Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[N:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.[C:20]1([C:26]#[C:27][C:28](O)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>ClCCCl>[C:20]1([C:26]#[C:27][C:28]([NH:19][CH:16]2[CH2:17][CH2:18][N:13]([C:9]3[S:8][CH:12]=[CH:11][N:10]=3)[CH2:14][CH2:15]2)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC1CCN(c2nccs2)CC1
Reactant: O=C(O)C#Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C#Cc1ccccc1)NC1CCN(c2nccs2)CC1
Yield: 51.2 %

Procedure:
A solution of 500 mg (1.68 mmol) 1-(thiazol-2-yl)piperidin-4-amine trifluoroacetate, 332 mg (2.02 mmol) 3-phenylpropiolic acid and 1.17 ml DIPEA in DCE (20 ml) was stirred for 5 h at RT. Subsequently, the reaction solution was washed with water and a sat. aqueous Na2CO3 soln and dried over MgSO4. After filtering and concentration in vacuo, column chromatography (SiO2, chloroform) was performed on the residue, yielding 267 mg (0.86 mmol, 51%) 3-phenyl-N-(1-(thiazol-2-yl)piperidin-4-yl)propiolamide. MS [MH+] 312.1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:47][N:48]([CH3:63])[N:49]([CH3:62])[C:50](=[O:61])[C@H:51]([NH:59][CH3:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:13])[N:59]([CH3:60])[C@@H:51]([C:50]([N:49]([CH3:62])[N:48]([CH3:63])[CH3:47])=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N(C)N(C)C
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)N(C)C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Then (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (0.35 g, 1.07 mmol) was dissolved in methylene chloride (20 ml) and a mixture of 1-hydroxy-7-azabenzotriazole (0.15 g, 1.07 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.07 mmol) was added and stirred for 30 min. Then a mixture of (2R)-2-methylamino-3-phenylpropionic acid trimethylhydrazide (0.21 g, 0.89 mmol) and diisopropylethylamine (0.20 ml) was added and the mixture was stirred overnight. Methylene chloride (30 ml) was added and the mixture was washed with water (10 ml). The organic layer was washed with aqueous sodium bicarbonate (10 ml) and brine (50 ml), dried (MgSO4), filtered, concentrated to an oil, and chromatographed on silica (40 g) with heptane:ethyl acetate (3:7) to give 0.43 g of N-methyl-N-((1R)-1-(N-methyl-N-[(1R)-2-phenyl-1-(N,N',N'-trimethylhydrazinocarbonyl)ethyl]carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester as an oil.
Reaction SMILES: C([Li])CCC.C(P([CH2:12][S:13]([O:16][CH2:17][CH3:18])(=[O:15])=[O:14])(CC)=O)C.[Cl:19][C:20]1[S:24][C:23]([CH:25]=O)=[CH:22][CH:21]=1>C1COCC1>[CH2:17]([O:16][S:13]([CH:12]=[CH:25][C:23]1[S:24][C:20]([Cl:19])=[CH:21][CH:22]=1)(=[O:14])=[O:15])[CH3:18]
Reactant: O=Cc1ccc(Cl)s1
Reactant: CCOS(=O)(=O)CP(=O)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOS(=O)(=O)C=Cc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (1.6 mL of a 2.5 M solution in hexanes, 4.0 mmol) is added dropwise to a solution of ethyl diethylphosphorylmethanesulfonate (1.0 g, 3.8 mmol), prepared as described in Tetrahedron, 1987, 43(21), 5125, at −78° C. in THF (15 mL). The mixture is stirred for 20 min. then 5-chloro-2-thiophenecarboxaldehyde (0.45 mL, 4.2 mmol) is slowly added. The yellow mixture is stirred at −78° C. for 1 h then allowed to warm to room temperature overnight. The bulk of the solvents are evaporated and the residue is treated with water (2 mL) and extracted with CH2Cl2. