Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:16]=[N:17][C:18]([CH:21]=O)=[CH:19][CH:20]=4)[CH:11]=[C:10]([C:23]([NH:25][CH2:26][C:27]4[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=4[CH3:33])=[O:24])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:16]=[N:17][C:18]([CH2:21][N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[CH:19][CH:20]=4)[CH:11]=[C:10]([C:23]([NH:25][CH2:26][C:27]4[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=4[CH3:33])=[O:24])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)nc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-formylpyridin-3-yl)-1H-indazole-4-carboxamide (0.1 g, 0.212 mmol) in methanol (2 mL) was added acetic acid (0.013 g, 0.212 mmol) and morpholine (0.056 g, 0.636 mmol) and stirred it at room temperature for 3 h. Then NaBH3CN (0.014 g, 0.212 mmol) was added to it and the reaction mixture stirred at room temperature overnight. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give corresponding 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-(morpholinomethyl)pyridin-3-yl)-1H-indazole-4-carboxamide (0.049 g, 43.4%). LCMS: 541.30 (M+1)+; HPLC: 94.30% (@ 254 nm) (Rt; 5.379); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 8.98 (s, 1H), 8.62 (t, 1H, J=4.4&4.8 Hz), 8.39 (s, 1H), 8.21 (s, 2H), 7.90 (s, 1H), 7.56 (d, 1H, J=8.4 Hz), 5.88 (s, 1H), 5.35-5.31 (m, 1H), 4.39 (d, 2H, J=4.8 Hz), 3.65 (s, 2H), 3.60 (t, 4H, J=4&4.4 Hz), 2.44 (bs, 4H), 2.21 (s, 3H), 2.15 (bs, 2H), 2.11 (s, 3H), 2.05-1.98 (m, 2H), 1.89 (bs, 2H), 1.75-1.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([S:12][CH3:13])[C:3]=1[CH3:14].[CH3:15][C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17].[H-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:8])[CH2:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])=[C:4]([S:12][CH3:13])[C:3]=1[CH3:14]
Reactant: CC(=O)C1CC1
Reactant: COC(=O)c1ccc(Cl)c(C)c1SC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1c(C(=O)CC(=O)C2CC2)ccc(Cl)c1C
Yield: 84.5 %

Procedure:
A mixture of methyl 4-chloro-3-methyl-2-(methylsulphenyl)benzoate (19.5 g) and cyclopropyl methyl ketone (13.4 g) in dry tetrahydrofuran was added to a stirred heated suspension of sodium hydride (80% oil dispersion, 4.8 g) in dry tetrahydrofuran. The mixture was stirred and heated at reflux for 2 hours. It was cooled and hydrochloric acid (2 ml) was added. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with water, saturated aqueous sodium bicarbonate, water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 1-(4-chloro-3-methyl-2-methylsulphenylphenyl)-3-cyclopropylpropan-1,3-dione (20.19 g) as a yellow oil, NMR(CDCl3) 0.9(m,2H), 1.2 (m,2H), 1.7(m,1H), 2.3(s,3H), 2.65(s,3H), 5,85 (s,1H), 7.15(d,1H), 7.3(d,1H), 15.7-16.0(bs,1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH:25][C:26](=[O:28])[CH3:27])[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)=[O:6].[CH3:29]I>>[C:26]([N:25]([C:24]1[CH:23]=[CH:22][C:4]([C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH2:9][CH2:8]2)=[O:6])=[CH:3][C:2]=1[CH3:1])[CH3:29])(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1C
Reactant: CI
Product: CC(=O)N(C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1C

Procedure:
In a manner analogous to that described in Example 5, 5 g of 1-[3-methyl-4-(N-acetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine are methylated with 0.8 g of methyl iodide to form 1-[4-(N-acetyl-N-methylamino)-3-methylbenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine and converted into the hydrochloride having a melting point of 195°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.N12CCN(CC1)CC2.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[S:22].CCOCC>CN(C=O)C>[CH3:19][N:20]([CH3:24])[C:21](=[S:22])[O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CN(C)C(=S)Cl
Reactant: COc1cc(C)cc(O)c1
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(C)cc(OC(=S)N(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a mixture of 3-methoxy-5-methylphenol (7) (3.39 g, 24.5 mmol) and 1,4-diazabicyclo[2.2.2]octane (5.50 g, 49.0 mmol) in DMF (20 mL) was added dimethylthiocarbamoyl chloride (8) (6.06 g, 49.0 mmol) portionwise. The reaction mixture was stirred at room temperature overnight and 500 mL of ether was added. The organics were washed with water (150 mL), brine (2×50 mL), dried (Na2SO4), and concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 4:1) gave O-3-methoxy-5-methylphenyl dimethylcarbamothioate (9) (5.05 g, 91%) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=O)=[C:4]([N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)[CH:3]=1.[NH:21]1[C:28](=[O:29])[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[O:23]>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:6][C:27]3([CH:14]4[CH:15]([CH3:20])[O:16][CH:17]([CH3:19])[CH2:18][N:13]42)[C:25](=[O:26])[NH:24][C:22](=[O:23])[NH:21][C:28]3=[O:29])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: CC1CN(c2cc(Br)c([N+](=O)[O-])cc2C=O)CC(C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Product: CC1CN2c3cc(Br)c([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)C2C(C)O1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 39.2 %

