Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:13][CH2:14][CH:15]([NH2:18])[CH2:16][F:17]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([S:8]([NH:18][CH:15]([CH2:16][F:17])[CH2:14][F:13])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: NC(CF)CF
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(NC(CF)CF)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
2-Chloropyridine-5-sulfonyl chloride (18 g, 85 mmol) was added to a solution of 1,3-difluoro-2-propylamine hydrochloride (11.2 g, 58.1 mmol) in pyridine (25 mL) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 mL) and washed with 3N aq. HCl (3×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane (2×50 mL) and filtered to provide the title compound as an off-white solid (15.7 g, 70%). 1H NMR (500 MHz, CDCl3): δ 8.79 (1H, d, J=2.4 Hz), 8.17 (1H, dd, J=2.6 Hz, 2.5 Hz), 7.49 (1H, d, J=8.2 Hz), 5.25 (1H br s), 4.58 (2H, m), 4.47 (2H, m), 3.77 (1H, m).
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.Cl.Cl.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([N:32]2[CH2:37]CNC[CH2:33]2)[N:23]=1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([N:32]2[CH2:37][CH2:18][N:16]([CH2:15][C:4]3[C:5]4[CH2:6][CH2:7][C:8]5[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=5[C:10]=4[NH:2][N:3]=3)[CH2:19][CH2:33]2)[N:23]=1
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Reactant: c1ccc2cc(N3CCNCC3)ncc2c1
Agent: Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: c1ccc2c(c1)CCc1c(CN3CCN(c4cc5ccccc5cn4)CC3)n[nH]c1-2
Yield: 8.9 %

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.40 g), 4-isoquinolin-3-yl-piperazine dihydrochloride (0.31 g) and diisopropylethylamine (1.0 cm3) in DMF (5 cm3) was heated under argon at 80° C. for 48 hours. The mixture was cooled, then poured into water (50 cm3) and extracted with 50% diethyl ether-ethyl acetate (2×50 cm3). The organic extracts were dried (MgSO4), filtered and concentrated to give a brown oil that crystallised on standing. The material was recystallised twice from ethyl acetate-hexane to give the title compound (0.038 g; 9%) as grey granules, m.p. 228°-230° C. (from EtOAc-hexane); Found: C, 75.0; H, 6.3; N, 17.3. C25H25N5.0.25(H2O) requires C, 75.0; H, 6.4; N, 17.5%. δH (360 MHz; d6 -DMSO) 2.54-2.57 [4H, m, N(CH2)2 ], 2.71 (2H, t, J 7.0, --CH2 --), 2.88 (2H, t, J 7.0, --CH2 --), 3.50-3.57 [4H, m, N(CH2)2 ], 3.59 (2H, broad s, --CH2N), 6.94 (1H, s, 1 of ArH), 7.15-7.28 (4H, m, 4 of ArH), 7.53 (1H, t, J 7.8, 1 of ArH), 7.65 (2H, d, J 8.2, 2 of ArH), 7.85 (1H, d, J 8.1, 1 of ArH), 8.96 (1H, s, 1 of ArH), 12.56 and 12.96 (1H, 2 x broad s, NH); m/z (CI+ ; NH3) 396 (MH+ ; 8%), 214 (68), 185 (50), 132 (50), 130 (80), 87 (70) and 61 (100).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](N)(=[O:12])[CH:10]=[CH2:11].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]1([N:7]2[CH2:11][CH2:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(N)=O
Reactant: NNc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: O=C1CCN(c2ccccc2)N1

Procedure:
Phenylhydrazine (10.8 g, 0.1 mol), and acrylamide (7.8 g, 0.11 mol), pulverized potassium hydroxide (12.5 g, 0.22) and a catalytic amount of tetrabutylammonium bromide is refluxed for 30 minutes. The precipitate is filtered and washed with toluene. The crystalline sold is dissolved in water. Acidification with acetic acid, filtration and drying gives 1-phenyl-3-pyrazolidone.
Reaction SMILES: C1(O)C=CC=CC=1.CC(C)([O-])C.[K+].N[C:15]1[N:24]=[C:23]([NH2:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[F:26])[N:16]=1>CS(C)=O.O>[NH2:25][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[F:26])[N:16]=[CH:15][N:24]=1
Reactant: Nc1nc(N)c2c(F)cccc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncnc2cccc(F)c12
Temperature: 25 °C

