Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH:38]1[CH2:49][CH2:48][CH2:47][C@H:39]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>O1CCCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([N:38]1[CH2:49][CH2:48][CH2:47][C@H:39]1[C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])=[O:12])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 6.3 g of Z-Thr(tBu)-OH and 2.34 ml of N-methylmorpholine in 100 ml of tetrahydrofuran are added at -17°C 3.0 ml of chloroformic acid-isobutylester, the batch stirred for 20 minutes at this temperature, then reacted with 6.7 g of H-Pro-OtBu in 100 ml of tetrahydrofuran. The batch is allowed to stand at room temperature overnight, then filtered, the filtrate evaporated to dryness under vacuum, the residue dissolved in ethyl acetate and extracted several times with dilute aqueous citric acid solution, dilute aqueous sodium carbonate solution, and saturated sodium chloride solution. The resulting oily compound shows in the thin-layer chromatogram on silica gel:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[CH:15][C:13]=2[N:14]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[NH2:32].CCN(C(C)C)C(C)C.O>CCOC(C)=O>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[NH:32][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([C:4]3[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=3[CH3:9])[NH:11][C:12]=2[CH:18]=1)=[O:20]
Reactant: Cc1cccc(C)c1-c1nc2ccc(C(=O)Cl)cc2[nH]1
Reactant: Nc1ccc2ccccc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(C)c1-c1nc2ccc(C(=O)Nc3ccc4ccccc4c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carbonyl chloride HCl salt (160 mg) and naphthalen-2-ylamine (72 mg) was added DIPEA (0.27 mL). The resulting solution was stirred for at room temperature for 18 h then the mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by an amino column using hexanes/ethyl acetate (1:4) as eluent and gave 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid naphthalen-2-ylamide as a white solid; MS (ESI)m/z 392 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]([NH:13][CH2:14][CH:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:28]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:28])[CH:9]=[C:10]([C:11]([NH:13][CH2:14][CH:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CNC(=O)c2ccc3c(N)ncnn23)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CNC(=O)c2cc(Br)c3c(N)ncnn23)C1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 2-({[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]amino}methyl)morpholine-4-carboxylate (100 mg, 0.27 mmol) in THF (5 mL) was cooled to −50° C. and treated with 1,3-dibromo-5,5-dimethylhydantoin (37 mg, 0.13 mmol) in portions over 30 min. The reaction was then quenched with satd. Na2SO3 and warmed to rt. The product was extracted with EtOAc, dried (MgSO4), and concentrated. The crude product was triturated with EtOAc and filtered. A white solid was collected (60 mg, 50%). MS [M+H]+=545.96, 456.86; LCMS RT=2.90 min.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]([OH:27])=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:30]=1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:25]([O:27][C:12]1[CH:13]=[CH:2][CH:3]=[C:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:11]=1)=[O:26])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCOC(=O)c1cccc(O)c1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CCOC(=O)c1cccc(OC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)c1
Yield: 99.7 %

Procedure:
Allyl 3-hydroxybenzoate (2.82 g, 15.8 mmol), 3,4,5-tribenzyloxybenzoic acid (10.7 g, 23.1 mmol), DMAP (5.51 g, 26.5 mmol), and CH2Cl2 (200 mL) were combined and stirred under a nitrogen atmosphere. EDC.HCl (5.51 g, 28.8 mmol) was added to the mixture and the reaction was allowed to reflux overnight under a nitrogen atmosphere. The reaction was then extracted with 5% citric acid (2×), saturated aqueous sodium bicarbonate (2×), and brine (1×), dried over MgSO4, filtered, and concentrated in vacuo to obtain a solid (9.46 g, 99%) that was used without further purification.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[C:1](=[O:20])([S:28][C:25]1[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: Nc1ccc(S)cc1
Product: CCCCCCCCC=CCCCCCCCC(=O)Sc1ccc(N)cc1
Yield: 73.5 %

Procedure:
Oleic acid (2.82 g) and 1.88 g of p-aminothiophenol were reacted in the same manner as in Reference Example 11 to obtain 2.86 g of the objective compound (yield: 74%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=O.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[CH:3]=[O:2])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)C1CCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1C=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.5 g) in toluene (40 mL) at −78° C. was added dropwise diisobutylaluminium hydride (20 mL of a 1.5 M solution in toluene) maintaining the temperature below −65° C. The reaction mixture was stirred at −78° C. for 2 hours and then quenched with methanol (10 mL). The mixture was then diluted with diethyl ether (50 mL), potassium sodium tartrate tetrahydrate was added and the mixture stirred vigorously for 20 min at room temperature. The two phases were then separated and the aqueous layer extracted with dichloromethane (2×50 mL). The combined organics were then washed with brine (100 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.68 g).
