Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]=[C:5]([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3]1.[CH2:16]([Mg]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)C1C=CC=CC=1.[Mg]>C(OCC)C>[CH2:16]([C:5]1([CH3:9])[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][N:2]([CH3:1])[C:7](=[O:8])[NH:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Cc1nc(=O)n(C)nc1-c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Solvent: ClCc1ccccc1
Product: CN1N=C(c2ccccc2)C(C)(Cc2ccccc2)NC1=O

Procedure:
2,5-Dimethyl-6-phenyl-1,2,4-triazin-3(2H)-one (3.2 g) was added to a stirred solution of benzylmagnesium chloride prepared from benzyl chloride (9.99 g) and magnesium turnings (1.92 g) in diethyl ether (48 ml) at room temperature. The reaction mixture was treated in a similar manner to that of Example 30 to give 5-benzyl-2,5-dimethyl-6-phenyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.6 g), m.p. 174.2°~175.3° C. recrystallized from a mixture of chloroform and diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[C:25]([O:28][CH2:29][C:30](Cl)=O)(=[O:27])[CH3:26]>O1CCCC1>[C:25]([O:28][CH2:29][C:30]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:24])[C:10]2[N:11]=[C:12]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:13][C:14]=2[C:15](=[O:16])[N:17]=1)(=[O:27])[CH3:26]
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)OCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (200 mg, 0.545 mmol) in Tetrahydrofuran (THF) (2726 μl) at 0° C. was added acetoxyacetyl chloride (117 μl, 1.090 mmol). The mixture was stirred at 50° C. for 3 h, then quenched with methanol and concentrated. The residue was subjected to silica gel chromatography (0-5% methanol/dichloromethane) followed by reversed-phase HPLC purification to provide [4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-7-oxo-4,7-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl]methyl acetate. (49 mg, 20%); LC/MS: MS (ES+) m/e 449 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (s, 3H), 2.42 (s, 3H), 3.52 (m, 4H), 3.67 (m, 4H), 5.03 (s, 2H), 5.50 (s, 2H), 6.54 (d, J=7.6 Hz, 1H), 7.17 (m, 1H), 7.39 (d, J=7.8 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[OH-].[Na+]>O1CCOCC1.C(O)C>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[C:4]([CH:9]=1)[C:3]([OH:19])=[O:2])(=[O:11])=[O:12]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1-c1nccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Yield: 50 %

Procedure:
5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid is prepared by saponification of 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid methyl ester in the presence of sodium hydroxide (2N) in a mixture of dioxane and ethanol at 80 deg for 30 minutes. Brow solid, 50% yield, MS (m/e): 282.2 (M−H, 100%)
Reaction SMILES: I[C:2]1[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH3:17])[CH:9]=2)[CH:6]=1.[F:22][C:23]([F:35])([F:34])[C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])I.CN(C=O)C>C1(C)C=CC=CC=1.[Cu]>[CH3:17][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[CH2:7][N:5]1[CH:6]=[C:2]([C:26]([F:29])([F:28])[C:25]([F:30])([F:31])[C:24]([F:32])([F:33])[C:23]([F:35])([F:34])[F:22])[C:3]([C:18]([F:21])([F:20])[F:19])=[N:4]1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Cc1cc(Cn2cc(I)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Agent: [Cu]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Temperature: 132.5 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrobenzyl)-3-trifluoromethyl-1H-pyrazole (2.47 g), copper powder (1.14 g), nonafluoro-1-iodobutane (4.15 g) and DMF (16 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 130-135° C. After cooling to room temperature, the reaction mixture was diluted with toluene (50 ml) and an insoluble matter was filtered with Celite and washed with toluene. The filtrate was concentrated under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-nonafluorobutyl-3-trifluoromethyl-1H-pyrazole (1.50 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[O:30])[CH2:25][CH2:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:34]3[CH:33]=[CH:32][C:31]([C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[O:30])=[CH:36][CH:35]=3)=[N:7][C:6]1=2
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(n3)N(Cc3c(F)ccc(F)c3Cl)CCN4)cc2)CC1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 4-(4-Methylpiperazine-1-carbonyl)phenylboronic acid pinacol ester using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:18])/[CH2:11][CH2:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[CH:3]\[C:4]([NH2:6])=[O:5].S[CH2:20][CH2:21][OH:22].C(N(CC)CC)C>CO>[OH:22][CH2:21][CH2:20][CH2:15][CH:14]([CH3:16])[C:13](=[O:17])[CH2:12][CH2:11]/[C:10](/[CH3:18])=[CH:9]/[CH2:8][CH2:7]/[C:2](/[CH3:1])=[CH:3]/[C:4]([NH2:6])=[O:5]
Reactant: OCCS
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=C\C(N)=O)CC/C=C(\C)CCC(=O)C(C)CCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.1 g (0.016 mol) of (E,E)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienamide in 125 ml of methanol is treated with 3.5 ml of 2-mercaptoethanol and 7 ml of triethylamine. The solution is stirred at room temperature for 18 hours. After removing the solvent the residue is taken up three times in toluene and freed from solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-methanol 10:1. There is obtained (2E,6E)-12-(2-hydroxyethyl)-3,7,11-trimethyl-10-oxo-2,6-dodecadienamide which exhibits the following absorption bands in the IR spectrum: 3340 cm-1, 3201 cm-1, 2924 cm-1, 1707 cm-1, 1669 cm-1, 1608 cm-1, 1409 cm-1, 1369 cm-1, 1305 cm-1, 1046 cm-1, 1012 cm-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=[CH:14]2.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=[CH:14]3)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)ccc21
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ccc2cc(-c3ccncc3)ccc21
Yield: 216.6 %

