Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[CH2:11](Br)[C:12]#[CH:13].[Br-].[NH+]1C=CC=CC=1>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:13][C:12]#[CH:11]
Reactant: Cc1cc(O)c(S)c(=O)o1
Reactant: C#CCBr
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: C#CCSc1c(O)cc(C)oc1=O
Reaction time: 1 h

Procedure:
A solution of 39.5 g. (0.250 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone in 250 ml. of pyridine was cooled to 15°C. in an ice bath. Propargyl bromide (29.7 g., 0.250 mole) was then added in one portion, causing the temperature of the reaction mixture to rise to 53°C. When the temperature began to subside, the flask was placed on the steam bath and heated at 80°C. for one hour, during which pyridinium bromide by-product precipitated. The reaction mixture was then cooled and poured into a mixture of ice and 500 ml. of concentrated hydrochloric acid. After this mixture had been kept cold in an ice bath for one hour, the crystalline product, which formed, was collected on a filter and dried; m.p. 143.5°-146°C., weight 27.2 g. More product was obtained by extraction of the filtrate with methylene chloride, giving a total yield of 41.9 g., (85 percent). Two recrystallizations (Darco) from ethanol afforded the pure 4-hydroxy-6-methyl-3-propargylthio- 2-pyrone as light tan crystals, m.p. 148°-149°C. (dec.).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:28])=[CH:24][C:25]([OH:27])=[CH:26][C:21]=2[S:20][C:19]=1[CH3:29].[CH3:31][C:32]1[C:37]([CH2:38]O)=[CH:36][CH:35]=[C:34]([C:40]([F:43])([F:42])[F:41])[N:33]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:28])=[CH:24][C:25]([O:27][CH2:38][C:37]3[C:32]([CH3:31])=[N:33][C:34]([C:40]([F:43])([F:41])[F:42])=[CH:35][CH:36]=3)=[CH:26][C:21]=2[S:20][C:19]=1[CH3:29]
Reactant: COC(=O)Cc1c(C)sc2cc(O)cc(Cl)c12
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)sc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a mixture of tri-n-butylphosphine (0.418 mL), methyl(4-chloro-6-hydroxy-2-methyl-1-benzothiophen-3-yl)acetate (151.2 mg) and (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (112 mg) and THF (5.0 mL) was added ADDP (423 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (165 mg). The solid was crystallized from EtOAc-hexane.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH2:34]([N:36]([CH2:37][CH3:38])[C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29])[CH3:35]
Reactant: CCNCC
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with diethylamine hydrochloride (15 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 46 mg of the title compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+].[CH2:41]([OH:43])[CH3:42]>>[CH3:42][C:41]([NH:1][C:4]1[CH:5]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[CH:7]=[CH:8][CH:9]=1)=[O:43]
Reactant: CCO
Reactant: COC(=O)c1ccc(CCCc2ccccc2OCc2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(CCCc2ccccc2OCc2cccc(NC(C)=O)c2)cc1
Temperature: 70 °C

