Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:24][CH2:23][N:22]([C@@:25]4([CH3:38])[CH2:29][CH2:28][N:27]([C:30](=S)[NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[CH2:26]4)[C:12]=3[N:13]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:15]=2)=[CH:6][N:5]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(O)C>[CH3:36][C:32]1([CH3:35])[CH2:33][O:34][C:30]([N:27]2[CH2:28][CH2:29][C@@:25]([N:22]3[C:12]4[N:13]=[C:14]([N:16]5[CH2:17][CH2:18][O:19][CH2:20][CH2:21]5)[N:15]=[C:10]([C:7]5[CH:8]=[N:9][C:4]([NH2:3])=[N:5][CH:6]=5)[C:11]=4[CH2:24][CH2:23]3)([CH3:38])[CH2:26]2)=[N:31]1
Reactant: CC(C)(CO)NC(=S)N1CC[C@](C)(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)C1
Solvent: ClCCl
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC(N2CC[C@](C)(N3CCc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)C2)=N1
Temperature: 25 °C
Reaction time: 23 h
Yield: 36.3 %

Procedure:
Methyl iodide (15.2 μL, 0.24 mmol) was added to a solution of (S)-3-(4-(2-aminopyrimidin-5-yl)-2-morpholino-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-3-methylpyrrolidine-1-carbothioamide (38.0 mg, 0.074 mmol) and diisopropylethylamine (28.3 μL, 0.16 mmol) in DCM (0.74 mL) and ethanol (0.74 mL) and the mixture was stirred at room temperature for 23 h. The reaction mixture was partitioned between DCM and 50% brine solution. The organic layer was separated, dried with Na2SO4, filtered and concentrated. The residue was purified by preparative SFC (Cosmosil 3-hydroxyphenyl bonded 150×21.2 mm, 5 μm, 100A column) eluting with 15%-50% CO2 in MeOH with a flow rate of 80 mL/min, at 100 bar to give the title compound (12.9 mg, 36%) as a white solid. 1H NMR (700 MHz, DMSO-d6) δ 8.72 (s, 2 H), 6.99 (s, 2 H), 3.94-3.86 (m, 2 H), 3.74 (d, J=10.4 Hz, 1 H), 3.68-3.59 (m, 8H), 3.55-3.52 (m, 1 H), 3.11-3.06 (m, 2 H), 2.41 (dt, J=12.4, 7.9 Hz, 1 H), 2.10 (ddd, J=12.4, 7.3, 5.0 Hz, 1 H), 1.29 (s, 3 H), 1.17-1.10 (m, 6 H). m/z (APCI+) for C24H33N9O2 479.9 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([O:18]C)=[O:17])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[C:8]([C:16]([OH:18])=[O:17])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OCCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(C(=O)O)c2c1CCCCO2

Procedure:
To a solution of 5 g (19.0 mmol) of methyl 6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate in 10 ml of methanol is added 10 ml of a 10% aqueous sodium hydroxide solution in a single portion at room temperature. The reaction mixture is heated to reflux and maintained at that temperature for 2 hours. After cooling, methanol is removed in vacuo and the residue is diluted with water. The pH of the solution is adjusted to 7 with 1N HCl and the solution is extracted with CH2Cl2. The combined organic extracts are dried over MgSO4, filtered and concentrated. Flash chromatography (30% EtOAc/hexanes) gives 6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]([CH3:13])[CH3:12].[BH3-]C#[N:17].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH2:17])[CH2:10][N:11]([CH3:13])[CH3:12]
Reactant: CN(C)CC(=O)c1ccc(Cl)cc1Cl
Reactant: [BH3-]C#N
Agent: [Na+]
Product: CN(C)CC(N)c1ccc(Cl)cc1Cl

Procedure:
In a manner similar to Preparation 21 react 1-(2,4-dichlorophenyl)-2-(dimethylamino)ethanone with NH4OAc and NaCNBH3 to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]#[N:14])[C@H:10]([O:15][C:16](=[O:18])[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.C(Cl)(Cl)Cl.CC(O)=O.O=[Pt]=O>[C:16]([OH:18])(=[O:15])[CH3:17].[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[C@H:10]([O:15][C:16](=[O:18])[CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C#N
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN
Reaction time: 16 h

