Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)c(COCc2ccccc2)n1
Yield: 13 %

Procedure:
As described for Example 63, 4-(2-benzyloxymethyl-1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (200 mg, 0.58 mmol) using 4-fluorobenzotrifluoride instead of 4-fluoroacetophenone was converted to the title compound (38 mg, 13%) which was obtained as a light yellow gum. MS: m/e=490.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=2[CH:21]=1.[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=3[CH:21]=2)=[CH:28][CH:27]=1)(=[O:24])[CH3:23]
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(NC(C)=O)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-diethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C1(O)CCCCC1>O>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: OC1CCCCC1
Solvent: O
Product: O=[N+]([O-])c1ccccc1NC1CCN(Cc2ccccc2)CC1
Temperature: -15 °C

Procedure:
A mixture of 38 parts of 1-(phenylmethyl)-4-piperidinamine, 40 parts of 2-chloronitrobenzene, 32 parts of sodium carbonate, a few crystals of potassium iodide in 320 parts of cyclohexanol is stirred and refluxed for 22 hours. After cooling, 300 parts of water are added. The organic layer is separated, diluted with 160 parts of water are added. The organic layer is separated, diluted with 160 parts of benzene and the whole is washed three times with 150 parts of water; the organic layer is dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in a mixture of 40 parts of 2,2'-oxybispropane and 160 parts of hexane. After cooling to -15° C, the precipitate is filtered off and the filtrate is set aside. The precipitate is recrystallized from 160 parts of 2,2'-oxybispropane and filtered off, yielding 18.5 parts of N-(2-nitrophenyl)-1-(phenylmethyl)-4-piperidinamine; mp. 93.4°-94.6° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.COCCOC.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:21]=[CH:20][N:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1F
Solvent: COCCOC
Solvent: O
Product: Fc1ccccc1-c1cc(Cl)ncn1
Temperature: 80 °C
Reaction time: 9 h
Yield: 33.5 %

Procedure:
A reaction vessel was charged with 0.258 g of tetrakistriphenylphosphine palladium, 1.143 g of 2-fluorophenylboronic acid, and 3.153 g of tripotassium phosphate n-hydrate, to which 36 ml of 1,2-dimethoxyethane, 9 ml of water, and 1.106 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 9 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.519 g of 4-chloro-6-(2-fluorophenyl)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C.O1CCOCC1>[NH4+].[Cl-].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(c2ncccc2C(F)(F)F)CC1
Temperature: 200 °C
Yield: 63.6 %

Procedure:
A mixture of the amine from Step 7D (200 mg, 0.68 mmol), 2-chloro-3-(trifluoromethyl)pyridine (200 mg, 1.36 mmol), DIEA (0.36 mL, 2.04 mmol), and 1,4-dioxane (0.10 mL) was heated in the Emrys Creator microwave to 200° C. for 1 h. The mixture was diluted with sat. NH4Cl (20 mL) and EtOAc (50 mL). The organic phase washed with 10% HCl (25 mL), H2O (3×25 mL), and brine (25 mL), dried (MgSO4), and concentrated. The resulting yellow oil was purified by SiO2 chromatography (elution with 10 to 30% EtOAc-hexanes), and lyophilized to afford the title compound (0.19 g), a white solid, 64%.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[N+:20]([O-:22])=[O:21])=[N:8][N:7]=[N:6]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[N+:20]([C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[S:10][C:9]1[N:5]([CH2:4][CH2:3][NH:2][S:24]([CH3:23])(=[O:26])=[O:25])[N:6]=[N:7][N:8]=1)([O-:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
To a suspension of 4.9 g (14.1 mmol) of 1-(2-aminoethyl)-5-(2,4-dinitrophenylthio)tetrazole hydrochloride in 100 ml of pyridine was added 1.5 ml (2.2 g, 19.2 mmol) of methanesulfonyl chloride. The mixture was stirred for 1.5 hours, then an additional 0.5 ml of methanesulfonyl chloride was added and the mixture was stirred another hour. The pyridine was removed by evaporation and the residue was dissolved in a small volume of dimethylformamide. Water was added to the solution and the resulting precipitate was collected by filtration, washed with watr and air dried. The precipitate was dissolved in a minimum amount of dimethylformamide and the solution was diluted with ethyl acetate and treated with Darco G-60. The mixture was filtered and evaporated to dryness to give a syrupy residue which was crystallized from ethyl acetate to give 5-(2,4-dinitrophenylthio)-1-(2-methanesulfonamidoethyl)tetrazole.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CO.[CH3:34][N:35]([CH3:61])[CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][S:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)(=[O:50])=[O:49])=[CH:43][CH:42]=1>C1COCC1>[CH3:61][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([N:47]([CH3:1])[S:48]([C:51]2[CH:52]=[CH:53][C:54]([C:57]([F:59])([F:60])[F:58])=[CH:55][CH:56]=2)(=[O:50])=[O:49])=[CH:45][CH:46]=1
Reactant: CN(C)CCCCOc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCCCOc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of 98 mg (0.375 mmol) triphenylphosphine in 0.5 ml THF was treated at 0° C. with 0.06 ml (0.375 mmol) DEAD, then with 0.012 ml (0.3 mmol) methanol in 0.33 ml THF and finally with 104 mg (0.25 mmol) of N-[4-(4-Dimethylamino-butoxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide in 0.3 ml THF. The reaction mixture was stirred over night at RT, evaporated and extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were dried over Na2SO4 evaporated and purified by flash column chromatography on silica gel with CH2Cl2/MeOH (99:1 to 95:5) to yield 80 mg (74%) of N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, mp: 151-153° C.; MS: 431 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=O.O.[NH2:16][NH2:17]>C(O)C>[OH:14][N:12]1[C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[N:17]=[N:16]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: On1nnc2ccc(C(F)(F)F)cc21
Yield: 89.5 %

