Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](NC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.[BH3-]C#N.[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27]>CO>[CH2:1]([NH:27][C:26]1[CH:28]=[CH:29][C:30]([F:31])=[C:24]([Cl:23])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(NCc2ccccc2)cc1Cl
Temperature: 23 °C
Reaction time: 18 h

Procedure:
Benzylaniline (3.69 g, 34.8 mmol), AcOH (1.11 mL), and NaBH3CN were added to a solution of 3-chloro-4-fluoroaniline (5.07 g, 34.8 mmol) in MeOH (200 mL) containing molecular sieves. The resulting mixture was stirred at 23° C. for 18 h. Sieves were removed by filtration and the filtrate was concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and CH2Cl2 (50 mL, 2×20 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (SiO2, 0-12% EtOAc/hexanes gradient) to give N-benzyl-3-chloro 4-fluoroaniline (7-1) 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 6.93 (dd, J=8.8, 5.8 Hz, 1H), 6.62 (dd, J=6.1, 3.1 Hz, 1H), 6.44 (ddd, J=8.9, 3.7, 3.1 Hz, 1H), 4.27 (s, 2H), 3.98 (brs, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:35][CH2:36][CH:37](CO)[OH:38]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH:37]([OH:38])[CH2:36][OH:35])=[O:19])=[CH:22][CH:23]=1
Reactant: OCC(O)CO
Reactant: COC(=O)c1ccc(NCCCCCCCCCCCBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCBr)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-(11-bromoundecylamino)benzoate, 280 mg. of glycerol, and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 2,3-dihydroxypropyl 4-(11-bromoundecylamino)benzoate.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH2:11][CH2:10]1.[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:44](O)=[O:45])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:44]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:14][CH2:13]1)=[O:45])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OCCCCCCCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Reactant: O=C(O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
First, 3 g of 2,3-difluoro-1-[trans-4-(13-hydroxytridecyl)cyclohexyl]benzene, 3 g of 2,2-bis(6-benzyloxyhexyl)acetic acid, 2.2 g of triphenylphosphine, and 30 ml of tetrahydrofuran were placed in a 100 ml flask. Then, 1.5 g of ethyl azodicarboxylate was added dropwise to the reaction mixture under ice water cooling. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 5.4 g of 13-[trans-4-(2,3-difluorophenyl)cyclohexyl]tridecyl 2,2-bis(6-benzyloxyhexyl)acetate (Y: 97%). The compound thus obtained had a purity of 93.7% by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[C:12]([CH3:25])=[N:13][N:14]([CH3:24])[C:15]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23])O.COCCN(S(F)(F)[F:36])CCOC.C(=O)(O)[O-].[Na+]>ClCCl>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]1[N:14]([CH3:24])[N:13]=[C:12]([CH3:25])[C:11]=1[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[F:36]
Reactant: Cc1nn(C)c(-c2c(F)cccc2F)c1C(O)c1ccc(F)cc1F
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nn(C)c(-c2c(F)cccc2F)c1C(F)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of α-(2,4-difluorophenyl)-5-(2,6-difluorophenyl)-1,3-dimethyl-1H-pyrazole-4-methanol (i.e. the product of Example 4) (70 mg, 0.20 mmol) in dichloromethane (2 mL) at −78° C. was added bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®) (40 μL, 0.24 mmol). The reaction mixture was stirred overnight at room temperature, and then cooled to −78° C. and saturated aqueous sodium bicarbonate solution (3 mL) was added dropwise. The resulting mixture was extracted with dichloromethane (3×) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by MPLC (50% ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (30 mg)
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]([CH2:19][CH2:20][NH:21][S:22]([C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1)(=[O:24])=[O:23])[C:7](=[O:18])[CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[S:22]([NH:21][CH2:20][CH2:19][N:6]([C:7](=[O:18])[CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])[CH2:5][C:4]([OH:34])=[O:3])(=[O:23])=[O:24]
Reactant: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(CC(=O)N(CCNS(=O)(=O)c2nc3ccccc3s2)CC(=O)O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
N-[2-(Benzothiazole-2-sulfonylamino)-ethyl]-N-[(thymin-1-yl)-acetyl]-glycine ethyl ester (5.10 g, 10 mmol) was suspended in tetrahydrofuran (20 mL) and the solution of lithium hydroxide monohydrate (1.03 g, 25 mmol) in water (20 mL) was added. The reaction mixture was stirred for 1 h. at ambient temperature. The aqueous solution was acidified by the dropwise addition of 1N HCl at 0° C. The title compound was extracted with ethyl acetate (3×10 mL), the combined extracts were dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness in vacuo to afford the desired product (4.57 g, 95%). 1H NMR (500 MHz; DMSO-d6) δ 11.30 (s, 0.6H), 11.28 (s, 0.4H), 8.88 (s, 0.6H), 8.77 (s, 0.4H), 8.27 (d, 1H), 8.18 (d, 1H), 7.69˜7.64 (m, 2H), 7.31 (s, 0.6H), 7.23 (s, 0.4H), 4.64 (s, 1.2H), 4.45 (s, 0.8H), 4.21 (s, 0.8H), 3.98 (s, 1.2H), 3.52 (t, 1.2H), 3.38 (s, 2H), 3.21 (t, 0.8H), 1.73 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][N:19]3[C:23]([C:24](OC)=[O:25])=[N:22][CH:21]=[N:20]3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:28][NH2:29]>CO>[CH3:28][NH:29][C:24]([C:23]1[N:19]([CH2:18][C:8]2[N:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=[N:10][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:20]=[CH:21][N:22]=1)=[O:25]
Reactant: CN
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Solvent: CO
Product: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12