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with CH2Cl2 to give the title compound as a yellow solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[Cl:28].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CS(C)=O.O>[CH3:17][O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:13]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:8]=[C:7]([C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])[S:15][C:14]=23)=[CH:23][C:22]=1[Cl:28]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC1
Reactant: COC(=O)Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2ccnc3cc(C(=O)N4CCC4)sc23)cc1Cl
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of azetidin-1-yl-(7-chloro-thieno[3,2-b]pyridin-2-yl)-methanone (21a) (930 mg, 3.70 mmol), (2-chloro-4-hydroxy-phenyl)-acetic acid methyl ester (49e) (740 mg, 3.70 mmol), and Cs2CO3 (1.82 g, 7.40 mmol) in 7 mL of DMSO was heated at 100° C. for overnight and cooled to room temperature. EtOAc and water were added. The organic layer was washed three times with water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc:CHCl3:MeOH (1:1:0.04) to provide 640 mg of white solid as the intermediate 49f. 1H NMR (300 MHz, CD3OD) δ 8.47 (d, 1H, J=5.46 Hz), 7.74 (s, 1H), 7.43 (d, 1H, J=8.48 Hz), 7.32 (d, 1H, J=2.45 Hz), 7.15–7.10 (m, 1H), 6.73 (d, 1H, J=5.47 Hz), 4.67–4.54 (m, 2H), 4.24–4.13 (m, 2H), 3.80 (s, 3H), 3.65 (s, 2H), 2.48–2.33 (m, 2H). LCMS (ESI+) [M+H]/z Calc'd 417, found 417.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[P:25](Cl)(Cl)=[O:26]>>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[P:25]1(=[O:26])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: COc1ccc(P(=O)(Cl)Cl)c(OC)c1
Product: COc1ccc(P2(=O)c3ccccc3CN2c2ccccc2)c(OC)c1
Yield: 66 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 2,4-dimethoxyphenyl phosphonic dichloride. The reaction of the dilithio compound and the 2,4-dimethoxyphenyl phosphonic dichloride was conducted at -76° C. to yield 1-(2,4-dimethoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (7.2 g, 66% yield) as a white solid having a melting point of 173°-175° C. and the following analysis:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][N:9]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:10]([CH3:11])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NCCC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CC(C)N(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A solution of 0.935 g (0.005 mole) of 3-isopropylamino-propanoic acid tert-butyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.6 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]-propanoic acid tert-butyl ester (IV-43).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31](O)(=[O:33])=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.S(Cl)(Cl)=O.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40].O>CN(C)C=O>[CH2:39]([N:41]([CH2:42][CH3:43])[S:31]([C:5]1[C:6](=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1)(=[O:32])=[O:33])[CH3:40]
Reactant: CCNCC
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)N(CC)CC)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.8 %