Reaction SMILES: [ClH:1].[CH2:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][C:20]3([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4]>C(OC(=O)C)(=O)C>[ClH:1].[CH2:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:28][C:26](=[O:27])[C:20]4([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[N:19]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)[CH2:3][CH3:4]
Reactant: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)O)CCCCC3)cc2)CC1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CCCN1CCN(c2ccc(C3=NC4(CCCCC4)C(=O)O3)cc2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
After a suspension of 631 mg (1.54 mmol) of 1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid hydrochloride in 18 ml of acetic anhydride was stirred at 100° C. for 1 hour, the reaction solution was concentrated under reduced pressure. Toluene was added to the obtained residue, it was distilled off under reduced pressure three times, and acetic anhydride was removed by azeotropic distillation to obtain 500 mg (83%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[C:11]([O:18][C:19]([F:22])([F:21])[F:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:24]1[N:29]=[N:28][C:27]([N:30]([CH3:41])[CH:31]2[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]2[N:29]=[N:28][C:27]([N:30]([CH3:41])[CH:31]3[CH2:36][C:35]([CH3:37])([CH3:38])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]3)=[CH:26][CH:25]=2)=[C:11]([O:18][C:19]([F:22])([F:21])[F:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1OC(F)(F)F
Product: CN(c1ccc(-c2ccc(OCc3ccccc3)cc2OC(F)(F)F)nn1)C1CC(C)(C)NC(C)(C)C1

Procedure:
(4-(Benzyloxy)-2-(trifluoromethoxy)phenyl)boronic acid (1.2 g, 61% pure, 2.307 mmol) and Intermediate 1-1 (246 mg, 0.871 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. Compound 6-(4-(benzyloxy)-2-(trifluoromethoxy)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine was obtained as a beige solid (405 mg, 90% yield) after flash column chromatography purification. MS (M+1)=515.5.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[O:13][CH2:12][C:11](=[O:15])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]>CC#N>[O:15]=[C:11]1[NH:10][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:14]=2[O:13][CH2:12]1
Reactant: COC(=O)c1cccc2c1OCC(=O)N2
Solvent: CC#N
Product: O=C1COc2c(cccc2C(=O)O)N1

Procedure:
prepared by saponification of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid methyl ester. LC-MS: tR=0.56 min; [M+CH3CN+H]+=235.0.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][CH:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[C:20]=1[OH:21])[CH3:14].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(OCC)C>[CH:22]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]([CH3:14])[CH3:12])[C:20]=1[O:21][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5])([CH3:24])[CH3:23]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1OC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of phthalic anhydride (0.84 g, 5.6 mmol) and propofol (1 g, 5.6 mmol) was added triethylamine (0.65 g, 6.4 mmol) and a catalytic amount of DMAP. The reaction mixture was brought to 90° C., stirred for 14 h, cooled to room temperature and diluted with ethyl ether (100 mL). The organic layer was washed with 10% aqueous citric acid solution (2×50 mL). The phases were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was sufficiently pure to be carried to the subsequent step.
