Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.7 %

Procedure:
To a solution of 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (1.5 g, 07.5 mmol) in dry DCM (40 mL) was added triethylamine (2.59 mL, 18.8 mmol) and 4-chlorobenzenesulfonyl chloride (3.15 g, 10.5 mmol) and the reaction stirred at room temperature for 48 h. To the reaction was added resin supported-triamine (5 g) and the mixture stirred for 4 h. The reaction mixture was filtered and the filtrate washed with 0.5 M HCl (aq., 100 mL) followed by water (100 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was dissolved in DCM (40 mL) and TFA (10 mL) was added. The solution was stirred for 20 min. The solvent was evaporated and the residue tajen up in DCM (40 mL) and washed with 50% aqueous sodium bicarbonate (100 mL) followed by water (100 mL). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound (1.62 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:34])[CH3:33]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:27]([C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)#[N:28]
Reactant: CN(C)C=O
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(Cl)nccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12
Yield: 65.6 %

Procedure:
To a solution of N-(1-chloroisoquinolin-5-yl)-N′-[4-(trifluoromethyl)benzyl]urea (Example 69) (250 mg, 0.7 mmol) in DMF (5 ml) was added zinc cyanide (43 mg, 0.37 mmol) and tetrakis(triphenylphosphine)palladium (76 mg, 0.07 mmol). The reaction was heated at 80° C., under an atmosphere of nitrogen, for 72 hr, with the addition of extra tetrakis(triphenylphosphine)palladium (76 mg, 0.07 mmol) after 16 hr. Reaction mixture was quenched with water and extracted with ethyl acetate (3×5 ml), dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using an eluant system of 3% methanol/97% DCM increasing to 5% MeOH/95% DCM. Recrystallisation in ethanol of a small portion of product gave a pure sample of the title compound (50 mg, 65.6%). m/z (ES+) 371, 373 (M+H)+.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].O1CCCC1.[Cl:13][C:14]1[C:18]([F:20])([F:19])[C:17]([F:22])([F:21])[C:16]([F:24])([F:23])[C:15]=1Cl>CCOCC>[CH:1]1([O:6][C:15]2[C:16]([F:24])([F:23])[C:17]([F:21])([F:22])[C:18]([F:19])([F:20])[C:14]=2[Cl:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: FC1(F)C(Cl)=C(Cl)C(F)(F)C1(F)F
Reactant: OC1CCCC1
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: FC1(F)C(Cl)=C(OC2CCCC2)C(F)(F)C1(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
Cyclopentanol (23 g, 0.27 mol) and sodium metal (5.6 g, 0.24 mol) were refluxed with 25 ml dry tetrahydrofuran (THF) overnight. The reaction mixture was diluted with 200 ml of dry ether and then added to 1,2-dichlorohexafluorocyclopentene (49 g, 0.2 mol) in 100 ml of dry ether at room temperature with stirring over 20 minutes. After the completion of the addition, the reaction mixture was heated to reflux for 2 hours. The reaction mixture was poured into ice water (150 ml) and the organic layer was separated. Then the aqueous layer was extracted with 4 portions of 100 ml of ether. Next, the organic layer and the ether extracts were combined and dried over CaCl2 overnight. Thereafter, the solvent was distilled out at atmospheric pressure. That which remained was distilled under reduced pressure to give the desired 2-chlorohexafluorocyclopentenyl cyclopentyl ether in 79% yield based on the 1,2-dichlorohexafluorocyclopentene used.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.Cl.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(O)C.C([O-])(O)=O.[Na+]>O>[CH:14]1[CH:15]=[CH:16][CH:17]=[C:12]2[C:13]=1[C:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C:2]=1[NH:18]2
Reactant: O=C1Cc2ccccc2C1
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: c1ccc2c(c1)Cc1[nH]c3ccccc3c1-2
Temperature: 80 °C

