Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:32]([O-:34])=[O:33])=[C:20]([CH2:23][S:24][C:25]([C:27]3[O:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1.[Na+].[C:36]1(=[O:65])[N:40]([C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][C:50]([O:52][N:53]3[C:57](=[O:58])[CH2:56][CH:55](S(O)(=O)=O)[C:54]3=[O:63])=[O:51])=[CH:43][CH:42]=2)[C:39](=[O:64])[CH:38]=[CH:37]1>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:32]([OH:34])=[O:33])=[C:20]([CH2:23][S:24][C:25]([C:27]3[O:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1.[CH2:56]1[C:57](=[O:58])[N:53]([O:52][C:50]([CH2:49][CH2:48][CH2:47][C:44]2[CH:45]=[CH:46][C:41]([N:40]3[C:39](=[O:64])[CH:38]=[CH:37][C:36]3=[O:65])=[CH:42][CH:43]=2)=[O:51])[C:54](=[O:63])[CH2:55]1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSC(=O)c3ccco3)CS[C@H]12)c1csc(N)n1
Reactant: O=C(CCCc1ccc(N2C(=O)C=CC2=O)cc1)ON1C(=O)CC(S(=O)(=O)O)C1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSC(=O)c3ccco3)CS[C@H]12)c1csc(N)n1
Product: O=C(CCCc1ccc(N2C(=O)C=CC2=O)cc1)ON1C(=O)CCC1=O
Reaction time: 0.21 h

Procedure:
Ceftiofur sodium (82 mg)(The Upjohn Co., Kalamazoo, Mich.) was dissolved in 500 μL PBS-A, and 10 mg sulfosuccinimidyl 4-(p-maleimidophenyl)-butyrate (s-SMPB)(Pierce, Rockford, Ill.) in 20 μL DMF was added. The resulting mixture was stirred for 10-15 min, added dropwise to 30 mg BSA-SH (1.5 mL of a 20 mg/mL stock solution), stirred overnight at ambient temperature, and then dialyzed exhaustively against PBS-A. Similarly, 52 mg ceftiofur sodium in PBS-A and 5 mg s-SMPB in 20 μL N,N-dimethylformamide (DMF) were added dropwise to 20 mg of OVA-SH (1 mL of a 20 mg/mL stock solution), and the mixture was stirred overnight at ambient temperature and dialyzed exhaustively against PBS-B (0.05M sodium phosphate, 0.075M sodium chloride in deionized water, pH 7.2). These conjugates were abbreviated as BSA-S-SMPB-Cef and OVA-S-SMPB-Cef, respectively.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7]2/[C:8](=O)[C:9]3[CH:10]=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[N:13][C:14]=3[CH2:15][CH2:16]/2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([CH3:33])[CH:26]=1)[NH2:24]>C(O)C>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[N:13][C:14]=4[CH2:15][CH2:16]3)=[N:24]2)=[CH:26][C:27]=1[CH3:33])#[N:30]
Reactant: COC(=O)c1ccc2c(n1)CC/C(=C\C1CCCC1)C2=O
Reactant: Cc1cc(NN)ccc1C#N
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(C)c2)C1C1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In a dried reaction flask, (E)-methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylate (prepared according to the step (1) of Example 1) (0.428 g, 1.50 mmol) and 4-hydrazino-2-methylbenzonitrile hydrochloride (0.287 g, 1.56 mmol) were dissolved in ethanol (20 mL). In the protection from light and under the nitrogen atmosphere, the reaction solution was stirred at 80° C. for 8 hr. The reaction solution was concentrated under a reduced pressure to produce a crude reddish black viscous liquid (0.698 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:8]([O:10]C)=[O:9].CO>O1CCCC1>[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([F:22])([F:20])[F:21])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
A 5 N sodium hydroxide aqueous solution (13 mL) was added to a mixed solution of methyl 5-chloro-2-(4-chloro-2-trifluoromethylphenyl)pentanoate (5.3 g) in tetrahydrofuran (15 mL)-methanol (15 mL), and the mixture was stirred at room temperature for two hours and 10 minutes. After adding ice water to the reaction solution, the organic solvent was evaporated from the reaction solution under reduced pressure. The resulting aqueous layer was washed with heptane. The aqueous layer was made acidic with 5 N hydrochloric acid under ice-cooling, followed by extraction with ethyl acetate twice. The combined ethyl acetate layers were washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 4.75 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 77.6 g (0.54 mol) of 2-chloro-4-fluorotoluene, 95.6 g (0.54 mol) of N-bromosuccinimide, 1 g of benzoyl peroxide, and 1000 ml of carbon tetrachloride were refluxed for 3 h. The resulting mixture was cooled to room temperature and then filtered through a glass frit (G3). The precipitate was additionally washed with 3×100 ml of carbon tetrachloride. The combined filtrate was evaporated to dryness. Fractional distillation of the residue gave pure title product, bp 97-99° C./10 mm Hg. Yield 106 g (88%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][N:9]1[C:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12](=[O:24])[N:11]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:10]1=[O:31].