Procedure:
A solution of phenol (optionally substituted) in dimethyl suiphoxide was added to a stirred mixture of potassium tert-butoxide in dimethyl suiphoxide at room temperature. After 15 minutes 2,4-diamino-5-fluoroquinazoline was added all at once (as the solid) and the mixture was heated to ca 50° C. for 7 hours. After cooling to room temperature the suspension was diluted with water, the solid collected by is filtration, washed, recrystallized from ethanol or n-butyl acetate and dried at 50° C. in vacuo. In particular, 4-Amino-5-fluoroquinazoline was prepared from 2,6-difluorobenzonitrile (Lancaster, Acros) according to the published method (J. Heterocyclic. Chem. 28, 1357 (1991)).
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.CC1CNCC(C)N1.[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.[CH3:36][CH:37]1[NH:42][CH:41]([CH3:43])[CH2:40][N:39]([S:44]([C:47]2[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH2:38]1>>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:51](=[O:52])[C:50]2[CH:54]=[CH:55][C:47]([S:44]([N:39]3[CH2:38][CH:37]([CH3:36])[NH:42][CH:41]([CH3:43])[CH2:40]3)(=[O:46])=[O:45])=[CH:48][CH:49]=2)=[CH:25][C:24]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: CC1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC(C)N1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: CC1CNCC(C)N1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC1CN(S(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC(C)N1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 570 mg of 2,6-dimethylpiperazine via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 119 mg of 4-(3,5-dimethylpiperazin-1-ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3,5-dimethylpiperazin-1-ylsulfonyl)benzamide. MS (Q1) 485.4 (M)+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:6]([C:17]([O:19][CH3:20])=[O:18])[CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@@H:6]([C:17]([O:19][CH3:20])=[O:18])[CH2:5]1
Reactant: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](N)CCN1C(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 98 %

Procedure:
(2R,4R)-1-tert-butyl 2-methyl 4-azidopiperidine-1,2-dicarboxylate (22.5 g, 79 mmol) was dissolved in methanol (400 mL), Pd/C (10%, 6 g) was added, and the apparatus was flushed three times with N2 and H2. The reaction mixture was hydrogenated at a pressure of 50 psi at room temperature for 20 hours, filtered through Celite and rinsed with methanol and then concentrated under reduced pressure to give the amine as a colorless oil 20 g (96%). GC-MS: 258 (t=2.8 min).
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[C:17]([O:21][CH2:22][CH2:23]O)(=[O:20])[CH:18]=[CH2:19].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:17]([O:21][CH2:22][CH2:23][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)(=[O:20])[CH:18]=[CH2:19]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: C=CC(=O)OCCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Yield: 17.8 %

Procedure:
At room temperature, 500 mg of biotin (Compound i, product of Merck & Co., Inc.), 200 mg of 2-hydroxyethyl acrylate, 20 ml of thionyl chloride and 20 ml of toluene were mixed. The resulting mixture was refluxed for 2 hours. The solvent was then distilled off under reduced pressure. The residue was subjected to column chromatography by using a chloroform-methanol solvent mixture. By removal of the solvent, 100 mg of 2-biotinylethyl acrylate (Compound A) was obtained as a powdery substance (yield: 14%).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]4)[N:13]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:25][C:23]1([CH3:26])[CH2:24][CH:19]([NH:18][C:14]2[N:13]=[C:12]([C:7]3[C:6]4[C:10](=[CH:11][C:3]([OH:2])=[CH:4][CH:5]=4)[NH:9][CH:8]=3)[CH:17]=[CH:16][N:15]=2)[CH2:20][C:21]([CH3:28])([CH3:27])[NH:22]1
Reactant: COc1ccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(O)ccc34)n2)CC(C)(C)N1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
[4-(6-Methoxy-1H-indol-3-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (150 mg, 0.4 mmol) was suspended in 6 ml of DCM under argon. After cooling to 0° C., boron tribromide (1.64 ml of a 1M solution in DCM, 1.64 mmol) was added slowly. The cooling bath was removed after 30 minutes and stirring was continued for 16 hours. The reaction was quenched by adding 8 ml of MeOH at 0° C. and the product crystallised from this solution in form of its hydrobromide salt. Yield: 155 mg (94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[C:14]1([N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][C:22](O)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OC(=O)C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:22](=[O:23])[CH2:21][N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: O=C(O)CN(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=O)CN(c2ccccc2)c2ccccc2)cc1OC
Yield: 66.9 %

