Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH2:9][NH:8]2)=[CH:4][CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:17][S:18]([N:8]1[CH2:9][C:10](=[O:14])[NH:11][C:12](=[O:13])[N:7]1[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CNN(Cc2ccc(Cl)cc2)C(=O)N1
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CC(=O)NC(=O)N1Cc1ccc(Cl)cc1
Yield: 60.3 %

Procedure:
Into a 50 ml round bottomed flask equipped with a calcium chloride drying tube and a magnetic stirrer were placed 5 ml of dry pyridine and 1 g of 2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5 dione. The mixture was then stirred and cooled in an ice bath, 0.5 g of methanesulfonyl chloride was added dropwise. After the product had been added the mixture was brought to ambient temperature and stirred for 5 hours. The solvent was then removed in vacuum and the residue was neutralized with dilute hydrochloric acid. The crystals obtained were filtered off and recrystallized from alcohol to yield 0.8 g of 1-methane sulfonyl-2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 145°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:35][C@H:36]3[CH2:45][O:44][C@H:43]4[C@@H:38]([O:39][CH:40]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[O:41][CH2:42]4)[CH2:37]3)=[N:24][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:35][C@H:36]3[CH2:45][O:44][C@H:43]4[C@@H:38]([O:39][CH:40]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[O:41][CH2:42]4)[CH2:37]3)=[N:24][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@@H]6COC(c7ccccc7)O[C@H]6C5)n(COCC[Si](C)(C)C)c4cc3Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(-c3ccc(-c4ccc(C(=O)O)cc4)cc3)c(Cl)cc21
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a stirred solution of methyl 4′-(6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano-[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxylate (474 mg, 0.651 mmol) in THF (5.2 mL) under nitrogen was added a 2.5N aqueous solution of NaOH (5.2 mL, 10.4 mmol). The mixture was allowed to stir at 40° C. for 24 hours. The mixture was then cooled to room temperature and diluted with water (40 mL). The mixture was acidified with 1N aqueous HCl and extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound as a yellow solid. LC-MS: calculated for C38H40ClN3O7Si 713.23, observed m/e: 714.21 (M+H)+ (Rt 2.85/4 min).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: NCc1ccccc1
Product: N#Cc1c(NCc2ccccc2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 407 mg (3.80 mmol) of benzylamine to give 43 mg (35% of theory) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:5]=1[O:30][CH3:31])(=[O:3])[CH3:2]>[Ni].O1CCCC1>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[NH2:19])=[C:6]([CH2:24][CH2:25][C:26]([F:28])([F:27])[F:29])[C:5]=1[O:30][CH3:31])(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)ccc(OCCCOc2cccc([N+](=O)[O-])c2)c1CCC(F)(F)F
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1c(C(C)=O)ccc(OCCCOc2cccc(N)c2)c1CCC(F)(F)F