Procedure:
79.3 A suspension of (3S,4S)-3-acetoxy-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (89 mg) in 10 ml of AcOEt and 0.2 ml of chloroform, 0.2 ml of AcOH and 4 mg of PtO2 was hydrogenated at 22° C. and atmospheric pressure for 16 h. The suspension was filtered and the filtrate evaporated to give (3S,4R)-3-acetoxy-4-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester acetate. Colorless semisolid. MS 259.3 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]2=[O:23])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C([O-])(O)=O.[Na+]>O.C1COCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:25][CH:24]=3)[C:8]2=[O:23])=[CH:14][CH:15]=1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(N)cc3)C2=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccc(CN2CCN(Cc3ccc(NS(C)(=O)=O)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.8 %

Procedure:
To a solution of 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-imidazolidin-2-one (F) (410 mg, 1.22 mmol) and triethylamine (0.2 mL, 1.44 mmol) in abs. THF there was added a solution of methanesulphonyl chloride (0.12 mL, 1.56 mmol) in 0.8 mL of abs. THF within a period of 20 min. The reaction mixture was stirred over a period of 15 h at RT, sat. NaHCO3 solution (10 mL) was added, and the mixture was stirred for 30 min. H2O (30 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic phases were washed with sat. NaCl solution, dried over Na2SO4, and the solvent was removed in vacuo. Following purification, by column chromatography, of the residue (SiO2, EtOAc/cyclohexane 2:1), there were obtained the desired product N-{4-[3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-ylmethyl]phenyl}methanesulfonamide (4) (70 mg, 14% of theory, mp: 166-168° C.) and N-{4-[3-(4-tert-butylbenzyl)-2-oxoimidazolidin-1-ylmethyl]phenyl}-N,N-bis(methanesulfonyl)imide (G) (160 mg, mp: 184-187° C.).
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](Cl)=[O:16])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:32]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:32]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:45])[CH3:46])[NH:42][C:15](=[O:16])[C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C@@H:12]([C:10]([O:9][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)OCOC(=O)C(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Pivaloyloxymethoxycarbonyl)-2,4-(R*,R*)-dibenzylbutyryl chloride (1.2 g) in 10 ml of methylene chloride is added slowly to a solution of 0.60 g of (L)-leucine benzyl ester and 0.30 ml of triethylamine in 20 ml of methylene chloride. The reaction is stirred overnight at room temperature. The solution is washed with 2N hydrochloric acid, then with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to give N-[4-pivaloyloxymethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-L-leucine benzyl ester.
Reaction SMILES: Br[CH:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:15])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:35]([NH2:38])(=[NH:37])[CH3:36]>C(#N)C.C(Cl)(Cl)Cl>[CH3:36][C:35]1[NH:37][C:8]2[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[N:5]([C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=3)=[O:15])[CH2:4][CH2:3][C:2]=2[N:38]=1
Reactant: CC(=N)N
Reactant: COC(=O)c1ccc(C(=O)N2CCC(Br)C(=O)c3ccccc32)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)N2CCc3nc(C)[nH]c3-c3ccccc32)cc1OC
Temperature: 90 °C
Yield: 43.7 %

Procedure:
To a suspension of methyl 4-(4-bromo-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl-2-methoxybenzoate (240 mg) and potassium carbonate (767 mg) in acetonitrile (8 ml) was added acetamidine hydrochloride (472 mg) and the mixture was heated at 90° C. for 3 hours. After cooling, the reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography (SiO2; 30 g, ethyl acetate) to give methyl 4-(2-methyl-1,4,5,6-tetrahydro-imidazo[4,5-d][1]benzazepin-6-yl)carbonyl-2-methoxybenzoate (95 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:24])[C:11]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:7]=1)=[O:5])C.[OH-].[Na+]>>[N:18]1([C:11]2[C:10]([F:24])=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]3[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:13][C:12]=2[F:17])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Yield: 78.5 %