Procedure:
In a 1-L flask were charged 36.55 g of 2-indanone (Aldrich, Mw=−132.16, 276.6 mmol), 40.00 g of phenyl-hydrazine hydrochloride (Aldrich, 99%, Mw=144.61, 276.6 mmol) and 0.3 L of i-PrOH. The suspension was warmed to 80° C. in about 30 minutes and the slurry changed color from yellow to dark brown under stirring. The reaction mixture was stirred at 80° C. for 1.5 hours and then was cooled to room temperature in about 30 minutes. The slurry was siphoned into 1.0 L of water containing 34.85 g of NaHCO3, thus obtaining a fine dispersion of a green product (no heat evolution was observed). The slurry was then filtered on a G4 frit, washed with water, dried in air under moderate vacuum for 24 h until to achieve constant weight.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+].Cl>O.C(O)(C)C>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 11.5 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To 1,106 g of L-arginine were added 6,919 g of isopropyl alcohol and 2,964 g of water. Thereto were concurrently added dropwise 1,522 g of lauroyl chloride (manufactured by Nippon Oil and Fats Co., Ltd.) and 27 wt % NaOH aqueous solution over a period of 2 hours with the pH being maintained at 10.5 to 11.5 and the reaction temperature being maintained at 10 to 13° C. After 1 hour of aging, the reaction mixture was warmed to 50° C. and adjusted to pH 3.8 by adding concentrated hydrochloric acid to dissolve the reaction product completely. Thereafter, the pH was adjusted to 6.0 by adding 27 wt % NaOH aqueous solution to precipitate crystals and the resulting slurry was gradually cooled to 10° C. with stirring. When the slurry was cooled to 10° C., the crystals were collected by filtration and washed with 10 kg of water and 4.4 kg of isopropyl alcohol, successively. The resulting washed crystals were dried under reduced pressure to obtain 2,081 g of mono-Nα-lauroyl-L-arginine as flake-shaped crystals (yield 92.3%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:8](OC)([O:9]C)[CH2:7][CH2:6][O:5][CH2:4]1.O.Cl>C1COCC1>[CH3:1][O:2][C@H:3]1[C:8](=[O:9])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: CO[C@@H]1COCCC1(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1COCCC1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A stirred mixture of (R)-3,4,4-trimethoxytetrahydro-2H-pyran (as prepared in the previous step, 141 g, 0.80 mol), in THF (3.6 L) and H2O (1.1 L) in an ice/acetone bath at <0° C., was treated with a solution of HCl (conc., 595 mL, 7.21 mol) added via addition funnel over 45 min while keeping temperature <3° C. After the addition was complete, the reaction was allowed to stir for 1.5 h at 0° C. The reaction was evaporated until ˜1.9 L of concentrate remained. The concentrated was transferred to a separatory funnel and extracted with CH2Cl2 (3×1 L). The combined organic fractions were washed with sat. NaHCO3 (1 L), brine (1 L), dried over MgSO4, filtered and evaporated to afford the title compound (71.4 g, 69%, Chiral GC 92% ee) as an oil which solidified upon standing. Optical Rotation: [α]25(D) −6.97° (c=0.8222, MeOH); Elemental Analysis calc for C6H10O3: C, 53.59; H, 7.58. Found: C, 53.64; H, 7.65.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:33][CH2:34][S:35][CH3:36])[NH:5][C:6](=[O:32])[CH2:7][N:8]([CH2:20][C@@H:21]([NH:26][CH2:27][C@@H:28]([NH2:31])[CH2:29][SH:30])[C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:9][C:10]1[CH:11]=N[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[C:38](C(O)=O)(F)(F)F>>[NH2:31][C@@H:28]([CH2:29][SH:30])[CH2:27][NH:26][C@@H:21]([C@@H:22]([CH3:25])[CH2:23][CH3:24])[CH2:20][N:8]([CH2:9][C:10]1[C:19]2[C:16](=[CH:15][CH:14]=[CH:13][CH:18]=2)[CH:17]=[CH:38][CH:11]=1)[CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:37])[CH2:33][CH2:34][S:35][CH3:36])=[O:32]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)OC)Cc1cnc2ccccc2c1)NC[C@@H](N)CS
Product: CC[C@H](C)[C@@H](CN(CC(=O)N[C@@H](CCSC)C(=O)O)Cc1cccc2ccccc12)NC[C@@H](N)CS

