (d, J=1 Hz, 3.0H), 5.69 (m, 1H), 7.33 (dd, J=1, 8.4 Hz, 5.7H); 13C NMR (75.5 MHz, D2O/NaOD) δ: 185.47, 168.65, 150.74, 131.00, 127.20, 108.64, 96.78, 58.48, 45.27, 35.37, 27.37; Analysis calc'd for C12H17N3O5.0.2 H2O: C, 50.24; H, 6.11; N, 14.65; found: C, 50.09; H, 6.03; N, 14.60.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([CH3:10])[N:4]=1.[CH3:11][N:12]([CH3:16])[C:13](Cl)=[S:14]>>[CH3:11][N:12]([CH3:16])[C:13](=[S:14])[O:9][C:7]1[N:6]=[C:5]([CH3:10])[N:4]=[C:3]([CH2:2][Cl:1])[CH:8]=1
Reactant: CN(C)C(=S)Cl
Reactant: Cc1nc(O)cc(CCl)n1
Product: Cc1nc(CCl)cc(OC(=S)N(C)C)n1

Procedure:
4-Chloromethyl-6-hydroxy-2-methyl-pyrimidine is reacted with N,N-dimethylthiocarbamoyl chloride analogously to the process described in Example 86 in order to produce 4-chloromethyl-2-methyl-6-pyrimidinyl N,N-dimethylthiocarbamate which is required as the starting material in Example 30. This product is obtained in the form of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br.Br[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[N:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[CH:31][CH:32]=1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccccc21
Reactant: BrCc1ccncc1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(OCc5ccncc5)cc4)CC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A mixture of (1R)-1′-{[1-(4-hydroxyphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (15 mg, 0.043 mmol), 4-(bromomethyl)pyridine hydrobromide (13 mg, 0.052 mmol), Cesium Carbonate (56 mg, 0.17 mmol), and Tetra-n-butylammonium iodide (1.6 mg, 0.004 mmol) in Dimethyl sulfoxide (0.3 ml) was stirred at r.t. overnight. Then the desired product was obtained from the mixture by prep-HPLC (10.0 mg, yield: 53%). LCMS: m/z 441.1 (M+H)+; 463.1 (M+Na)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:14][C:11]2[CH:10]=[CH:9][C:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CBr)cc1
Reactant: Oc1ccc([C@H]2CC[C@H](O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc([C@H]3CC[C@H](O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a suspension of p-(trans-4-hydroxycyclohexyl)phenol (67.62 mmol, 13.00 g) in acetone (400 mL) is added 1-bromomethyl-4-methoxybenzene (74.38 mmol, 10.57 mL) and potassium carbonate (81.14 mmol, 11.33 g). The mixture is stirred for 64 h at room temperature and filtered. The filtrate is concentrated and recrystallized from CH2Cl2 (100 mL) to give the title compound (15.1 g, 71%) as a white solid. 1H NMR (400 MHz, CDCl3): 1.34-1.49 (m, 4H), 1.87-1.90 (m, 2H), 2.02-2.07 (m, 2H), 2.38-2.45 (m, 1H), 3.61-3.68 (m, 1H), 3.79 (s, 3H), 4.93 (s, 2H), 6.88 (d, 2H, J=8.8 Hz), 6.89 (d, 2H, J=8.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 7.32 (d, 2H, J=8.8 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:15])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].O([CH2:24][CH3:25])S(C(F)(F)F)(=O)=O>C1COCC1.C(OCC)(=O)C>[CH2:24]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][C:6]([O:5][CH2:3][CH3:4])=[O:15])[CH3:25]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)CNc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN(CC)c1ccccc1
Reaction time: 1.5 h
Yield: 17.2 %

Procedure:
NaH (224 mg, 5.6 mmol of 60% dispersion) was washed 3 times with hexanes and dried via vacuum aspiration. To the dry NaH was added a solution of N-phenylglycine ethyl ester (1 g, 5.6 mmol) in THF (28 mL) at 0° C. After stirring 1.5 h, ethyl triflate (0.7 mL, 5.6 mmol) was added via syringe. The resulting solution was stirred at ambient temperature over 18 h. The mixture was diluted with ethyl acetate and washed with 1M HCl and brine. The organics were dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded the title compound as a light yellow oil (200 mg, 17%). MS (ES+) m/z 208 (MH+).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][CH2:36][C:37]([N:39]([CH3:40])[CH3:41])=[O:38])[C:30]([N:32]([CH3:33])[CH3:34])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)CC[C@H](N)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CCC(=O)N(C)C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.58 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 70-2 (5.64 mmol, crude form) as starting materials, respectively 0.64 g (Isomer A, colorless powder) and 1.14 g (Isomer B, colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [O:1]=[C:2]1[CH:11](CCC(O)=O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1>C(OC(=O)C)(=O)C>[CH2:10]1[C:9]2=[CH:8][CH:7]=[CH:6][C:5]3=[C:4]2[N:3]([C:2](=[O:1])[CH2:11][CH2:10]3)[C:2](=[O:1])[CH2:11]1
Reactant: O=C(O)CCC1Cc2ccccc2NC1=O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCc2cccc3c2N1C(=O)CC3
Temperature: 100 °C