[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:27][CH2:26][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:4]6[S:5][CH:6]=[CH:7][C:3]=6[CH3:2])[C:10]5=[O:31])[CH2:30][CH2:29]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cc1ccsc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5sccc5C)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-methylthiophen-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191 mg; compound B96) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10) and HBTU (167 mg) in DCM (4 ml) in the presence of DIPEA (0.28 ml) according to the procedure described in example 55 to afford the title compound after purification by flash column chromatography as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(CC(=O)C(=O)O)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H](O)C(=O)O)cc1Cl
Temperature: -35 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere a mixture of 2.6 g (12.23 mmol) 3-(3-chloro-4-methyl-phenyl)-2-oxo-propionic acid and 2.1 mL (15.1 mmol) triethylamine in 40 mL THF was cooled to −35° C. Then a solution of 5.87 g (18.30 mmol) (1R)—B-chlorodiisopinocampheylborane in 20 mL THF was added dropwise so that the reaction temperature remained between −35° C. and −25° C. The cooling bath was removed and the reaction mixture was stirred overnight at RT. While cooling with ice 30 mL 1 M NaOH and 60 mL diethyl ether were added dropwise and the mixture was stirred for 15 min. The aqueous phase was separated off, the organic phase was extracted twice with 20 mL 1 M NaOH and once with 20 mL water. The combined aqueous phases were acidified with semiconc. HCl while cooling with ice, extracted twice with 60 mL EtOAc and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH2:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:32]2[CH2:33][CH2:34][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CCN1CCNCC1
Product: CCN1CCN(C(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CC1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-ethylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-ethylpiperazine-1-carbonyl)benzamide. MS (Q1) 483 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][NH:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[CH:20]1([CH2:25]O)[CH2:24][CH2:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C(Cl)[Cl:59]>>[CH:20]1([CH2:25][N:10]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]2=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1.[ClH:59]
Reactant: OCC1CCCC1
Reactant: O=c1[nH]cc(-c2ccncc2)n1-c1ccc(F)cc1
Reactant: ClCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cl
Product: O=c1n(CC2CCCC2)cc(-c2ccncc2)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
128 mg of 1-(4-Fluorophenyl)-5-(pyridin-4-yl)-4-imidazolin-2-one (the compound of Example 1), 61 μl of cyclopentylmethanol, 197 mg of triphenylphosphine and 295 μl of diethyl azodicarboxylate were dissolved in 2.5 ml of methylene chloride, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=19:1). The obtained compound was treated with hydrochloric acid, to give 75 mg of the title compound as powder.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.[NH2:14][NH2:15].Cl.Cl.NN.O>C(O)CO>[Br:1][C:2]1[C:3]([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:14][NH:15][CH:11]=1
Reactant: Oc1nc2ccccc2cc1Br
Reactant: NN
Agent: Cl
Solvent: OCCO
Solvent: O
Product: Brc1c[nH]nc1Nc1ccccc1

Procedure:
The bromohydroxyquinoline (1.97 g, 8.79 mmol) was dissolved in 21 ml of ethylene glycol and hydrazine hydrate (4.2 ml) was added. To this mixture were added 1.3 g (12.2 mmol) of hydrazine dihydrochloride, and the resulting mixture was heated to reflux and stirred under nitrogen. The resulting material was poured onto 300 ml of H2O. The mixture was extracted with CH2Cl2, basified with NaHCO and extracted further with CH2Cl2. The combined organic portions were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to give a brown oil, yielding bromoanilinopyrazole (i.e., 3-(2-amino-5-bromophenyl)pyrazole).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCOCC1.C(O)(C)(C)C.CCCCCCC.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][S:19]([C:12]1[C:13]([CH3:18])=[N:14][C:15]2[C:10]([C:11]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:9][C:8]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:17][CH:16]=2)(=[O:21])=[O:20]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1S(C)(=O)=O