Procedure:
N-[2(S)-(2(R)-amino-3-mercaptopropylamino)-3(S)-methylpentyl]-N-(3-quinolylmethyl)-glycyl methionine methyl ester Anal. calculated for C27H43N5O3S2. 3.85 CF3CO2H: C, 42.15; H, 4.78; N, 7.08; Found: C, 41.96; H, 5.01; N, 7.48.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][C:19]([N:21]3[CH2:28][CH2:27][C:24]4([CH2:26][CH2:25]4)[C@H:23]([OH:29])[CH2:22]3)=[O:20])[CH2:10][C@H:9]2[CH3:30])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].C(O)(=O)C>CO.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][C:19]([N:21]3[CH2:28][CH2:27][C:24]4([CH2:26][CH2:25]4)[C@H:23]([OH:29])[CH2:22]3)=[O:20])[CH2:10][C@H:9]2[CH3:30])=[CH:4][C:3]=1[C:31]([F:32])([F:33])[F:34]
Reactant: C[C@@H]1CN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(=O)C=CN1c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1CN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(=O)CCN1c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 24 h
Yield: 95.6 %

Procedure:
A solution of 0.049 g (0.1 mmol) of (R)-1-(4-chloro-3-trifluoromethyl-phenyl)-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-1,2,3,4-tetrahydro-[1,4]diazepin-5-one (73% ds) and 0.006 ml (0.1 mmol) of acetic acid in 2 ml MeOH was treated with 0.005 g of PtO2 and was stirred over H2-atmosphere for 1 days. After filtration and evaporation, the residue was reevaporated (3 times) with toluene and the solvent was removed under vacuum to give 0.048 g (98%) of the titled compound as white foam. MS: 502.21 (MH+, Cl).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[NH:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[CH2:9][CH2:8]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]3[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Acetyl chloride (179 mg) was added to a solution of 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline dihydrochloride (1 g) and diisopropylethylamine (735 mg) in methylene chloride that was cooled at 0° C. and the mixture was stirred for 2 hours and allowed to warm to room temperature. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a colourless foam (0.655 g); 1H NMR Spectrum: (DMSO d6) 1.54-1.78 (m, 2H), 1.91-2.10 (m, 5H), 3.29-3.41 (m, 2H), 3.66-3.76 (m, 1H), 3.78-3.88 (m, 1H), 3.93 (s, 3H), 4.74 (m, 1H), 7.20 (s, 1H), 7.27 (t, 1H), 7.44-7.55 (m, 2H), 7.87 (s, 1H), 836 (s, 1H), 9.54 (s, 1H); Mass Spectrum: (M+H)+ 445.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][C:59](C)(C)C)=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(N[CH:70](C1C=CC=CC=1)[C:71](O)=O)=O>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH:46]7[CH2:45][CH:44]([CH2:70][CH2:71]7)[N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Yield: 46.6 %

Procedure:
This compound was synthesized using the procedure used to synthesize [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-phenyl-acetic acid (0.079 g, 0.380 mmol) giving the title compound (0.100 g, 46.6% yield) as a white solid. LCMS-ESI+: calc'd for C49H52N8O6: 848.40 (M+); Found: 849.50 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(CO)cc2)c(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(C=O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-methanol, prepared as described in Example 50, (0.5 g, 1.26 mmol) was dissolved in CHCl3 (10 mL) and Dess-Martin periodinane (0.59 g, 1.39 mmol) was added. The reaction was stirred at 25° C. for 16 h, dissolved in EtOAc (100 mL), and the EtOAc was washed with sat sodium thiosulfate solution (20 mL), water (20 mL) and brine, dried and stripped in vacuo. The residue was chromatographed on silica gel using 20% EtOAc/hexanes eluent to give 4-[6-methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-benzaldehyde (472 mg, 95% yield) as an amorphous solid. mass spec. (AP+): m/z 395 (M+1).
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: N#Cc1ccc(Cl)nc1
Product: CN(CCNc1ccc(C#N)cn1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl) [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methylamine and 2-chloro-5-cyanopyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]methyl{2-[(5-cyano(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[C:5]([I:10])=[CH:4][N:3]=1.[Br:11]CC1C(Cl)=NC(Cl)=C(F)C=1>>[Br:11][CH2:8][C:6]1[C:5]([I:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Reactant: OCc1cc(Cl)ncc1I
Product: Clc1cc(CBr)c(I)cn1
Yield: 60 %