Reaction SMILES: Cl.[C@@H:2]12[CH2:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:11][CH2:10]1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(#N)C.[Cu](I)I>[C@@H:2]12[CH2:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[C:19]([C:31]#[C:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH2:11][CH2:10]1
Reactant: COc1ccc(Br)cc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C#Cc2ccccc2)cc1C1CCN([C@@H]2C[C@@H]3CC[C@H]2C3)CC1

Procedure:
1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(5-bromo-2-methoxyphenyl) piperidine hydrochloride (compound no. 187) (60 mg, 0.15 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (11 mg, 0.015 mmol) and copper iodide (6 mg, 0.030 mmol) were suspended in anhydrous acetonitrile (500 μL) in a microwave vial and treated with phenylacetylene (77 mg, 0.75 mmol), followed by triethylamine (250 μL). The vial was flushed with nitrogen, capped and microwaved at 140° C. for 20 min. The reaction was diluted with methanol (750 μL), filtered (Whatman 0.20 μm PTFE) and subjected to reverse-phase HPLC purification (5-50% CH3CN/0.08% TFA) to yield 1-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-4-(2-methoxy-5-(phenyl-ethynyl)phenyl)piperidine (compound no. 64) as the TFA salt. LC/MS (RP-C18, 10-99% CH3CN/0.05% TFA gradient over 5 min) m/z 386.2 [M+H]+, retention time 2.86 min.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:32]([O:34]C)=[O:33])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([O:29][CH3:30])=[C:24]([CH3:31])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:36]=[CH:37][CH:38]=[CH:39][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:32]([OH:34])=[O:33])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([O:29][CH3:30])=[C:24]([CH3:31])[CH:23]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:36]=[CH:37][CH:38]=[CH:39][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(OC)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.3 mg (0.47 mmol) LiOH*H2O in 8 mL water was added to a solution of 160 mg (0.31 mmol) (R)-2-(4-methoxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 15 mL THF and the reaction mixture was stirred for 1 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 150 mL water and acidified with 2 M HCl. The precipitate formed was separated off and dried.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:26]>O1CCOCC1.CO>[ClH:26].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-n2ccnc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1ccc(-n2ccnc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.63 mL) was added to a solution mixture of the obtained methyl 2-(benzyloxy)-4-(1H-imidazol-1-yl)benzoate (0.13 g) in dioxane (0.65 mL) and methanol (0.65 mL), followed by stiffing at room temperature for 3 hours. Under ice-cooling, 6 mol/L hydrochloric acid (0.21 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid substance was collected by filtration. Dioxane (1 mL) and a 4 mol/L hydrogen chloride-dioxane solution (0.5 mL) were added to the obtained solid substance, followed by stirring at room temperature for 1 hour. The solid substance was collected from the reaction mixture by filtration to obtain 0.097 g of 2-(benzyloxy)-4-(1H-imidazol-1-yl)benzoic acid hydrochloride as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[OH:31][C:32]([CH3:39])([CH3:38])[CH2:33][NH:34][C:35]([NH2:37])=[NH:36]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:37]=[C:35]([NH:34][CH2:33][C:32]([CH3:39])([OH:31])[CH3:38])[N:36]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)CNC(=N)N
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one (9) (50 mg, 0.155 mmol) in DMF (1288 μl), 1-(2-hydroxy-2-methylpropyl)guanidine and potassium carbonate (107 mg, 0.773 mmol) were added and the reaction mixture was stirred at 120° C. for 2 hours. The crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (23.8 mg, 39%).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.C([NH:26][CH2:27][CH2:28][NH2:29])(OC(C)(C)C)=O.Cl>>[NH2:26][CH2:27][CH2:28][NH:29][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Product: COc1ccc2c(c1)CCn1c-2cc(NCCN)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and N-Boc-ethylenediamine as in Example 1 d, followed by treatment with HCl. 1H-NMR as mixture of two isomers (400 MHz, d6-DMSO) δ 9.25-8.40 (1H), 8.32 and 7.70 (d, 1H), 8.12 and 8.02 (br, 3H), 7.07-7.00 (m, 2H), 6.80 and 6.33 (s, 1H), 4.04 and 3.98 (t, 2H), 3.88 and 3.85 (s, 3H), 3.80 and 3.61 (q, 2H) and 3.08-2.94 (4H); MS (ESI) (M+H)+ 287. The spectrum acquired at 333K showed single isomers.