Procedure:
The title compound is prepared according to the procedure described by K. Takeda [J. Org. Chem., 50, 273, (1985)]. A mixture of 4-chloro-3-nitro-α,α,α-trifluorotoluene (50.0 g, 0.22 moles) and hydrazine hydrate (33.0, 0.33 moles) in absolute ethanol (75 ml) is refluxed for 24 h. After removal of the solvent under reduced pressure, the residue is dissolved in 10% aqueous sodium carbonate solution. The solution is washed with ether to remove the starting material and acidified with concentrated HCl to precipitate the product, which is washed with water and dried to obtain 40.0 g of the title compound. This product is recrystallized from ether.
Reaction SMILES: [Na].[NH:2]([C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:3].[C:13](#[N:17])[C:14]([CH3:16])=[CH2:15]>C(O)C>[NH2:17][C:13]1[CH:14]([CH3:16])[CH2:15][N:2]([C:4]2[S:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[N:3]=1
Reactant: NNc1nc2ccccc2s1
Reactant: C=C(C)C#N
Agent: [Na]
Solvent: CCO
Product: CC1CN(c2nc3ccccc3s2)N=C1N

Procedure:
A 0.5 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 16.5 g. of 2-hydrazinobenzothiazole is added followed by 6.7 g. of methacrylonitrile. The reaction mixture is refluxed for 4 hours, then is cooled. Some of the ethanol is removed in vacuo and the precipitate is collected by filtration to give 20.6 g. of the desired product as colorless prisms, m.p. 207°-209° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([CH3:19])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[Na+].[Na+].Cl>C(O)C.O>[OH:18][CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]([CH3:3])([CH3:19])[C:5]([OH:7])=[O:6]
Reactant: CCCCC(=O)CCCCCC(C)(C)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: CCCCC(O)CCCCCC(C)(C)C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
Sodium borohydride (8.0 g, 0.21 mol) was added in portions to 2,2-dimethyl-8-oxododecanoic acid (27.02 g, 0.11 mol) in ethanol (200 mL), followed by addition of Na2CO3 (5 g) while the reaction mixture was gently refluxed. The reaction mixture was stirred at 40-50° C. for 3.5 h and at 60° C. for 1 h. Water (100 mL) and aqueous HCl (10%, 100 mL) were added. The mixture was extracted with ethyl acetate (3×80 mL). The organic solutions were combined, washed with water (100 mL) and brine (2×50 mL), and dried over MgSO4. The solvent was evaporated and the residue was purified twice by column chromatography (silica gel, ethyl acetate/heptane=1:3). Coevaporation with toluene and drying in high vacuo at 70° C. for 1 h gave 8-hydroxy-2,2-dimethyldodecanoic acid (9.6 g, 35%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.5-6.5 (br, 1H), 3.60 (m, 1H), 1.53-1.29 (m, 17H), 1.21 (s, 6H), 0.91 (t, J=6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 185.0, 73.0, 43.1, 41.5, 38.2, 38.0, 31.2, 28.8, 26.5, 26.0, 25.9, 23.8, 15.1. HRMS (LSIMS, gly): Calcd for C14H29O3 (MH+): 245.2116, found: 245.2107. HPLC: 97.1% pure. Elemental analysis (C14H28O3): Calcd for C, 68.81; H, 68.67. Found: C, 68.67; H, 11.64.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7](O)=[O:8].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][S:2][C:3]1[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([Cl:23])=[O:8]
Reactant: CCCCCCc1cccc(C=CC(=O)O)c1SC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCc1cccc(C=CC(=O)Cl)c1SC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-methylthio-3-n-hexylcinnamic acid (1.39 g, 0.005 mmol) in 25 ml of CH2Cl2 is added oxalyl chloride (0.9, 0.01 mmol) and DMF (0.365 g, 0.005 mmol) with cooling in an ice bath. The bath was removed and the reaction mixture stirred at room temperature for 2 hours to afford 2-methylthio-3-n-hexylcinnamic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([NH2:13])([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]([NH:13][C:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[CH:17][C:16]([Cl:15])=[CH:24][CH:23]=2)=[O:26])([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C(C)(N)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(C)(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Racemic 2-amino-2-methyl-3-phenyl-propionic acid methyl ester (200 mg, 0.87 mmol) and 5-chloro-1H-indole-2-carboxylic acid (170 mg, 0.87 mmol) were coupled according to Procedure A (2:1 dichloromethane/dimethylformamide solvent) and the product purified by chromatography on silica gel eluted with 10% ethyl acetate in hexanes. Yield 286 mg, 89%; HPLC (60/40) 9.63 minutes (85%); TSPMS 371/373 (MH+, 