Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.[S:45]1[C:49]2[CH:50]=[CH:51][C:52]([NH2:54])=[CH:53][C:48]=2[N:47]=[CH:46]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]2[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]3[C:2]([NH:54][C:52]4[CH:51]=[CH:50][C:49]5[S:45][CH:46]=[N:47][C:48]=5[CH:53]=4)=[N:3][CH:4]=[C:5]([CH2:34][N:35]4[CH2:40][CH2:39][N:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]4)[CH:6]=3)[N:9]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: Nc1ccc2scnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4scnc4c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
A mixture of 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 128; 60.0 mg, 0.097 mmol) and benzo[d]thiazol-5-amine (29.0 mg, 0.193 mmol)(Maybridge, Trevillet, UK) in THF (1.0 mL) at 0° C. was treated with LiHMDS (1.0 M in THF, Aldrich, St. Louis, Mo.) (483 μL, 0.483 mmol) dropwise via syringe. The reaction was stirred at 0° C. for 15 min, then was quenched with sat. aq. NH4Cl (3 mL). The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with a gradient of 10-35% EtOAc in DCM with 1% MeOH to give N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)benzo[d]thiazol-5-amine (51.0 mg, 0.068 mmol, 70.3% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 9.16 (1H, br. s.); 8.99 (1H, s); 8.40-8.54 (2H, m); 7.84 (1H, d, J=8.8 Hz); 7.58 (1H, d, J=8.6 Hz); 7.12-7.25 (4H, m); 6.77-6.92 (4H, m); 4.93 (2H, s); 4.89 (2H, s); 4.15 (2H, s); 3.79 (12H, d, J=18.0 Hz); 3.35-3.51 (2H, m); 2.87-2.97 (2H, m); 2.85 (3H, s); 2.69 (3H, s). m/z (ESI, positive ion) 752 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH2:22][O:23][CH3:24])([CH3:21])[CH2:19][OH:20])=[O:16])=[CH:8][C:7]=2[CH3:27])#[CH:2].I[CH3:29].[H-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH2:19][O:20][CH3:29])([CH3:21])[CH2:22][O:23][CH3:24])=[O:16])=[CH:8][C:7]=2[CH3:27])#[CH:2]
Reactant: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(CO)COC)cc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(COC)COC)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (120 mg) in dry THF (7 ml) NaH (19 mg, 60% in oil) was added at room temperature under a nitrogen atmosphere. After 30 minute iodomethane (30 □l) was added to the reaction mixture. After stirring during 5 h one equivalent of NaH and one equivalent of iodomethane were added. The mixture was stirred overnight at room temperature, then quenched with water and diluted with ethyl acetate. The water phase was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography (cyclohexane/ethyl acetate/dichloromethane, 1:1:1) to give 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-methoxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (46 mg) as a light brown oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:14]3[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]1=2.[Li].[Li][S:33][CH3:34]>O1CCOCC1.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:14]2[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:4][CH2:3][CH2:2][S:33][CH3:34])[C:17]=2[CH:16]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCCBr
Reactant: [Li]SC
Agent: [Li]
Solvent: C1COCCO1
Solvent: O
Product: CSCCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Reaction time: 9 h

