Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:21])(=O)=O>C(=O)(O)[O-].[Na+]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[C:6]([O:14][CH3:21])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)N1CC(=O)c2cc(F)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: COc1cn(C(C)=O)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 1.6 g of 1-acetyl-5-fluoroindolin-3-one, 1.9 g of powdered sodium hydroxide and 28 ml of dimethyl sulfate was stirred at room temperature for two hours. After the addition of 240 ml of saturated sodium bicarbonate solution the mixture was stirred overnight and subsequently filtered. The residue was taken up in 100 ml of ether and 100 ml of ethyl acetate. The solution was dried over sodium sulfate, filtered and evaporated. There were obtained 1.47 g (86%) of 1-acetyl-5-fluoro-3-methoxyindole as greenish crystals with m.p. 124°-125°.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][C:35]=1[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3cc(C(F)(F)F)ccc3F)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.4 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-fluoro-5-trifluoromethylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.00 mg, 40.4% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.67 (m, 2H), 7.55 (m, 2H), 7.50–7.40 (m, 3H), 7.30–7.10 (m, 3H), 7.17 (d, 1H, J=8.9 Hz), 7.07 (apparent d, 1H, J=6.7 Hz), 6.97 (apparent d, 1H, J=7.8 Hz), 5.37 (apparent dd, 1H, J=4.2, 8.1 Hz), 3.37 (m, 2H), 2.93 (m, 2H), 2.63 (s, 1H), 2.50 (apparent sept, partially hidden, 1H, J=7.9 Hz), 2.30–2.10 (m, 6H), 1.85 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 542.7 (M+H)+.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[CH3:19][O:20][C:21]([CH2:23]P(=O)([O-])[O-])=[O:22].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:38][C:39]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:40]=1[CH:41]=O.[Cl-].[NH4+]>O1CCCC1>[F:38][C:39]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:40]=1/[CH:41]=[CH:23]\[C:21]([O:20][CH3:19])=[O:22]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COC(=O)CP(=O)([O-])[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 18-crown-6 (30 g, 110 mmol), bis(2,2,2-trifluororethyl) (methoxycarbonylmethyl)phosphonate (6 mL, 28 mmol) in tetrahydrofuran at −78° C. was added potassium hexamethyldisilazide (0.5M in toluene) (50 mL, 25 mmol) followed by 2,4-difluorobenzaldehyde (4 g, 28 mmol). The reaction mixture was stirred at this temperature for 8 hours and slowly warmed to room temperature over 24 hours. The reaction mixture was then poured into a saturated solution of ammonium chloride (200 mL). The phases were separated, the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification of the residue by column chromatography using pentane:ethyl acetate (99:1-98:2) as eluent afforded the desired product as a colourless oil, 5.1 g (91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:23][CH2:22][C@@H:21]([NH:24]C(=O)OCC2C=CC=CC=2)[CH2:20]1>CO.[Pd]>[NH2:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:6]=2)[CH2:20]1
Reactant: O=C(N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Under an N2 atmosphere, Pd/C (10% weight, 140 mg) was added to a solution of (R)-benzyl 1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate (1.37 g, 5.3 mmol) in MeOH (10 mL). After purging twice with N2 and evacuating the atmosphere in the flask containing the reaction mixture, the reaction was stirred under an H2 atmosphere overnight. The mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to obtain (R)-2-(4-(3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (940 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 8.41 (m, 1H), 7.73 (m, 2H), 7.40 (m, 1H), 7.28 (m, 1H), 6.94 (m, 1H), 6.85 (m, 1H), 4.15 (m, 2H), 3.99 (m, 1H), 3.77 (m, 1H), 3.68 (m, 1H), 2.20 (m, 1H), 1.86 (m, 1H) ppm. LC/MS: m/z 325.3 (M+H)+ at 1.68 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:19]([N+:21]([O-:23])=[O:22])[CH3:20])[CH:15]=2)[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C=O.[CH3:26][O:27][Na]>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([N+:21]([O-:23])=[O:22])([CH3:20])[CH2:26][OH:27])[CH:15]=2)[N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CO[Na]
Reactant: CCCCCCCOc1ccc2cc(C(C)[N+](=O)[O-])ccc2n1
Agent: C=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc2cc(C(C)(CO)[N+](=O)[O-])ccc2n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 111.5 %