Procedure:
2.0 g of Raney nickel are added to a solution of 10 g of 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]propoxy}-nitrobenzene in 100 ml of tetrahydrofuran and the starting substance is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. Evaporation of the filtrate under reduced pressure gives 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]propoxy}-aniline as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(CC)CC>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2]
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(C(F)(F)F)cn2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A degassed (argon) solution of 152 mg (0.50 mmol) 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid ethyl ester (example 13A]), 124 mg (0.55 mmol) 2-bromo-5-(trifluoromethyl)pyridine and 0.21 ml (1.5 mmol) Et3N in 5 ml acetonitrile was treated with 18 mg (0.03 mmol) of PdCl2(PPh3)2 and 3 mg (0.03 mmol) of CuI. After stirring for 3 h at room temperature the reaction mixture was partitioned between cold aqueous 10% KHSO4 and ether (three times). Washing of the organic layer with aqueous 10% NaCl solution, drying (Na2SO4) and evaporation of the solvents, followed by flash chromatography (SiO2, n-heptane/EtOAc 95:5 to 9:1) yielded 170 mg of the title compound as yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][N:25]=1)[CH3:22].[Cl-].[Li+]>O1CCOCC1.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:21][CH3:22])=[N:25][CH:26]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Reactant: CCOc1ccc([Sn](C)(C)C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCOc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (VP4) (5.00 g, 14.8 mmol) was mixed with 2-ethoxy-5-trimethylstannylpyridine (VP8) (5.06 g, 17.8 mmol), Pd(PPh3)4 (0.68 g, 0.59 mmol) and lithium chloride (0.12 g, 2.9 mmol) in dioxane (40 ml) and the mixture was refluxed under nitrogen (7 hours). After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-ethoxypyridin-5-yl)phenyl]oxazoline was obtained, 3.86 g, m.p. 119° C.; 1H NMR (CDCl3, ppm): 1.42, 4.35, OCH2CH3; 4.40, 4.84, 5.51, oxazoline; 6.79, 7.77, 8.36, pyridine; 7.00, 7.41, 7.54, phenyl.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:23]1[CH:24]=[CH:25][C:20]([NH:19][N:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=3)[CH2:16]2)=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc3c(c2)CN(Nc2ccncc2)CC3)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc2c(c1)CN(Nc1ccncc1)CC2
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A mixture of 7-benzyloxy-2-(4-pyridinylamino)-1,2,3,4-tetrahydroisoquinoline (5.68 g) and 5% palladium-on-carbon (1.1 g) in methanol (85 mL) was shaken on a parr hydrogenation apparatus at ambient temperature, starting at an initial pressure of 55 psi. After 2 hrs an additional 1.1 g of catalyst was added, the pressure was increased to 55 psi, and the mixture was shaken for an additional 5 hrs. An additional 0.75 g of catalyst was added, the pressure was increased to 55 psi, and the mixture was shaken until hydrogen uptake ceased. The reaction mixture was filtered through a pad of Celite, and the pad was washed with methanol. Concentration of the filtrate gave 3.4 g (82%) of product. Recrystallization from ethanol gave the analytical sample, mp 236-239° C. (dec).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH:8]([CH2:12][C:13]([OH:15])=O)[C:9](O)=[O:10])[CH:6]=1.[NH2:16]C(N)=O>O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH:8]2[CH2:12][C:13](=[O:15])[NH:16][C:9]2=[O:10])[CH:6]=1
Reactant: NC(N)=O
Reactant: O=C(O)CC(Cn1cc(I)cn1)C(=O)O
Solvent: O
Product: O=C1CC(Cn2cc(I)cn2)C(=O)N1
Temperature: 25 °C

Procedure:
The solution of 2-((4-iodo-1H-pyrazol-1-yl)methyl)succinic acid (170 mg, 0.52 mmol) and urea (72 mg, 1.50 mmol) was stirred neat at 130° C. for 12 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-((4-iodo-1H-pyrazol-1-yl)methyl)pyrrolidine-2,5-dione. MS ESI calc'd. for C8H9IN3O2 [M+H]+ 306. found 306. 1H NMR (400 MHz, CD3OD) δ 7.70 (s, 1H), 7.50 (s, 1H), 4.62-4.43 (m, 2H), 3.48-3.37 (m, 1H), 2.85-2.68 (m, 1H), 2.61-2.49 (m, 1H).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[C:8]1(=[O:18])[O:13][C:11](=O)[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[O:18]=[C:8]1[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)/[C:11](=[CH:2]/[C:1]([OH:4])=[O:3])/[O:13]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)/C=C1\OC(=O)c2ccccc21
Temperature: 30 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To 402 ml (4.26 moles) of acetic anhydride was added 150.0 g (1.01 moles) of phthalic anhydride and 124 g (1.26 moles) of potassium acetate in a 2 liter 3 neck flask. The resulting slurry was heated to 130°-135° C. for 1 hour and 20 minutes then cooled to 75°-80° C. and 1500 ml of toluene were added. The slurry was allowed to cool to 30° C. and granulate for 1 hour. The solids were recovered by filtration, washed with 300 ml of methylene chloride and air dried. The dried solids were repulped in 1500 ml H2O at 20°-25° C., allowed to granulate for 1 hour and oven dried at 50° C. overnight with an air bleed to give a yield of 52% (100.0 g) of the title compound: mp 245-250° C.;
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[OH:37][CH2:38][CH2:39][CH2:40]C(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([CH2:40][CH2:39][CH2:38][OH:37])[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)CCCO
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(CCCO)ccc3c1)n2C1CCCCC1
Yield: 90 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 5-hydroxy-pentan-2-one (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (96 mg, 90% yield). MS: 430.23 (M+H+); HPLC Procedure A, retention time=6.84 min, 82.48% purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:28][C:25]1[CH:26]=[N:27][C:22]([CH2:21][N:19]([CH3:20])[CH3:18])=[CH:23][CH:24]=1
Reactant: CN(C)Cc1ccc(N)cn1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Yield: 8.2 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (330 mg, 1.06 mmol) was reacted with 6-[(dimethylamino)methyl]pyridin-3-amine (200 mg, 1.32 mmol) to afford the desired product (37 mg, 8%) as an orange oil: ESI MS m/z 425 [C21H21BrN4O+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[NH:22]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:23][C:24](O)=[O:25].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:8]([O:7][C:5](=[O:6])[C@@H:4]([NH:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH2:3][NH:2][C:24](=[O:25])[CH2:23][NH:22][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)CNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
Amine 1-5 (0.42 g, 1.25 mmol), Cbz—Gly—OH (288 mg, 1.38 mmol), NMM (0.55 mL, 5.0 mmol) and BOP (829 mg, 1.88 mmol) were combined in 6 mL DMF. After stirring overnight the solvent was evaporated, the residue was taken up in EtOAc, the organic solution was washed with water (2×), 5% KHSO4, sat. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 60% EtOAc/hexane) provided 5-6 as a white glass.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[CH:12](I)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:12]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11])([CH3:14])[CH3:13]
Reactant: CC(C)I
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OC(C)C)c(C)c1
Yield: 74.2 %

