Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])([CH3:10])[CH3:9].[O:16]([C:23]1[CH:33]=[CH:32][C:26]([C:27](OCC)=[O:28])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>O1CCCC1>[O:28]=[C:27]([C:26]1[CH:32]=[CH:33][C:23]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:24][CH:25]=1)[CH2:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
nButyllithium (2.5 M, 7.9 ml, 19.76 mmol) was added at −20° C. to a solution of di-iso-propylamine (3.29 ml, 23.24 mmol) in tetrahydrofuran (40 ml). The reaction mixture was stirred for 15 minutes under nitrogen at −20° C. then the mixture was allowed to cool down to −78° C. tert-Butylacetate (2.64 ml, 19.67 mmol) was added and the mixture was stirred at −78° C. for 20 minutes. A solution of ethyl 4-phenoxybenzoate (2.17 g, 8.94 mmol) in tetrahydrofuran (5 ml) was further added to this and the resulting mixture was stirred at −78° C. for 50 minutes. A saturated solution of NH4Cl was added and the whole was extracted with EtOAc. The organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 8% Et2O in petroleum ether to afford the title compound as a colourless oil (1.53 g, 55% yield). MS (ES+) m/e=313. 1H NMR (CDCl3) δH 1.47 (9H, s), 3.88 (2H, s), 7.02 (2H, d), 7.10 (2H, d), 7.24 (1H, t), 7.43 (2H, t), 7.94 (2H, d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18]([NH2:31])=[N:19][C:20]([C:22]3[C:27]([NH2:28])=[N:26][C:25]([NH2:29])=[C:24]([Cl:30])[N:23]=3)=[O:21])[CH2:12]2)[CH:5]=1.[CH3:33]I>CC(C)=O.CN(C)C=O>[Cl-:30].[NH2:28][C:27]1[C:22]([C:20]([N:19]=[C:18]([NH2:31])[NH:17][CH:13]2[CH2:14][CH2:15][CH2:16][N@+:11]([CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:32])[CH:5]=3)([CH3:33])[CH2:12]2)=[O:21])=[N:23][C:24]([Cl:30])=[C:25]([NH2:29])[N:26]=1
Reactant: CI
Reactant: COC(=O)c1cccc(CN2CCC[C@H](NC(N)=NC(=O)c3nc(Cl)c(N)nc3N)C2)c1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C[N@+]2(C)CCCC(NC(N)=NC(=O)c3nc(Cl)c(N)nc3N)C2)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 35 mg (0.066 mmol) (S)-3-{3-[N′-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-piperidin-1-ylmethyl}-benzoic acid methyl ester (intermediate 10) and 100 μl (0.7 mmol) methyl iodide in 2 ml acetone/dimethylformamide (1:1) is stirred at room temperature overnight. Then the reaction mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC (gradient of methanol and water+0.2% trifluoroacetic acid, 25° C.). Fractions containing the title compound were concentrated under reduced pressure, treated with excess HCl in methanol and evaporated again.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.[C:22](=O)([O-:24])[O-:23].[Cs+].[Cs+].Br[CH2:29][CH2:30][OH:31].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:22]([OH:24])=[O:23].[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[O:17][CH2:29][CH2:30][OH:31])[CH:5]=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: OCCBr
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCCO)c3)c12
Product: O=CO
Temperature: 60 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
To a solution of 3-(8-amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (28 mg, 0.1 mmol) in anhydrous DMF (1 ml) was added cesium carbonate (49 mg, 0.15 mmol) followed by a solution of 2-bromoethanol (12.5 mg, 0.1 mmol) in DMF (0.5 ml). The reaction was stirred at 60° C. overnight. The reaction was poured onto saturated NaHCO3 (10 ml) and extracted with EtOAc (2×10 ml). The combined organics were washed with water (10 ml) and aqueous brine solution (3×10 ml), dried (MgSO4), filtered and concentrated in vacuo. Purification by mass-directed HPLC gave 2-[3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenoxy]-ethanol formic acid salt (4.0 mg, 12%) as an off-white solid: 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 7.48-7.41 (m, 2H), 7.13-7.09 (m, 2H), 7.01 (d, 1H, J=10.3 Hz), 6.93 (d, 1H, J=5.8 Hz), 4.14 (t, 2H, J=4.9 Hz), 4.03-3.97 (m, 1H), 3.92 (t, 2H, J=4.9 Hz), 2.61-2.51 (m, 4H), 2.15-2.10 (m, 1H), 2.06-2.01 (m, 1H), 3H not observed (NH2 & OH); LCMS (ES+) m/z 325.08 [MH+] at Rt 2.39 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][C:10]([CH2:21][CH2:22][O:23][CH3:24])(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+]>CC(C)=O.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH:10]([CH2:21][CH2:22][O:23][CH3:24])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCOC)(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)C(CCOC)CC(=O)c1ccc(Br)cc1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
To a 150 mL flask was added diethyl 2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-methoxyethyl)malonate (1.59 g, 3.59 mmol) dissolved in acetone (16 mL) and ethanol (16 mL), followed by addition of 1N aqueous sodium hydroxide solution (3.6 mL). The reaction mixture was then heated at 55° C. for 3 h. The reaction mixture was concentrated in vacuo to remove solvents, the residue redissolved in dimethoxyethane (32 mL), and the reaction mixture heated at 80° C. for 3 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (50 mL) and water (50 mL), and stirred for 15 minutes until almost all color was extracted into the organic layer. The layers were separated, the aqueous layer was extracted with additional ethyl acetate (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo, to afford ethyl 4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate (1.06 g, 86%). No further purification of this material was required. LC-MS ret. time 3.18 min, m/z 342.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.35 (t, 3H), 1.77-1.92 (m, 1H), 1.94-2.10 (m, 1H), 3.05-3.2 (m, 2H), 3.35-3.50 (m, 3H), 4.09-4.25 (m, 2H), 7.60 (d, 2H), 7.83 (d, 2H).