Procedure:
2-(heptyloxy)-6-(1-nitroethyl)quinoline (1.823 g, 5.77 mol) and paraformaldehyde (346 mg, 11.54 mmol, 2.0 eq.) were dissolved in THF (10 mL). CH3ONa (115 mg, 2.13 mmol, 0.37 eq.) in methanol (2 mL) was added to the solution. The mixture was stirred at 80° C. under nitrogen atmosphere for 15 h. The mixture was extracted with ethyl acetate and the organic layer was concentrated and purified by silica gel column chromatography using petroleum/ethyl acetate (5/1) as eluent to give product as a slight red oil (823 mg, 43%). ESI-MS: 347.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.56 (q, 1H), 6.93 (d, 1H), 4.62 (d, 1H), 4.47 (t, 2H), 3.90 (d, 1H), 2.15 (s, 3H), 1.84-1.80 (m, 2H), 1.49-1.24 (m, 8H), 0.89 (t, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[N:6]=[CH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=Cc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1N=Cc1ccccn1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
2,6-Diisopropylaniline (2.0 g, 11.3 mmol) was added to a solution of picolinaldehyde (1.2 g, 11.3 mmol) in toluene (200 mL) in a round bottom flask equipped with a Dean-Stark trap, followed by the addition of a catalytic amount of p-toluenesulfonic acid (0.1 g). The reaction mixture was refluxed for 18 h to remove water. The reaction mixture was cooled to rt, and then washed once with water (100 mL), and the toluene was removed under reduced pressure. The resulting residue was purified by chromatography on silica gel to give the desired product (1.2 g, 40% yield) as a pale green solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(F)c(N2CCCCC2)cc1Cl
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 4.8 g (25 mmol) of 2-chloro-4,5-difluoronitrobenzene in 14.4 g of toluene is introduced into a 100 ml three-necked flask fitted with dropping funnel, precision-ground glass stirrer and reflux condenser. 4.3 g (50 mmol) of piperidine are added dropwise to this solution at room temperature and with stirring over the course of 1 hour. The mixture is then stirred at room temperature for a further 2 hours. The reaction solution formed in the reaction is washed three times with 35 ml of water in each case and dried. Removal of the solvent gives 5.3 g (21 mmol) of 2-chloro-5-fluoro-4-piperidinonitrobenzene. This corresponds to a yield of 82.0%, based on 2-chloro-4,5-difluoronitrobenzene used.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.C(NC(C)C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[N:8][C:9]([Cl:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: Cc1cccc(N)c1
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)nc1Nc1cccc(C)c1

Procedure:
2,4-Dichloropyrimidine-5-carboxylic ethyl ester and m-toluidine were allowed to undergo the reaction in acetonitrile in the presence of diisopropylamine to obtain 2-chloro-4-[(3-methylphenyl)amino]pyrimidine-5-carboxylic ethyl ester. Said ester compound was hydrolyzed in THF with 1 M sodium hydroxide aqueous solution, and the resulting carboxylic acid compound was allowed to react with oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF and then treated with a mixture of aqueous ammonia and ice to obtain 2-chloro-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide. F: 263.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([Li])[CH2:17][CH2:18]C.C(Br)C=C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:18][CH:17]=[CH2:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Reactant: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCCc1cccc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of (tert-butoxy)-N-(6-methyl(2-pyridyl))carboxamide in tetrahydrofuran (0.1 M) was added n-butyl lithium (2.1 eq) at −78° C. and the solution was warmed to 25° C. and stirred for 1 hr. The solution was then cooled back down to −78° C. followed by addition of allyl bromide (1.5 eq) and continued strirring for 1 hr. The reaction was quenched with saturated ammonium chloride, diluted with ethyl acetate and separated. The organic layer was washed with brine and dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (5% EtOAc/Hexane). EI-MS m/z 249(M+H)+
Reaction SMILES: [C:1](OC(=O)CC)(=O)CC.[O:10]=[S:11]1(=[O:36])[CH:16]=[CH:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:34])[CH:31](F)F)[O:25][C:24]3=[O:35])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>N1C=CC=CC=1.ClCCl>[O:10]=[S:11]1(=[O:36])[CH:16]=[CH:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:34])[CH2:31][CH3:1])[O:25][C:24]3=[O:35])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
Propionic anhydride (0.136 ml, 1.06 mmol) is added dropwise to the crude amine hydrochloride prepared in Step 1 of Example 15 (0.316 g, 0.88 mmol) in a mixture of pyridine (4 mL) and dichloromethane (4 mL). The mixture is stirred for 4 hours and then evaporated to dryness. The residue is purified by PTLC (10% methanol/dichloromethane) to give the title compound as white solid (0.28 g, 80%). M.p. 144–7° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][CH2:10][C:11]#[N:12])=[C:4]([CH3:13])[N:3]=1.[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][CH3:18]>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([CH2:9][CH2:10][C:11]#[N:12])=[C:6]([NH:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:7]=1
Reactant: CCCCCN
Reactant: Cc1nc(N)nc(Cl)c1CCC#N
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1CCC#N
Reaction time: 8.5 h
Yield: 55 %