Procedure:
A mixture of 1-(4-hydroxy-3-methyl-phenyl)-ethanone 10 g, isopropyl iodide 13.6 g, potassium carbonate 18.4 g and acetone 250 ml was stirred with heating under reflux for twelve hours. The reaction mixture was filtered and the resulting filtrate was concentrated under reduced pressure, and the resulting residue was subjected to a silica gel column chromatography to give 1-(4-isopropoxy-3-methyl-phenyl)-ethanone 9.5 g.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.O=C[C:24]([Cl:27])([Cl:26])[Cl:25].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]([C@@H:10]1[O:15][CH:6]([C:24]([Cl:27])([Cl:26])[Cl:25])[NH:8][C@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1OC(C(Cl)(Cl)Cl)N[C@H]1c1ccccc1
Temperature: 20 °C
Yield: 91 %

Procedure:
A solution of 3.0 g of methyl (2R,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-3-phenylpropionate, of 5 cm3 of chloral and of 0.05 g of pyridinium p-toluenesulphonate in 40 cm3 of anhydrous toluene is heated at reflux with distillation of the solvent. 15 cm3 of solvent are distilled and then 5 cm3 of chloral and 0.05 g of pyridinium p-toluenesulphonate are added. 20 cm3 of solvent are distilled and then 5 cm3 of chloral as well as 30 cm3 of anhydrous toluene are added. 25 cm3 of solvent are distilled and 5 cm3 of chloral and 35 cm3 of anhydrous toluene are added. 25 cm3 of solvent are distilled and then the solution is cooled to a temperature in the region of 20° C. The organic solution is washed with water (2 times 50 cm3), dried over sodium sulphate and concentrated to dryness under reduced pressure at approximately 50° C. The residue obtained is purified by liquid chromatography on silica gel, the eluent being an ethyl acetate/cyclohexane (1/3 by volume) mixture. There are thus obtained, with a yield of 91%, 3.0 g of (4S,5R)-5-methoxycarbonyl-4-phenyl-2-trichloromethyl-1,3-oxazolidine whose characteristics are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([OH:26])=O)[NH:13][C:12]43[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:34][N:35]1[C:39]([CH2:40][NH2:41])=[CH:38][N:37]=[CH:36]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:41][CH2:40][C:39]4[N:35]([CH3:34])[CH:36]=[N:37][CH:38]=4)=[O:26])[NH:13][C:12]43[CH2:31][CH2:30][C:29]([CH3:32])([CH3:33])[CH2:28][CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cn1cncc1CN
Reactant: CC1(C)CCC2(CC1)N[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Product: Cn1cncc1CNC(=O)[C@@H]1NC2(CCC(C)(C)CC2)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1ccnc(Cl)c1F
Yield: 39.6 %