Procedure:
Compound 1 (1.00 g, 1.96 mmol) obtained in Example 1 was dissolved in 20 ml of dimethylformamide. To the solution was dropwise added 0.29 ml (3.92 mmol) of thionyl chloride under ice-cooling, and the resulting mixture was stirred at room temperature for 10 minutes. After ice-cooling, 1.02 ml (9.80 mmol) of diethylamine was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for one hour. The mixture was poured into 50 ml of water and extracted three times with 20 ml of chloroform. The extract was washed successively with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by column chromatography (eluent: 65% ethyl acetate/hexane), followed by recrystallization from cyclohexane/toluene to give 320 mg (yield 30%) of Compound 2 as a pale yellow powder.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>C(#N)C>[Cl:18][C:15]1[N:16]=[CH:17][C:12]([CH2:11][NH:10][C:3]([S:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:13][CH:14]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 62 %

Procedure:
To a refluxing mixture of 6.61 g of 1,1-bis(methylthio)-2-nitroethylene and 100 ml of acetonitrile was added a solution of 4.28 g of 5-aminomethyl-2-chloropyridine in 10 ml of acetonitrile dropwise over a period of 3 hours and 30 minutes and the whole mixture was further refluxed for 2 hours. After cooling, the insolubles (by-product; 1,1-bis(6-chloro-3-pyridylmethylamino)-2-nitroethylene) were filtered off and the filtrate was concentrated and washed with ethyl acetate to give 4.83 g of 1-(6-chloro-3-pyridylmethylamino)-1-methylthio-2-nitroethylene. The ethyl acetate washings were concentrated and the residue was purified by column chromatography (eluent: dichloromethane-methanol (30:1)) to give a further crop (1.15 g) of the same compound.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:31])[C:19]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)=O>O1CCCC1>[C:3]1([C:2]2[NH:9][C:18]([CH3:31])=[C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: CC(Br)C(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1-c1cccc2ccccc12

Procedure:
A suspension consisting of 50.1 g (0.32 mol) of benzamidine hydrochloride, 133 g (0.96 mol) of potassium carbonate, and 250 mL of tetrahydrofuran was heated under reflux for one hour, and the foregoing toluene solution of 2-bromo-1′-propionaphthone was added dropwise over 50 minutes. After completion of addition, heated under reflux for 2 hours. Next, the reaction mixture was concentrated in vacuo, the resulting concentrate was diluted with 200 mL of toluene, and the solution was poured into 600 mL of water. The mixture was stirred to precipitate a solid. This solid was collected by filtration, successively washed with toluene and water, and then dried to obtain a crude crystal as a desired material. This crude crystal was recrystallized from DMF to obtain 48.1 g (yield: 52.9%) of a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21]([O:24][CH2:25][CH3:26])(=[O:23])C>>[CH2:25]([O:24][C:21](=[O:23])[NH:1][CH2:2][CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])[C:26]1[CH:15]=[CH:16][CH:17]=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)CCCCCNC(=O)OCc4ccccc4)c3C2=O)C(=O)N1
Yield: 48 %

Procedure:
A solution of 6-benzyloxycarbonylamino-hexanoic acid(2.65 g, 10 mmol) in thionyl chloride (15 ml) was heated to reflux 1 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo to give (5-chlorocarbonyl-pentyl)-carbamic acid benzyl ester as tan oil. The oil was used without further purification. (5-Chlorocarbonyl-pentyl)-carbamic acid benzyl ester was dissolved in THF (50 ml). To this solution was added 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.37 g, 5 mmol). The resulting suspension was to reflux for 4 hours. The solvent was evaporated in vacuo and the resulting solid was partially purified by flash chromatography (60/40 ethyl acetate/hexane) to give a light yellow solid. The solid was recystallized from minimal ethyl acetate to give 1.24 g (48%) of product as an off-white solid: mp 122–125 ° C.; 1H NMR (DMSO-d6) 11.18 (s, 1H), 9.70 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.34–7.24 (m, 6H), 5.16 (dd, J=5.1 and 12.6 Hz, 1H), 5.00 (s, 2H), 3.02–2.84 (m, 3H), 2.65–2.43 (m, 4H), 2.12–2.05 (m, 1H), 1.65–1.15 (m, 6H; 13C NMR (DMSO-d6) 172.75, 171.95, 169.77, 167.72, 166.67, 156.08, 137.29, 136.57, 136.09, 131.43, 128.32, 127.70, 126.21, 118.25, 116.90, 65.08, 48.92, 36.47, 30.94, 30.67, 29.14, 25.77, 24.47, 21.99; Anal. Calcd. For C27H28N4O7: C, 62.30; H, 5.42; N, 10.76. Found: C, 62.40; H, 5.31; N, 10.48.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:15]12[CH:23]([N:24]3[CH2:27][C:26]([CH2:50][C:51]#[N:52])([N:28]4[CH:32]=[C:31]([C:33]5[C:34]6[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=6[N:36]=[CH:37][N:38]=5)[CH:30]=[N:29]4)[CH2:25]3)[CH:19]([CH2:20][NH:21][CH2:22]1)[CH2:18][O:17][CH2:16]2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([N:21]1[CH2:20][CH:19]2[CH:23]([N:24]3[CH2:25][C:26]([CH2:50][C:51]#[N:52])([N:28]4[CH:32]=[C:31]([C:33]5[C:34]6[CH:41]=[CH:40][NH:39][C:35]=6[N:36]=[CH:37][N:38]=5)[CH:30]=[N:29]4)[CH2:27]3)[CH:15]([CH2:16][O:17][CH2:18]2)[CH2:22]1)=[O:6]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5C6CNCC5COC6)C4)c3)ncnc21
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2C3COCC2CN(C(=O)c2ccnc(C(F)(F)F)c2F)C3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a mixture of 3-fluoro-2-(trifluoromethyl)isonicotinic acid (50.0 mg, 0.239 mmol) and {1-(3-oxa-7-azabicyclo[3.3.1]non-9-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (128 mg, 0.239 mmol) in DMF (2 mL) were added triethylamine (0.100 mL, 0.717 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (127 mg, 0.287 mmol). The mixture was stirred at room temperature for 2 hours. Direct purification with prep-LCMS (pH=10) afforded 50 mg (30% yield) of the desired product. LCMS found: 696.3 (M+1)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12].C(O)(=O)C>C(OC(=O)C)(=O)C>[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc2ccccc2c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=S(=O)(O)c1cccc2ccccc12

