Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32]([OH:34])=O.[O:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][NH2:41]>ClCCl>[O:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][NH:41][C:32](=[O:34])[CH2:31][N:15]1[CH2:16][CH2:17][C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:13]
Reactant: NCc1ncco1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1ncco1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.050 g, 0.169 mmol; Example 1C) and oxazol-2-ylmethanamine (0.018 g, 0.186 mmol) were stirred together in dichloromethane (0.5 mL) at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 (Analogix®) column and the product eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (Flow=30 mL/minute) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.38-7.19 (m, 10H), 7.05 (s, 1H), 6.68 (s, 1H), 4.48 (d, J=5.6, 2H), 4.08 (s, 2H), 3.53 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (ESI+) m/z 376.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:4]1)=[O:1]
Reactant: CC(C)(C)OC(=O)NC1CCCC(CO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of tert-butyl [3-(hydroxymethyl)cyclohexyl]carbamate (0.51 g, 2.2 mmol) in methylene chloride (10 mL) at 0° C. was added Dess-Martin periodinane (1.1 g, 2.7 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched with aq. 1N NaOH solution and extracted with methylene chloride. The combined organic layers were washed with water and then brine, dried over MgSO4, concentrated, and then purified on silica gel column (eluting with 20-50% EtOAc in hexanes) to give the desired product (0.3 g, 59%). LCMS calculated for C12H21NO3Na (M+Na)+: m/z=250.2. Found: 250.1.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22](O)(=[O:31])[C:23]1[C:24]([O:29][CH3:30])=[CH:25][CH:26]=[CH:27][CH:28]=1>>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:2]2([CH3:1])[CH2:6][C:5]3[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=3[O:3]2)[CH2:17][CH2:18]1)=[O:31]
Reactant: COc1ccccc1C(=O)O
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: COc1ccccc1C(=O)N1CCN(CC2(C)Cc3c(C)c(N)c(C)c(C)c3O2)CC1
Yield: 42 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and o-anisic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 42%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[C:23]([C:25]([NH:27][C:28]4[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=4[F:35])=[O:26])[CH:22]=[CH:21][C:20]=3[F:36])[CH:15]=[CH:14][N:13]=2)[NH:9][CH:8]=1)=[O:6].C(N(CC)C(C)C)(C)C.Br[CH2:47][C:48]([O:50][CH3:51])=[O:49].O>CN(C=O)C>[F:36][C:20]1[CH:21]=[CH:22][C:23]([C:25]([NH:27][C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=2[F:35])=[O:26])=[CH:24][C:19]=1[O:18][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([C:10]2[NH:9][CH:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:47][C:48]([O:50][CH3:51])=[O:49])=[O:6])[CH:11]=2)[CH:17]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCN)c[nH]4)c3)c2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CNCCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-(2-aminoethyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide (80 mg, 0.16 mmol) in 10 ml of anhydrous DMF, were added N,N-diisopropylethylamine (60 mg, 0.47 mmol) and methyl bromoacetate (30 mg, 0.20 mmol). The mixture was stirred at room temperature for 1 hour and poured into 100 ml of water. The precipitates were filtered, washed with water, and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3˜5% of methanol in chloroform to give methyl ({2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]ethyl}amino)acetate as white solid. Yield: 38 mg, 41%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.C1(C)C=CC=C([O:15][C:16](=[NH:20])[NH:17][C:18]#[N:19])C=1.[ClH:22]>C(O)(C)C>[ClH:22].[ClH:22].[NH:6]1[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:18]([NH:17][C:16]([NH2:20])=[O:15])=[NH:19])[N:8]=[CH:7]1
Reactant: Cc1cccc(OC(=N)NC#N)c1
Reactant: NCCc1c[nH]cn1
Agent: Cl
Solvent: CC(C)O
Product: N=C(NCCc1c[nH]cn1)NC(N)=O