Procedure:
A mixture of pyridine-4-boronic acid (5.0 g, 0.041 mol), tert-butyl 5-bromo-indole-1-carboxylate (11.8 g, 0.04 mol), 2 M aqueous sodium carbonate (80 mL, 0.16 mol), tetrakis(triphenylphosphine)palladium(0) (0.92 g, 0.0008 mol), ethanol (19 mL) and toluene (175 mL) was boiled under reflux for 12 h. The experiment was repeated with the double amount of starting materials, e.g. 10 g of pyridine-4-boronic acid. The combined reaction mixture from the two experiments was poured onto a saturated sodium chloride solution (brine), and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate followed by ethyl acetate/triethylamine 95:5) to give tert-butyl 5-pyridin-4-yl-indole-1-carboxylate (25.5 g, 61%), which was dissolved in a mixture of methanol (500 mL), tetrahydrofuran (200 mL) and 15% aqueous sodium hydroxide (25 mL). The mixture was boiled under reflux for 1 h, concentrate in vacuo to 200 mL and poured onto brine. The aqueous phase was extracted with a mixture of ethyl acetate and tetrahydrofuran, and the combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was precipitated from a cold mixture of methanol and tetrahydrofuran to give the title compound as a creamy solid (9.5 g, 54%). A second crop of the title compound was obtained from the mother liquor (1.7 g, 9%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][C@H:29]([CH3:35])[CH2:30][NH:31][C:32](=[O:34])[CH3:33])[N:21]=[CH:20][N:19]=2)=[CH:13][C:12]=1[CH3:36]>>[F:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][C@H:29]([CH3:35])[CH2:30][NH:31][C:32](=[O:34])[CH3:33])[N:21]=[CH:20][N:19]=2)=[CH:13][C:12]=1[CH3:36]
Reactant: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: Fc1cccc(CCl)c1
Product: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(C)c3)c12
Yield: 46 %

Procedure:
The procedure described in Example 3 was repeated using 1-(chloromethyl)-3-fluorobenzene and N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide (obtained as described in Example 86, preparation of starting materials) to give the title compound as a white solid in 46% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.77 (s, 3H), 2.26 (s, 3H), 3.41 (dt, 1H), 3.58 (dt, 1H), 4.86 (m, 1H), 5.18 (s, 2H), 7.01 (d, 1H), 7.16 (td, 1H), 7.22 (d, 1H), 7.30 (m, 3H), 7.42 (m, 1H), 7.54 (d, 1H), 7.62 (dd, 1H), 7.68 (t, 1H), 8.22 (t, 1H), 8.43 (s, 1H), 9.95 (s, 1H); Mass spectrum MH+ 475.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH2:10][NH:11][CH3:12].[OH-].[Na+]>C(Cl)Cl>[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH2:10][N:11]([CH3:12])[C:1](=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CNCC(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=C(C)C(=O)N(C)CC(OC)OC