Procedure:
1,2,3,4-Tetrahydro-2-oxo-3-quinolinepropanoic acid (2.1 g, 0.0096 mole) is dissolved in acetic anhydride (10 ml) and the solution is heated to 100° C. for one hour. Excess acetic anhydride is removed at reduced pressure and the residual anhydride is removed by addition of toluene and repeated concentration. The solid is recrystallized from ethyl acetate to yield pure 1,2,6,7-tetrahydro-3H,5H-benzo[ij]quinolizine-3,5-dione, mp 136°-140° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[CH3:27])[CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:19]([CH3:18])[CH:20]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1ccc(CN)cc1C
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1C

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 3,4-dimethylbenzylamine in DME. ES-MS m/e (%): 320 (M+H+, 100).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)/[CH:20]=[CH:21]/N(C)C)=[CH:15][C:14]=1[O:26][CH3:27]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:21][CH:20]=2)=[CH:15][C:14]=1[O:26][CH3:27]
Reactant: N#Cc1ccnc(NN)c1
Reactant: COc1cc(C(=O)/C=C/N(C)C)ccc1Cl
Agent: Cl
Product: COc1cc(-c2ccnn2-c2cc(C#N)ccn2)ccc1Cl
Yield: 74 %

Procedure:
The title compound was prepared in 74% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-1-(4-chloro-3-methoxyphenyl)-3-(dimethylamino)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 3.82 (3H, s), 6.53 (1H, d, J=2.0 Hz), 6.78 (1H, d, J=2.4 Hz), 6.89 (1H, d, J=1.6 Hz), 7.32 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=5.2, 1.2 Hz), 7.78 (1H, d, J=1.2 Hz), 8.07(1H, s), 8.39 (1H, dd, J=5.2, 0.8 Hz). [M+H] Calc'd for C16H11ClN4O, 311; Found, 311.
Reaction SMILES: [OH:1][C:2]1([CH3:16])[CH2:5][CH:4]([NH:6]C(=O)OC(C)(C)C)[C:3]1([CH3:15])[CH3:14].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:6][CH:4]1[CH2:5][C:2]([CH3:16])([OH:1])[C:3]1([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CC(C)(O)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CC(N)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-hydroxy-2,2,3-trimethylcyclobutyl)carbamate (1.0 equiv.) in anhydrous DCM (0.5 M) was added trifluoroacetic acid (1.0 M) at 0° C. and the mixture was stirred at room temperature for 30 min. After removal of the volatile solvents, the residue was neutralized by ammonia MeOH solution and the final resulting mixture was concentrated to give the crude title product which was used for the next step without further purification. MS (ESI) m/z 130.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([N:18]=[CH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)[C:10]=23)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>CN1C(=O)N(C)CC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)[C:10]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccc(-c5cccnc5)cc4)c23)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN1CCN(C)C1=O
Product: Clc1cccc(Nc2ncnc3[nH]nc(NCc4ccc(-c5cccnc5)cc4)c23)c1
Reaction time: 1 h

Procedure:
With ice-cooling, 10.3 ml (10.3 mmol) of DISAL-H are added to 550 mg (1.29 mmol) of 4-(3-chloro-phenylamino)-3-{[4-(pyrid-3-yl)-phenyl]-methyleneamino}-1H-pyrazolo[3,4-d]pyrimidine that have been dissolved in 25 ml of DMEU and the reaction mixture is stirred for 60 min. 15 ml of ethyl acetate are added and the mixture is stirred for 5 min and diluted with 300 ml of methanol and 1 ml of water; 20 g of Na2SO4 are added and after 15 min the mixture is filtered and the filtrate is concentrated by evaporation in a rotary evaporator. The residue is poured into 0.5 liter of water and 0.7 liter of ethyl acetate, and the aqueous phase is separated off and extracted twice more with ethyl acetate. The organic phases are washed 20 times with water (until DMEU-free) and finally with brine, dried (Na2SO4) and concentrated by evaporation. Stirring in methanol and filtration until clear and stirring in ethyl acetate and diethyl ether yield 4-(3-chloro-phenylamino)-3-[4-(pyrid-3-yl)-benzylamino]-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf=0.47 (CHCl3/methano/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=6.4; FAB-MS: (M+H)+=428.
Reaction SMILES: CO[N:3]=[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH3:5]>[Ni].N.CO>[N:12]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:4]([NH2:3])[CH3:5])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CON=C(C)c1ccccc1N1CCOCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(N)c1ccccc1N1CCOCC1
Reaction time: 11 h
Yield: 96.3 %

