Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(=O)C(NC1C=CC(N2CCOCC2)=CC=1)=O)[NH2:2].[Cl:20][C:21]1[CH:22]=[C:23]([NH:34][C:35](=[O:40])[C:36](OC)=[O:37])[CH:24]=[C:25]([Cl:33])[C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:34][C:35](=[O:40])[C:36]([NH:1][NH2:2])=[O:37])[CH:24]=[C:25]([Cl:33])[C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: COC(=O)C(=O)Nc1cc(Cl)c(N2CCOCC2)c(Cl)c1
Reactant: NNC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Product: NNC(=O)C(=O)Nc1cc(Cl)c(N2CCOCC2)c(Cl)c1

Procedure:
Following the general procedure of Intermediate 18, using methyl [(3,5-dichloro-4-morpholin-4-ylphenyl)amino](oxo)acetate as starting material, the title compound (Intermediate 100) was obtained; 1H NMR δ 3.08 (4H, t), 3.67 (4H, t), 4.62 (2H, s), 7.93 (2H, s), 10.31 (1H, broad s), 10.83 (1H, broad s); MS m/e MH+ 333.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=CC=CC=1C.CC1C(C)=CC(C)=[CH:12][C:11]=1[OH:18].C=O.O.O.[C:23](O)(=O)[C:24](O)=[O:25]>O.O1CCOCC1>[CH3:23][CH2:24][O:25][CH2:12][CH2:11][O:18][C:6]([CH3:1])=[O:7]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: O=C(O)C(=O)O
Reactant: Cc1cccc(O)c1
Agent: C=O
Solvent: C1COCCO1
Solvent: O
Product: CCOCCOC(C)=O

Procedure:
Into 2000-ml autoclave were charged 86.5 g (0.8 mol) of m-cresol, 27.2 g (0.2 tool) of 2,3,5-trimethylphenol, 75.0 g (0.925 tool) of formalin (37% by weight aqueous formaldehyde solution), 7.56 g (0.06 mol) of oxalic acid dihydrate, 384.5 g of dioxane and 77.5 g of water. Thereafter, the autoclave was immersed in an oil bath and the internal temperature thereof was kept at 140° C. to effect polycondensation for 6 hours. Thereafter, the internal temperature of the autoclave was returned to the neighborhood of room temperature, and the reaction mixture was taken out and allowed to stand until the suspension was separated to two layers, after which the resin layer was taken out. Thereto was added 432 g of ethyl cellosolve acetate, and unreacted formaldehyde, dioxane and water were removed by distillation under reduced pressure, to obtain an ethyl cellosolve acetate solution. The solution thus obtained was washed with water to remove the oxalic acid used as a catalyst and the ethyl cellosolve acetate and water were removed by distillation under reduced pressure to recover Resin A [hereinafter referred to as "Resin A (8)"].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])CCCN=[N+]=[N-].CO.C(Cl)(Cl)[Cl:30]>[Pd]>[ClH:30].[CH3:1][O:2][C:3](=[O:26])[C@@:4]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([CH2:20][CH2:19][CH2:4][NH2:5])[NH:5][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: ClC(Cl)Cl
Reactant: COC(=O)[C@H](Cc1ccccc1)N(CCCN=[N+]=[N-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@](CCCN)(Cc1ccccc1)NC(=O)OC(C)(C)C
Product: Cl

Procedure:
(S)-BOC-(2-benzyl)-3-azidopropyl glycine methyl ester (0.19 g, 0.52 mmol) is dissolved in methanol/chloroform (15:1) (8 ml) and hydrogenated at atmospheric pressure over 10% palladium on carbon for 5 hours. The mixture is filtered, concentrated in vacuo, and the residue triturated with ether/benzene and reconcentrated to give (S)-BOC-(2-benzyl)-ornithine methyl ester hydrochloride.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.Cl.[Cl:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][O:37][CH2:38][C:39]([NH2:41])=[NH:40])[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl.CN(C=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][O:37][CH2:38][C:39]2[NH:41][C:8](=[O:10])[C:7]3[CH:6]=[C:5]([F:11])[CH:4]=[N:3][C:2]=3[N:40]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: N=C(N)COCCc1cccc(Cl)c1
Reactant: O=C(O)c1cc(F)cnc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1[nH]c(COCCc2cccc(Cl)c2)nc2ncc(F)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.3 %