Procedure:
47.5 g. histamine (0.401 mole) and 71.66 g. (0.409 mole) O-m-tolyl-N-cyanoisourea are combined in 500 ml. of isopropanol. The mixture is then heated for 10 minutes to reflux, refluxed for one hour, and the reaction mixture is stripped to an oil. The oil is taken up in 2 l. of isopropanol and 102 ml. conc. HCl, heated 25 minutes to reflux, refluxed for 35 minutes, cooled slowly, then with ice. The mixture is filtered to obtain 1-[2-(4-imidazolyl)ethylamidino]urea dihydrochloride as a crude product. This is recrystallized from MeOH/CH3CN to obtain 1-[2-(4-imidazolyl)ethylamidino]urea dihydrochloride with a m.p. of 180.5°-181.5° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>ClCCl.[OH-].[Na+]>[N:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccncn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: NC1CCN(c2ccncn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a solution (1-pyrimidin-4-yl-piperidin-4-yl)-carbamic acid tert-butyl ester (1.00 g, 3.59 mmol) in dichloromethane (16 mL) was added HCl (2 M in diethylether, 8.98 mL, 18.0 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was then diluted with NaOH (2 N) at 0° C. and extracted with dichloromethane. The combined organic extracts were then dried over sodium sulfate and filtered to afford the title compound (511 mg, 80%) as a light yellow solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]([CH3:21])[C:14]1=[O:22]>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]([CH3:21])[C:14]1=[O:22]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(=O)[nH]c(=O)n(-c2ccc(F)cc2Cl)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(=O)[nH]c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
Nitric acid (70% real, 8.3 mL, 0.131 mol) is added to a solution of 1-(2-chloro-4-fluorophenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (32.4 g, 0.119 mol) in concentrated sulfuric acid while maintaining the reaction mixture temperature below 10° C. After the addition is complete, the reaction mixture is stirred at room temperature for 30 minutes, cooled to 10° C. and diluted with ice-water. The resultant aqueous mixture is filtered to obtain a solid which is washed with water and air-dried to give the title product as a white solid (28.5 g, mp 135°-139° C.).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:26](O)=[O:27])[CH2:3][C:4]1[N:8]=[CH:7][N:6](C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH:5]=1.[NH2:46][C@@H:47]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C@@H:48]([OH:54])[C@H:49]([CH:51]1[CH2:53][CH2:52]1)[OH:50].N1CCCCC1>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)[C:26]([NH:46][C@@H:47]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C@@H:48]([OH:54])[C@H:49]([CH:51]1[CH2:52][CH2:53]1)[OH:50])=[O:27]
Reactant: O=C(N[C@@H](Cc1cn(C(=O)OCC2c3ccccc3-c3ccccc32)cn1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)[C@@H](O)C1CC1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described in Example 1, paragraph (c), by the condensation of Fmoc-His(Fmoc)-OH and (1S,2R,3S)-3-amino-1-cyclopropyl-4-phenyl-1,2-butanediol followed by cleavage of the protecting groups using piperidine in methylene chloride there was obtained (S)-α-amino-N-[(1S,2R,3S)-1-benzyl-3-cyclopropyl-2,3-dihydroxypropyl]-imidazole-4-propionamide as a colourless foam, MS: 359 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])C)=[O:8].[CH2:14]1[N:19]([C:20]2[C:25](C#N)=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15]1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:12]=[C:6]2[C:5]([CH:13]=[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[NH:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)cc1C(=O)N(C)C
Reactant: N#Cc1ccccc1N1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccc2N2CCOCC2)cc2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A 1.8 M lithium diisopropylamide THF solution (5.39 ml, 9.69 mmol) was diluted with THF (10 ml). To the diluted solution, a solution obtained by dissolving the 5-chloro-2,N,N-trimethylbenzamide (383 mg, 1.94 mmol) prepared in step A in THF (5 ml) was added dropwise at −78° C. A solution obtained by dissolving 2-(4-morpholino)benzonitrile (438 mg, 2.33 mmol) in THF (5 ml) was further added to the mixture. The obtained mixture was stirred at −78° C. for 30 minutes. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The obtained yellow oil product was crystallized from hexane/ethyl acetate (3:1), so as to obtain 7-chloro-3-(2-morpholin-4-ylphenyl)-2H-isoquinolin-1-one (575 mg; yield: 87%) in the form of a colorless crystal.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)=[CH:8][C:7]([C:20]([NH2:22])=[O:21])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:35][C:32]3[CH:31]=[CH:30][C:29]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:34][CH:33]=3)[N:11]=2)=[CH:8][C:7]([C:20]([NH2:22])=[O:21])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(C(N)=O)cc1-c1ccnc(S(C)(=O)=O)n1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1nc(C(N)=O)cc1-c1ccnc(Oc2ccc(N3CCNCC3)cc2)n1
Yield: 20 %