Procedure:
A mixture of the bromide (58) (60.0 mg, 0.124 mmol) prepared as described in example 172 and lithium thiomercaptide (13 mg, 0.2481 mmol) in p-dioxane (5 mL) was refluxed for 16 h. A further 10 mg of LiSMe was added and refluxing was continued for a further 9 h. The mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to drynessto give the sulfide (130 directly (47.1 mg, 84%) which crystallised from ethyl acetate/petroleum ether as an orange powder, mp 218–220° C. 1H NMR δ [(CD3)2SO] 11.07 (br s, 1H), 9.39 (br s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.80 (s, 1H), 7.61–7.56 (m, 2H), 7.53–7.43 (m, 3H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 4.52 (t, J=6.9 Hz, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.01 (m, 2H), 2.00 (s, 3H). FABMS found [M+H]+: 453.0840, 451.0859. C24H20ClN2O3S requires 453.0854, 451.0883.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]([CH2:15][O:16][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=3)=[C:13]([CH3:17])[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CO
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C#N)cn1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 7.9 g, 181 mmol, 1.5 eq.) in THF (65 mL) was added within 30 minutes at room temperature a solution of [3-(4-Fluorophenyl)-5-methyl-isoxazol-4-yl]-methanol (25.0 g, 121 mmol) and 6-chloronicotinonitrile (16.7 g, 121 mmol) in THF (120 mL) and the resulting mixture was stirred for one hour. A solution of citric acid (18.5 g, 96.5 mmol) in water (185 mL) was added to the reaction mixture within 30 minutes. From the resulting THF/water mixture THF was distilled off under reduced pressure at a jacket temperature of 60° C. and replaced by ethanol. In total 284 g of ethanol were added. The resulting suspension was stirred for one hour at room temperature. The crystals were filtered off, washed with a mixture of ethanol (60 mL) and water (60 mL) and subsequently dried at 50° C./<25 mbar to afford 36.5 g (91% corrected yield) of the title nitrile as an off-white solid with an assay of 93% (w/w).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.P(Cl)(Cl)([Cl:26])=O>C(#N)C>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(O)nncc3c2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Ethyl 3-(1-hydroxyphthalazin-6-yl)-4-methylbenzoate (5.5 g) was suspended in acetonitrile (50 mL), and was treated with phosphorus oxychioride (3 mL, 36 mmol). The mixture was stirred at 90° C. for 4 h. The mixture was concentrated to remove all solvent, and redissolved in ethyl acetate (200 mL). The organic solution was washed with water (3×20 mL), brine (20 mL), and was dried over anhydrous Na2SO4, and concentrated in vacuo to give ethyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13](C([Sn])=C(CCCC)CCCC)[CH2:14]CC>COCCOC.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:13]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([O:11][CH3:12])[CH:3]=1)=[CH2:14]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1cc(Br)cc2[nH]ccc12
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Product: C=Cc1cc(OC)c2cc[nH]c2c1
Temperature: 90 °C
Yield: 113.3 %

Procedure:
To a solution of 6-bromo-4-(methyloxy)-1H-indole (900 mg, 3.98 mmol) in 1,2-dimethoxyethane (20 mL) was added tributylvinyltin (1.74 mL, 5.96 mmol). The reaction mixture was degassed with argon and then treated with dichlorobis(tri-o-tolylphosphine)palladium (153 mg, 0.19 mmol). The mixture was heated at 90° C. for 65 hours. The mixture was filtered through a pad of celite, washed with ethyl acetate and then the filtrate concentrated in vacuo. The product was purified by silica gel chromatography eluting with 2-50% ethyl acetate in hexane to yield the title compound (D8), (781 mg).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7](Cl)[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[Cl:18][C:19]1[CH:25]=[C:24]([I:26])[CH:23]=[C:22]([Cl:27])[C:20]=1[NH2:21]>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:21][C:20]3[C:19]([Cl:18])=[CH:25][C:24]([I:26])=[CH:23][C:22]=3[Cl:27])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: Nc1c(Cl)cc(I)cc1Cl
Reactant: Clc1nc2ccc(Br)cc2c2c(Cl)nccc12
Product: Clc1cc(I)cc(Cl)c1Nc1nc2ccc(Br)cc2c2c(Cl)nccc12

Procedure:
The title compound was prepared according to the procedure in (Example 3, Method C, Step 4) using 9-bromo-1,5-dichlorobenzo[c]-2,6-naphthyridine and 2,6-dichloro-4-iodoaniline as the starting materials.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16].C1COCC1>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:15](=[O:16])[N:8]([CH:9]([CH3:11])[CH3:10])[C:6]=2[CH:7]=1
Reactant: CC(C)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1c(=O)[nH]c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.8 %

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)isopropylamine (Step 1 of Example 9, 5.85 g, 30 mmol) and 10% Pd—C (600 mg) in MeOH was stirred under atmosphere of hydrogen gas at room temperature for 12 h. The catalyst was filtered off on a pad of Celite, and the filtrate was evaporated under reduced pressure. To the residue was added 1,1′-carbonyldiimidazole (4.5 g, 28 mmol) and THF (100 μL) and then stirred at 100° C. for 10 h. After cooling, the volatile materials were removed under reduced pressure and the residue was partitioned between ethylacetate and H2O. After extraction with ethylacetate (3 times), the combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (2:1) to give 3.47 g (60%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].C(N(S(F)(F)[F:38])CC)C>ClCCl>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:38])[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCCc1c(OCc2ccc(C(F)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzonitrile (5.0 g, 12.06 mmol) and dichloromethane (100 mL) is stirred at −78° C. Diethylaminosulfur trifluoride (1.8 mL, 13.74 mmol) is added, the cold bath is removed, and the reaction is stirred at room temperature 1 hr. The reaction mixture is diluted with water (100 mL), the layers are separated, and the aqueous layer is extracted with dichloromethane (2×100 mL). The organic layers are combined, washed with water (50 mL), dried over magnesium sulfate, filtered, and concentrated to give 5.1 g, 100%, of the title compound as a tan solid. LCMS M+1=418.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][Cl:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[Cl:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][Cl:15])[S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 743.4 %