Procedure:
3,4-Dimethoxyphenethylamine (8.05 g) and N,N-diphenylglycine (10 g) were heated for 2 hours at 190° C. After cooling, the reaction mixture was dissolved in ethylacetate. The resulting solution was washed with a 5% sodium bicarbonate aqueous solution and water and then dried. The solvent was distilled off from the solution to give crystals of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N,N-diphenylamino)acetamide (11.5 g), mp 88° to 93° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.C(Cl)(Cl)=O.[C:12]1([NH:18][C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[NH:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[OH-].[Na+].[C:35]([OH:44])(=[O:43])[C@@H:36]([C@H:38]([C:40]([OH:42])=[O:41])[OH:39])[OH:37]>C1(C)C=CC=CC=1.C(Cl)Cl.C(O)(C)C>[C:40]([C@@H:38]([C@H:36]([C:35]([OH:44])=[O:43])[OH:37])[OH:39])([OH:42])=[O:41].[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[N:20][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[N:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCCC1=O
Reactant: N=C(Nc1ccccc1)N1CCCC1
Agent: O=C(Cl)Cl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCCC1=NC(=Nc1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a cooled solution of 1.98 g (0.02 mole) of 1-methyl-2-pyrrolidone in dry toluene is added 3.95 g (0.04 mole) of phosgene. The resulting mixture is allowed to stir under N2 to room temperature over 45 minutes to give white crystals. The excess COCl2 and solvent are removed with the aid of a filter stick (under N2). Fresh toluene is added, then removed under vacuum in order to remove residual phosgene. The crystals are washed in this way with fresh toluene two more times and then dissolved in dry CH2Cl2 followed by the addition of 1.89 g (0.01 mole) of N-phenyl-1-pyrrolidinecarboximidamide and 1.01 g (0.01 mole) of triethylamine. The resulting mixture is stirred overnight under N2. The mixture is taken to dryness in vacuo, the residue dissolved in CH2Cl2 and the latter solution treated with NaOH (50%) in ice. The organic layer, which contains the free base form of the product, is separated, dried over anhydrous K 2 CO3, filtered and taken to dryness in vacuo affording an oily residue. The oil is dissolved in isopropanol followed by addition of L-(+)-tartaric acid to about pH 6-7. The resulting crystals are recrystallized from isopropanol to give pure product, N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide L-(+)-tartrate, m.p. 155°-156° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[CH2:24][CH2:25][CH2:26][CH3:27]>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.CS(C)=O>[CH2:23]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:33][CH:34]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(-c2ccc(I)cc2)cc1
Reactant: CCCCCOc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)cc1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
20.1 g of 4′-iodobiphenyl-4-carboxylic acid, 13.1 g of sodium carbonate and 21.4 g of glycol ester of 4-n-pentoxyphenylboronic acid are introduced into 260 g of dimethyl sulfoxide (DMSO) and, after addition of 160 mg of PdCl2(PPh3)2, heated at 100-110° C. for 2 hours. The solid is filtered off at 40° C., washed with dimethyl sulfoxide and suspended in 100 ml of water. It is then heated to 80° C., and 47 g of 37% strength sulfuric acid are added dropwise over the course of 1 hour. The mixture is stirred at 80° C. for a further 30 minutes, cooled at 40° C. and filtered. Drying and crystallization from dimethylacetamide results in 18 g (81%) of 4″-n-pentoxy-[1,1′:4′,1″]-terphenyl-4-carboxylic acid with a purity of >99%.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)=[N:19][CH:20]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccc(-c2cccc3c2oc2ccccc23)nc1
Yield: 75.8 %