Procedure:
A mixture of Example 49B (1.3 g, 5.54 mmol) and Raney nickel (14 g) in a mixture of 20% NH3 in methanol (140 mL) was hydrogenated at 60 psi for 11 hrs. The reaction was filtered and concentrated to dryness under reduced pressure to give 1.1 g of the title compound. MS (ESI+) m/z 207 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][C:14]([N+:22]([O-])=O)=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H].Cl.[Sn](Cl)Cl>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][C:14]([NH2:22])=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCc2nc3ccc([N+](=O)[O-])cc3c(C)c2CC1
Agent: Cl
Agent: Cl[Sn]Cl
Product: CCOC(=O)N1CCc2nc3ccc(N)cc3c(C)c2CC1
Yield: 95 %

Procedure:
9-Amino-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared from 9-nitro-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester by reduction with nascent hydrogen, generated in situ by concentrated hydrochloric acid and tin(II)chloride, at a temperature of 60°-80° C.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:27][Cl:28].[ClH:36]>C1(C)C=CC=CC=1>[ClH:28].[ClH:36].[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:27][C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Yield: 80.6 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 2.8 g (0.01 mole) and 2.2 g (0.01 mole) of 3,4,5-trimethoxybenzyl chloride were dissolved in 20 ml of toluene, and heated at the refluxing temperature for 4.5 hours. After the reaction liquid was left to cool, dry hydrogen chloride gas was passed through the reaction liquid while cooling the liquid to precipitate crystals of 1-(3,3-diphenylpropyl)-4-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride, which were recrystallized from an ethanol and ether mixed solvent to obtain 4.3 g of pure crystals (80.6% yield) with a melting point of 178°C.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([S:17]([NH:20][C@H:21]([C:29]([OH:31])=O)[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18])[CH:9]=[CH:8]2.C(OCC)C.S(Cl)([Cl:39])=O>>[N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([S:17]([NH:20][C@H:21]([C:29]([Cl:39])=[O:31])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18])[CH:9]=[CH:8]2
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2cc1OC
Reactant: O=S(Cl)Cl
Agent: N#N
Solvent: CCOCC
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.00 g of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride.
Reaction SMILES: C([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])(OCC1C=CC=CC=1)=O.[C:46]([NH:56][C@H:57]([C:59]([OH:61])=O)[CH3:58])([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47]>>[C:46]([NH:56][C@H:57]([C:59]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:42])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])=[O:61])[CH3:58])([O:48][CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:47]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Yield: 79 %

Procedure:
From 0.63 g (1.01 mM) of carbobenzoxy-glycyl-phenylalanyl-leucyl-arginine and 0.38 g (1.11 mM) of p-nitrophenyl ester of carbobenzoxy-alanine, in a manner similar to that described hereinbefore, 0.56 g (79%) of carbobenzoxy-alanyl-glycyl-phenylalanyl-leucyl-arginine with m.p. of 147°-149° C. is obtained. [α]D25 =-4.0 (c 0.5, dimethylformamide). Rf1 =0.33 (C), Rf2 =0.35 (D), Rf3 =0.67 (chloroform:methanol: 32% acetic acid 60:45:20) (E).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8](Br)[CH2:9][CH2:10][Cl:11])=[O:7])=[CH:4][CH:3]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[Na+].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][CH2:10][Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(c1ccc(F)cc1)C(Br)CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(F)cc1)C(CCCl)Oc1ccccc1

Procedure:
The 1-p-Fluorobenzoyl-1-phenoxy-3-chloropropane is prepared as follows: a solution of 30 g. of 1-p-fluorobenzoyl-1-bromo-3-chloropropane in 100 cc. anhydrous acetone is added slowly, during half an hour and with stirring, to a suspension of 10.1 g. of phenol, 1.08 g. sodium iodide and 25.2 g. K2CO3 in 350 cc. anhydrous acetone. When the addition is complete, the mixture is refluxed for 12 hours. The solid contained therein is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residual oil is fractionated in a vacuum and the product is collected as a yellow oil. (b.p. 165°-70°C/0.6 Torr).