Procedure:
0.805 g (2,04 mmoles) of 7-piperazinyl-1-(1,1 dimethylethyl)-1,4-dihydro-6,8-difluoro-4-oxo-3-quinolinecarboxylic acid ethyl ester was hydrolyzed with 1,05 mL 2N NaOH for two hours. The solution was evaporated to dryness neutralized with 5% acetic acid (pH 7.0). The solid was filtered to give 0.585 g of titled compound.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1C=CC=CC=1>[CH2:8]([O:4][C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH3:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: CCC(=O)C(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CCC(=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A mixture of 2-oxobutyric acid (11.5 g, 113 mmol), and benzyl alcohol (14.0 mL, 135 mmol) in benzene (100 mL) was heated to reflux under a Dean-Stark water separator. After refluxing for 16 hrs˜2 mL of water had collected in the trap (˜100% of theoretical). The reaction mixture was allowed to cool to ambient temperature, and then concentrated under reduced pressure to afford a pale yellow oil. The crude material was purified by flash chromatography eluting with a gradient from 0% to 15% ethyl acetate/hexane to afford 2-oxo-butyric acid benzyl ester (13.0 g, 60% yield) as a clear colorless oil. 1H-NMR (400 MHz, CDCl3): δ 7.42-7.35 (5H, m), 5.28 (5H, s), 2.87 (2H, q, J=7.2 Hz), 1.12 (3H, t, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10]([NH2:13])=[N:9]2)=[CH:4][CH:3]=1>C(O)C.Cl[Cu]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC1=NN(c2ccc(Br)cc2)CC1
Agent: Cl[Cu]
Solvent: CCO
Product: Nc1ccn(-c2ccc(Br)cc2)n1
Reaction time: 3 h
Yield: 50.5 %

Procedure:
In the same apparatus and following the same modalities as in Example 1, 1 g (0.00416 mole) of 1-(p-bromophenyl)-3-amino-2-pyrazoline was suspended in 10 ml of ethanol with addition of 0.04 g (0.0004 mole) of CuCl and of 0.013 g (0.0002 mole) of Cu, under an oxygen head. Oxidation was concluded after about 3 hours. The oxidized product was recovered as in Example 1, thus obtaining 0.5 g of 1-(p-bromophenyl)-3-aminopyrazole, of melting point 122°-123° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[ClH:16]>[Pd].C(O)C>[ClH:16].[ClH:16].[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-n2ccnc2)cc1
Reaction time: 1.33 h
Yield: 96 %

Procedure:
A mixture of 4-(imidazol-1-yl)nitrobenzene (89.60 g, 0.474 mol) and 10% palladium on carbon (4.50 g) in ethanol (1200 ml) and 5N HCl (189 ml) was hydrogenated in two batches at 40 psi for 80 minutes. Water (450 ml) was then added to dissolve the product and the catalyst was removed by filtration, washing with more water, and the combined filtrates were evaporated in vacuo, using finally a freeze drier, to give 105.4 g (96%) of the title compound as a cream solid. δH (250 MHz, D2O) 7.22 (2H, d, J=8.8 Hz), 7.35 (1H, t, J=2.1 Hz), 7.44 (2H, d, J=9.0 Hz), 7.59 (1H, t, J=1.8 Hz), 8.89 (1H, t, J=1.5 Hz).
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:7][CH3:8])=[N:5][CH3:6].Cl.[C:10](Cl)(=O)[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH3:8][NH:7][C:4]1[N:5]([CH3:6])[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:2][N:3]=1
Reactant: CN=C(NC)NN
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: I
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: CNc1nnc(-c2ccncc2)n1C
Temperature: 160 °C
Yield: 26.2 %