Procedure:
A mixture of 4-bromo-2-(2,6-dimethylmorpholin-4-yl)-5-nitrobenzaldehyde (from Step 2) (989 mg, 2.88 mmol) and barbituric acid (369 mg, 2.88 mmol) in isopropanol (15 mL) is sealed in a 20 mL scintillation vial and shaken at 85° C. for 2.5 hours. The product is adsorbed onto silica gel and purified by silica gel chromatography using a gradient from 20% EtOAc in CH2Cl2 to 25% EtOAc in CH2Cl2 as eluent. Product is isolated and dried (20 Torr, 100° C.) to give 512 mg of yellow solid. 1H NMR (DMSO-d6) δ 11.90, 11.62, 7.79, 7.36, 4.32, 3.87, 3.47-3.63, 2.94, 2.81, 1.15, 0.94.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][N:25]=[C:24]([CH3:27])[C:23]=4[NH2:28])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][N:25]=[C:24]([CH3:27])[C:23]=4[NH:28][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:31]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH2:9]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CCC1
Reactant: Brc1cccc(-c2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5)n4)cc3)cc2)CCC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclobutanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyridine.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]([CH3:12])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:9][C:10]1([CH3:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)Oc2ccccc2O1
Reaction time: 24 h

Procedure:
A mixture of catechol (55 g, 0.5 moles), acetone (150 ml), benzene (150 ml) and p-toluenesulfonic acid (15 mg) was refluxed in a Soxlet extractor containing 140 g of baked 4Å molecular sieves for 24 hours, as described in E. R. Cole, et al., Aust. J. Chem. 33, 675 (1980). The sieves were replaced with fresh sieves and refluxing continued for another 24 hours. The solvents were removed in vacuo and the residue was triturated with 1 liter of hexane. The light yellow solution was decanted and washed with 10% NAOH until the washes were colorless. The organic layer was dried (Na2SO4) and evaporated to 32.4 g (43%) of title compound as an oil which was used without further purification. 1H-NMR(CDCl3): δ=1.73 (s,6H); 6.78 (s,4H).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[NH:22][C@@H:21]([C@@H](O)C)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C@H:18]2[N:22]3[C@@H:21]([C@H:9]([CH3:10])[O:8][C:1](=[O:7])[C:2]3=[O:4])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: C[C@H](O)[C@H]1CC[C@@H](c2ccc(Cl)cc2)N1
Reactant: CCOC(=O)C(=O)OCC
Product: C[C@@H]1OC(=O)C(=O)N2[C@@H]1CC[C@H]2c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Diethyl oxalate (5 mL) was added to (S)-1-[(2R,5S)-5-(4-chlorophenyl)pyrrolidine-2-yl]ethanol (570 mg). Stirring was continued for 2 hours at 120° C. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), and the title compound (470 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:23])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27]Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:11][N:10]3[CH2:27][CH2:26][CH2:25][O:23][C:9]=23)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2[nH]nc(O)c2-c2ccc(F)cc2)cc1
Reactant: BrCCCBr
Product: CS(=O)(=O)c1ccc(-c2nn3c(c2-c2ccc(F)cc2)OCCC3)cc1

Procedure:
Alternatively, the desired compound was prepared according to the method of Example 5D, starting with 4-(4-fluorophenyl)-3-hydroxy-5-(4-(methylsulphonyl)phenyl)-pyrazole and substituting 1,3-dibromopropane in place of 1,2-dibromo ethane (yield: 150 mg, 81%). MS (APCI+) m/z 373 (M+H)+; (APCI−) m/z 371 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ2.27 (m, 2H), 3.23 (s, 3H), 4.20 (t, J=7 Hz, 2H), 4.38 (d, J=7 Hz, 2H), 7.20 (m, 4H), 7.60 (d, J=9 Hz, 2H), 7.87 (d, J=9 Hz, 2H); Anal. calc. for C19H17FN2O3S; C, 61.27; H, 4.60; N, 7.52. Found: C, 60.93; H, 4.48; N, 7.34.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.Cl[CH2:11][CH2:12][N:13]([CH2:21][CH2:22]Cl)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:13]1[CH2:21][CH2:22][C:7]([C:8]#[N:9])([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:11][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccncc2)CC1