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccccc2)c1S(C)(=O)=O
Temperature: 120 °C
Yield: 398.5 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (3 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3 mg) and cesium carbonate (121 mg, 0.37 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-phenyl-quinoline (compound of example 2) (100 mg, 0.26 mmol) in dioxane/tert.-butanol 1:1 (15 ml) was added, followed by piperidine (0.027 ml, 0.031 mmol). The tube was sealed and heated at 120° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate 40:60 to give a yellow solid (47 mg, 46%). MS: m/z=381 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[C:11](=O)[NH:10][C:9]3=O)=[C:4]([F:16])[CH:3]=1.B(F)(F)F.CCOCC.S(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[C:4]([F:16])[CH:3]=1
Reactant: O=C1NC(=O)C2(c3ccc(Br)cc3F)CC12
Agent: FB(F)F
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1cc(Br)ccc1C12CNCC1C2

Procedure:
To a solution of 1-(4-bromo-2-fluoro-phenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione (2.5 g, 8.8 mmol) in THF (20 mL) were added BF3.OEt2 (1.8 mL, 1.8 mmol) and BH3.Me2S (11.0 mL, 22.0 mmol) at r.t. The reaction mixture was refluxed for 3 h and progress of the reaction was monitored by TLC. On completion, the reaction mixture was quenched with 20% HCl (10 mL) and solvent evaporated, residue was washed with diethylether (10 mL). The aqueous layer was neutralized with sodium carbonate and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The title compound was obtained as brown liquid in crude form (1.22 g, 54%) and was as such used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccc(OC)cc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccc(OC)cc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(4-methoxyphenyl)benzoic acid (50 mg, 0.1184 mmol) and morpholine (21 mg, 0.2413 mmol) were dissolved in methylene chloride (30 ml), then WSC-HCl (68 mg, 0.3547 mmol) was added thereto and the mixture was stirred for 16 hours at room temperature. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (30 mg, 0.0613 mmol, 52%).
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[CH2:3][NH2:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]([N:35]=[C:36]=[S:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][C:2]([NH:6][C:36]([NH:35][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[S:37])([CH3:5])[CH2:3][NH:4][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(N)CN
Reactant: O=C(N=C=S)c1ccccc1
Product: CC(C)(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=S)NC(=O)c1ccccc1
Yield: 44 %

Procedure:
2-Methyl-N-1-tritylpropane-1,2-diamine, prepared from 2-methylpropane-1,2-diamine and trityl chloride (EP1204654) in yield of 44%, was coupled with benzoylisothiocyanate to give N-(2-methyl-1-(tritylamino)propan-2-ylcarbamothioyl)benzamide (US2008/45579) which was then reacted with lithium hydroxide to give 1-(2-methyl-1-(tritylamino)propan-2-yl)thiourea. Yield 79%. 1H NMR (400 MHz, CDCl3) δ 7.40-7.12 (m, 16H), 6.30 (s, 1H), 2.38 (d, J=8.3, 2H), 2.15 (t, J=8.3, 1H), 1.31 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:14][CH:13]([F:15])[CH2:12][N:11]([CH:16]3[CH2:19][O:18][CH2:17]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22][C:23]1[N:28]=[C:27]([N:29]([CH:39]2[CH2:41][CH2:40]2)CC2C=CC(OC)=CC=2)[C:26]2=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]2[N:24]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:14][CH:13]([F:15])[CH2:12][N:11]([CH:16]3[CH2:19][O:18][CH2:17]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22][C:23]1[N:28]=[C:27]([NH:29][CH:39]2[CH2:40][CH2:41]2)[C:26]2=[N:42][CH:43]=[C:44]([C:45]#[N:46])[N:25]2[N:24]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C5COC5)CC(F)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCN(C3COC3)CC(F)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
(+/−) 2-((2-chloro-5-cyano-3-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (89 mg, 0.138 mmol) was taken up in DCE (1 mL) and anisole (0.076 mL, 0.692 mmol) was added, followed by TFA (0.640 mL, 8.30 mmol). The reaction was stirred at rt overnight. An additional 1 ml of TFA was added, and the reaction was stirred at rt for 4 h. The solvent was removed in vacuo and the material dissolved in MeOH. The material was loaded onto an SCX column (5 g, benzenesulfonic acid sorbent) and the column was flushed with MeOH, then 1:1 DCM/7N NH3/MeOH to obtain the product. The solvent was removed in vacuo and the crude material was purified by preparative HPLC. 2-((2-chloro-5-cyano-3-(6-fluoro-4-(oxetan-3-yl)-1,4-diazepan-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (12 mg, 0.023 mmol, 16.6% yield) was obtained as a yellow solid.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)(O)=O.CNC1CCN(CC2C=CC=CC=2)CC1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[NH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Agent: CCOP(=O)(C#N)OCC