Procedure:
A mixture of 1000 mg (4.35 mmol) N-amino-N′,N″-dimethyl-guanidine hydriodide (Henry; Smith; J. Amer. Chem. Soc.; 73; 1951; 1858) and 774 mg (4.35 mmol) isonicotinoyl chloride hydrochloride in pyridine (3 mL) was heated under microwave irradiation for 5 min at 160° C. Aq. sat. K2CO3 was added and the mixture was extracted with CHCl3. The organic phase was dried and concentrated. Recrystallization from EtOH, water and EA gave 216 mg (26%) of the title compound. 1H NMR (DMSO-d6): 2.85 (d, 3 H) 3.45 (s, 3 H) 6.25 (d, 1 H) 7.65 (m, 2 H) 8.67 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[CH:13]=[N:12][CH:11]=2)[N:5]=[C:4]([OH:18])[CH:3]=1.[Li]CCCC.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CO>[Cl:24][C:13]1[N:14]([CH:15]([CH3:16])[CH3:17])[C:10]([CH2:9][S:8][C:6]2[N:5]=[C:4]([OH:18])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:11][N:12]=1
Reactant: Cc1cc(O)nc(SCc2cncn2C(C)C)n1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O)nc(SCc2cnc(Cl)n2C(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
In a 250 mL round bottom flask, 6-methyl-2-({[1-(propan-2-yl)-1H-imidazol-5-yl]methyl}sulfanyl)pyrimidin-4-ol (260 mg, 1.0 mmol) was dissolved in THF (20 mL) at −78° C. BuLi (0.88 mL, 2.2 mmol) was added dropwise. After 1 hour, hexachloroethane (360 mg, 1.5 mmol) was added. The resulting mixture was stirred at 0° C. for 2 hours. A few drops of methanol were added to quench the reaction. Then, the solvent as removed under vacuum, and the crude was purified by column chromatography to provide the title compound as a white solid (200 mg, 87% yield); 1H NMR (400 MHz, CD3OD): δ 1.45 (d, 6H), 2.20 (s, 3H), 4.46 (s, 2H), 4.62 (m, 1H), 6.02 (bs, 1H), 6.84 (s, 1H); M+299.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5]OC.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=1)=[CH:5][NH:24][C:23]1[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=1
Reactant: COC=C(C(=O)OC)C(=O)c1ccc(C)c(C)c1
Reactant: Nc1ccc(F)cc1
Product: COC(=O)C(=CNc1ccc(F)cc1)C(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
1 g (4.03 mmol) of the crude 2-(3,4-dimethyl-benzoyl)-3-methoxy-acrylic acid methyl ester 1a and 0.40 g (3.63 mmol) of 4-fluoroaniline were heated neat at 100° C. for 2 h. The reaction solution was cooled to room temperature and the crude product precipitated out of solution. The crude material was recrystallized from dichloromethane/hexane to yield 0.70 g of 2-(3,4-dimethyl-benzoyl)-3-(4-fluoro-phenylamino)-acrylic acid methyl ester 2g as brown crystalline solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=3[Cl:36])[CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[N:17]=2)=[CH:12][CH:11]=1>CN(C=O)C>[Cl:36][C:35]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=1[N:18]1[C:19](=[O:21])[NH:20][C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)=[N:17]1
Reactant: C1CCNC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(CBr)cc3)[nH]c2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(CN4CCCC4)cc3)[nH]c2=O)c1
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a cold solution of pyrrolidine (0.060 g, 0.830 mmol) in DMF was added NaH (0.034 g, 0.830 mmol) at 0° C. and stirred the reaction mass for 1 h. Then solution of N-(3-(3-(4-(bromomethyl)phenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)-4-chlorobenzyl)pivalamide (Intermediate-103, 0.200 g, 0.419) in DMF was added at 0° C. and continued stirring at 5-10° C. for 2-3 h. The reaction mass was quenched in ice and pH adjusted to 6-7 and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified by column chromatography on basic alumina, eluting with 5% MeOH:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.23 (s, 9H), 1.79 (br s, 4H), 2.53 (br s, 4H), 3.66 (s, 2H), 4.48 (d, J=5.7 Hz, 2H), 6.08 (m, 1H), 7.26-7.54 (m, 5H), 7.79 (d, J=7.8 Hz, 2H); MS (m/z): 468.51 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][C:4]#[CH:5].[O:7](C(OC(C)(C)C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O>C(Cl)Cl>[C:11]([O:10][C:8](=[O:7])[NH:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C#CCCCN
Solvent: ClCCl
Product: C#CCCCNC(=O)OC(C)(C)C