Procedure:
A mixture of methyl 4-[3-(2-(3-nitrophenylmethyloxy)-phenyl)propyl]benzoate (0.25 g), tin (II) chloride dihydrate (0.7 g) in ethanol (10 ml) was heated at 70° C. for 45 minutes, cooled and poured onto ice. The pH of the solution was adjusted to 8 with sodium bicarbonate and extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), dried (magnesium sulphate), filtered and evaporated. The residue was purified by subjecting to chromatography on silica gel using ethyl acetate hexane (1:9) as eluant. There was thus obtained methyl 4-[3-(2-(3-aminophenylmethyloxy)phenyl)propyl]benzoate (185 mg). b: - Methyl 4-[3-(2-(3-methylcarbonylaminophenylmethyloxy)-phenyl) propyl]benzoate was prepared from methyl 4-[3-(2-(3-amino-phenylmethyloxy)phenyl)propyl]benzoate (preparation described in note a) as follows:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH:23][CH:24]([CH3:26])[CH3:25])[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].CCN(C(C)C)C(C)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH:23][CH:24]([CH3:26])[CH3:25])[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: Cc1cc(-c2nc(-c3ccc(C(O)CN)cc3)no2)nc(NC(C)C)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(-c2nc(-c3ccc(C(O)CNS(C)(=O)=O)cc3)no2)nc(NC(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of rac-2-amino-1-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol (39 mg, 0.11 mmol) and DIPEA (30 μL, 0.176 mmol) in DCM (6 mL) at 0° C. is added dropwise a solution of mesylchloride (10 μL, 0.132 mmol) in DCM (2 mL). The reaction mixture is stirred at 0° C. for 1 h, and then at rt for another hour. The reaction mixture is evaporated and purified by prep. TLC eluting with DCM/7M NH3 in MeOH 10:1 to give rac-N-(2-hydroxy-2-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl)-methanesulfonamide (19 mg) as a white solid; tR=0.89 min; [M+H]+=432.99.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]1[N:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[C:16](=[O:26])[C:15]2=[C:27](Br)[CH:28]=[CH:29][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([Zn]C#N)#[N:40]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]1[N:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[C:16](=[O:26])[C:15]2=[C:27]([C:39]#[N:40])[CH:28]=[CH:29][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Zn]C#N
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2ccc(Br)c2c(=O)n1-c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2ccc(C#N)c2c(=O)n1-c1cc(F)cc(F)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
In a reactor vessel (S)-tert-butyl (3-(benzyloxy)-1-(5-bromo-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (0.81 g, 1.37 mmol) was dissolved in 32 mL dimethylformamide. Dicyanozinc (0.4 g, 3.49 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.64 g, 0.55 mmol) were added under argon conditions. The reaction was stirred at 120° C. overnight. The crude was filtered through a plug of Celite and washed several times with ethyl acetate. The combinated filtrates were evaporated and washed with water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using SP1 ® Purification System (0% to 40%, hexane-ethyl acetate) to obtain 0.58 g (77% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>O>[Br:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2nnc3n2-c2ccc(Br)cc2C(c2ccccn2)=NC3)CC1
Reaction time: 24 h

Procedure:
A stirred mixture of 1,8-dibromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine (2.19 g.) and 1-methylpiperazine (10 ml.) is kept under nitrogen at 125°-130° C. for 15.5 hours and at 135°-145° C. for 24 hours. It is then cooled, mixed with cold water, treated with a little sodium bicarbonate and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is treated successively with xylene and toluene with concentration after each addition and the resulting material is chromatographed on silica gel (150 g.) with mixtures of chloroform and methanol containing 5-10% methanol. The product thus obtained is crystallized from methanol-ethyl acetate to give 8-bromo-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in 4 crops as follows: 0.799 g., melting point 250.5°-253.5° dec; 0.062 g., melting point 248.5-249.5° dec; 0.344 g., melting point 250°-252° dec., and 0.206 g., melting point 245.5°-247.5° dec. The analytical sample has a melting point of 252°-253° dec.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:30][C:31]([C:33]1([O:36][CH3:37])[CH2:35][CH2:34]1)=[NH:32]>>[CH3:37][O:36][C:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH2:35][CH2:34]1
Reactant: COC1(C(=N)NO)CC1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: COC1(c2noc(C3CC(c4ccc(CC(F)(F)F)cc4)CN(C(=O)N4CCSCC4)C3)n2)CC1

Procedure:
According to General Method 6A, 93.1 mg (0.224 mmol) of the compound from Example 45A and 32.0 mg (0.246 mmol) of N-hydroxy-1-methoxycyclopropanecarboximidamide from Example 64A were reacted. Yield: 31.1 mg (27% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([O:14][CH2:15][CH2:16]OC1C=CC=C(C)C=1C)=[O:13].CC1C(C)=CC=CC=1OCC(OCC)=O.[CH3:41][C:42]1[C:47]([CH3:48])=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:49]CC(OC)=O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([O:14][CH2:15][CH2:16][CH2:49][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([CH3:48])[C:42]=1[CH3:41])=[O:13]
Reactant: Cc1cccc(OCCOC(=O)N2CCCc3c(Br)cccc32)c1C
Reactant: COC(=O)CCc1cccc(C)c1C
Agent: CCOC(=O)COc1cccc(C)c1C
Product: Cc1cccc(CCCOC(=O)N2CCCc3c(Br)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 2-(2,3-dimethylphenoxy)ethyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate except that ethyl 2-(2,3-dimethylphenoxy)acetate was replaced by methyl 3-(2,3-dimethylphenyl)propanoate. LCMS, [M+Na]+=426.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=O)[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].CO>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 6-nitro-4-H-benzo[1,4]oxazin-3-one (7.84 g, 40.38 mmol) in tetrahydrofuran (100 mL) was added a solution of 2.0M borane-methyl sulfide complex in tetrahydrofuran (91 mL, 181 mmol). The mixture was heated to reflux for 4.5 hours then allowed to stir overnight at room temperature. Methanol was added slowly to react with unreacted borane-methyl sulfide complex, which resulted a violent evolution of gas. When this subsided, excess methanol was added and the solution heated to reflux. After 2 hours the solution was cooled, the solvent evaporated under vacuum, and the residue triturated with ethyl acetate/hexane. An orange solid was filtered off which was rinsed with hexane, to yield 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a solid product. More of the solid was recovered as a second crop from the filtrate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=O)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:27][OH:28]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=[N:27][OH:28])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: ON=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
22.6 g of 3-chloro-2-(4-chloro-3-formylphenyl)-5-trifluoromethylpyridine, 6.5 g of sodium bicarbonate and 5.4 g of hydroxylamine hydrochloride in 100 ml of tetrahydrofuran were stirred at 23° C. for 24 hours. The tetrahydrofuran was then removed, after which the residue was taken up in 100 ml of methylene chloride. The solution was washed twice with 100 ml of water. The solid formed during this was removed, washed with water and dried. Concentration of the organic phase resulted in a residue which was purified by chromatography on silica gel with cyclohexane/ethyl acetate (7:3). Yield: 26.1 g (82%) of colorless crystals; melting point: 173°-174° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[H][H]>C(O)C.[Pd]>[C@@H:9]1([NH:8][C:6]2[CH:5]=[C:4]([CH3:18])[N:3]=[CH:2][N:7]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: Cc1cc(N[C@H]2CCc3ccccc32)nc(Cl)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N[C@H]2CCc3ccccc32)ncn1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
2-Chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]-6-methylpyrimidine-4-amine (1.95 g, 7.5 mmol) was dissolved in ethanol (5 mL) and 10% Pd/C (0.140 g, 0.13 mmol) was added. The flask was filled with hydrogen and stirred overnight. At that time, TLC indicated complete conversion. Palladium was filtered off and the solvent was removed in vacuo. The residue was purified using chromatography on silica gel using gradient 50 to 100% ethyl acetate in hexane to afford the title compound (1.65 g, 93%). LC/MS: Rt=1.51 min, ES+ 226 (AA standard).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH:15]([O:16]C(=O)C2C=CC=CC=2)[CH2:14][CH:13]([CH:25]=[CH:26][P:27]([O:32]CC)([O:29]CC)=[O:28])[O:12]1.NC1NC(=O)C2N=NN(C3OC(C=CP(=O)(O)O)CC3O)C=2N=1>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[O:12][CH:13]([CH:25]=[CH:26][P:27](=[O:28])([OH:29])[OH:32])[CH2:14][CH:15]1[OH:16]
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2cnc3c(N)ncnc32)O1)OCC
Agent: Nc1nc2c(nnn2C2OC(C=CP(=O)(O)O)CC2O)c(=O)[nH]1
Product: Nc1ncnc2c1ncn2C1OC(C=CP(=O)(O)O)CC1O
Yield: 76.8 %