Procedure:
50 mg (0.155 mmol) of 1-tert-butyl-5-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide were dissolved in 1.5 mL of dry DMF; then, 30 mg (0.17 mmol) of 4-piperazin-1-yl-phenol and 64 mg (0.464 mmol) of potassium carbonate were added. The final suspension was stirred at 70° C. for 1 h then the final mixture was purified by preparative HPLC/MS to provide the title compound (20%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:19])([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][C:10]([NH2:12])=O)=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CCOCC.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:19])([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:10][NH2:12])=[CH:6][CH:7]=1
Reactant: NC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: NCCC(O)(c1ccc(Br)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
To 1.0 g (3.1 mmole) of 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propionamide and 0.8 g (0.02 mole) of sodium borohydride in 60 ml of dry tetrahydrofuran at 0° C. and under N2, was added dropwise over 20 minutes 4.6 g (0.03 mole) of boron trifluoride ethyl etherate in 20 ml of dry tetrahydrofuran. The mixture was stirred for 48 hours at room temperature, and then cautiously hydrolyzed with water. Alcalization with 2M NaOH and extraction with ether gave after evaporation a semi-crystalline residue. Recrystallization from ether-petroleum ether gave 0.6 g (63%) of the amine, m.p. 95°-115° C. NMR-spectrum (COCl3): 2H(2.4, 1-CH2)m : 2H(3.0, 2-CH2)m : 3H(3.6, --OH, --NH2)b : 6H(7.1-8.0 ArH)m : 2H(8.6)m ##STR31##
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Br:24][C:25]1[N:26]=[CH:27][NH:28][C:29]=1[C:30](O)=[O:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:24][C:25]1[N:26]=[CH:27][NH:28][C:29]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1[nH]cnc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Br)c2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (36.1 mg, 0.105 mmol), 4-bromo-1H-imidazole-5-carboxylic acid (20.0 mg, 0.105 mmol) and diisopropylethyl amine (0.0366 mL, 0.210 mmol) in DMF (5 ml) was added HATU (39.8 mg, 0.105 mmol) and the mixture was stirred at rt for 30 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-bromo-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (11.0 mg, 0.021 mmol, 20% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27-8.50 (m, 1H), 8.11 (s, 1H), 7.76-7.89 (m, 2H), 7.74 (s, 1H), 7.50 (dd, 1H), 7.37 (t, 1H), 4.50 (d, 2H). LC-MS (ES+) m/z 516.90, [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1.N1C=CC=CC=1.[S:28]1[CH:32]=[N:31][N:30]=[C:29]1[SH:33].BrBr>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][S:6][C:7]2[N:12]=[C:11]([OH:13])[C:10]([S:33][C:29]3[S:28][CH:32]=[N:31][N:30]=3)=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Sc1nncs1
Reactant: C[C@H](CO)Nc1cc(O)nc(SCc2cccc(Cl)c2)n1
Agent: BrBr
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2)nc(O)c1Sc1nncs1
Reaction time: 1 h

Procedure:
The product of Example 3 (0.12 g), pyridine (50 μl) and 1,3,4-thiadiazole-2-thiol (0.18 g) were dissolved in DMF (3 ml) and bromine (18 μl) added dropwise. The reaction mixture was stirred for 1 h before being purified directly by reverse phase HPLC (95-75% 0.02M ammonium hydroxide/acetonitrile) to yield the title product as a white solid. Yield 0.15 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[C:14](Cl)(C1C=CC=CC=1)([C:21]1C=CC=CC=1)[C:15]1C=CC=CC=1>C(Cl)Cl>[CH3:4][C:3]1([CH3:5])[CH2:2][NH:1][CH2:15][C@@H:14]([CH3:21])[NH:6]1
Reactant: CC(C)(N)CN
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CNCC(C)(C)N1
Reaction time: 40 h

Procedure:
A mixture of 1,2-diamino-2-methylpropane (XXVI, 10 ml) and triethylamine (20 ml) in methylene chloride (400 ml) is cooled to -40°. Trityl chloride (26 g) in methylene chloride (75 ml) is added dropwise and the reaction is allowed to warm to 20-25° and stir for 40 h. After a standard basic workup (methylene chloride, sodium bicarbonate and magnesium sulfate) the residue is chromatographed (silica gel; ethyl acetate/methanol, 9/1), to provide the desired compound, mp 97-98°; IR (mineral oil) 2956, 2925, 2869, 2855, 1487, 1462, 1449, 747 and 708 cm-1 ; NMR (CDCl3) 7.51, 7.27, 7.17, 1.94-2.01, 1.71-1.82 and 1.12 δ; MS (m/e) 273, 258, 243, 165 and 58.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[C@H:17]([CH3:28])[CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][NH:18][C@H:17]([CH3:28])[CH2:16]1
Reactant: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl (2R)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate (1.40 g, 3.56 mmol, 1.00 equiv), dichloromethane (15 mL). Trifluoroacetic acid (3.80 g, 33.3 mmol, 9.40 equiv) was added at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 0.90 g (86% yield) of 4-(3-fluoro-4-[[(3R)-3-methylpiperazin-1-yl]methyl]phenyl)morpholine as yellow oil. LCMS (ESI, m/z): 294 [M+H]+.
Reaction SMILES: [F:1][C:2]([C:5]1[C:6](=[O:19])[C:7](N)=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[CH3:11])([F:4])[F:3].Cl.N([O-])=[O:22].[Na+]>O>[F:1][C:2]([C:5]1[C:6](=[O:19])[C:7]([OH:22])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[CH3:11])([F:4])[F:3]
Reactant: O=N[O-]
Reactant: Cc1c(C(F)(F)F)c(=O)c(N)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1c(C(F)(F)F)c(=O)c(O)nn1-c1ccccc1
Reaction time: 1 h
Yield: 89 %