Procedure:
Using the above procedure, a methacrylamide monomer was prepared from 23.23 g methacryloyl chloride, 24.53 g N-methylaminoacetaldehyde dimethyl acetal, 42 g NaOH (20% aqueous solution), and 90 ml methylene chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](I)[CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([Br:24])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Brc1cccc(I)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1cccc(Br)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1-bromo-3-iodobenzene in analogy to Example 1a): MS (ISP): 460.1 (M+H)+ and 359.9 ((M-Boc)+H)+ (100%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:12])[N:4]=1.[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22]O)=[CH:19][CH:18]=1)[CH3:15]>Cl>[CH3:13][N:14]([CH2:16][C:17]1[O:21][C:20]([CH2:22][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:12])[N:6]=2)=[CH:19][CH:18]=1)[CH3:15]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: CNC1=NS(=O)N=C1NCCS
Agent: Cl
Product: CNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
When 3-methylamino-4-(2-mercaptoethylamino)-1,2,5-thiadiazole 1-oxide [prepared in Step A] is treated with about one equivalent of 5-dimethylaminomethyl-2-furan-methanol in concentrated hydrochloric acid according to the procedure described in Example 25, Step B, the title compound is thereby produced; identical to the product of Example 18.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:3]=1.O.[NH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:5]=[C:6]([NH2:22])[C:7]=1[O:8][CH3:9]
Reactant: N
Reactant: COc1c(Cl)nc(-c2ccc(Cl)c(OC)c2F)nc1Cl
Solvent: O
Product: COc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1Cl
Temperature: 125 °C
Yield: 88 %

Procedure:
4,6-Dichloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxy-pyrimidine (500 mg, 1.5 mmol) was suspended in ammonia saturated ethanol (10 mL) and heated in a CEM microwave at 125° C. for 30 min. The mixture was poured into 15 mL water and extracted with ethyl acetate thrice. The combined organic phases were washed once with brine, dried and evaporated to give the title compound (420 mg, 88% yield: 1H NMR (DMSO-d6) δ 7.59 (dd, 1H), 7.45 (br s, 2H), 7.39 (dd, 1H), 3.91 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:18]([C:17]3[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=3[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc2c(c1)CNCC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(Cl)cc2C1

Procedure:
Prepared in analogy to example 1.1 from 7-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [82771-60-6]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.[CH3:24][N:25]1[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]1.C([BH3-])#N.[Na+]>CC(O)=O.CO>[CH3:20][C:16]1([CH3:21])[NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:1][CH2:30][C:29]5[N:25]([CH3:24])[CH:26]=[N:27][CH:28]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(N)cc43)sc2C(=O)N1
Reactant: Cn1cncc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cncc1CNc1ccc2c(c1)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
To a stirred solution of Example 42 (0.03 g, 0.10 mmol) in 5% AcOH in MeOH (1 mL) was added 1-methyl-5-imidazolecarboxaldehyde (0.01 g, 0.14 mmol). The reaction mixture was stirred at r.t. for 20 minutes. Sodium cyanoborohydride (0.02 g, 0.39 mmol) was then added, and the reaction mixture stirred for a further 10 minutes before being concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.01 g, 32%) as a yellow oil. δH (CDCl3) 8.28 (1H, s), 8.17 (1H, s), 7.22 (1H, s), 7.17 (1H, d, J 2.6 Hz), 6.82 (1H, d, J 8.7 Hz), 6.47 (1H, dd, J 8.9 and 2.8 Hz), 5.82 (1H, s), 4.34 (2H, s), 4.29-4.22 (2H, m), 4.19-4.11 (2H, m), 3.86 (3H, s), 2.86 (2H, s), 1.39 (6H, s). LCMS (ES+) 425.42 (M+H)+, RT 1.85 minutes (Method 1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[O:8].CC(=CC)C.Cl([O-])=[O:15].[Na+].P([O-])(O)(O)=O.[Na+].Cl>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:15])=[O:8]
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1occc1Br
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1occc1Br
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 3-bromofuran-2-carbaldehyde (25.0 g) and 2-methyl-2-butene (45.4 mL) in tert-butanol (250 mL) was added dropwise a solution of 80% sodium chlorite (40.5 g) and sodium dihydrogen phosphate (51.5 g) in water (350 mL) at room temperature, and the mixture was stirred overnight. To the reaction mixture was added 1M hydrochloric acid (300 ml), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (5/1) and recrystallized from hexane/ethyl acetate to give the title compound (20.3 g). 1H NMR (300 MHz, CDCl3) δ 6.66 (1H, d, J=1.9 Hz), 7.58 (1H, d, J=1.9 Hz).
Reaction SMILES: [NH2:1][C@:2]1([CH2:9][C:10]#[C:11][C:12]2[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:13]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]>CC#N.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:7][N:4]1[CH2:5][CH2:6][C@@:2]2([N:1]=[C:11]([C:12]3[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)[N:13]=3)[CH2:10][CH2:9]2)[C:3]1=[O:8]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@@]2(N)CCN(C)C2=O)n1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C2=N[C@]3(CC2)CCN(C)C3=O)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 105 %