Procedure:
Triethylamine (3.1 mL, 22.2 mmol) was added dropwise to a suspension of N,N-bis(2-chloroethyl)amine hydrochloride (2.0 g, 11.2 mmol) in dichloromethane and the mixture was stirred at room temperature for 20 minutes. The mixture was then cooled in an ice bath and methanesulfonyl chloride (1.41 g, 1.1 mmol) was added dropwise. The cooling bath was removed and the mixture was stirred for 4 hours at room temperature. Water was added to the reaction mixture and the organic layer was washed with 2M aqueous hydrochloric acid, water, dried (MgSO4) and evaporated to give the title compound (1.80 g, 73%) as a white solid.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:32][CH:31]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C(O)CCCCC=Cc1ccc(F)cc1
Yield: 85.4 %

Procedure:
5-Carboxypentyl-triphenylphosphonium bromide (20 g) and 4-fluorobenzaldehyde (6.5 g) were subjected to substantially the same reaction as in Reference Example 1. The reaction product was isolated by means of a silica gel chromatography to afford 7-(4-fluorophenyl)-6-heptenoic acid (8.3 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][C:5]=2[N:6]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2cc(-c3ccccc3)ccc2o1
Yield: 32.3 %

Procedure:
2-Methyl-5-phenyl-benzoxazole 48 (1.05 g, 5.0 mmol), N-bromosuccinimide (89 mg, 5.0 mmol) and azodilsobutyronitrile (AIBN) (41 mg, 0.25 mmol) in 10 ml of CCl4 was heated to reflux. After 5 hrs an additional 50 mg AIBN were added and the mixture was refluxed overnight. The mixture was diluted, washed with water, dried and concentrated. The crude product was chromatographed to give about 465 mg 2-bromomethyl-5-phenyl-benzoxazole 49.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][NH:27][C:28]1[C:29]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:30][CH:31]=[CH:32][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([C:11]([C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=3[CH:5]=2)=[O:13])[CH2:36][CH2:35]1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CNc1cccnc1N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1cccnc1N1CCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1
Reaction time: 2 h

Procedure:
5-Fluoroindole-2-carboxylic acid (98 mg) and 1,1'-carbonyldiimidazole (95 mg) are dissolved in dry THF (1 ml) and stirred for 2 hr at 20°-25°. The resulting solution is added via canula to a -10° cooled solution of 4-[3-(methylamino)-2-pyridinyl]piperazine (117 mg) in dry THF (1 ml). The reaction mixture is then allowed to reach 20°-25° overnight. The reaction mixture is then diluted with ethyl acetate, washed with saturated sodium bicarbonate and saline, dried over magnesium sulfate, and concentrated to give a solid, which is purified on a silica gel flash column eluting with hexane/ethyl acetate (1/1). The appropriate fractions are pooled and concentrated to give a solid. Recrystallization of the solid from ethyl acetate/ether gives the title compound, mp 194°-195°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:12]=1.C[OH:27]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]([NH2:23])=[O:27])=[CH:20][CH:19]=2)[N:12]=1
Reactant: CO
Reactant: Cc1cc(C)c(Nc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Solvent: O
Product: Cc1cc(C)c(Nc2ccnc(Nc3ccc(C(N)=O)cc3)n2)c(C)c1
Yield: 56 %