Procedure:
128 g (1 mole) of naphthalene are dissolved in 102 g (1 mole) of acetic anhydride in an apparatus with a stirrer and a means for the supply of sulphuric acid, a dephlegmator, cooler and vacuum-receiver. Then 98 g (1 mole) of a 100% sulphuric acid are added to the solution of naphthalene in acetic anhydride for 60 minutes at a temperature of 60° C. The removal of the forming acetic acid is effected under vacuum under a residual pressure of 1 to 10 mm Hg. After discontinuation of distillation of acetic acid, i.e. on completion of the reaction of naphthalene sulphonation, there are obtained 208 g (1 mole) of naphthalene-α-sulphonic acid and 118 g (2 moles) of glacial acetic acid. The resulting naphthalene-α-sulphonic acid is poured to 224 g (4 moles) of a preliminary prepared melt of potassium hydroxide having a temperature of 180° C. under vigorous stirring. Then the melt temperature is raised to 285° C. for 5 minutes and the melt is maintained at this temperature for 5 minutes to complete the fusion process. On expiration of 10 minutes, the melt is cooled to a temperature of 80° C., diluted with 200 g of water and the resulting aqueous solution containing potassium α-naphtholate and potassium sulphite is supplied into a mixer provided with a cooling jacket, whereinto a solution of 98 g (1 mole) of sulphuric acid in 400 g of water has been preliminarily charged. Then the resulting mixture is cooled to a temperature of 10° C. and the precipitated α-naphthol is separated from the aqueous solution of the mixture of potassium sulphite, potassium sulphate and non-precipitated α-naphthol and β-naphthol by filtration. The yield of α-naphthol with a purity of 99.5% is 115 g (0.8 mole) as calculated for the employed naphthalene which corresponds to 80% of the theoretical value. The filtrate is treated with an equal volume of carbon tetrachloride and, after separation of the aqueous layer and distilling-off carbon tetrachloride, there are obtained 25 g (0.17 mole) of α-naphthol with a purity of 95%. The total yield of α-naphthol is 97% of the theoretical as calculated for the employed naphthalene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH3:13]C1C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[CH3:11])[C:5]([O:7][CH3:13])=[O:6]
Reactant: Cc1c(O)cc(C(=O)O)cc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cc(O)c(C)c(O)c1