Procedure:
Compound 12.2 (103 mg, 68% yield) was synthesized from compound 12.1 (200 mg, 0.41 mmol) using the procedure for the preparation of compound 10.2. 1H NMR (D2O) δ 2.10 (m, 1H), 2.19 (m, 1H), 4.62 (m, 1H), 4.87 (m, 1H), 5.95 (m, 2H), 6.16 (m, 1H), 8.03 (s, 1H), 8.09 (s, 1H). 31P NMR (D2O) d 10.07. LRMS (ESI) MH+ C11H14N5O5P requires 328.2. Found 328.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@@H:6]2[CH2:9][OH:10].C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:10][CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]3[CH2:8][C@@H:7]2[C:2]3([CH3:11])[CH3:1])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CC1(C)[C@H]2CC[C@H](CO)[C@@H]1C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol (7.0 mL, 44.2 mmol) and triethylamine (13.5 mL, 97.0 mmol) in dichloromethane (60 mL) was cooled to 0° C. A solution of 4-methylbenzene-1-sulfonyl chloride (10.9 g, 57.4 mmol) in dichloromethane (20 mL) was added drop wise at 0° C. The reaction was stirred at room temperature for 16 hours. The mixture was washed with saturated aqueous NaHCO3 and the aqueous layer was extracted twice with dichloromethane. The organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:23]([O:27][C:28]([NH:30][CH:31]([C:35]([F:38])([F:37])[F:36])[C:32]([OH:34])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C[N:40]1[CH2:45][CH2:44][O:43]C[CH2:41]1.Cl.OC1CN(O)C1>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[CH:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:24])([CH3:25])[CH3:26])[C:32]([N:40]1[CH2:45][CH:44]([OH:43])[CH2:41]1)=[O:34]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(F)(F)F
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)N1CC(O)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
TBTU (6.87 g, 21.4 mmol) was added to a stirred suspension of 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropanoic acid, which is commercially available, in DCM (50 mL). NMM (4.4 mL, 40 mmol) and 3-hydroxyazetidinol hydrochloride (2.48 g, 22.6 mmol) were added. The mixture was stirred at rt for 4 h. The turbid solution was diluted with DCM (70 mL) and washed with NaHCO3 solution (saturated, 1×100, 2×20 mL). After drying (Na2SO4) the solvent was evaporated under reduced pressure. The residue was stirred at rt with isohexanes (60 mL) to yield the title product (3.97 g, 97%) as a colourless powder. 1H NMR (500 MHz, DMSO-d6) δ 7.86-8.05 (1H), 5.71-5.87 (1H), 4.86-5.03 (1H), 4.27-4.54 (2H), 4.04-4.15 (1H), 3.78-3.97 (1H), 3.56-3.68 (1H), 1.38-1.4 (9H). Ratio of rotamers ˜6:4.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH2:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:17]=[C:18]([CH3:20])[CH:19]=1>C(Cl)Cl>[CH:13]([C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH:17]=[C:18]([CH3:20])[CH:19]=1)=[O:12]
Reactant: Cc1cc(CO)cc(NC(=O)OC(C)(C)C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(C=O)cc(NC(=O)OC(C)(C)C)c1

Procedure:
To a suspension of PCC (1.36 g, 6.32 mmol) in CH2Cl2 (10 mL) was added a solution of tert-butyl 3-(hydroxymethyl)-5-methylphenylcarbamate (1.0 g, 4.2 mmol) in CH2Cl2 (10 mL) at room temperature. After 18 hours the mixture was filtered through a pad of Celite® and concentrated. Flash column chromatography (15% EtOAc/hexanes) gave tert-butyl 3-formyl-5-methylphenylcarbamate as a white solid. 1H-NM (300 MHz, CDCl3) δ 9.90 (s, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.39 (s, 1H), 6.59 (bs, 1H), 2.40 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([CH2:6][C:7]([N:9]([CH3:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[N+:18]([O-])=O)=[O:8])([O:3][CH2:4][CH3:5])=[O:2].C(O)C.[BH4-].[Na+].Cl>[Pd](Cl)Cl.O>[C:1]([CH2:6][C:7]([N:9]([CH3:21])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[NH2:18])=[O:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CC(=O)N(C)c1ccc(OC)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)N(C)c1ccc(OC)cc1N

Procedure:
5 g. of N-carbethoxy acetyl N-methyl 4-methoxy 2-nitro aniline are dissolved in 50 cc. of hot ethanol. After cooling, 15 cc. of water and 3 cc. of a 2% solution of palladium chloride are added. Then 5 cc. of a 20% aqueous solution of sodium borohydride are introduced, while cooling. This is agitated for thirty minutes, without allowing the temperature to exceed 40° C. Then, the excess of reagent is decomposed by acidifying to pH = 2 with hydrochloric acid. After cessation of the gaseous emission, the medium is filtered then neutralised with addition of ammonium hydroxide, N-carbethoxy acetyl N-methyl 4-methoxy o-phenylene diamine precipitates. The precipitate is filtered, washed with water, filtered with suction and dried. Thus, there are obtained 3.75 g of N-carbethoxy acetyl N-methyl 4-methoxy o-phenylene diamine, which is purified by recrystallization in ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH3:32])[C:25]([F:26])([F:28])[F:27])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(C)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OC)C(F)(F)F)c23)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (100.7 mg, 0.236 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (14.2 mg, 0.354 mmol) at 0° C. After 30 min, to the mixture was added methyl iodide (73.5 μL, 1.180 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (85.5 mg, 0.194 mmol, 82%).