Procedure:
Methyl 1-((6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate was treated with excess methylamine in methanol in a sealed tube at 80° C. for several hours until the reaction was completed as judged by TLC or LC analysis. Solvent was evaporated and the crude product was purified by chromatography (SiO2 column, eluted with 50% acetone). m/e+ 361 for C20H21N6O [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.13 (d, J=0.6 Hz, 1H), 7.87 (d, J=8.1 Hz, 2H), 7.65 (s, 1H), 7.57 (d, J=9.3 Hz, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.08 (dd, J=1.2, 9.3 Hz, 1H), 6.32 (s, 2H), 3.06 (d, J=5.1 Hz, 3H), 2.50 (bs, 1H), 2.41 (s, 3H), 2.31 (s, 3H) ppm; 13C-NMR (75 MHz, CDCl3, δ) 158.440, 150.38, 146.788, 146.587, 138.174, 131.289, 129.586, 129.413, 128.819, 128.612, 122.655, 122.094, 117.100, 113.447, 44.395, 26.393, 21.605, 18.714 ppm.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][C@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH2:32][C@H:31]([NH2:35])[CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@H](N)C5)n4)n[nH]c3cn2)cn1
Yield: 71.7 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (S)-tert-butyl piperidin-3-ylcarbamate were reacted and the product was deprotected to give 173 as a white solid (71.7% over two steps). 1H NMR (400 MHz, DMSO) δ 1H NMR (400 MHz, DMSO) δ 9.03 (d, J=1.2 Hz, 1H), 8.59 (d, J=1.2 Hz, 1H), 8.34 (s, 1H), 7.95 (s, 1H), 7.67-7.60 (m, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.46 (d, J=8.9 Hz, 1H), 4.21 (d, J=12.7 Hz, 1H), 3.90 (s, 3H), 3.02-2.93 (m, 1H), 2.84-2.74 (m, 2H), 2.00-1.92 (m, 2H), 1.88-1.77 (m, 2H), 1.67-1.52 (m, 2H), 1.39-1.28 (m, 1H). LC/MS: m/z 375.1 [M+1]
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CO>O1CCCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C

Procedure:
In a 350 mL sealed pressure flask were mixed 1-bromo-4-nitrobenzene (4.00 g, 19.80 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (6.74 g, 21.78 mmol), and sodium carbonate (4.41 g, 41.6 mmol) in tetrahydrofuran (60 ml), water (30 ml), and methanol (10 ml). The mixture was put through three vacuum/nitrogen purge cycles. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (0.485 g, 0.594 mmol) was added, and the reaction mixture was heated overnight at 70° C. under nitrogen. The reaction mixture was cooled, diluted with ethyl acetate and water, and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].S(=O)(=O)(O)O.N([O-])=O.[Na+].NC(N)=O.[I-:25].[K+].COC1C=CC(O)=CC=1>O>[I:25][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1C#N
Reactant: [I-]
Agent: COc1ccc(O)cc1
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: O
Product: N#Cc1ccc(I)cc1C#N
Temperature: 0 °C
Yield: 71.7 %