100%);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[CH:19]=[CH:20]C2N(O)N=[N:24][C:22]=2[CH:23]=1.N1CCCCC1.CCN(CC)CC>C(Cl)Cl>[CH3:16][C:10]1([CH3:17])[C@@H:11]([C:13]([N:24]2[CH2:20][CH2:19][CH2:18][CH2:23][CH2:22]2)=[O:15])[CH2:12][C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCCCC2)C1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.79 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.500 g, 2.057 mmol) in DCM (20 ml) EDCI (0.472 g, 2.469 mmol) and HOBt (0.378 g, 2.469 mmol) were added at 0° C. and after 10 minutes, piperidine (0.4 ml, 4.115 mmol) and Et3N (1.42 ml, 10.288 mmol) were added drop wise and the reaction mass was allowed to stir at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, sat. NaHCO3 solution, water, 1N HCl, water, saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude residue was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum to afford the title compound. Wt: 0.400 g; Yield: 62.79%; 1H NMR (300 MHz, CDCl3): δ 4.77 (d, 1H, J=8.4 Hz), 3.89-3.78 (m, 1H), 3.77-3.67 (m, 1H), 3.49-3.28 (m, 3H), 2.87-2.76 (m, 1H), 2.40-2.18 (m, 2H), 1.70-1.46 (m, 6H), 1.43 (s, 9H), 1.33 (s, 3H), 0.87 (s, 3H); Mass: [M+1]+ 311 (35%), [M+Na]+ 333 (100%); IR (KBr, cm−1): 3337, 2939, 1712, 1628, 1522, 1456, 1445, 1388, 1353, 1366, 1288, 1264, 1254, 1217, 1172, 1047, 1026, 1013, 976; M.R: 176.0° C.-178.0° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH2:10][NH:9][S:8]2(=[O:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CS(C)=O>[O:13]=[S:8]1(=[O:14])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11][CH2:10][N:9]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CBr
Reactant: O=S1(=O)NCCCN1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CN1CCCN(c2ccccc2)S1(=O)=O
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To 2-phenyl-1,2,6-thiadiazinan 1,1-dioxide (400 mg, 1.89 mmol) in DMSO (15 mL), were added K2CO3 (522.4 mg, 3.78 mmol) and ethyl bromoacetate (379.1 mg, 2.27 mmol). The reaction mixture was agitated for 4 hr and extracted with ethyl acetate and brine. The organic layer was dried over MgSO4 and the residue was purified by silica gel column chromatography to yield ethyl 2-(1,1-dioxido-6-phenyl-1,2,6-thiadiazinan-2-yl)acetate (468 mg, 1.56 mmol, 83%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.45-7.34 (m, 3H), 7.30-7.25 (m, 1H), 4.28-4.20 (q, J=7.1 Hz, 2H), 4.03 (s, 2H), 3.82-3.73 (m, 4H), 1.99-1.91 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([C:22]#[N:23])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:32])[F:31])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C([OH:37])(C)(C)C>O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([C:22]([NH2:23])=[O:37])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:31])[F:32])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: Cc1nc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Solvent: O
Product: Cc1nc(C(N)=O)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridine-2-carbonitrile (47.2 mg, 0.100 mmol) in tert-butyl alcohol (2 mL) potassium hydroxide (22.4 mg, 0.400 mmol). The reaction mixture was stirred at 80° C. for 5 min. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 30-80% ethyl acetate/n-hexane gradient mixture to give a title compound as a colorless amorphous (16.6 mg, 0.0399 mmol, 34%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>CN(C=O)C>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:16]3[CH2:21][N:20]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Reactant: Clc1ncccn1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(c2ncccn2)C3)cc1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
1-Ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (d, 0.15 mmol), chloropyrimidine (0.21 mmol) and i-PrN2Et (0.6 mmol) were mixed in DMF (0.6 mL) in a microwave reaction tube. The mixture was heated to 120° C. and stirred for 15 min. After cooling to room temperature, the mixture was diluted with DMF. The resulting mixture was purified by reverse-phase HPLC to give 1-ethyl-3-(4-(4-morpholino-6-(pyrimidin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (e): 1H NMR (500 MHz, DMSO) δ 8.71 (s, 1H), 8.47 (d, J=4.8, 2H), 8.21 (d, J=8.8, 2H), 7.51 (d, J=8.8, 2H), 6.77 (t, J=2.5, 1H), 6.18 (m, 1H), 4.99 (s, 2H), 4.68 (s, 2H), 3.78 (m, 8H), 3.20-3.15 (m, 2H), 1.26 (t, J=6.9, 3H); LC-MS: m/z=+447 (M+H)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>CN(C=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][NH:14][C:15]([NH2:17])=[S:16])=[O:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NNC(N)=S
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1ccccc1N
Temperature: 70 °C
Reaction time: 20 h
Yield: 46.6 %