Procedure:
A mixture of 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (0.00303 mol) and NaBO3.4H2O (0.00911 mol) in CH3OH (30 ml) and H2O (10 ml) was stirred and refluxed for 4 days. The reaction mixture was cooled. The precipitate was filtered off and the precipitate (!) was purified by flash column chromatography over silica gel (eluent: CH2Cl2/CH3OH gradient from 100/0 to 95/5). The desired fractions were collected and the solvent was evaporated, yielding 0.586 g (56%) of 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide (comp. 40). The filtrate (!) was purified by reversed-phase HPLC (eluent gradient: ((0.5% ammoniumacetate in H2O)/CH3CN 90/10)/CH3OH/CH3CN (0 minutes) 75/25/0, (44 minutes) 0/50/50, (57 minutes) 0/0/100, (61.1-70 minutes) 75/25/0). Three desired fraction groups were collected and their solvent was evaporated, yielding 0.18 g of 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide, N3-oxide (comp. 49) and 0.030 g of 4-[[4-(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]-amino]benzamide, N1-oxide.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3].ClC(N(C)C)=C(C)C.[CH2:27]([O:30][C:31](=[O:67])[C:32]([N:52]1[C@H:55]([SH:56])[C@@H:54]([C@H:57]([O:59][C:60]([O:62][CH2:63][CH:64]=[CH2:65])=[O:61])[CH3:58])[C:53]1=[O:66])=[P:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:28]=[CH2:29].CN(C1C=CC=CN=1)C>C(Cl)Cl.[Ag].N1C=CC=CC=1>[CH2:27]([O:30][C:31](=[O:67])[C:32]([N:52]1[C@H:55]([S:56][C:14](=[O:16])[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:18][CH:17]=2)[C@@H:54]([C@H:57]([O:59][C:60]([O:62][CH2:63][CH:64]=[CH2:65])=[O:61])[CH3:58])[C:53]1=[O:66])=[P:33]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)Nc1ccc(OCC(=O)O)cc1
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Agent: [Ag]
Agent: CC(C)=C(Cl)N(C)C
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)Nc1ccc(OCC(=O)S[C@@H]2[C@@H]([C@@H](C)OC(=O)OCC=C)C(=O)N2C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1.25 h

Procedure:
1 g of 4-(allyloxycarbonylamino)-phenoxyacetic acid is suspended in 2 ml of CH2Cl2 and 0.6 ml of 1-chloro-1-dimethylamino-2-methylprop-1-ene is added thereto. The mixture is stirred for 75 minutes and is then added dropwise, over a period of 5 minutes, to a solution of 1.74 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester, 50 mg of dimethylaminopyridine and 0.41 ml of pyridine in 30 ml of absolute methylene chloride. The title compound is obtained after working up analogously to Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][NH2:22]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:22][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=C(O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2cccc(Br)c2)nc2cccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.018 mole) 1,1'-carbonyldiimidazole (2.9 g, 0.018 mole), and anhydrous tetrahydrofuran (200 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 4 hours. The nitrogen flow was stopped and a solution of methylamine in tetrahydrofuran (36 ml of 1M) was added. The solution was stirred at room temperature under nitrogen for 1/2 hour. The reaction mixture was filtered and concentrated in vacuo and the residue triturated in water (100 ml) and filtered. The filter cake was recrystallized from tetrahydrofuran-isopropyl ether, giving 4.6 g (74%). Recrystallization from isopropyl alcohol-isopropyl ether gave 4.4 g of off-white needles, mp 199°-201° C.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:8]=[C:7]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=O)[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[O:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1.C1C=CC=CC=1>ClCCCl>[F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:8]=[C:7]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[S:34])[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[O:4]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=c1ccccn1C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Solvent: ClCCCl
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)C(n1ccccc1=S)=CC(CF)(CF)O2
Yield: 69.5 %

Procedure:
A mixture of 0.13 g of 2,2-bisfluoromethyl-6-nitro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran, 83 mg of a Lawesson's reagent, 1 ml of benzene and 1 ml of 1,2-dichloroethane was refluxed for 3 hours and the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, CH2Cl2), and then, recrystallized from a mixture of ethyl acetate and hexane to obtain 0.05 g of 2,2-bisfluoromethyl-6-nitro-4-(1,2-dihydro-2-thioxo-1-pyridyl)-2H-1-benzopyran represented by the following formula having a melting point of 209°-210° C.
Reaction SMILES: [OH:1]C(P(O)O)(C1C=CC(C)=CC=1)C.ClCC(O)C.CN(C1C=CC=CN=1)C.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCCC1.CCOCC>[C:35]([NH:34][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)([NH:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:1]
Reactant: Cc1ccc(C(C)(O)P(O)O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(O)CCl
Agent: CN(C)c1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
1-hydroxy-1-p-tolylethylphosphonous acid (0.2 g., 0.01M), 1-chloro-2-propanol (0,094 g., 0.01M) and dimethylaminopyridine (0.01 g) are stirred in tetrahydrofuran (5 ml.) at 5° C. Dicyclohexylcarbodiimide (0.23 g., 0.001M) is added portionwise over 1 hour. On completion of the reaction (monitored by 31P NMR) ether (10 ml) is added and the dicylohexylurea formed is filtered off. Evaporation of the filtrate gives an oil which is purified by chromatography on silica using 5% methanol in chloroform as eluant. There is obtained 1-chloromethylethyl (1-hydroxy-1-p-tolylethyl)phosphinate.