Procedure:
Dibenzo[b,d]furan-4-ylboronic acid (9.5 g, 44.8 mmol), 2,5-dichloropyridine (7.0 g, 47.0 mmol), Pd(PPh3)4 (2.6 g, 2.2 mmol) and potassium carbonate (18.6 g, 134 mmol) were added to dimethoxyethane (75 mL) and water (75 mL). The reaction mixture was degassed with nitrogen before being heated to reflux overnight. EtOAc and water were added, the organic layer separated and the aqueous layer was extracted with 3×50 mL dichloromethane and dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product was chromatographed on silica gel with dichloromethane to yield 11.7 g of crude product. The product was crystallized from hexane to give 9.5 g (76%) of 5-chloro-2-(dibenzo[b,d]furan-4-yl)pyridine as white needles. The product was confirmed by GC/MS.
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([Cl:47])=[C:16]([NH:22][C:23]4[N:28]=[C:27]([N:29]([CH:39]5[CH2:41][CH2:40]5)CC5C=CC(OC)=CC=5)[C:26]5=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]5[N:24]=4)[CH:17]=[C:18]([C:20]#[N:21])[CH:19]=3)[CH2:10][CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[C:1]([N:4]1[CH2:7][CH:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]([Cl:47])=[C:16]([NH:22][C:23]4[N:28]=[C:27]([NH:29][CH:39]5[CH2:40][CH2:41]5)[C:26]5=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]5[N:24]=4)[CH:17]=[C:18]([C:20]#[N:21])[CH:19]=3)[CH2:10][CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5CN(C(C)=O)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)N1CC(N2CCN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)C1
Temperature: 50 °C
Yield: 55.6 %

Procedure:
To a solution of 2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (110 mg, 0.169 mmol) in DCE (1.1 mL) and anisole (0.108 mL, 0.985 mmol) was added TFA (0.296 mL, 3.84 mmol) slowly drop wise at room temperature and the reaction mixture was heated at 50° C. for overnight. The reaction mixture was concentrated to remove solvent completely; the resultant residue was washed with hexane to remove anisole. The residue was diluted with Ethyl acetate, washed with aq. ammonia solution, brine, dried over Na2SO4 and concentrated. The crude material was purified by reverse phase HPLC, the fractions were concentrated and the resultant solid was dissolved in HPLC grade Chloroform (20 ml), washed with 10% NaHCO3 solution, brine, dried over Na2SO4 and concentrated. The solid was dissolved in Acetonitrile/water (1:3). Froze the mixture using a dry-ice acetone bath and then dried under lyophilization for 2 days. Lyophlization afforded 2-((3-(4-(1-acetylazetidin-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg) as a off white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[S:8])[CH2:6][O:5][C:4]1=[S:9])[CH3:2].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:7](=[S:8])[C:6](=[CH:23][C:21]2[O:22][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH3:10])=[CH:19][CH:20]=2)[O:5][C:4]1=[S:9])[CH3:2]
Reactant: CCN1C(=S)COC1=S
Reactant: COc1ccccc1-c1ccc(C=O)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN1C(=S)OC(=Cc2ccc(-c3ccccc3OC)o2)C1=S
Yield: 95 %