Procedure:
The compound (400 mg, 0.81 mmol) obtained in Step 1 of Example 17 and 1-(1-methyl-1H-imidazole-5-yl)methanamine (95 mg, 0.98 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 12 to give 188 mg (41%) of the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (0.300 g, 0.77 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.219 g, 1.0 mmol) according to the general procedure VI. Obtained as a white foam (0.15 g, 48%). MS (ISP) 406.2 [(M+H)+]; mp 68-90° C.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[C:13]3[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[O:35])[CH:30]=[CH:31][CH:32]=2)O1>>[CH3:18][N:14]1[CH:15]=[CH:16][N:17]=[C:13]1/[CH:12]=[CH:11]/[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:31]3[CH:30]=[C:29]([NH:33][C:34]([NH:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[O:35])[CH:28]=[CH:27][CH:32]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Cn1ccnc1/C=C/c1ccn2c(I)cnc2c1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Product: Cn1ccnc1/C=C/c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1

Procedure:
1-(3-{7-[(E)-2-(1-Methyl-1H-imidazol-2-yl)-vinyl]imidazo[1,2-a]pyridin-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (86 mg) was prepared according to Procedure B3d using 3-Iodo-7-[(E)-2-(1-methyl-1H-imidazol-2-yl)-vinyl]imidazo[1,2-a]pyridine (170 mg, 0.49 mmol) and 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea. 1H NMR (400 MHz, Me-d3-OD): 8.74 (1H, d), 8.01 (3H, d), 7.77-7.66 (2H, m), 7.64-7.50 (4H, m), 7.45-7.32 (2H, m), 4.04 (3H, s), 4.01-3.89 (2H, m). MS: [M+H]+441
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]([O:11]CC)=O)[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[CH3:17][NH2:18]>ClCCl.O>[CH3:17][N:18]1[C:9](=[O:11])[CH2:8][N:7]2[N:6]=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[C:3]2[CH2:2]1
Reactant: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CCl
Reactant: CN
Solvent: ClCCl
Solvent: O
Product: CN1Cc2cc([N+](=O)[O-])nn2CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of 313b (1.0 g, 4.0 mmol) in dichloromethane (30 mL) was added a solution of CH3NH2 (1.07 g, 12.0 mmol, 35% in methanol). This reaction mixture was stirred at room temperature for 3 h and diluted with water (30 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residual was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 313c (450 mg, 57%) as a yellow solid. MS-ESI: [M+H]+ 196.9
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([C:17]2[CH:18]=[N:19][C:20](S(CCC)(=O)=O)=[N:21][CH:22]=2)[CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:20]1[N:21]=[CH:22][C:17]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=2[O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:18][N:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCS(=O)(=O)c1ncc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cn1
Reactant: NCc1ccccc1
Product: O=C(O)COc1ccc(Cl)cc1-c1cnc(NCc2ccccc2)nc1

Procedure:
The title compound was prepared from the product of example 20 step (iv) and benzylamine by the method of example 20 step (v).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](Cl)([OH:12])[C:6](O)=[C:5]2Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20].Cl.O1CCOCC1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[NH:20][C:19]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:17]([Cl:16])[CH:18]=1
Reactant: OC1=C(Cl)c2cc(F)ccc2NC1(O)Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cc(F)ccc2n1
Yield: 47.4 %

Procedure:
Prepared using general procedure 1; 6-Fluoro-2,4-dichloroquinolinediol (2.5 g, 13.95 mmol), 3,4-dichloroaniline (4.5 g, 27.91 mmol), 5 mL of 4 M HCl in dioxane (20 mmol) were irradiated to 180° C. (400 W max) for 40 min. Pouring onto methanol followed by collection of the solids, afforded 2.136 g of material (6.61 mmol, 47%). 1H NMR (300 MHz, DMSO): 11.48(s, 2H), 8.74(s, 1H), 7.92(dd, 1H, J=10.70, 2.60 Hz), 7.65(d, 1H, J=8.88 Hz), 7.56(d, 1H, J=2.42 Hz), 7.49(d, 1H), 7.33(m, 2H), 5.89(s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[N:14]1([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26]([CH:31]=O)=[CH:25]3)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:31][C:26]1[NH:27][C:28]3[C:24]([CH:25]=1)=[CH:23][C:22]([O:21][CH2:20][CH2:19][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:30][CH:29]=3)[C:7](=[O:13])[NH:8]2
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2c(CCO)cccc2N1
Product: O=C1Nc2cccc(CCO)c2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
4-(2-Hydroxy-ethyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.