Procedure:
Prepare by the method of example 30.2 using 4-pyridylacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-butoxycarbonyl-ethanamine (11 mmol). Purify to give the title compound.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:19]([O:21]C)=[O:20])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:9]=1>C1COCC1.O>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[N:9]=1
Reactant: COC(=O)C1(c2ccc(-c3csc(N)n3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(-c2ccc(C3(C(=O)O)CC3)cc2)cs1

Procedure:
Lithium hydroxide monohydrate (0.24 g, 5.8 mmol) was added to a mixture of methyl 1-[4-(2-amino-1,3-thiazol-4-yl)phenyl]cyclopropanecarboxylate (0.2 g, 0.73 mmol) in THF (3.0 ml) and water (1.0 mL), and the resulting mixture was refluxed for 30 minutes. Then the reation mixture was concentrated and the residue was adjusted to be acidic (pH=˜3) by 1N HCl aqueous solution. The precipitate fromed was filtered and washed with water to afford the desired product. LC-MS: 261.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][C:8]=1[CH3:9].C([Mg]Cl)(C)C.[CH:16]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[C:30]1=[O:39])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([OH:38])([C:6]3[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[OH:10])[C:30]2=[O:39])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc(O)ccc1C
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Product: COc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 116.5 %

Procedure:
To a stirred solution of 3-methoxy-4-methylphenol (Jorgensen, E. C., et al., J. Med. Chem. (1971), 14:1199-202) (7.5 g, 54.3 mmol) in dichloromethane (160 mL) was added isopropylmagnesium chloride (29.0 mL, 2 M in tetrahydrofuran, 58 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min followed by the addition of 1-benzhydrylindoline-2,3-dione (10.4 g, 36.3 mmol). The reaction mixture was stirred at ambient temperature for 10 min and concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate (300 mL) and washed with saturated ammonium chloride solution (2×200 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one (19.10 g) as a crude brown oil: MS (ES−) m/z 450.3 (M−1).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.[C:18]([OH:22])(=[O:21])[CH2:19][SH:20]>C(O)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([S:20][CH2:19][C:18]([OH:22])=[O:21])[N:3]1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)CS
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Solvent: CC(=O)O
Product: O=C(O)CSC1c2ccccc2C(=O)N1Cc1cccs1
Yield: 83.2 %

Procedure:
To a solution of compound 12 (5.45 gm, 22.2 mmol) in acetic acid (50 mL) at room temperature was added thioglycolic acid (1.85 mL, 26.7 mmol) and the resulting reaction mixture was allowed to stir at reflux for 18 hours. The reaction mixture was concentrated in vacuo and triturated with ethyl ether to provide 5.9 gm of 15 as a white solid (7.08 gm theoretical, 83% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[CH3:13][NH2:14]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:14][CH3:13])=[O:8]
Reactant: CN
Reactant: O=C(Cl)/C=C/c1cccc(Br)c1
Solvent: c1ccccc1
Product: CNC(=O)/C=C/c1cccc(Br)c1