Procedure:
To a solution of 2,5-difluoropyridine-3-carboxylic acid (150 mg, 0.94 mmol) in CH2Cl2 (5 ml) at 0° C. was added oxalylchloride (97 μl, 1.13 mmol) dropwise followed by 2 drops of DMF. The reaction mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was concentrated in vacuo and used in the next step without further purification. The crude acid chloride was dissolved in MeCN (5 ml) and N,N-diisopropyl ethyl amine (345 μl, 2.67 mmol) was added followed by 2-[2-(3-chlorophenyl)-ethoxy]-acetamidine hydrochloride salt (222 mg, 0.89 mmol) (prepared as described in example 79.2). The reaction mixture was stirred at room temperature for 16 h and then heated to reflux for an additional 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a residue which was partitioned between water and ethyl acetate. The organic phases were combined, washed with 1N HCl, sat. NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude residue which was triturated with ether (3×5 ml) to give the desired product 2-[2-(3-chlorophenyl)-ethoxymethyl]-6-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one (65 mg, 0.19 mmol; 22%) as an off white solid. MS: m/e=334.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:18]1([CH2:21][C:22](=[O:33])[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=2)[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([CH2:21][C:22](=[O:33])[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[N:25]=2)[CH2:19][CH2:20]1
Reactant: Nc1ccncc1
Reactant: CS(=O)c1nccc(CC(=O)CC2CC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Nc2ccncc2)n1)CC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
To a solution of 4-aminopyridine (328 mg, 3.49 mmol) in THF (2.344 mL) cooled to −78° C. was added LHMDS (583 mg, 3.49 mmol). The reaction was warmed to rt and stirred for 15 minutes. The reaction was again cooled to −78° C. and 1-cyclopropyl-3-[2-(methylsulfinyl)pyrimidin-4-yl]propan-2-one (7) (277 mg, 1.162 mmol) was added as a solution in THF (2 mL). The reaction was warmed to rt and stirred for 1 hour. The reaction was quenched by slow addition of saturated ammonium chloride and the volatiles evaporated. The residue was then partitioned between water and DCM. The organic layer was washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude residue was purified by Biotage™ silica gel chromatography [2-10% MeOH in DCM with 1% triethylamine] to afford the desired product as a yellow oil (269 mg, 86%). MS (ES+): m/z=269.2 (100) [MH+2]. HPLC: tR=0.69 minute over 3 minutes. Purity: >95% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([NH:7][CH:8](Br)[C:9]([NH2:11])=[O:10])=[O:6].[CH3:16][SH:17].C(N(CC)CC)C.CCOCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([NH:7][CH:8]([S:17][CH3:16])[C:9]([NH2:11])=[O:10])=[O:6]
Reactant: CS
Reactant: NC(=O)C(Br)NC(=O)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSC(NC(=O)c1cccc(Cl)c1)C(N)=O
Reaction time: 72 h

Procedure:
To a solution of 3-chlorobenzoylamino(bromo)acetamide (5.5 g) in anhydrous tetrahydrofuran (100 ml) containing methyl mercaptan (slight excess) was added 1 equivalent of triethylamine and the mixture kept for 72 hrs. The solution was filtered and the filtrate evaporated to give an oil which solidified on treatment with ether. Crystallisation of the solid from ethyl acetate gave the product (0.67 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([NH:15][CH:16]([CH:24]([OH:49])[CH2:25][CH:26]([NH:34][C:35]([O:37][CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])(C(C)(C)C)(C)C>CO.C[Si](Cl)(C)C>[OH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([NH:15][C@H:16]([C@@H:24]([OH:49])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[O:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]
Reactant: CC(C)(C)[Si](C)(C)OCCCOC(=O)NC(Cc1ccccc1)CC(O)C(Cc1ccccc1)NC(=O)OCCCO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCCCO)OCCCO
Reaction time: 2.25 h
Yield: 19.6 %

Procedure:
A 0.170 g (0.237 mmol) of the compound from Example 337B above was dissolved in 2 mL of methanol to which 30 μL of trimethylsilyl chloride was added and stirred for 2.25 hours. The solvent was removed and the crude product chromatographed on silica gel, eluting with 2% and 5% methanol in methylene chloride. The solvent was removed and the product dried to afford 22.7 mg of the title compound. MS M/Z (DCI/NH3): 489 (M+H), 506 (M+NH4). Proton NMR (DMSO): δ 1.45 (t, 2H), 1.60 (m, 4H), 2.55-2.75 (4H), 3.40 (m, 2H), 3.55 (br, 1H), 3.74-3.96 (18H), 4.44 (t, 2H), 4.62 (d, 1H), 6.63 (d, 1H), 6.89 (d, 1H), 7.07-7.27 (10H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][N:18]([CH2:26][CH2:27][OH:28])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=2)[N:3]=1.CCN(CC)CC.[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([O:49][CH3:50])=[O:48])#[CH:39].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)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>[C:21]([O:20][C:19]([N:18]([CH2:17][C:16]1[CH:29]=[CH:30][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:39]#[C:38][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH2:46][C:47]([O:49][CH3:50])=[O:48])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)[CH2:26][CH2:27][OH:28])=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CN(CCO)C(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl(2-hydroxyethyl)carbamate (A71) (0.518 g, 1.15 mmol), Et3N (0.75 mL), methyl 2-(2-ethynylphenyl)acetate (K1) (0.242 g, 1.39 mmol), PdCl2(PPh3)2 (0.041 g, 0.058 mmol), CuI (0.022 g, 0.116 mmol) and PPh3 (0.030 g, 0.12 mmol) in DMF (4.5 mL) was heated under microwave irradiation at 120° C. for 15 minutes. The volatiles were evaporated in vacuo and the residue purified using silica gel column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 20-50% EtOAc in cyclohexane) to give the title compound A72 as an orange foam (0.589 g, 86%); 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.48-7.28 (m, 6H), 4.49 (brs, 2H), 3.97 (s, 2H), 3.72 (m, 5H), 3.47 (brs, 2H), 3.01 (brs, 1H), 1.51 (s, 9H). LCMS-B: rt 8.350 min; m/z 585 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]([CH3:26])[C@H:3]([N:16]1[CH:20]=[C:19]([C:21](OCC)=[O:22])[N:18]=[CH:17]1)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[NH4+:28].CO[CH2:31][CH2:32]OC>>[CH2:31]([C:17]1[N:16]([C@H:3]([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[C@@H:2]([OH:1])[CH3:26])[CH:20]=[C:19]([C:21]([NH2:28])=[O:22])[N:18]=1)[CH3:32]
Reactant: CCOC(=O)c1cn([C@H](COc2ccc3ccccc3c2)[C@H](C)O)cn1
Reactant: COCCOC
Reactant: [NH4+]
Agent: [OH-]
Product: CCc1nc(C(N)=O)cn1[C@H](COc1ccc2ccccc2c1)[C@H](C)O

Procedure:
A mixture of ethyl 1-{(1R,2S)-2-hydroxy-1-[(2-naphthyloxy)methyl]propyl}-1H-imidazole-4-carboxylate (0.25 g), 28% ammonium hydroxide (14 mL) and 1,2-dimethoxyethane (7 mL) was heated at 100° C. in the stainless steel bottle for 24 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (gradient elution; 20:1 to 10:1 chloroform-methanol) to give the product, which was recrystallized from 5:1 ethyl acetate-ethanol (6 mL) to give ethyl 1-{(1R,2S)-2-hydroxy-1-[(2-naphthyloxy)methyl)propyl}-1H-imidazole-4-carboxamide (0.12 g).
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:10]=2)[C:5]1=O)([CH3:3])[CH3:2].Cl.O1CCOCC1>O>[CH:1]([CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=2)[CH2:12]1)([CH3:3])[CH3:2]
Reactant: CC(C(=O)O)c1ccc2c(c1)C(=O)C(C(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)CC(C(C)C)C2

Procedure:
A mixture of 15g. of 2-(2-isopropyl-1 -oxoindan-6-yl)propionic acid, 40g. of zinc amalgam, 50 ml. of conc. hydrochloride acid, 200 ml. of dioxane and 30 ml. of water was heated under reflux for 15 hours. After completion of the reaction, the reaction mixture was extracted with ether and the ether extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract and the residue was recrystallized from n-hexane to give 9.5g. of the desired product as colorless crystals of m.p. 90° - 91.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[O:31])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: O=C(CCl)c1cccc(F)c1
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2ccccc23)c2ccc(Cl)cc21)c1cccc(F)c1

Procedure:
Following the general procedure III as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 2-chloro-1-(3-fluoro-phenyl)-ethanone gave the title compound. ES-MS m/e (%): 517.4(M+H+).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:14]([O:25][CH2:26]C)(=[O:24])[C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1>CN(C)C=O>[CH3:26][O:25][C:14](=[O:24])[C:15]1[CH:23]=[CH:22][C:20]([O:21][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.5 %

Procedure:
Imidazole (3.47 g, 51.0 mmol) and t-butyldimethylsilyl chloride (3.84 g, 25.5 mmol) were added to a solution of ethyl vanillate (5.0 g, 25.5 mmol) in N,N-dimethylformamide (50 mL) at room temperature, and the mixture was stirred at room temperature for three hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=10:1) to give the title compound (7.90 g, 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CNCCOC
Product: COCCN(C)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using (2-methoxy-ethyl)-methyl-amine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 2.98 (t, 2H, J=7 Hz); 3.22 (s, 3H); 3.28 (s, 3H); 3.58 (m, 4H); 3.85 (m, 2H); 7.21 (m, 2H); 7.50 (m,2H); 7.93 (d, 2H, J=9 Hz); 8.20 (m, 3H); 8.45 (d, 1H, J=5 Hz); 8.69 (bt, 1H); 12.13 (bs, 1H). MS (ion spray) m/z 455 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.O>CCOCC>[N:7]1([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: N#CCCCN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCCCN1CCOCC1
Temperature: -55 °C
Reaction time: 5 h

Procedure:
14.8 g lithium aluminium hydride were weighed under N2 atmosphere into a round-bottomed flask. The substance was cooled down to −55° C. and 150 ml ether was added dropwise. The suspension was allowed to stir; then 30 g 4-Morpholin-4-yl-butyronitrile were dissolved in 200 ml ether and the solution was added dropwise to the reaction mixture. Again 200 ml ether were added to the mixture and the reaction was stirred at room temperature overnight. At the next day the mixture was cooled down to less than 10° C. and 35 ml H2O were added carefully. After five hours the mixture was fritted and the residue was washed with 300 ml ether. The filtrate was dried, concentrated and finally distilled under vacuum. The product fractions were collected at 74-78° C. and 2.1-1.6 Torr. The purity of the colourless oil was judged by gas chromatography, GC-MS and 1H-NMR.
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7].CCC.[CH3:14][Si:15](OC)([O:18][CH3:19])[O:16][CH3:17]>O1CCCC1>[CH3:14][Si:15]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])([O:18][CH3:19])[O:16][CH3:17]
Reactant: CO[Si](C)(OC)OC
Reactant: CC(C)(C)N
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCC
Product: CO[Si](C)(NC(C)(C)C)OC
Temperature: 25 °C