Procedure:
3,5-dihydroxy-4-methylbenzoic acid (5.0 g, 29.79 mmol, 1.0 eq) and PTSA (1.13 g, 5.94 mmol, 0.2 eq) were dissolved in 50 ml of methanol, and the mixture was heated to reflux for 6 h. Methanol was evaporated. The resultant solid was washed with 10% sodium bicarbonate solution. The aqueous solution was extracted thrice with ethyl acetate. The combined organic layer was dried over sodium sulphate and evaporated under vacuum. Yield: 5.25 g (96%). 1H NMR (400 MHz, DMSO-d6): δ 1.98 (s, 3H), 3.78 (s, 3H), 6.93 (s, 2H), 9.53 (s, 2H). LCMS: (ES+) m/z=183 (M+H) Method: Column: Phenomenex Luna C18 (4.6×30) mm, 5 micron Mphase A: 10% MeOH-90% H2O-10 mM NH4OAc Mphase B: 90% MeOH-10% H2O-10 mM NH4OAc
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].CON(C)[C:8]([C:10]1[CH:24]=[CH:23][C:13]2[N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:15]=[N:16][C:12]=2[CH:11]=1)=[O:9].[NH4+].[Cl-].O>C1COCC1>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N:14]1[C:13]2[CH:23]=[CH:24][C:10]([C:8](=[O:9])[CH2:2][CH3:1])=[CH:11][C:12]=2[N:16]=[CH:15]1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of EtMgBr (0.72 mL, 1 mol/L) was added to N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carboxamide (70 mg, 0.24 mmol) in THF at 0° C. under argon. The mixture was stirred at 0° C. for 2 h. A solution of NH4Cl was added, carefully, to quench the reaction. The mixture was poured into water and extracted with EtOAc. The organics were washed sequentially with water and brine, then dried (Na2SO4). Removal of solvent followed by SiO2 chromatography afforded 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one as a colorless oil (45 mg, 72% yield).
Reaction SMILES: NC1CCCC(=[O:8])C=1.BrCC(=O)C(OCC)=O.[Br:18][CH2:19][C:20](=[C:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][C:27]1=[NH:33])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(OCC)(=O)C>[Br:18][CH2:19][C:20](=[C:26]1[CH2:31][C:30](=[O:8])[CH2:29][CH2:28][C:27]1=[NH:33])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NC1=CC(=O)CCC1
Reactant: CCOC(=O)C(CBr)=C1C(=N)CCCC1=O
Agent: CCOC(=O)C(=O)CBr
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CBr)=C1CC(=O)CCC1=N
Temperature: 60 °C

Procedure:
111.1 g. 1-Aminocyclohex-1-en-3-one (see Arch. Pharm., 294, 763/1961) are added at 30° C., with stirring, to 760 ml. ethyl bromopyruvate. The reaction mixture is then heated to 60° C. for 8 hours. After cooling, the reaction mixture is mixed with 200 ml. ethyl acetate and 1000 ml. diethyl ether and filtered with suction. After washing the solid product with diethyl ether, there are obtained 247 g. (85% of theory) ethyl 3-bromo-2-(2-imino-6-oxocyclohexylidene)-propionate; m.p. 170°-175° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:16])[C:12]([O:14]C)=[O:13].C([O-])([O-])=O.[K+].[K+]>CO.O.O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:16])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C(=O)c1c[nH]c2c(Br)ncc(OC)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)O)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 59.3 %

Procedure:
To a solution of methyl 2-(7-bromo-4-methoxy-6-azaindol-3-yl)-2-oxoacetate (0.083 g, 0.265 mmol) in MeOH—H2O (3:1, 3 mL) was added 1M aqueous K2CO3 (1.1 mL, 1.1 mmol). The mixture was stirred at room temperature for 14 h and then it was diluted with H2O (2 mL). The volatiles were removed under reduced pressure and the remaining solution was acidified to pH 1-2 using 6N HCl. The resulting suspension was cooled at 0° C., the precipitate was filtered and the filtercake was washed with H2O and then ether. After drying in vacuo, this gave the title compound (0.047 g, 59%) as a light yellow solid: