Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[CH3:25][CH:26]([CH3:31])[CH2:27][C:28](Cl)=[O:29]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH3:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[CH:11]=2)=[CH:3][C:2]=1[NH:1][C:28](=[O:29])[CH2:27][CH:26]([CH3:31])[CH3:25]
Reactant: CC(C)CC(=O)Cl
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)CC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
To a solution of N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (185 mg, 0.572 mmol) in N,N-dimethylacetamide (5 mL) was added 3-methylbutanoyl chloride (71.0 μL, 0.579 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (176 mg, 72%) as a white solid.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.C([O-])([O-])=O.[K+].[K+].[CH:24]1([N:30]([CH2:37][CH2:38][OH:39])[C:31](=[O:36])/[CH:32]=[CH:33]/[CH2:34]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O>[OH:39][CH2:38][CH2:37][N:30]([CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)[C:31]([CH:32]=[CH:33][CH2:34][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)=[O:36]
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: O=C(/C=C/CBr)N(CCO)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C=CCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Into 200 ml of N,N-dimethylformamide and 50 ml of water was added 16 g of 6-hydroxycarbostyril and 17 g of K2CO3, while the mixture was stirred at a room temperature, 31 g of N-cyclohexyl-N-(2-hydroxyethyl)-γ-bromocrotonamide was added dropwise. After the addition the reaction mixture was stirred for 3 hours and was concentrated. To the residue thus obtained 500 ml of chloroform was added and washed with water, a dilueted NaOH aqueous solution and water. The organic layer was concentrated. The residue thus obtained was recrystallized from methanol-water to obtain 27 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]-2-propenyloxy}-carbostyril as in the form of colorless needle-like crystals. The chemical structure of this substance was identified by the NMR spectrum and the data of elementary analysis.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.[OH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:16])[CH2:27]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Oc1cccc2c1CNC2
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(O)c4C3)c(F)cc2c1=O
Yield: 19.3 %

Procedure:
136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 130 mg of 4-hydroxyisoindoline hydrobromide, 114 mg of 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 37 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:8])[NH:5][CH2:4][NH:3]1.[H][H]>[Ni]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:8])[N:5]=[CH:4][NH:3]1
Reactant: [H][H]
Reactant: CC1CC(C)(C)NCN1
Agent: [Ni]
Product: CC1CC(C)(C)NC=N1

Procedure:
Anal. Calc.ed for C7H16N2 : N, 21.85. Found: N, 21.6 Nuclear magnetic resonance spectrum, solvent CDCl3, δ in ppm; 3.82 s, 2H; 2.87 m, 1H; 1.42 & 1.65, 2d's, 2H; 1.02 d, 3H; 1.08 & 1.13 2s's, 6H; 1.67 s, 2H exchangeable with D2O. A sample of 12.8 grams of 4,4,6-trimethylhexahydropyrimidine and 0.5 grams of 60% nickel catalyst on kieselguhr was heated for 8 hrs. at 185°-187° C. During this time the theoretical amount of hydrogen gas was evolved.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]2[C:15]=1C=CC(=O)N2)[O:6][Si](C(C)(C)C)(C)C)=[N+:2]=[N-:3].C(OC1C=CC([C@@H](O)CBr)=CC=1[CH2:51][O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])C1C=CC=CC=1>>[N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:20]([CH2:51][O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[CH:15]=1)[OH:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CN=[N+]=[N-])ccc1OCc1ccccc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 1, using Intermediate 7 in place of (R)-8-(benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one. ES/MS calcd. for C22H31N3NaO3Si+ 436.2. Found m/z=436.2 (M+Na)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH2:7]([N:9]1[C:13]2[N:14]=[CH:15][C:16]([C:25]3[O:29][N:28]=[C:27]([CH2:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:26]=3)=[C:17]([NH:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:12]=2[CH:11]=[N:10]1)[CH3:8].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:7]([N:9]1[C:13]2[N:14]=[CH:15][C:16]([C:25]3[O:29][N:28]=[C:27]([CH2:30][CH:31]4[CH2:36][CH2:35][N:34]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:33][CH2:32]4)[N:26]=3)=[C:17]([NH:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:12]=2[CH:11]=[N:10]1)[CH3:8]
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCNCC4)no3)cnc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCN(S(C)(=O)=O)CC4)no3)cnc21
Temperature: 25 °C
Reaction time: 31 h

Procedure:
Methanesulphonyl chloride (1.16 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and pyridine (0.5 ml) in chloroform (1 ml) at room temperature. After stirring at room temperature for 31 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 5 g) and the cartridge was eluted sequentially with chloroform, ethyl acetate and methanol. Fractions containing the desired product were evaporated in vacuo. The resulting residue was further purified on a SPE cartridge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Example 176. LCMS showed MH+=490, TRET=2.97 min.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[C:6]([S:10]([NH2:12])=[O:11])([CH3:9])([CH3:8])[CH3:7]>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:1]1(=[N:12][S:10]([C:6]([CH3:9])([CH3:8])[CH3:7])=[O:11])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1CCC1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1CCC1
Reaction time: 0.17 h
Yield: 77 %

Procedure:
A mixture of titanium (IV) ethoxide (22.4 mL, 107 mmol) and cyclobutanone (5.37 mL, 71.0 mmoL) in tetrahydrofuran (120 mL) was stirred for 10 minutes. Tert-butanesulfinamide (7.17 g, 59.0 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the residue dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulphate and concentrated to give N-cyclobutylidene-2-methylpropane-2-sulfinamide (9.51 g, 77%) as a pale yellow oil which was used directly without purification.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([CH2:16][C:17]3[CH:18]=[N:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[CH:13]=[N:12][C:11]=2[O:25][CH2:26][CH3:27])[CH:7]=[CH:8][CH:9]=1.[OH-:29].[Na+].OO>CO>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([CH2:16][C:17]3[CH:18]=[N:19][C:20]([C:23]([NH2:24])=[O:29])=[N:21][CH:22]=3)[CH:13]=[N:12][C:11]=2[O:25][CH2:26][CH3:27])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOc1ncc(Cc2cnc(C#N)nc2)nc1-c1cccc(OC(F)F)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CCOc1ncc(Cc2cnc(C(N)=O)nc2)nc1-c1cccc(OC(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 5-(6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)pyrimidine-2-carbonitrile (Example 1, 100.00 mg, 0.26 mmol) in MeOH (1.3 mL) was added aq. NaOH (0.78 mL, 0.78 mmol), followed by hydrogen peroxide (0.78 mL, 0.79 mmol) The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was concentrated, and the precipitate filtered and washed with water to obtain the title compound as a white solid (70 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 8.27 (s, 1H), 8.12 (br s, 1H), 7.91-7.84 (m, 1H), 7.81 (t, J=1.8 Hz, 1H), 7.72 (br s, 1H), 7.52 (s, 1H), 7.44-7.02 (m, 2H), 4.42 (q, J=7.0 Hz, 2H), 4.25 (s, 2H), 1.35 (t, J=7.0 Hz, 3H). [M+H]=402.26.
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH2:3][CH:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[C:22]2[C:17](=[C:18]([CH3:23])[CH:19]=[CH:20][CH:21]=2)[CH2:16]1
Reactant: Cc1ccccc1CN(C)CC(O)c1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cccc2c1CN(C)CC2c1ccc2ccccc2c1
Reaction time: 24 h
Yield: 62 %

Procedure:
The product from Step A (1.25 g, 4.1 mmol) was dissolved in trifluoroacetic acid (TFA, 7.5 mL), then trifluoroacetic anhydride (TFAA, 7.5 mL) was added. After stirring for 24 h, the solvents were removed in vacuo, the residue was dissolved in MeOH, and the solvent was removed in vacuo. The residue was dissolved in aqueous NH4OH, then extracted twice with CH2Cl2. The extract was dried over Na2SO4, filtered, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (40 g) eluting with 5% to 30% EtOAc/hexanes with 1% Et3N to give 2,8-dimethyl-4-naphthalen-2-yl-1,2,3,4-tetrahydroisoquinoline (0.73 g, 61%) as a clear, dark yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.66-7.88 (m, 4H), 7.38-7.48 (m, 2 H), 7.26 (dd, J=8.3, 1.6 Hz, 1 H), 6.93-7.04 (m, 2 H), 6.74 (d, J=7.2 Hz, 1 H), 4.45 (t, J=6.9 Hz, 1 H), 3.75 (d, J=15.4 Hz, 1 H), 3.51 (d, J=15.4 Hz, 1 H), 3.06 (ddd, J=11.2, 5.6, 0.9 Hz, 1 H), 2.67 (ddd, J=11.4, 8.5 Hz, 1 H), 2.48 (s, 3 H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C@@:10]([CH2:14][OH:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].I[CH2:33][C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([CH2:14][O:15][CH2:33][C:34]3[CH:35]=[C:36]([C:44]([F:46])([F:47])[F:45])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=3)([CH2:11]2)[CH:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2C[C@@]2(CO)[C@@H]1c1ccccc1
Reactant: FC(F)(F)c1cc(CI)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC2(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
To Intermediate 19, one enantiomer being (1S,2S)-1-hydroxymethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.40 g, 1.4 mmol) in THF (10 mL) at −78° C. was added potassium bis(trimethylsilyl)amide (0.5M/toluene, 4.1 mL, 2.1 mmol) dropwise and the mixture was stirred for an additional 5 minutes. 1-Iodomethyl-3,5-bis-trifluoromethyl-benzene (0.69 g, 1.9 mmol) in THF (4 mL) was added and the reaction stirred at −78° C. for 10 minutes, then allowed to warm to room temperature and stirred for 2 hours. Water was added cautiously and the solvent removed at reduced pressure. The residue was partitioned between H2O and EtOAc, the organics were washed with brine and dried over calcium sulfate, filtered and concentrated to an oil. The crude product was purified by flash chromatography by elution with a gradient of hexanes to 20% EtOAc/Hexanes to give the title compound (0.52 g, 73% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:8][CH2:7][N:6]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:4].C(NCC)C>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:4]
Reactant: COC(=O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1C(=O)OC(C)(C)C
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperazine-1,2,4-tricarboxylic acid 1-tert-butyl ester 4-(9H-fluoren-9-ylmethyl) ester 2-methyl ester (2.03 mmol) in DMF (4.0 mL) was added diethylamine (5%) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified using ethyl acetate/methanol (10%). ESI-MS m/z: 245(M+1), UV retention time: 0.78 min.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]([NH2:25])=[O:24])[C:18]([NH2:22])=[N:19]2)=[CH:14][CH:13]=1>CCCCCC>[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]3[C:23](=[O:24])[NH:25][C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[N:22][C:18]3=[N:19]2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1cc2ccc(F)cc2nc1N
Solvent: CCCCCC
Product: CCOC(=O)c1nc2nc3cc(F)ccc3cc2c(=O)[nH]1
Temperature: 160 °C

Procedure:
Diethyl oxalate (47.5 g., 0.326 mole) and 7-fluoro-2-aminoquinoline-3-carboxamide (3.7 g., 0.015 mole) are mixed together and heated at 160° C. for 7 hours. The reaction mixture is cooled to room temperature, hexane (300 ml.) added, and the brown solid which precipitates filtered off, and washed with hexane (60 ml.). It is then slurried in hot chloroform (250 ml.) and the insoluble material removed by filtration. The hot filtrate is decolorized with charcoal, filtered and dried (Na2SO4). The light brown solid which precipitates upon cooling is filtered off and recrystallized from isopropyl alcohol. Yield = 1.04 g. (29.2%) of the title ethyl ester. M.P. 248°-251° C.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][CH:8]=1.C(O[CH2:15][CH3:16])(=O)C>>[CH:9](=[O:10])/[CH:6]=[CH:5]/[CH2:4][CH2:3][CH2:8][CH2:7][CH2:5][CH2:4][CH2:3][CH2:8][CH2:7][CH2:6][CH2:9][CH2:15][CH3:16]
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(C)=O
Product: CCCCCCCCCCCCC/C=C/C=O

