Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]2[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])[CH2:18]2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:20]2[CH2:21][C@H:17]([CH2:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][CH:14]=3)[CH2:18][C@H:19]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1C(=O)Cn1cncn1
Yield: 33 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 141, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (39 mg, 33%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.57 (d, 2H), 7.35-7.08 (m, 7H), 7.05-6.90 (m, 4H), 5.23 (q, 2H), 4.56-4.47 (m, 1H), 3.87-3.74 (m, 1H), 3.39-3.29 (m, 1H), 2.79-2.62 (m, 3H), 2.04-1.89 (m, 2H). MS (EI) for C28H25F2N5O3. found 517.9 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[N:7]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[Br:16])[CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1Br
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 144A (12.37 g, 40.1 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added cesium carbonate (19.62 g, 60.2 mmol) and iodomethane (5.02 mL, 80 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and was partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 40% to 100% ethyl acetate in hexane) to provide the title compound. MS (ESI+) m/z 322 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[OH:8][OH:9].[OH-:10].[Na+].[Na+].[Cl-]>>[CH:5]([O:4][C:2]([O:8][O:9][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:10])=[O:3])([CH3:7])[CH3:6]
Reactant: [OH-]
Reactant: CC(C)OC(=O)Cl
Reactant: OO
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)OC(=O)OOC(=O)OC(C)C

Procedure:
Following the Example II procedure, IPP is prepared at the rate of 50 pph in an average assay of greater than 98% from 85 pph of isopropyl chloroformate, 28.5 pph of 50% H2O2, 160 pph of 20% NaOH and 50 pph of saturated NaCl solution.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[N:3]=[C:4]4[C:10]([C:11]([C:13]5([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)cc2)CC1

Procedure:
4-{4-[7-(1-Methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester following general procedures as described in these Examples. M+H=504.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:5](=[O:17])[NH:4][C:3]=1[C:18]1[N:19]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1.CCN(C(C)C)C(C)C.[CH:40]1([N:45]=[C:46]=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl>[CH:40]1([NH:45][C:46]([N:4]2[C:3]([C:18]3[N:19]([C:23]4[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=4)[CH:20]=[CH:21][N:22]=3)=[C:2]([CH3:1])[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[C:5]2=[O:17])=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C=NC1CCCC1
Reactant: Cc1c(-c2nccn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2nccn2-c2ccc(C#N)cc2)n(C(=O)NC2CCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
4-[5′-Methyl-2′-oxo-1′-(3-trifluoromethyl-phenyl)-2′,3′-dihydro-1′H-[2,4′]biimidazolyl-1-yl]-benzonitrile (Example 59, 108 mg, 0.26 mmol) was suspended in dry DCM (5 ml) and DIPEA (130 μl, 3 eq.) was added followed by cyclopentyl isocyanate (90 μl, 88 mg, 0.79 mmol). The mixture was heated and stirred at 45° C. for 24 h. The solvent was removed in vacuo and the residue purified by chromatography eluting with EtOAc, thereby yielding the title compound (100 mg, 73%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>>[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1
Reactant: COCCN
Reactant: Clc1ccn2nccc2n1
Product: COCCNc1ccn2nccc2n1
Temperature: 65 °C
Yield: 108.1 %

Procedure:
A stirred mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine [29274-24-6], (525.5 mg, 3.4 mmol) and 2-methoxy-ethylamine (3.0 mL, 34.5 mmol) was heated to 65° C. for 17 h, cooled and partitioned between brine (pH adjusted to 8 with saturated aqueous sodium bicarbonate) and ethyl acetate. Extract was dried (MgSO4) and evaporated to yield 706.4 mg of light yellow solid. LRMS (ESI) m/z 193.1 [(M+H)]+, calc'd for C9H12N4O: 192.22.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[N:21]=[C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:18][CH:17]=1)=[O:14].[BH4-].[Na+].Cl.C(Cl)Cl.CO.[CH3:36][C:37]([CH3:39])=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[NH:12][C:13]([NH:15][C:16]1[N:21]=[C:20]([CH:22]2[CH2:23][CH2:24][N:25]([CH:37]([CH3:39])[CH3:36])[CH2:26][CH2:27]2)[CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(C)=O
Reactant: O=C(Nc1cccc(C2CCNCC2)n1)Nc1ccnc2c(F)cccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCC(c2cccc(NC(=O)Nc3ccnc4c(F)cccc34)n2)CC1

Procedure:
To a solution of 50 mg of 1-(8-fluoro-quinolin-4-yl)-3-(1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-urea (example 62) (0.137 mmol) in 50 ml of acetone were added 26 mg of sodium borohydride (0.684 mmol) in small portions. The reaction was slightly exotherm. After stirring the reaction mixture over night a small amount of 2M HCl was added to the reaction mixture up to a pH of 3 to destroy the excess of sodium borohydride. After neutralization with sodium bicarbonate, acetone was evaporated under reduced pressure, water added to the residue, the reaction mixture extracted three times with DCM, the organic phases combined and dried over sodium sulfate and the solvent evaporated under reduced pressure. 45 mg of the desired product were obtained as off white powder (yield: 81%) after column chromatography (silica gel, DCM/MeOH 98/2).
Reaction SMILES: [OH-].[Na+].[NH:3]([CH2:5][C:6]([OH:8])=[O:7])[CH3:4].[CH:9]([N:12]=[C:13]=[O:14])([CH3:11])[CH3:10]>O>[CH:9]([NH:12][C:13](=[O:14])[N:3]([CH2:5][C:6]([OH:8])=[O:7])[CH3:4])([CH3:11])[CH3:10]
Reactant: CNCC(=O)O
Reactant: CC(C)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)NC(=O)N(C)CC(=O)O
Reaction time: 2 h

Procedure:
To a solution of 4 g of sodium hydroxide in 75 ml of water was added 10 g of sarcosine portionwise. The solution was cooled and treated with 11.5 ml of isopropyl isocyanate. After 2 h, the reaction mixture was washed with diethyl ether and the aqueous phase acidified with concentrated HCl to <pH 2. The product was extracted twice with ethyl acetate to give 10.45 g of a white solid which was taken on to the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=O)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>CCO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[N:24][OH:25])[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Reaction time: 0.17 h

Procedure:
To a solution of 1′-benzylspiro[indene-1,4′-piperidin]-3(2H)-one lab (38 g, 0.15 mol) in EtOH (300 mL), hydroxylamine hydrochloride (18 g, 0.30 mol) and sodium acetate (19.5 g, 0.275 mol) were added. The mixture was refluxed for 4 hours and the solvent removed under reduced pressure. The residue was diluted with 150 mL water and 100 mL CH2Cl2. After the mixture was stirred for 10 min, the resulting white solid was collected by filtration. The organic phase in the filtrate was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4. After evaporation of the solvent under reduced pressure, a yellow oil was obtained. The oil was crystallized from EtOAc to yield 1′-benzylspiro[indene-1,4′-piperidin]-3(2H)-one oxime 1ac as an off-white solid. 1H NMR (CD3OD, 400 MHz) δ 7.64 (d, J=8.0 Hz, 1H), 7.55-7.57 (m, 2H), 7.38-7.50 (m, 5H), 7.29-7.33 (m, 1H), 4.25 (s, 2H), 3.41 (d, J=12.4 Hz, 2H), 3.08 (t, J=12.0 Hz, 2H), 2.95 (s, 2H), 2.20-2.28 (m, 2H), 1.68 (d, J=14.4 Hz, 2H).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][C:2]1=O.[O:8]=[C:9]([CH3:17])[CH2:10][S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:16][O:15][C:13]([C:12]1[S:11][C:10]([C:9](=[O:8])[CH3:17])=[C:1]2[CH2:5][CH2:4][CH2:3][C:2]=12)=[O:14]
Reactant: O=C1CCCC1=O
Reactant: COC(=O)CSCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(C)=O)c2c1CCC2
Yield: 4.5 %

Procedure:
Stir a mixture of Cyclopentane-1,2-dione (2.00 g, 20.4 mmol), methyl 2-(2-oxopropylthio)acetate (3.31 g, 20.4 mmol) and potassium carbonate (5.63 g, 40.8 mmol) in DMF (40 mL) at 80° C. for 4 hours. Filter off the mixture and remove the solvent under vacuum. Purify the residue by a flash column on silica gel eluting with PE:EtOAc (8:1 to 6:1) to afford 3-Acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester as a pale yellow solid (206 mg, 4.5%). MS (m/z): 225 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][Zn]C.C1(C)C=CC=CC=1>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:37])[N:7]=2)=[C:9]([C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[N:10]=1)([CH3:16])[CH3:15]
Reactant: C[Zn]C
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.269 mmol) and dimethyl zinc in toluene (0.269 mL, 0.539 mmol), the title compound was obtained as a yellow solid (105 mg, 72% yield). MS (ESI): 537 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4]([CH3:13])[N:3]=1.[N:14]1([CH2:20][CH2:21]N)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C([N:25](CC)CC)C>>[ClH:1].[ClH:1].[CH3:13][C:4]1[N:3]=[C:2]([CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:7]2[O:8][CH:9]([NH2:25])[C:10](=[O:12])[NH:11][C:6]=2[N:5]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Reactant: CCN(CC)CC
Product: Cc1nc(CCN2CCOCC2)c2c(n1)NC(=O)C(N)O2
Product: Cl
Yield: 50.1 %

Procedure:
According to Example 20, a mixture containing 1 g of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 1.01 g of triethylamine and 0.65 g of 2-(4-morpholinyl)-ethylamine is refluxed for 40 hours to give 0.46 g (25%) of the product, m.p.: 233°-237° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].[F:34][C:35]1[CH:36]=[N:37][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[N:39][CH:40]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[N:37]=[CH:36][C:35]([F:34])=[CH:40][N:39]=3)[CH2:42][CH2:43]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: NC1(c2ncc(F)cn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.089 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.023 g (44%). 1H NMR (400 MHz, CD3OD): δ 8.59 (d, J=0.4 Hz, 2H), 7.98-7.94 (m, 2H), 7.87 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.18 (s, 1H), 4.09 (s, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.79-1.76 (m, 2H), 1.52-1.48 (m, 2H). 19F NMR (376.57 MHz, CD3OD) δ−77.62 (TFA), −112.36, −122.73, −145.58 LCMS: (ES+) m/z=587.2 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.Cl.[C:11]1([C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]3[CH:21]([CH2:22][NH:23][CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:27]1([C:17]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:25]3[CH:21]([CH2:22][N:23]([C:7](=[O:9])[CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccs3)CC12
Reaction time: 1 h
Yield: 74 %

Procedure:
N,N'-Carbonyldiimidazole (0.81 g) is added to a solution of 2-(2-thienyl)acetic acid (0.71 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.6 g) and triethylamine (0.7 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 2 hours at +5° C. and for 16 hours at 20° C. and is then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (10 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-thienyl)acetyl]-4-perhydroisoindolone (1.5 g) melting at 206° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1ccc(N)c(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.8 %