Procedure:
A solution of trans 3-bromocinnamoyl chloride (5 g) in dry benzene (100 ml) was added with stirring to an ethereal (200 ml) solution of methylamine (3 g). After the addition was complete, a slow stream of methylamine gas was bubbled through the reaction mixture at room temperature for 1 hour. Solvent and excess amine were removed under reduced pressure. The crude product was triturated with water, filtered, and recrystallized from ethanol-water to give trans 3-bromo-N-methylcinnamamide, m.p. 147°-147.5° C. NMR, IR, and elemental analysis were consistent with this structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([C@H:9]([C:11](=[O:38])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:31]3[CH:36]=[CH:35][C:34](Cl)=[CH:33][CH:32]=3)[C:18](=[O:30])[N:19]([C:23]3[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=3)[CH2:20][C:21]=2[N:22]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[C:1]([O:5][C:6](=[O:39])[N:7]([CH3:8])[C@H:9]([C:11](=[O:38])[NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:18](=[O:30])[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][C:21]=2[N:22]=1)[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](C(=O)Nc1ccc2c(n1)CN(c1ccc(Cl)cc1)C(=O)N2c1ccc(Cl)cc1)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)Nc1ccc2c(n1)CN(c1ccccc1)C(=O)N2c1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a solution of {(S)-1-[1,3-bis-(4-chloro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Example 21, product from Step 3) (100 mg, 0.18 mmol) in MeOH (10 mL) were added triethylamine (100 μL, 0.7 mmol, 4 equiv) and Pd/C (10%, 30 mg) and the mixture was hydrogenated overnight. The catalyst was filtered, the filtrate evaporated. The residue was dissolved in EtOAc and washed with H2O. The organic phase was dried (MgSO4), filtered and evaporated. The crude material was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-60%) to afford methyl-[(S)-1-(2-oxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrido[3,2-d]pyrimidin-6-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (35 mg). MS: [M+H]+=502.
Reaction SMILES: [OH:1][C:2]1[C:14](=[O:15])[N:6]2[CH2:7][CH:8]3[CH2:13][CH:12]([C:5]2=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][NH:10][CH2:9]3.C(N(C(C)C)CC)(C)C.[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C(Cl)Cl>[OH:1][C:2]1[C:14](=[O:15])[N:6]2[CH2:7][CH:8]3[CH2:13][CH:12]([C:5]2=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][N:10]([C:38]([O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:39])[CH2:9]3
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CNCC2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CC2CN(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
To ethyl 3-hydroxy-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,11-methanopyrimido[1,2-a][1,5]diazocine-2-carboxylate (0.26 g, 0.661 mmol) in CH2Cl2 (5 mL) was added diisopropylethylamine (0.576 mL, 3.31 mmol) and benzylchloroformate (0.102 mL, 0.727 mmol). The reaction mixture was stirred at 23° C. for 16 hours. HCl (1N, 15 mL) was then added to the reaction mixture and the organic material extracted with CH2Cl2 (3×15 mL) and ethyl acetate (3×15 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The organic material was purified by Silica gel column chromatography (Biotage flash chromatography system) eluting with gradient of ethyl acetate 100% to ethyl acetate methanol (1:9) to afford 0.036 g (13% yield) of the title compound. 1H NMR (400 MHz, MeOD) δ ppm 7.36 (5 H, s), 4.95-5.10 (2 H, m) 3.95-4.40 (2 H, br m), 2.75-3.30 (5 H, br m), 1.75-2.50 (4 H, m), 0.95-1.45 (4 H, m). LCMS (+ESI, M+H+) m/z: 414.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][NH:13][CH:14]([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([CH3:12])[CH:14]([CH3:16])[CH3:15])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: CNC(C)C
Reactant: O=C(O)c1ccc(Br)cc1F
Product: CC(C)N(C)C(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and N-methyl-2-propanamine.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[CH2:15](Br)[CH:16]=[CH2:17].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[CH2:17]([N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: C=CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and allyl bromide according to Method AC (after initial stirring at r.t. for 16 h, an additional 0.3 equivalent of sodium bis(trimethylsilyl)amide was added and the reaction mixture was stirred at 90° C. for 16 h) and was isolated as an amber oil (quantitative) that was used without further purification. LCMS (ES+) 235.0 (M+H)+, RT 3.09 minutes (Method 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:14]Br.S([O-])([O-])=O.[Na+].[Na+].O>C(O)(=O)C>[Br:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OC)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
2,4-Dimethoxybenzoic acid (30.0 g) was suspended in acetic acid (180 mL). A bromine (27.6 g)/acetic acid (60 mL) solution was slowly added dropwise to the suspension and, after completion of the dropwise addition, the mixture was stirred at 25° C. for 2 hrs, and the termination of the reaction was confirmed by HPLC. An aqueous solution of sodium sulfite (2.10 g) and water (360 mL) was added dropwise to the reaction mixture. After completion of the dropwise addition, the mixture was stirred at 25° C. for 1 hr. Precipitated crystals were collected by filtration, washed 4 times with water (150 mL), and vacuum dried to give 5-bromo-2,4-dimethoxybenzoic acid as white crystals (41.2 g, 96%).
Reaction SMILES: [NH2:1][CH:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[CH:10](OC)=[O:11]>>[CH:10]([NH:1][CH:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:11]
Reactant: CSCCC(N)C(N)=O
Reactant: COC=O
Product: CSCCC(NC=O)C(N)=O
Yield: 55 %

Procedure:
30 g (0.20 mole) DL-methionine amide were agitated with 250 ml methyl formate for two days at room temperature, during which fine, slightly yellow crystals developed. They were filtered off and recrystallized out of a mixture of 150 ml hexane and 160 ml ethanol. After cooling off, filtering, washing and drying, 23 g (55%) Nα -formyl-DL-methionine amide were obtained in the form of colorless crystals with a melting point of 121-122° C.
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:20][CH:21]([F:25])[C:22](F)=[O:23]>C1(C)C=CC=CC=1>[F:20][CH:21]([F:25])[C:22](=[O:23])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=CN1CCCCC1
Reactant: O=C(F)C(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Methyl 3-piperidin-1-ylacrylate (96.7%, 50.7 g, 289 mmol) and triethylamine (31.07 g, 307 mol) were initially charged in toluene (300 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (30.1 g 307 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (150 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. This gave methyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 69.7 g; purity according to GC: 92.3%; yield: 90%). 1H-NMR (CDCl3): δ=1.75 (m, 6H), 3.3 (m, 2H), 3.62 (m, 2H), 3.75 (s, 3H), 6.62 (t, 1H), 7.89 ppm (s, 1H).