Reaction SMILES: CS[N:3]=[C:4]=[O:5].[C:6]1([C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:13][CH2:14][CH2:15][SH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH2:30]Cl>>[C:6]1([C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:13][CH2:14][CH2:15][S:16][C:4]([NH:3][CH3:30])=[O:5])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CSN=C=O
Reactant: ClCCl
Product: CNC(=O)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Methylthioisocyanate (210 mg) was dissolved in anhydrous dichloromethane (5 ml). To the solution were added N-triphenylmethylcysteamine (1.00 g: 1.1 molar equivalent) while cooling with ice. The reaction solution was stirred at room temperature for 30 minutes and was concentrated under reduced pressure. The residue was dissolved in chloroform (50 ml) and well washed with water and a saturated solution of sodium chloride. The chloroform layer was dried by using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chroomatography using a solvent system of hexane/ethyl acetae (5:1 v/v) to obtain the desired substance (0.89 g) with a yield of 79%.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O.Cl[CH2:6][CH2:7][CH:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][C:19]([CH3:21])=[N:20][C:10]=2[O:9]1.[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)(C)C>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:1][N:2]([CH3:3])[CH2:6][CH2:7][CH:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][C:19]([CH3:21])=[N:20][C:10]=2[O:9]1
Reactant: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=O
Reactant: CNC
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc2c(n1)OC(CCN(C)C)CN(C)C2=O
Reaction time: 72 h

Procedure:
To 50 ml of freshly collected dimethylamine was added 5.0 g (0.020 mole) of 2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one hydrate[1:1]. The reaction flask was sealed tightly and left standing at room temperature for 3 days. The dimethylamine was evaporated in a stream of air. The residue was taken up in methylene chloride, washed twice with 1N sodium hydroxide and once with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The syrupy residue was treated with 2 equivalents of fumaric acid in isopropyl alcohol which yield 5.2 g (52%) of white crystals, m.p. 164°-165° C.
Reaction SMILES: P(Br)(Br)[Br:2].OC1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)=[N:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10](C)C=1C.C(=O)([O-])[O-].[K+].[K+].O1[CH2:39][CH2:38][CH2:37][CH2:36]1>C1C=CC=CC=1>[Br:2][CH2:36][C:37]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)=[N:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][C:38]=1[CH3:39]
Reactant: BrP(Br)Br
Reactant: C1CCOC1
Reactant: CC1=C(O)C(c2cccc([N+](=O)[O-])c2)=NC(c2ccccc2)N1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CBr
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of phosphorus tribromide (16.85 g) in a mixture of benzene (150 ml) and tetrahydrofuran (150 ml) was dropwise added a solution of 5-hydroxy-methyl-6-methyl-2-phenyl-4-(3-nitrophenyl)pyrimidine (30 g) in tetrahydrofuran (150 ml) under cooling at 7°-10° C. After stirring for 4 hours at the same temperature, the reaction mixture was poured into ice-water (200 ml), adjusted to pH 9.5 with saturated potassium carbonate and extracted with ethyl acetate (300 ml). After filtering off an insolble material, the organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from diethyl ether to give 5-bromomethyl-6-methyl-2-phenyl-4-(3-nitrophenyl)pyrimidine (29.08 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[C@H:39]([OH:40])[CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@H:35]4[C@H:39]([OH:40])[CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]4)=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl (3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][N:18]3[S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)(=[O:23])=[O:22])=[CH:14][CH:13]=2)=[O:11])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:35]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH:20]=[C:19]4[C:15]([CH2:16][CH2:17][N:18]4[S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)(=[O:22])=[O:23])=[CH:14][CH:13]=3)=[O:11])=[CH:5][C:4]=2[C:31]([F:34])([F:32])[F:33])=[N:2][N:37]=[N:36]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2nnn[nH]2)c(C(F)(F)F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CC2