Procedure:
Compound 25D (0.28 g, 60%) was prepared from 25C (0.38 g, 1.4 mmol) using a procedure similar to the synthesis of 1B. HPLC Rt=2.72 min.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=1.Cl[C:26]1[CH:27]=[C:28]2[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1>>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:19]=[CH:20][C:21]([CH2:23][O:24][C:26]3[CH:27]=[C:28]4[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][N:29]4[C:30](=[O:32])[N:31]=3)=[CH:22][C:4]=2[F:3])=[CH:8][C:9]=1[C:15]([F:18])([F:16])[F:17])#[N:12]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 4-(2-fluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]4=[O:35])[CH2:22][CH2:21]3)[NH:16][C:17](=[O:19])[CH:18]=1)=[O:12])[CH2:6][CH2:5]2.[C:36](=O)([O-])[O-].[Cs+].[Cs+].CI>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]4=[O:35])[CH2:22][CH2:21]3)[N:16]([CH3:36])[C:17](=[O:19])[CH:18]=1)=[O:12])[CH2:6][CH2:5]2
Reactant: O=C([O-])[O-]
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)[nH]c(=O)c1)N1CCc2cc(F)ccc21
Agent: [Cs+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1c(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(C(=O)N2CCc3cc(F)ccc32)cc1=O
Reaction time: 0.25 h

Procedure:
50 mg (0.11 mmol) of 4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-one were placed in 0.50 mL DMSO at RT. To this were added 88 mg (0.27 mmol) caesium carbonate and the mixture was stirred for 15 min. Then a solution of 6.5 μL (0.11 mmol) methyl iodide in DMSO was added and the mixture was stirred for 2 h at RT. More methyl iodide was added (3.3 μL, 0.055 mmol) and the mixture was stirred for a further 2 h at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: C([O:3][C:4]([C:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[N:7][N:8]=[C:9](Cl)[CH3:10])=O)C.O.[NH2:18][NH2:19]>C(O)(C)C>[NH2:18][N:19]1[C:4](=[O:3])[C:6]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:7][N:8]=[C:9]1[CH3:10]
Reactant: NN
Reactant: CCOC(=O)C(=NN=C(C)Cl)c1cccs1
Solvent: CC(C)O
Solvent: O
Product: Cc1nnc(-c2cccs2)c(=O)n1N
Reaction time: 8 h

Procedure:
234 g (0.92 mol) of crude 1-ethoxycarbonyl-4-chloro-4-methyl-1-thien-2-yl-2,3-diazabutadiene were dissolved in 600 ml of isopropanol and 125 g (2.5 mol) of hydrazine hydrate were added at 60° C., whilst stirring. Stirring was continued for 8 hours at 60° C. The reaction solution was concentrated to one-third and water was added. The solid which had precipitated was then filtered off, thoroughly rinsed with water and dried. 125g (65.3% of theory) of 4-amino-3-methyl-6-thien-2-yl-1,2,4-triazin-5-one of melting point 210° C. were obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1.[CH2:16]([O:18][CH2:19][CH2:20]Br)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:16]([O:18][CH2:19][CH2:20][NH:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1)[CH3:17]
Reactant: CCOCCBr
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCNC1CCc2cc3c(cc2C1)OCC3
Reaction time: 20 h

Procedure:
A mixture containing 7.8 g of the compound of Example 2, 6.7 g of 2-bromoethyl ethyl ether and 6.2 g of sodium carbonate in ethanol is brought to reflux with stirring for 20 hours.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[O:14][CH3:15])(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.[Cl-].[Na+].O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:16][C:1]([CH3:2])=[N:4][N:5]=2)=[C:8]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cc(Br)ccc1C(=O)NNC(C)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1-c1nnc(C)o1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
N′-Acetyl-4-bromo-2-methoxybenzohydrazide (720 mg, 2.51 mmol) and Burgess' Reagent (896 mg, 3.76 mmol) were dissolved in 10 ml of THF and stirred in the microwave at 120° C. for 30 minutes. The reaction was diluted with brine and extracted three times with EtOAc. Organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to a yellow oil. Chromatography on silica gel (0-50% EtOAc/DCM) gave a yellow solid (465 mg, 1.73 mmol, 69%).