Procedure:
A mixture of 2-bromo-4-isopropylaniline (5.05 g, 23.6 mmol), acetic anhydride (2.4 mL, 25 mmol), and triethylamine (3.5 mL, 25 mmol) in dichloromethane (25 mL) was stirred at ambient temperature for 4 days. The mixture was diluted with dichloromethane, washed sequentially with saturated aqueous Na2CO3 and 1M HCl, dried (MgSO4), filtered, and concentrated to provide the desired product (5.85 g). MS (DCI) m/e 256, 258 (M+H)+; 273, 275 (M+NH4)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]#[N:17])[C:10]=2[CH2:9][CH2:8][O:7]1.C(N)(=[O:20])C.C1COCC1>Cl[Zn]Cl.O>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH2:17])=[O:20])[C:10]=2[CH2:9][CH2:8][O:7]1
Reactant: CC(N)=O
Reactant: N#Cc1cccc2c1CCOC2C1=NCCN1
Agent: Cl[Zn]Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1CCOC2C1=NCCN1

Procedure:
The mixture of 1-(4,5-dihydro-1H-imidazol-2-yl)isochroman-5-carbonitrile (example 5, 75 mg), acetamide (39 mg), zink chloride (45 mg), THF (0.5 ml) and water (0.5 ml) was heated in a microwave reactor for 50 seconds at 320 W. The title compound was purified by applying method A. (Yield 15 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([NH2:14])=O)[CH:6]=[C:7]([CH:11]=1)[C:8]([NH2:10])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]#[N:14])[CH:6]=[C:7]([CH:11]=1)[C:8]#[N:10]
Reactant: COc1cc(C(N)=O)cc(C(N)=O)c1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C#N)cc(C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.1 %

Procedure:
A suspension of the 5-methoxyisophthalamide (3.1 g, 16 mmol) in a dichloromethane (27 mL) at 0° C. was treated with pyridine (5.2 mL, 65 mol) and then trifluoroacetic anhydride drop-wise (5.4 mL, 39 mmol). The reaction was stirred at 0° C. for 20 minutes and then stirred overnight at ambient temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane afforded 940 mg (46%) of the 5-methoxyisophthalonitrile as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CO[C:17](OC)([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:18][C:17]1([CH3:19])[O:12][CH2:11][CH:10]([C:4]2([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:13][O:14]1
Reactant: OCCC1(C(CO)CO)CCCCC1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OCC(C2(CCO)CCCCC2)CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.3 %

Procedure:
To a solution of 2-[1-(2-hydroxyethyl)cyclohexyl]propane-1,3-diol (200 mg) in acetone (10 mL) were added 2,2,-dimethoxypropane (206 mg) and p-toluenesulfonic acid (17 mg) at room temperature. After stirring the solution at room temperature for 48 hours, a saturated aqueous sodium bicarbonate solution was added thereto, and it was concentrated under reduced pressure. To the resulting residue were added diethyl ether and water, and it was extracted with diethyl ether. The organic layer was washed in turn with 0.5N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, hexane:ethyl acetate=1:1 to 1:2) to give the title compound (190 mg).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:7]=[C:6]([NH:16][S:17]([CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])[C:5]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34].[CH3:35][OH:36]>>[CH3:35][O:36][C:4]1[N:9]=[C:8]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:7]=[C:6]([NH:16][S:17]([CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])[C:5]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]
Reactant: CO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)CCC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCC(C)(C)C)nc(-c2ncccn2)nc1OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Sodium hydride (80% oil dispersion 132 mg) was cautiously added to a suspension of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-3,3-dimethyl-1-butanesulfonamide (Preparation 2)(420 mg) in dry methanol (12 ml) divided equally between two 10 ml Wheaton reacti-vials™, and the resulting mixtures stirred at 100° C. for 3 hours. The reactions were then combined and partitioned between ethyl acetate (40 ml) and 2N aqueous hydrochloric acid (20 ml) and the organic phase separated. The aqueous was extracted with ethyl acetate (20 ml) and the organic phases combined, washed (water 2×20 ml), dried (Na2SO4) and evaporated under reduced pressure. Column chromatography on silica eluting with a solvent gradient of dichloromethane:methanol 99:1 changing to 97:3 gave N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-3,3-dimethyl-1-butanesulfonamide as an off-white coloured foam (265 mg).