Procedure:
4-Aminophthalonitrile (40 g, 0.28 mol) was slowly added to 80 ml of concentrated sulfuric acid and the mixture was stirred with cooling (below 25° C.) until dissolution was complete. After cooling below 15° C., ice water (175 ml) was slowly added to precipitate the amine bisulfate. A solution of sodium nitrite (20 g, 0.29 mol) in 40 ml of water was then added at such a rate as to maintain the temperature at 0°-10° C. After stirring the solution for an additional 15 minutes, a few crystals of urea were added to decompose any excess sodium nitrite. The homogeneous solution was then poured into a breaker containing potassium iodide (75 g, 0.45 mol) dissolved in 150 ml of water. After the evolution of nitrogen had ceased and a negative test with alkaline p- methoxyphenol indicated that the reaction was complete, the brown precipitate was collected by suction filtration and washed with 10% sodium bisulfite, with saturated sodium bicarbonate and finally with water. Recrystallization from ethanol-water afforded 51 g (72%) of the desired product, m.p. 141°-142° C.
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28]CC4C=CC(OC)=CC=4)=[O:27])=[C:15]([CH:18]=[CH:19][C:20]4[S:24][CH:23]=[N:22][C:21]=4[CH3:25])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[Cl-].[Na+]>C(Cl)Cl.CO>[NH2:10][CH:11]1[C:38](=[O:39])[N:13]2[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH:18]=[CH:19][C:20]3[S:24][CH:23]=[N:22][C:21]=3[CH3:25])[CH2:16][S:17][C@H:12]12
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3scnc3C)CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ncsc1C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
p-Methoxybenzyl 7-phenylacetamido-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylate (trans-isomer) (0.720 g, 1.28 mmol) was dissolved in methylene chloride (3 ml). The resultant solution was poured into a solution of phosphorus pentachloride (0.800 g, 3.84 mmol) and pyridine (1.04 ml, 12.8 mmol) in methylene chloride (20 ml) at -30° C. The resultant solution was stirred for 3 hours under ice-cooling and poured into methanol (20 ml) as pre-cooled to -30° C., followed by stirring the mixture for 1 hour at ambient temperature. The reaction solution obtained was poured into a mixture of aqueous saturated sodium chloride solution (20 ml) and methylene chloride (20 ml), and the resulting mixture was stirred for 1 hour. The mixture was cooled to stand until it separated into the aqueous phase and organic solvent phase. The aqueous phase separated out was extracted with methylene chloride (20 ml) and the methylene chloride extract was combined with the organic phase mentioned above. The combined organic phase was washed with aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified chromatographically on a column of silica gel (Wako gel C-300) (20 g) as developed with benzene-ethyl acetate (3:1) as the development solvent. The titled compound, 7-amino-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid (trans-isomer) p-methoxybenzyl ester (0.443 g, 78%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:19](=[O:20])[O:21][CH2:22][CH3:23])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.0 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liter of dichloromethane was added 4.7 ml of ethyl chloroformate and 8.9 ml of diisopropylethylamine. The mixture was stirred for 3 hours at room temperature, concentrated in vacuo to a volume of 500 ml, filtered and the solid washed with 200 ml of dichloromethane to give a tan powder, 11.4 g, mp 232°-235° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.CC#N.N1C=CC=CC=1.[C:18]1([O:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[Cl:8][C:4]1[N:3]=[C:2]([NH:1][C:25](=[O:26])[O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Nc1cncc(Cl)n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(Nc1cncc(Cl)n1)Oc1ccccc1
Reaction time: 18 h
Yield: 51.9 %