Procedure:
A thermometer an addition funnel and a condenser were fitted to a stirrer-equipped one liter, four-necked flask. The flask was charged with one mol of isopropylmagnesium chloride in 500 ml of tetrahydrofuran (THF). The addition funnel was charged with 1.02 mol (75 g) of tert-butylamine which was slowly added to the stirred isopropylmagnesium chloride. The reaction was mildly exothermic and there was immediate evolution of propane gas. After completion of the addition (2 hours), the contents were refluxed for 30 minutes to complete the evolution of the gas. The reaction mixture was cooled to room temperature and one mol (135 g) of methyltrimethoxysilane was added to the stirred reaction mixture over a period of one hour. The reaction was mildly exothermic and the contents were refluxed at a pot temperature of 75° C. for 30 minutes to complete the reaction. The methyl(t-butylamino)dimethoxysilane was filtered under nitrogen atmosphere from the magnesium methoxychloride. The salt cake was washed with diethyl ether (2×200 ml) to obtain the residual methyl(t-butylamino)dimethoxysilane. The solvent was distilled to a pot temperature of 90° C. and the residue was distilled under reduced pressure to yield 138 g of methyl(t-butylamino)dimethoxysilane as a colorless oil (purity>98%); bp 107° C./135 mm. The yield was 82% of theoretical.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]([C:15]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.O>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[NH2:1][C:2]1[N:3]=[C:4]([CH:26]=[CH2:27])[C:5]([C:15]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(-c2nc(Cc3ccccc3)c(N)nc2Cl)c(C=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1nc(N)c(Cc2ccccc2)nc1-c1ccc(OC)cc1C=O
Temperature: 110 °C
Yield: 55.7 %

Procedure:
Under an argon atmosphere, to a solution of 2-(5-amino-6-benzyl-3-chloropyrazin-2-yl)-5-methoxybenzaldehyde (7) (2.28 g, 6.44 mmol) in deaerated toluene (30 mL) were successively added dichlorobis(triphenylphosphine)palladium(II) (226 mg, 322 mol), tributyl(vinyl)tin (3.75 mL, 12.8 mmol) and tetra-n-butylammonium chloride (3.50 g, 12.6 mmol) at room temperature. The mixture was heated to reflux for 1.5 hours (oil bath temperature at 110° C.). After cooling to room temperature, to the mixture was added water and the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1) followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (silica gel mixed with 10 wt % potassium fluoride, n-hexane/ethyl acetate=3/1) to give 2-(5-amino-6-benzyl-3-vinylpyrazin-2-yl)-5-methoxybenzaldehyde (8) (1.24 g, 3.59 mmol, 55.5%) as a reddish brown oily substance. TLC Rf=0.27 (n-hexane/ethyl acetate=3/1); 1H NMR (500 MHz, CDCl3) δ 3.92 (s, 3H), 4.15 (s, 2H), 4.50 (s, 2H), 5.39 (dd, 1H, J=2.0, 11.0 Hz), 6.33 (dd, 1H, J=2.0, 17.0 Hz), 6.57 (dd, 1H, J=11.0, 17.0 Hz), 7.20-7.28 (m, 4H), 7.30-7.36 (m, 2H), 7.41 (d, 1H, J=8.5 Hz), 7.55 (d, 1H, J=3.0 Hz), 9.88 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 41.0, 55.7, 110.6, 120.5, 121.0, 127.2, 128.5 (2C), 129.1 (2C), 132.3, 132.9, 134.4, 136.1, 136.5, 138.7, 140.2, 145.2, 151.5, 159.8, 191.5.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
23 g (105 mmol) of methyl 5-bromonicotinate and 26 g (126 mmol, 1.2 eq.) of 4-trifluoromethoxyphenylboronic acid were reacted according to General Method 1A. Yield: 14 g (41% of theory)
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[C:9]([NH:8][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)(=[O:11])[CH3:10]
Reactant: NNc1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(NC(C)=O)c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 46 %

Procedure:
1.08 g of phenylhydrazine was dissolved in 10 ml of pyridine, and 0.78 g of acetic anhydride was added thereto under cooling with ice, followed by stirring for 20 minutes. Then, 2.0 g of 4-methoxybenzoyl chloride was added thereto, followed by stirring at room temperature for 15 hours. After water was added to the reaction mixture, the product was extracted with ethyl acetate. The organic layer was washed with 5% hydrochloric acid and a 5% aqueous solution of sodium hydroxide, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by silica gel column chromatography (using a 40:1 mixture of chloroform and methanol as the eluent) to obtain 1.0 g of N′-acetyl-4-methoxy-N-phenylbenzohydrazide.