Procedure:
RF =0.5, petroleum ether (boiling point 35°-80° C./ethyl acetate 9:1; UV: blue coloration with anisaldehyde reagent (0.5 ml anisaldehyde, 50 ml glacial acetic acid, 1 ml H2SO4); boiling point (10-3Torr): 115° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ccccc1C(=O)NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(NCCO)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A round-bottomed flask was charged with 2,4,5-trichloropyrimidine (1.3 g, 4.4 mmol), 2-amino-N-(2-hydroxyethyl)benzamide (838 mg, 4.65 mmol), di-isopropyl-ethylamine (925 μL, 5.31 mmol) and 15 mL isopropanol. The flask was fitted with a reflux condenser and the reaction was heated to reflux and stirred for 18 h. A white solid appeared in the reaction mixture. The reaction was cooled to 0° C. and filtered and solid was washed with ether to afford 2-[(2,5-dichloro-4-pyrimidinyl)amino]-N-(2-hydroxyethyl)benzamide (1.3 g, 89%):
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[B:23](OC)([O:26]C)[O:24]C.Cl>CCCCCC.C1COCC1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:23]([OH:26])[OH:24])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COB(OC)OC
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A solution of n-butylithium (50.97 cm3, 0.1274 mol, 2.5M in hexane) was added dropwise to a cooled (−78° C.) stirred solution of 4-bromo-4′-octyloxybiphenyl (40.00 g, 0.1108 mol) in THF (400 cm3). After 1 h, trimethyl borate (23.05 g, 0.2216 mol) was added dropwise to the reaction mixture maintaining a temperature of −78° C. The reaction mixture was allowed to warm to room temperature overnight. 20% hydrochloric acid (350 cm3) was added and the resultant mixture stirred for 1 h. The product was extracted into diethyl ether (3×300 cm3). The combined organic layers were washed with water (300 cm3), dried (MgSO4), filtered and the filtrate evaporated down under partially reduced pressure. The crude product was stirred with hexane for 30 minutes and filtered off to yield a white powder (26.20 g, 73%, m.pt. 134–136° C.).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[NH:11][C:10]([CH3:12])=[N:9][CH:8]=1)=[O:6].[CH3:14]N(C(OC)OC)C>>[CH3:13][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH3:14])[C:10]([CH3:12])=[N:9][CH:8]=1)=[O:6]
Reactant: Cc1ncc(C(=O)C=CN(C)C)[nH]1
Reactant: COC(OC)N(C)C
Product: Cc1ncc(C(=O)C=CN(C)C)n1C
Temperature: 100 °C
Yield: 29 %

Procedure:
5-(3-Dimethylaminoprop-2-enoyl)-2-methylimidazole (350 mg, 1.95 mmol) was suspended in DMFDMA (14 ml) and the mixture stirred and heated at 100° C. for 56 hours. The excess DMFDMA was removed by evaporation and the residue purified by chromatography eluting with DCM/MeOH (94:6) to give the title compound 111 mg, (29%) as a solid. NMR (CDCl3): 2.40 (s, 3H), 3.00 (s, 6H), 3.88 (s, 3H), 5.50 (d, 1H), 7.47 (s, 1H), 7.65 (d, 1H); m/z 194.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(OCC)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1OS(C)(=O)=O
Reaction time: 5 h
Yield: 71.6 %

Procedure:
(1S,2S)-2-tert-Butoxycarbonylamino-1-cyclohexanol (646 mg) was dissolved in pyridine (4 ml), methane-sulfonyl chloride (378 mg) was added with ice cooling, and the mixture was stirred for 5 hours. After diethyl ether was added to the reaction mixture and washed 5 times with water, the resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (630 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.O.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([F:17])[F:16])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
4-bromo-2-chlorophenol (1.0 g, 4.8 mmol) was dissolved in DMF (35 ml) and water (5 ml) was added followed by sodium chloro(difluoro)acetate (2.0 g, 12 mmol) and cesium carbonate (3.1 g, 9.6 mmol). The mixture was stirred for 15 minutes at room temperature and then heated to 100° C. for 2 hours under nitrogen. The mixture was partitioned between water (50 ml) and tBuOMe (50 ml). The organic phase was separated, washed brine, dried over sodium sulphate, filtered, and concentrated in vacuo to give a crude product. The crude product was purified by silica gel chromatography eluting with 0-30% EtOAc in heptanes to give a title compound (0.83 g, 67% yield) as colourless oil.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:30])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:34]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:9][CH2:10]2)[C:15]1=[O:30])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCI
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(CC2CCCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN1C(=O)N(C2CCN(CC3CCCCC3)CC2)C(c2ccccc2)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 100 mg (0.25 mmol) of 3-[1-(cyclohexylmethyl)piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 2 ml of DMF, 22 mg (0.55 mmol) of sodium hydride (60%) were added at room temperature and stirred at about 60° C. for one hour. After allowing the reaction mixture to stand cool, a solution of 69 mg (0.38 mmol) of 1-iodobutane in 1 ml of DMF was added thereto at room temperature and stirred at about 60° C. for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform—10% methanol/chloroform) to give 88 mg (0.19 mmol) of the title compound as colorless oil.