Procedure:
A solution of pent-4-ynylamine (480 mg; Li, Y. et al. J. Am. Chem. Soc. 1996, 118, 9295) in DCM (5 mL) was treated with (BOC)2O at rt for 15 min. Evaporation gave the title compound as a colorless oil. 1H NMR (CDCl3) δ 4.68 (s, 1H), 3.24 (q, 2H), 2.25 (td, 2H), 1.97 (t, 1H), 1.70 (quint., 2H), 1.45 (s, 9H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH2:12][CH3:13])[C:10]([CH3:14])=[N:9][CH:8]=1)=O.C(=O)(O)O.[C:20]1([NH:26][C:27]([NH2:29])=[NH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[O-].[Na+].O>CC(N(C)C)=O>[NH:26]([C:27]1[N:29]=[C:5]([C:7]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:14])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CCn1c(C(=O)C=CN(C)C)cnc1C
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1C
Temperature: 110 °C
Yield: 52.5 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-ethyl-2-methylimidazole (Method 23; 2.10 g, 10.1 mmol), phenylguanidine hydrogen carbonate (2.2 g, 11.1 mmol) and sodium methoxide (1.2 g, 22.2 mmol) were suspended in anhydrous DMA (15 ml) and the mixture heated at 110° C. for 18 hours. The reaction mixture was allowed to cool to ambient temperature and poured into water (50 ml). The solution was extracted EtOAc (2×50 ml). The combined extracts were washed with water (2×50 ml) and then brine (2×50 ml), dried and the volatiles removed by evaporation. The residue was triturated with ether, collected by filtration and air dried to give the title compound (1.48 g, 53%) as a reddish brown solid. NMR 1.17 (t, 3H), 2.38 (s, 3H), 4.52 (q, 2H), 6.93 (t, 1H), 7.08 (d, 1H), 7.27 (t, 2H), 7.60 (s, 1H),7.62 (d, 2H), 8.35 (d, 1H), 9.35 (s, 1H); m/z 280.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12](/[CH:17]=[CH:18]/[C:19]#[N:20])[CH:13]=[CH:14][C:15]=1[Cl:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.C1COCC1>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:17][CH2:18][C:19]#[N:20])=[CH:11][C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(/C=C/C#N)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#CCCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2E)-3-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-chlorophenyl]acrylonitrile from the previous step (1 eq.) in toluene (0.01 M) was added at 80° C. benzenesulfonyl hydrazide (3×1 eq.) over 3 h. The reaction mixture was diluted with EtOAc and washed sequentially with water, sat. aq. NaHCO3 and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded a yellow oil. The residue was taken up in THF (0.1 M) and added tetrabutylammonium fluoride (1.0 M THF solution, 1.1 eq.). The resulting reaction mixture was stirred at RT for 2 h. After quenching the reaction with sat. aq. NH4Cl, the mixture was extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo and purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[N:13]=1)[CH2:9][C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.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>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[N:13]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[O:16][N:15]=1
Reactant: C#CCCc1nc(-c2ccccc2OC)no1
Reactant: Ic1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1noc(CCC#Cc2ccccn2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.6 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (12 mg, 0.07 mmol) and triethylamine (4.1 mL, 29 mmol), were added 2-iodopyridine (139 μL, 1.3 mmol) and Pd(PPh3)2Cl2 (46 mg, 0.07 mmol) under N2. A yellow suspension is obtained and after a few minutes of string at room temperature, was added a solution 5-(but-3-ynyl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole (299 mg, 1.3 mmol) in triethylamine (0.7 mL) under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 20 h under N2. Triethylamine was removed under reduce pressure and the crude product was purified by flash chromatography (Prepacked column 10 g, cyclohexane/AcOEt: from 60/40 to 50/50 as eluent) to afford 50 mg of 2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (13%) as brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH3:12])[N:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].CCN(C(C)C)C(C)C>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:15]([CH3:14])[O:16][CH3:17])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][CH3:12])[N:3]=1
Reactant: CNOC
Reactant: CCCNc1nc(N)nc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1nc(N)nc(N(C)OC)n1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A mixture of 6-amino-2-chloro-4-n-propylamino-[1,3,5]triazine (XXXVIII) (5 g, 26.65 mmol), N,O-dimethylhydroxylamine hydrochloride (13 g, 133.24 mmol) and DIPEA (27.5 g, 213.2 mmol) in EtOH (100 mL) was heated at 100° C. for 16 h, after which time the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (400 mL), which was washed with water (200 mL) and then with a brine solution (200 mL) and finally dried over Na2SO4. The solvent was removed under reduced pressure to yield N-(6-amino-4-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXIX) as a white solid (5 g, 89% yield). LCMS (ESI) m/z=213 (M+H)+.