Yield: 45.5 %

Procedure:
A solution of 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (30 mg, 0.06 mmol) in dimethylformamide (0.8 ml) was treated with sodium azide (71 mg, 1.1 mmol, 18 equiv.) and ammonium chloride (58 mg, 1.1 mmol, 18 equiv.). The solution was flushed with argon, then sealed and irradiated in microwave oven at 170° C. for 1 hour. The mixture was diluted with concentrated NaHCO3 and washed with ethyl acetate. The aqueous phase was acidified with HCl 1N to pH 1, then extracted twice with ethyl acetate. The combined organic phases were dried with Na2SO4 and the solvent evaporated to yield 15 mg (46% yield) of 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(1H-tetrazol-5-yl)-3-trifluoromethyl-phenyl]-amide as an orange foam, MS (ISP): m/e=547.2 (M−H), δH (300 MHz; d6-DMSO) 10.75 (1H, s), 8.41 (1H, s), 8.21 (1H, d), 7.97 (1H, s), 7.61-7.84 (5H, m), 7.56 (1H, t), 7.32 (1H, d), 3.98 (2H, t), 2.95 (2H, t).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH:28]([CH3:30])[CH3:29])[CH:22]=3)=[N:18][N:17]=2)=[CH:11][C:10]=1[CH2:31][CH3:32])C1C=CC=CC=1>CC(=O)OCC.C(O)(=O)C>[CH2:31]([C:10]1[CH:11]=[C:12]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([CH:28]([CH3:29])[CH3:30])[CH:22]=3)=[N:18][N:17]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[OH:8])[CH3:32]
Reactant: CCc1cc(-c2nnc(-c3cc(C)nc(C(C)C)c3)s2)cc(C)c1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCc1cc(-c2nnc(-c3cc(C)nc(C(C)C)c3)s2)cc(C)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
To a solution of 4-[5-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-[1,3,4]thiadiazol-2-yl]-2-isopropyl-6-methyl-pyridine (837 mg, 1.88 mmol) in EA (30 mL) 33% HBr in acetic acid (1 mL) is added. The mixture is stirred at rt for 3 h before it is diluted with EA, washed twice with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-ethyl-4-[5-(2-isopropyl-6-methyl-pyridin-4-yl)-[1,3,4]thiadiazol-2-yl]-6-methyl-Phenol (540 mg) as a pale yellow oil; LC-MS: tR=0.92* min, [M+1]+=354.14.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([NH2:8])[CH2:6][OH:7].C(N(CC)CC)C.[C:16](Cl)(Cl)=[S:17]>C1COCC1>[CH2:4]([CH:5]1[CH2:6][O:7][C:16](=[S:17])[NH:8]1)[CH2:3][CH2:2][CH3:1]
Reactant: S=C(Cl)Cl
Reactant: CCCCC(N)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC1COC(=S)N1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a stirred cold solution of DL-2-amino-1-hexanol (1.1 ml) in dry THF (10 ml) was added triethylamine (2.8 ml) followed by dropwise addition of thiophosgene (0.81 ml) in dry THF (9 ml). The mixture was then stirred for 18 h at 20° C., evaporated under reduced pressure and the residue partitioned between water and diethylether. The ether extract was dried with sodium sulphate filtered and evaporated. The residue was dissolved in the minimum of hot 1:1 dimethylether-hexane and crystallised on cooling to give 4-butyloxazolidine-2-thione, mp 71°-2°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:11])[O:9][CH3:10])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].CCN(C(C)C)C(C)C>C1COCC1>[CH3:10][O:9][N:8]([CH3:11])[C:6]1[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=[C:2]([NH:1][C:16](=[O:19])[CH2:17][CH3:18])[N:7]=1
Reactant: CCC(=O)Cl
Reactant: CCCNc1nc(N)nc(N(C)OC)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCNc1nc(NC(=O)CC)nc(N(C)OC)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
N-(6-amino-4-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXIX) (5 g, 23.58 mmol) was dissolved in THF (50 mL). Propionyl chloride (3.25 g, 35.38 mmol) and DIPEA (5.47 g, 42.44 mmol) were added at 0° C. The resultant mixture was stirred at ambient temperature for 10 min, then stirred at 70° C. for 16 h, after which time the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (250 mL), and this extract was washed with water (80 mL) and then with a brine solution (80 mL), and lastly dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (pet ether/ethyl acetate=5/1 to 2/1) to yield 930 mg (15%) of the desired product. The isolated free amine (930 mg, 3.47 mmol) was dissolved in H2O (10 mL) and 0.5 M HCl solution in H2O (10.4 mL) and then the solution was lyophilized to yield N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide (XL) as a colorless oil (1.06 g). LCMS: (ESI) m/z=269 (M+H)+. 