Procedure:
A solution of 2-amino-6-chloropyrazine (2.0 g, 15.44 mmol) in a mix of 1:1 THF:MeCN (20 mL), and pyridine (1.28, 16.2 mmol) was treated dropwise with phenylchloroformate (2.54 g, 16.2 mmol) in THF (10 mL). After stirring for 18 h, the resulting solid was collected and dried to provide the title compound (2 g, 53%).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH:30]2[N:35]([C:36]3[S:37][CH:38]=[CH:39][N:40]=3)[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]2)[CH:23]=1>CO>[ClH:1].[ClH:1].[ClH:1].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH:30]2[CH2:31][NH:32][CH2:33][CH2:34][N:35]2[C:36]2[S:37][CH:38]=[CH:39][N:40]=2)[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccs2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: c1cncc(OCC2CNCCN2c2nccs2)c1
Reaction time: 1 h
Yield: 46 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 3-((pyridin-3-yloxy)methyl)-4-(thiazol-2-yl)piperazine-1-carboxylate di-TFA salt (130 mg, 0.215 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 37.9 mg (46%) of the desired product as a white solid. LC-MS: RT=2.64 min, [M+H]+=277.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:32]=[CH:31][NH:30][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:32]=[CH:31][NH:30][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:25][CH2:26][N:27]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:28][CH2:29]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: c1cc2c(Nc3ccc4cn[nH]c4c3)nc(Nc3ccc(N4CCNCC4)cc3)nc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4cc[nH]c4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
To a suspension of N4-(1H-indazol-6-yl)-N2-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (9 mg, 0.021 mmol) and triethylamine (TEA) (0.010 mL, 0.072 mmol) in CH2Cl2 (1 mL) at room temperature, methanesulfonyl chloride (MeSO2Cl) (0.006 mL, 0.077 mmol) was added. After being stirred at room temperature for 3 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give N4-(1H-indazol-6-yl)-N2-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (2 mg), MS 504.3 (M+H) (Compound 8-1); and N4-(1-(methylsulfonyl)-1H-indazol-6-yl)-N2-(4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (1 mg), MS 582.4 (M+H) (Compound 8-2).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]([CH2:17][C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)[C:2](=[NH:1])[N:3]([CH2:17][C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)[C:4]=2[CH:10]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1nc2ccc(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N=c1n(Cc2ccc(Cl)cc2)c2ccc(Cl)cc2n1Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A mixture of 2-amino-5-chloro-benzimidazole (9.4 g, 56.1 mmol), 4-chlorobenzylchloride (9.93 g, 61.7 mmol), potassium carbonate (15.5 g, 112 mmol) and dimethyl formamide (150 ml) was stirred at 50° C. for 20 h. Water (150 ml) was added and the product was filtered off. The crude product was purified by chromatography using silica gel and a mixture of ethanol (5%) and dichloromethane as eluent. The product was isolated as the free base. Yield 0.37 g, 2%. M.p. 175-177° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:11]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2].Br[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:15][CH2:16][CH2:17][CH2:18]3)[N:11]2[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: CCC(Br)CC
Reactant: CCc1cc(C#N)ccc1N=C1NC2(CCCC2)CS1
Product: CCc1cc(C#N)ccc1N=C1SCC2(CCCC2)N1C(CC)CC

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 3-bromopentane according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-(3-pentyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [Br:1]Br.[OH:3][CH2:4][C:5]1[S:21][C:8]2[CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][N:11]([CH3:14])[CH2:12][CH2:13][C:7]=2[CH:6]=1.O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:6]1[C:7]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[S:21][C:5]=1[CH2:4][OH:3]
Reactant: CN1CCc2cc(CO)sc2C(c2ccccc2)C1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2c(sc(CO)c2Br)C(c2ccccc2)C1

Procedure:
Bromine (0.23 ml) was added dropwise to a stirred solution of 2-hydroxymethyl-6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine (1.20 g) and sodium acetate trihydrate (1.8 g) in acetic acid (60 ml) at room temperature. After 1 hour the solution was evaporated, the residue dissolved in water (100 ml), basified to pH~11 with 0.880 ammonia solution and extracted with dichloromethane (2×100 ml). The extracts were dried, filtered and evaporated to a brown oil (1.74 g). Chromatography on silica, eluting with 2% methanol in dichloromethane gave a solid (0.80 g) which was recrystallised from toluene (15 ml) to give the title product (m.p. 141°).