Procedure:
To a mixture of 3-ethyloxazolidine-2,4-dithione 6 (79 mg, 0.49 mmol), 5-(2-methoxyphenyl)-2-furaldehyde 9 (99 mg, 0.49 mmol) and sodium acetate (201 mg, 2.45 mmol) was added acetic acid (5 mL). As more of the desired product was formed, the reaction mixture color turned to a very red solution. The reaction mixture was refluxed overnight, then the excess solvent was removed in vacuo. The residue was diluted with ethyl acetate (100 mL), then washed with water (2×20 mL). The organic layer was dried with brine and MgSO4, then concentrated in vacuo. Flash column chromatography afforded the desired product 2 (M103) in 95% yield (160 mg, purple solid).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[S:3])[NH2:2].C([O-])(=O)C.[Na+].Br[CH:22]([CH:25]=O)[CH:23]=[O:24]>C1COCC1.C(O)(=O)C>[CH:23]([C:22]1[S:3][C:1]([N:4]2[CH2:8][CH2:7][CH2:6][C@H:5]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:2][CH:25]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(N)=S
Reactant: O=CC(Br)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1c1ncc(C=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To a solution of material from Example 78 (1.075 g, 4.67 mmol) in a mixture of THF (51.3 mL) and acetic acid (8.55 mL) is added sodium acetate (0.46 g, 5.60 mmol), followed by 2-bromomalonaldehyde (0.82 g, 5.13 mmol) and the reaction is stirred at room temp for 2 h. The solvent is removed in vacuo, the residue is partitioned between water and CH2Cl2 and the water layer is extracted with CH2Cl2 (1×20 mL). The organic layers are combined, partitioned with water and treated with solid sodium bicarbonate until the water layer has pH=8. The water layer is extracted with CH2Cl2 (2×25 mL), the organic layers are combined, washed with brine, dried over MgSO4, filtered and the solvent is removed in vacuo, The resulting residue is purified by BIOTAGE® Silica gel chromatography on a Thompson Single Step silica cartridge using an isocratic mixture of 40% ethyl acetate/60% CH2Cl2 to give 945 mg (68.1%) of the title compound as a yellow solid. LC/MS (Condition A): ret. T=3.23 min, (M+Na) 305.14. 1H NMR (400 MHz, chloroform-d) δ ppm 9.69 (1 H, s), 7.89 (1 H, s), 4.49 (1 H, br. s.), 3.36-3.87 (2 H, m), 2.32-2.51 (1 H, m), 2.03-2.29 (3 H, m), 1.46 (9 H, s).
Reaction SMILES: [C:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@:12]4([CH3:21])[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)#[CH:2].O1CCO[CH2:25][CH2:24]1.C(OC(O)O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.N1C=CC=CC=1>[C:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@:12]4([CH3:21])[C:17](=[CH:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH:16]=[C:15]([O:20][CH2:24][CH3:25])[CH2:14][CH2:13]4)#[CH:2]
Reactant: C1COCCO1
Reactant: C#C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CCC2=O
Agent: CCOC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: O
Product: C#C[C@]12CC[C@H]3[C@@H](CC=C4C=C(OCC)CC[C@@]43C)[C@@H]1CCC2=O
Temperature: 25 °C

Procedure:
A mixture of 1.2 g of 13-ethinyl-10-methyl-gon-4-ene-3,17-dione, 20 ml of dioxane, 2 ml of orthoformic acid ethyl ester and 60 mg of p-toluenesulphonic acid is stirred at room temperature for 3 3/4 hours with exclusion of light. The reaction mixture is poured into 150 ml of water containing 5 drops of pyridine and extracted twice with ethyl acetate and the organic layer is washed with water and saturated sodium chloride solution until neutral, dried and evaporated in a water pump vacuum. The crystalline crude 13-ethinyl-3-ethoxy-10-methyl-gona-3,5-dien-17-one, which is obtained, is then dissolved in 20 ml of dioxane and the solution is added dropwise, in the course of 30 minutes, to a solution, which is saturated with acetylene, of 6 g of a lithium acetylide/ethylenediamine complex in 60 ml of dioxane, whilst passing acetylene through the mixture at the same time. The reaction mixtue is then stirred for a further 15 minutes at room temperature and treated, whilst cooling, with saturated ammonium chloride solution and with ethyl acetate and the organic phase is washed successively with 1 N hydrochloric acid and saturated sodium chloride solution, dried and evaporated in a water pump vacuum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:5]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C1COCC1>[Cl:25][C:20]1[CH:19]=[C:18]([CH:5]2[CH:4]([CH2:3][CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(CCN)C(c2ccc(Cl)c(Cl)c2)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CCNS(C)(=O)=O)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (6RS,7RS)-7-(2-aminoethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (135 mg) obtained in Example 484, step A in THF (3.0 mL) were added triethylamine (0.145 mL) and methanesulfonyl chloride (0.054 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (157 mg).