1H NMR (500 MHz, DMSO): δ (ppm) 12.23 (s, 1H), 8.25-9.45 (m, 2H), 3.76-3.84 (m, 3H), 3.30-3.44 (m, 5H), 2.55-2.56 (m, 1H), 2.21-2.22 (m, 1H), 1.53-1.58 (m, 2H), 0.88-1.08 (m, 6H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:18][CH2:17]2)=[O:15])[CH2:3]1.[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:32]=1[C:33](Cl)=[O:34]>>[CH2:7]([N:5]1[C@H:4]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[CH2:20][CH2:21]2)=[O:15])[CH2:3][C@H:2]([NH:1][C:33](=[O:34])[C:32]2[C:31]([Cl:30])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:40])[CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N)CN2Cc2ccccc2)CC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](NC(=O)c3c(Cl)cccc3Cl)CN2Cc2ccccc2)CC1
Yield: 20 %

Procedure:
As described for Example 89e, 2-[4-(4-amino-1-benzyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (50.0 mg, 0.128 mmol) was converted, using 2,6-dichloro-benzoyl chloride instead of 2-chloro-benzoyl chloride, to the title compound (15 mg, 20%) as light yellow oil. MS m/e=562.2 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:9]([NH:17]C(=O)OC(C)(C)C)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[OH:29][C:27]([C:26]([F:31])([F:30])[F:25])=[O:28].[C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:9]([NH2:17])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1Cc2ccccc2N(c2ccccc2)C1

Procedure:
A solution of tert-butyl 1-phenyl-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (375 mg, 1.16 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (2 mL) at ambient temperature for 3 hours. The solvent was removed under reduced pressure and diethylether added. The solid that formed was filtered and dried to give 1-phenyl-1,2,3,4-tetrahydroquinolin-3-amine TFA salt as a yellow solid (350 mg). M.p.=201-203° C. 1H NMR (DMSO) 400 MHz δ 8.13 (s, br, 2H), 7.46 (m, 2H), 7.34 (m, 2H), 7.23 (m, 2H), 7.15 (m, 1H), 6.99 (m, 1H), 6.77 (dt, J=1.2 and 7.6 Hz, 1H), 6.59 (m, 1H), 3.86 (m, br, 2H), 3.56 (m, 1H), 3.27 (m, 1H), 2.90 (dd, J=5.2 and 12 Hz, 1H). LCMS m/e 225 (M+H).
Reaction SMILES: [NH:1]([C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67])[C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:62]([O:64][CH3:65])=[O:63])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57]C(C)(C)C)=[CH:53][CH:52]=1)=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:30][CH2:31][C:32](=[O:38])[O:33]C(C)(C)C)=[O:27])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:25])[NH2:24])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O.Cl>FC(F)(F)C(O)=O>[NH:1]([C:66]([O:68][CH2:69][C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)=[O:67])[C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:62]([O:64][CH3:65])=[O:63])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=1)=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:30][CH2:31][C:32](=[O:33])[OH:38])=[O:27])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:24])[NH2:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:31][C:32]([OH:38])=[O:33]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1)C(C)C
Reaction time: 1 h

Procedure:
1.2 g (1.1 mmoles) of Z-Lys(Boc)-Arg-Glu(OBut)-Val-Tyr(But)-OMe.HCl are dissolved in 10 ml of 90 percent strength trifluoroacetic acid. The mixture is allowed to stand for one hour at room temperature and is concentrated. The residue is partitioned between 150 ml of water and 100 ml of diethyl ether. The aqueous phase is stirred with a weakly basic ion exchanger in the acetate form. The exchanger is filtered off and the filtrate is freeze-dried. Yield 880 mg (89%), [α]D23 =-45.8° (c=1, in water).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:13][CH:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[CH:11]([OH:25])[CH:10]1[OH:26].CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([NH:8][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([Cl:23])[N:18]=1
Reactant: NC1CC(n2cnc3c(Cl)nc(Cl)nc32)C(O)C1O
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1S,2R,3S,5R)-3-amino-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate (0.304 g, 1.00 mmol) in THF (10 ml) is treated with DIPEA (0.387 g, 3.00 mmol) followed by propionyl chloride (0.093 g, 1.00 mmol). The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). MS (ES+) m/e 360 (MH+).