Procedure:
A suspension of 1-m.trifluoromethylphenyl-1,4-dihydro-3-amino-4-oxo-6-methylpyridazine (21 grams, 0.078 mole) in 400 ml of water is chilled. After the addition of 12N hydrochloric acid (14.5 ml), sodium nitrite (5.38 g) is added, drop by drop, with 50ml of water. After agitation of the mixture for one hour at 0° C., two hours at 20° C., and then ten minutes at 50° C., it is rechilled, filtered through sintered glass, and washed with water. The precipitate is dissolved in 1200 ml of tepid ethyl acetate. After drying over sodium sulfate, filtration and evaporation under vacuum, the product crystallizes after being dissolved in diethyl ether. There is obtained, after recrystallization from a 75/25 mixture of dioxane and diethyl ether, the Compound 1 (18.75 grams; yield=90%).
Reaction SMILES: [CH:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=O)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[CH:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:26])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Reaction time: 2 h

Procedure:
A mixture of 4-[2-(indan-1-yl)ethyl]-1-(4-carboxamido)phenylpiperazine (CXII, EXAMPLE 77, 0.7 g, 2 mmol), phosphorus oxychloride (0.93 ml, 10 mmol) in dimethylformamide (20 ml) is heated at 80° for 2 hr. The mixture is stirred for 2 hr and quenched with sodium hydroxide (20%) until the pH>13. The mixture is extracted with ethyl acetate (800 ml), and the organic phase is washed with saline, dried (magnesium sulfate), filtered and concentrated. The concentrate is purified by liquid chromatography on silica gel 60 (400 g), eluting with hexane/ethyl acetate (1/1). The appropriate fractions homogeneous by TLC are combined and concentrated to give the free base of title compound, which is converted into the hydrochloric acid salt and crystallized from hexane/ethyl acetate to give the title compound, mp 157°-158°, NMR (CDCl6, TMS) 7.62-6.92 and 3.94-1.46 δ.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:18]([O:31][CH3:32])=[C:19]([NH:21][C:22]([C:24]3[N:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=3)=[O:23])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:42])([F:41])[CH2:39][NH2:40].O>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:18]([O:31][CH3:32])=[C:19]([NH:21][C:22]([C:24]3[N:25]=[N:26][C:27]([NH:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[CH:28][CH:29]=3)=[O:23])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(NC(=O)c2ccc(Cl)nn2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Reactant: NCC(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1c(NC(=O)c2ccc(NCC(F)(F)F)nn2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 25 °C
Yield: 37 %

Procedure:
step 2—A solution of 312 (0.059 g, 0.1 mmol) and 2,2,2-trifluoroethylamine (0.5 mL) in NMP (1.0 mL) in a screw-capped test tube was heated to 100° C. After 18 h the solution was cooled to RT poured into H2O and extracted with EtOAc. The combined organics were washed sequentially with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane (6% to 60% EtOAc) to afford 0.029 g (37%) 6-(2,2,2-trifluoro-ethylamino)-pyridazine-3-carboxylic acid [5-(2-benzyloxy-pyridin-3-yl)-3-tert-butyl-2-methoxy-phenyl]-amide (314) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].Br.[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26]Br)[CH3:23].C(OCC)(=O)C.[ClH:36]>CN(C=O)C.C(OCC)(=O)C>[ClH:36].[CH2:22]([N:24]([CH2:28][CH2:29][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14])[CH2:25][CH3:26])[CH3:23]
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Reactant: CCN(CC)CCBr
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(C=O)c([N+](=O)[O-])c1OC
Temperature: 60 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
A solution of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (4.4 g, 22 mmol) in DMF (30 mL) was added with potassium carbonate (6.2 g, 24 mmol) and 2-(diethylamino)ethylbromide hydrobromide (6.2 g, 45 mmol), followed by stirring at 60° C. for 4 hours. Further, the reaction mixture was concentrated, added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain crude product. The obtained product was dissolved in ethyl acetate and the solution was added with 4 mol/L hydrogen chloride-ethyl acetate solution. The obtained white crystal was collected by filtration and dried to obtain 4-(diethylamino) ethoxy-3-methoxy-2-nitrobenzaldehyde hydrochloride (2.2 g, 29%).