Procedure:
Silver trifluoromethanesulphonate (22.69 mg, 0.09 mmol) was added to a solution of (3R)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (which may be prepared as described in Description 14) (343 mg, 0.88 mmol) in MeCN (20 mL) at 20° C. and the reaction was stirred for 18 hrs. The reaction was heated to 40° C. and stirring was continued for 3 days. Additional AgOTf (10 mol %) was added and stirring was continued at 40° C. for 18 hrs. The solvent was evaporated and the residue was purified using a Biotage Isolera with a 25 g SNAP cartridge, eluting with 0 to 100% (mixture of 1% of 2M NH3 in MeOH; 9% MeOH; 90% EtOAc)/EtOAc affording (5R)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one (D15) (359 mg, 0.924 mmol) as a light brown solid with a few % of impurities present. 300 MHz NMR δH (CDCl3) 1.89-2.00 (1H, m), 2.16-2.25 (1H, m), 2.59-2.72 (2H, m), 2.72 (3H, s), 2.92 (3H, s), 3.30-3.45 (2H, m), 3.55-3.78 (2H, m), 7.64 (1H, s), 7.79 (2H, d), 8.26 (2H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1.[OH-].[Na+]>CO>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:9]/[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
A mixture of 1-(4-chloro-2-phenylaminophenyl)-ethanone (1.7 g, 6.9 mmol), 4-formyl-benzoic acid methyl ester (1.14 g, 6.9 mmol) and NaOH (2 M aq, 2 mL) in MeOH (30 mL) was stirred at RT overnight. The precipitate formed was collected by filtration and dried in a vacuum oven to afford 0.7 g of 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-benzoic acid methyl ester as an orange solid. The mother liquors were acidified by adding glacial HOAc (99%) to pH 5, and the resulting mixture extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to yield 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-benzoic acid (350 mg).
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]>CO>[OH:3][C:4]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: Cc1ccccc1Sc1cccc(C=O)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1Sc1cccc(CO)c1O
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
Sodium borohydride (850 mg) was added slowly to a suspension of 2-hydroxy-3-(o-tolylthio)benzaldehyde (11 g) in methanol (50 ml) at temperature below 15° C., and the mixture was stirred at the same temperature for 15 minutes and then at room temperature for 30 minutes. Methanol was distilled off from the reaction mixture under reduced pressure, and the residue was dissolved in water, acidified with conc. hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated under reduced pressure. The residue was crystallized with aqueous ethanol to give 2-hydroxy-3-(o-tolylthio)benzyl alcohol (8.45 g), mp. 75°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[CH:8]1.[C:19](Cl)(=[O:23])[C:20]([Cl:22])=[O:21]>COC(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[C:9]([C:19](=[O:23])[C:20]([Cl:22])=[O:21])=[CH:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(Cn2ccc3cccnc32)c1
Solvent: COC(C)(C)C
Product: COc1cccc(Cn2cc(C(=O)C(=O)Cl)c3cccnc32)c1

Procedure:
1-(3-Methoxybenzyl)-7-azaindole (3.57 g, 15 mmoles) is dissolved in 50 mL of t-butyl methyl ether. A solution of 1.54 mL of oxalyl chloride (18 mmoles) in 10 mL of t-butyl methyl ether is added dropwise at 0° C. with stirring. Subsequently, the mixture is refluxed for 2 hours, after which the solvent is distilled off under vacuum. The resulting 1-(3-methoxybenzyl)-7-azaindole-3-yl-glyoxylic acid chloride is obtained as a solid residue, which is suspended in 50 mL of tetrahydrofuran (THF).
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[K+].[C:9](#[N:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)Cl>COCCOC.O>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[C:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: CSCS(C)=O
Reactant: N#Cc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CSC(=C(N)c1ccccc1)S(C)=O
Temperature: 25 °C
Yield: 69 %

Procedure:
1.753 Grams of methyl methylthiomethyl sulfoxide was dissolved in 20 ml of 1,2-dimethoxyethane, and to the solution 580 mg of potassium hydride was added under cooling with ice, and the system was stirred for one and half hours at room temperature. Upon addition of 1.460g of benzonitrile and subsequent stirring for 15 hours at room temperature and for one hour at 50° C., the system was added with 70 ml of methylene chloride and 2 ml of water, followed by stirring for one hour at room temperature. The mixture was dried with Glauber's salt, and filtrated. The filtrate was concentrated under reduced pressure and the resulting yellow solid was crystallized from methylene chloride-carbon tetrachloride-cyclohexane to obtain 2.208g of 1-methylsulfinyl-1-methylthio-2-amino-2-phenylethylene. The isolation yield was 69%.