Procedure:
A mixture of 3-(2-amino-4-chloro-6-methylpyrimidine-5-yl)propanenitrile (500 mg, 2.54 mmol), amylamine (2.94 ml) and dioxane (5 ml) was kept at 90° C. for 8.5 hours. The procedure according to pro-treatment of Example 23 was carried out to give the object compound (346 mg, 55.0%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22](Br)[S:21]2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][C:31](=[O:64])[NH:32][C@H:33]([C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52](B3OC(C)(C)C(C)(C)O3)=[CH:51][CH:50]=2)=[CH:47][N:48]=1)=[O:38])[CH:34]([CH3:36])[CH3:35]>>[CH3:29][O:30][C:31](=[O:64])[NH:32][C@H:33]([C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C:44]1[NH:45][C:46]([C:49]2[CH:50]=[CH:51][C:52]([C:22]3[S:21][C:20]4=[N:19][C:18]([NH:17][C:16]([C@@H:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])=[O:27])=[CH:25][N:24]4[CH:23]=3)=[CH:53][CH:54]=2)=[CH:47][N:48]=1)=[O:38])[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cn4cc(NC(=O)[C@@H]5CCCN5C(=O)CNC(=O)OC(C)(C)C)nc4s3)cc2)[nH]1)C(C)C
Yield: 8 %

Procedure:
Compound A39 was synthesized from compound 28 (0.106 mmol) and compound 8 (0.159 mmol), following the procedure as described for compound A1 (reaction time=2.5 hrs), as a white lyophilized powder in 8% yield. MS (ESI, EI+) m/z=762.27 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:24])[C:7]=1[C:8]1[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C:11]([NH2:17])=[C:12]([N+:14]([O-])=O)[CH:13]=1>[Pd].C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:24])[C:7]=1[C:8]1[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C:11]([NH2:17])=[C:12]([NH2:14])[CH:13]=1
Reactant: Nc1nc(-c2cccnc2)c(-c2c(F)cncc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(-c2c(F)cncc2F)c(-c2cccnc2)nc1N
Reaction time: 12 h
Yield: 98.9 %

Procedure:
A suspension of 3″,5″-difluoro-5′-nitro-3,2′:3′,4″-terpyridin-6′-amine (0.2 g, 0.608 mmol) and 10% palladium on carbon (0.04 g) in a mixture of THF/ethanol 40:60 (8 mL) was stirred under hydrogen atmosphere at 2.76 bar. After 12 h, the mixture was filtered through Celite® and the filter cake was washed with ethanol and THF. The combined filtrate and washings were evaporated to give the title compound as a solid (0.180 g, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CS(O[CH2:18][CH2:19][CH2:20][O:21][CH3:22])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH3:22][O:21][CH2:20][CH2:19][CH2:18][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[N:9]1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: COCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCCn1ncc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Yield: 45.7 %

Procedure:
A mixture of 6-nitro-1H-indazole (50 g, 0.307 mol), 3-methoxypropyl methanesulfonate (54.3 g, 0.323 mol) and K2CO3 (127 g, 0.921 mol) in CH3CN (1.5 L) was heated at 60° C. overnight. Water (1 L) was added and the CH3CN was removed under reduced pressure and the aqueous residue was extracted with EtOAc (3×500 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to give 1-(3-methoxypropyl)-6-nitro-1H-indazole (33 g, 46% yield). 1H NMR (400 MHz, CDCl3): δ8.47 (s, 1H), 8.13 (s, 1H), 8.01-7.99 (dd, J=8.8, 2.0 Hz, 1H), 7.83-7.81 (d, J=8.8 Hz, 1H), 4.61-4.57 (t, J=6.4 Hz, 2H), 3.29 (s, 3H), 3.26-3.23 (t, J=5.6 Hz, 2H), 2.23-2.17 (m, 2H).
Reaction SMILES: Cl.Br[C:3]1C=[CH:7][C:6]([C:9]2N=CC(C(N)=N)=CN=2)=[CH:5][CH:4]=1.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:31]=[CH:30][C:29]([C:32]([NH2:34])=[NH:33])=[CH:28][N:27]=2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:27]=[CH:28][C:29]([C:32]3[N:34]=[CH:9][C:6]([CH2:5][CH2:4][CH3:3])=[CH:7][N:33]=3)=[CH:30][N:31]=2)=[CH:24][CH:25]=1
Reactant: N=C(N)c1cnc(-c2ccc(Br)cc2)nc1
Reactant: N=C(N)c1cnc(-c2ccc(F)cc2)nc1
Agent: Cl
Product: CCCc1cnc(-c2cnc(-c3ccc(F)cc3)nc2)nc1