Agent: CNC1CCN(Cc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2ccccc2N1
Temperature: 0 °C

Procedure:
3 Grams of 6-carboxy-3,4-dihydrocarbostyril and 3.5 g of 4-methylamino-1-benzylpiperidine were dispersed in 40 ml of dimethylformamide, to this dispersion was added dropwise, under ice-cooled condition, 2.61 ml of diethyl cyanophosphate and 2.39 ml of triethylamine in 10 ml of dimethylformamide solution. The reaction mixture was stirred under ice-cooled condition for 1 hour, further stirred at room temperature for 2 hours, then the reaction mixture was poured into ice-water. Said mixture was extracted with chloroform, then extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography, and recrystallized from acetonitrile to yield 3 g of [N-methyl-N-(1-benzyl-4-piperidyl)amino]carbonyl]-3,4-dihydrocarbostyril.1/2-hydrate. White powdery substance. Melting point: 186°-188° C. (decomp.).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH:6]([Si:9]([C:16]#[CH:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7]>[Zn+2].[I-].[I-].C1(P(CC)C2C=CC=CC=2)C=CC=CC=1.ClCCl>[CH:13]([Si:9]([CH:6]([CH3:7])[CH3:8])([CH:10]([CH3:12])[CH3:11])[C:16]1[CH2:17][CH:5]=[C:3]([CH3:4])[CH2:2][CH:1]=1)([CH3:14])[CH3:15]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: C=CC(=C)C
Agent: CCP(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1=CCC([Si](C(C)C)(C(C)C)C(C)C)=CC1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
In a four-necked flask, 0.27 g (1.2 mmol) of CoBr2, 1.33 g (4.2 mmol) of ZnI2, 0.55 g (1.4 mmol) of diphenylphosphinoethane, and 60 ml of dichloromethane were added, and the mixture was stirred for 30 minutes at 30° C. Subsequently, 12.2 ml (122 mmol) of isoprene, 20 g (110 mmol) of triisopropylsilylacetylene, and 0.35 g (1.4 mmol) of Bu4NBH4 were added thereto, and the mixture was allowed to react for one hour at 30° C. Dichloromethane was evaporated, and then the residue was purified by silica gel flash column chromatography. Thus, 24.6 g of the title compound, triisopropyl(4-methyl-1,4-cyclohexadienyl)silane, was obtained at a yield of 89.7% (GC purity 80%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:9]([O-])=O.[Na+].[Sn](Cl)[Cl:14]>Cl.O>[ClH:14].[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][NH2:9]
Reactant: Nc1ccccc1I
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccccc1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
2-Iodoaniline (16 g, 73 mmol) was suspended in concentrated hydrochloric acid (100 mL), and then cooled to 0° C. in an ice bath. Sodium nitrite (6 g, 87.6 mmol) in water (25 mL) was added slowly to reaction mixture and then reaction allowed to stir at 0° C. for 1.5 hours. In a separate flask, tin (II) chloride (84.7 g, 182.5 mmol) was dissolved in concentrated hydrochloric acid (12 mL) and added slowly over 30 minutes to reaction mixture. The resulting suspension was allowed to warm to room temperature and stirred for 14 h. The solid was filtered off, and allowed to dry to afford 1-(2-iodophenyl)hydrazine hydrochloride (19 g, 96%). 1H NMR (CDCl3, 300 MHz) δ 7.82 (dd, 1H, J=1.1, 7.7 Hz), 7.39 (dt, 1H, 1.2, 7.7 Hz), 6.96 (dd, 1H, J=1.1, 8.1 Hz), 6.82 (dt, 1H, J=1.1, 7.5) ppm. MS (ApCI) 275 (M++CH3CN+H).
Reaction SMILES: [CH2:1]([O:5][N:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].C([BH3-])#N.[Na+]>>[F:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][NH:6][O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:13][CH:12]=1
Reactant: CC(C)CON=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CONCc1ccc(F)cc1
Yield: 65 %

Procedure:
Reduction of 4-fluorobenzaldehyde O-isobutyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil after chromatography (65% yield). 1HNMR 400 MHz (C6D6) δ (ppm): 0.87 (6H, d, J=6.75 Hz, CH3), 1.88 (1H, m, CH), 3.46 (2H, d, J=6.41 Hz, OCH2), 4.05 (2H, s, NCH2), 7.04 (2H, m, aromatics), 7.37 (2H, m, aromatics). Anal. calcd for C11H16FNO: C, 66.98; H, 8.17; N, 7.10. Found: C, 66.88; H, 7.97; N, 7.32.