Reaction SMILES: [Na+].[I-:2].CN[C@@H]1CCCC[C@H]1NC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.C(O)CCCC.CCCCC[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(OCC)(=O)C.[Cu]I>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[I:2][C:36]1[CH:35]=[CH:34][C:33]([CH3:32])=[CH:38][CH:37]=1
Reactant: CCCCCCCCCCCC
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: Cc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCO
Product: Cc1ccc(I)cc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
A Schlenk tube was charged with CuI (19.5 mg, 0.102 mmol, 5.0 mol %), NaI (450 mg, 3.00 mmol), evacuated and backfilled with argon. Racemic trans-N,N′-dimethyl-1,2-cyclohexanediamine (31.5 μL, 0.200 mmol, 10 mol %), 4-chlorotoluene (237 μL, 2.00 mmol), and n-pentanol (0.50 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 24 h. The resulting dark green-gray suspension was allowed to reach room temperature. Ethyl acetate (3 mL) and dodecane (internal GC standard, 460 μL) were added to the reaction mixture. A 50 μL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide 35% conversion of 4-chlorotoluene and 33% yield of 4-iodotoluene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:6]=2[CH:18]=1.[C:20](Cl)(Cl)=[S:21].C(=O)(O)[O-].[Na+]>ClCCl>[F:19][C:3]1[C:2]([N:1]=[C:20]=[S:21])=[CH:18][C:6]2[N:7]([CH2:11][C:12]3[N:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: Cc1nc(Cn2c(=O)sc3cc(F)c(N)cc32)no1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(Cn2c(=O)sc3cc(F)c(N=C=S)cc32)no1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
A mixture of 5-amino-6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (1.33 g), dichloromethane (10 ml) and ice (10 g) was prepared. To this mixture was added thiophosgene (0.7 g), and then portionwise added sodium bicarbonate at a temperature of 5° to 10° C. so as to make the mixture slightly alkaline. The mixture was stirred for 20 minutes, and tested to confirm whether the mixture was alkaline (if the mixture was acidic, then a further amount of sodium bicarbonate was added). The dichloromethane layer was separated, and the aqueous layer was extracted with fresh dichloromethane (10 ml×2). The dichloromethane layers were gathered together, washed with water, and distilled to remove the dichloromethane solvent therefrom. The resulting solid residue was recrystallized from a toluene-hexane solvent mixture, so that the aimed compound, i.e. 6-fluoro-5-isothiocyanato-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (1.49 g) was obtained. m.p. 168°-170° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:24]C)[N:13]3[CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:9]([NH2:26])[N:8]=2)[CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[NH2:26][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:24])[N:13]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(OCCC2CC2)nc2c1[nH]c(=O)n2CCC1CCCCO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To a solution of 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-9-[2-(tetrahydro-2H-pyran-2-yl)ethyl]-9H-purin-6-amine (84.7 mg, 0.234 mmol) in methanol (7.9 ml) at room temperature was added 4.0 M HCl in 1,4-dioxane (1.46 ml) to give a pale straw coloured solution. The reaction mixture was stirred at ambient temperature overnight (20 hours) and then evaporated in vacuo to give a colourless oil/gum. This material was re-dissolved in methanol and passed down a 5 g aminopropyl SPE cartridge (pre-conditioned in methanol), washed through with methanol and evaporated to give the title compound as a white solid (58.5 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][NH:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)C(C)C)(C)C.CS([C:33]1[N:38]=[C:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:36]=[CH:35][N:34]=1)(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:17][CH2:18][CH3:19])[C:33]2[N:38]=[C:37]([C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:48])([F:46])[F:47])=[CH:43][CH:44]=3)[CH:36]=[CH:35][N:34]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 17.4 %

Procedure:
To a mixture of ethyl {2-methyl-4-[(propylamino)methyl]phenoxy}acetate (652 mg, 2.46 mmol) and N,N-diisopropylethylamine (570 μL, 3.28 mmol) was added 2-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (495 mg, 1.64 mmol) and the resultant mixture heated at 100° C. for 16 h in a reactivial. The cooled reaction mixture was diluted with CH2Cl2 (30 mL), washed with water (20 mL), the aqueous extracted with CH2Cl2 (30 mL) and the CH2Cl2 extracts combined and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 90 g) eluted with cyclohexane:EtOAc 10:1 afforded the title compound as a colourless gum (139 mg).