Procedure:
Example 4 was repeated except that 2-(p-bromophenyl)-5-pyrimidinecarboxamidine hydrochloride and α-pentyl-62 -dimethylaminoacrolein in Example 4 were replaced by 2-(p-fluorophenyl)-5-pyrimidinecarboxamidine hydrochloride and α-propyl-62 -dimethylaminoacrolein, respectively, to obtain 2-(p-fluorophenyl)-5'-propyl-5,2'-bipyrimidinyl, which exhibited a C-N point of 199° C. and a N-I point of 203° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12](Cl)=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:15]([Cl:18])([Cl:17])[Cl:16])[NH:3]1.[CH2:19]([NH2:22])[CH2:20][CH3:21]>CO>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([NH:22][CH2:19][CH2:20][CH3:21])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][CH:4]([C:15]([Cl:18])([Cl:17])[Cl:16])[NH:3]1
Reactant: CCCN
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2
Solvent: CO
Product: CCCNC(=O)c1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2
Reaction time: 0.5 h

Procedure:
Powdered 3,4-dihydro-4-oxo-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazine-6-carbonyl chloride (5.0 g.) was stirred while a solution of n-propylamine (5 ml) in methanol (100 ml.) was added, the resulting solution was stirred for 30 minutes, and the solvent was evaporated under reduced pressure to give a sticky solid residue. The residue was triturated with water and the resulting suspension was stirred for 30 minutes and filtered. The solid product was washed with water, dried and crystallised from ethanol to give 3,4-dihydro-4-oxo-N-propyl-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazine-6-carboxamide, m.p. 228°-230° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][CH3:29])[C:16]2[C:17]([CH2:26][CH3:27])=[C:18]([CH:22]=[C:23]([Cl:25])[CH:24]=2)[C:19]([OH:21])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][CH2:64][C:65]1[C:66](=[O:73])[NH:67][C:68]([CH3:72])=[CH:69][C:70]=1[CH3:71]>CN(C=O)C>[Cl:25][C:23]1[CH:22]=[C:18]([C:19](=[O:21])[NH:63][CH2:64][C:65]2[C:66](=[O:73])[NH:67][C:68]([CH3:72])=[CH:69][C:70]=2[CH3:71])[C:17]([CH2:26][CH3:27])=[C:16]([N:15]([CH2:28][CH3:29])[CH:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:11]2)[CH:24]=1
Reactant: CCc1c(C(=O)O)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
A stirred solution of 3-[(4-{[(tert-butoxy)carbonyl]amino}cyclohexyl)(ethyl)amino]-5-chloro-2-ethylbenzoic acid (139 mg, 0.33 mmol) in anhydrous DMF (2.0 ml) at 0° C. under nitrogen, was treated with HATU (149 mg, 0.39 mmol) and DIPEA (114 μl, 0.65 mmol). The resulting solution was stirred for 10 minutes and then treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 61 mg, 0.36 mmol). The resulting suspension was stirred at 0° C. for 1 hour and then stirred at room temperature for 98.5 hours. The reaction mixture was treated with HATU (37 mg, 0.1 mmol), stirred for 1 hour and then 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 11 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for a further 23 hours and then partitioned between water (20 ml) and CH2Cl2 (20 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×10 ml). The combined organics were washed with a saturated solution of NaHCO3 (aq) (40 ml), water (20 ml), brine (2×20 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-13% MeOH/CH2Cl2) and triturated from ether/heptane (2.0 ml) with sonication and the liquor decanted. The remaining solid was dried under high vacuum to give the title compound (101 mg, 52%) as a beige solid. LC-MS 93%, 4.54 min (7 minute LC-MS method), m/z=559.2, 561.2. 1H NMR shows a mixture of cis/trans isomers.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:33])[N:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16](=[O:32])[CH:17]([NH:24]C(=O)OC(C)(C)C)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:12][CH2:11]3)[CH2:9][C:5]2=[CH:4][N:3]=1.C(OCC)(=O)C>Cl>[NH2:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:8]2[CH2:9][C:5]3=[CH:4][N:3]=[C:2]([CH3:1])[N:6]3[C:7]2=[O:33])[CH2:11][CH2:12]1)=[O:32]
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)CC1)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Yield: 29.8 %

Procedure:
tert-Butyl 2-(4-(5-methyl-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)-2-oxo-1-phenylethylcarbamate (0.43 g) obtained in Example 50a) was dissolved in concentrated hydrochloric acid (1.5 ml), and mixed at room temperature for 5 minutes. Ethyl acetate was added thereto, and the reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as colorless powder (0.10 g, 31%).