Procedure:
Isatoic anhydride (4.9 g) and thiosemicarbazide (2.8 g) were dissolved in 30 ml of DMF and the resulting mixture was stirred 20 h at 60 to 80° C. The solvent was removed under reduced pressure and the residue was recrystallized from methanol and ethanol to give 2.94 g of 1-(2-aminobenzoyl)thiosemicarbazide.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[H][H]>O1CCCC1.[Pd]>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7]
Reactant: [H][H]
Reactant: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCOCC2=O)cc1
Yield: 37.8 %

Procedure:
In an autoclave, 63 g (0.275 mol) of 4-(4-morpholin-3-onyl)nitrobenzene are dissolved in 200 ml of tetrahydrofuran, admixed with 3.1 g of Pd/C (5% ig) and hydrogenated at 70° C. and a hydrogen pressure of 50 bar for 8 h. The catalyst is filtered off, the solvent is then distilled off under reduced pressure and the product is purified by crystallization from ethyl acetate. 20 g of product are obtained as a colourless to bluish solid, in a yield of 37.6% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.CCN(C(C)C)C(C)C.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=1)=[O:7]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromobenzoic acid (10 g, 49.7 mmol), thionyl chloride (4.72 mL, 64.7 mmol), and DMF (1.5 mL) in toluene (80 mL) was stirred at 80° C. for 2 h. The mixture was cooled to 0° C., treated dropwise with DIPEA (19.11 mL, 109 mmol) followed by 4-trifluoromethoxyaniline (6.73 mL, 49.7 mmol) and the RM was allowed to warm to RT and stirred overnight. The mixture was diluted with EtOAc (150 mL), washed with 0.5 M HCl (2×100 mL), sat. NaHCO3 (2×100 mL) and brine (100 mL), dried over MgSO4 and the solvent was evaporated off under reduced pressure and the product was crystallized from n-heptane/EtOAc to afford the title compound. LC-MS (Condition 5) tR=1.37 min, m/z=360.1, 362.1 [M+H]+; 1H-NMR (400 MHz, MeOD) δ ppm 7.30 (d, J=8.80 Hz, 2H) 7.47 (t, J=7.95 Hz, 1H) 7.74-7.86 (m, 3H) 7.93 (d, J=7.82 Hz, 1H) 8.13 (s, 1H).