Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)/[CH:8]=[C:9](/[O:12][CH:13]([CH3:15])[CH3:14])\SC.[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18]>C(O)(C)C>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[NH:22][C:20](=[O:21])[C:19]([C:17]#[N:18])=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:8]=1
Reactant: N#CCC(N)=O
Reactant: CS/C(=C\C(=O)c1ccco1)OC(C)C
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)Oc1cc(-c2ccco2)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
Sodium (309 mg, 13.4 mmol) was dissolved in isopropanol (46 mL). Then, (Z)-1-(2-furyl)-3-isopropoxy-3-(methylsulfanyl)-2-propen-1-one (3.03 g, 13.4 mmol) and 2-cyanoacetamide (1.13 g, 13.4 mmol) were added thereto, followed by stirring overnight at room temperature. Ice-water was added to the reaction solution, and then the solid was collected by filtration, and washed with water and diethyl ether, to give the title compound (2.3 g, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][C:11]=1[NH2:12])=[O:5])[CH3:2].N1C=CC=CC=1.[C:28](Cl)(=[O:36])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:13](=[O:21])[C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:9][CH2:10][C:11]=1[NH:12][C:28]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(N)CCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(NC(=O)Oc2ccccc2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
Ethyl-4-amino-1-(4-chlorobenzoyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (7.0 g) was dissolved in methylene chloride (140 ml), pyridine (6.0 ml) and phenyl chlorocarbonate (6.0 ml) were added under ice cooling, and the resultant mixture was stirred at room temperature for 2 hours. To the reaction solution, water was added and the mixture was extracted with methylene chloride. After the organic layer was washed with citric acid solution and a saturated saline solution, the organic layer was dried over sodium sulfate, filtrated and concentrated. The resultant residue was subjected to medium-pressure column fractionation (solvent; ethyl acetate:hexane=20:80 to 60:40). The titled compound (8.35 g) was obtained as a white powder.
Reaction SMILES: O=[CH:2][CH2:3][NH:4][C:5]([C:7]1[CH:27]=[CH:26][C:10]2[N:11]([CH3:25])[C:12]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:13][C:9]=2[CH:8]=1)=[O:6].[F:28][C:29]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:28][C:29]1([F:35])[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:27]=[CH:26][C:10]3[N:11]([CH3:25])[C:12]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:13][C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC=O)ccc21
Reactant: FC1(F)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCN3CCC(F)(F)CC3)ccc21
Yield: 44.5 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2 (4,4-difluoro-piperidin-1-yl)-ethyl]-amide (45 mg) was prepared by following General Procedure P starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-oxo-ethyl)-amide (80 mg), 4,4-difluoro-piperidine (36 mg), and Na(OAc)3BH (65 mg) in DCM (2 mL). LC/MS: m/z 504.5. 1H NMR (DMSO-d6, 400 MHz): δ 8.97-8.88 (m, 1H), 8.14-8.12 (m, 1H), 7.97-7.96 (m, 1H), 7.88-7.80 (m, 1H), 7.56-7.52 (m, 2H), 7.43-7.40 (m, 1H), 4.08-4.05 (m, 1H), 3.74-3.69 (m, 7H), 3.57-3.47 (m, 1H), 3.46-3.17 (m, 3H), 2.46-2.43 (m, 3H), —NH proton signal was not observed.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([OH:31])=O)[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.C(Cl)Cl.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[C:9]([C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[O:31])[CH:22]=1)=[N:8][CH:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCN(C)CC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
The 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (119 mg, 0.23 mmol) was suspended in 8 ml of methylene chloride containing 10 equivalent of N-methylpiperizine, 1.1 equivalent of HBTU and 4.0 equivalent of triethylamine. The mixture was stirred at room temperature overnight and then evaporated to remove solvents. The residue was extracted with ethyl acetate and water. The organic layer was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded on a preparative HPLC for purification to give 6,7-Dimethoxy-1-{3-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethoxy]-benzoyl}-isoquinoline-4-carboxylic acid as a fluffy solid (39 mg, 35%). ES-MS calcd for C26H27N3O7 (m/e) 493.5, obsd 494.4 (M+H).
Reaction SMILES: [NH2:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[S:19][C:9]2[CH2:10][N:11]([C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4].C(O)(=O)C>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:7]2[C:8]3[CH2:13][CH2:12][N:11]([C:14]([CH:16]4[CH2:18][CH2:17]4)=[O:15])[CH2:10][C:9]=3[S:19][C:6]=2[NH:5][C:3](=[O:4])[CH:2]([CH3:29])[N:1]=1
Reactant: CC(N)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC1N=C(c2ccccc2Cl)c2c(sc3c2CCN(C(=O)C2CC2)C3)NC1=O
Yield: 23.9 %

Procedure:
12.95 g of 2-(2-aminopropionylamino)-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine was dissolved in 260 ml of toluene and 90 ml of pyridine, to which 5.4 g of acetic acid was added, followed by heating under reflux for 5 hours. After removal of the solvent by distillation, benzene was added and the resultant crystals were collected by filtration to obtain 2.96 g of the intended compound. The mother liquor was subjected to silica gel column chromatography (elution solvent: ethyl acetate:hexane=4:6) to obtain 3.84 g of the intended compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:15][C@@H:14]3[CH2:16][CH2:17][C@H:10]2[CH2:11][NH:12][C:13]3=O)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(N(CC)CC)C.Cl[C:33]1[N:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([F:43])[CH:39]=2)[N:34]=1>C1COCC1.CC(N(C)C)=O>[F:43][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([N:12]1[CH2:11][C@@H:10]3[CH2:17][CH2:16][C@@H:14]([CH2:15][N:9]3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:13]1)[N:42]=[CH:41]2
Reactant: COc1ccc(N2C[C@@H]3CC[C@H]2CNC3=O)cc1
Reactant: Fc1ccc2nc(Cl)ncc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1ccc(N2C[C@@H]3CC[C@H]2CN(c2ncc4cc(F)ccc4n2)C3)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,5S)-6-(4-methoxyphenyl)-3,6-diazabicyclo[3.2.2]-nonan-2-one (E-4, 0.108 g, 0.438 mmol, 1.0 equiv) in THF (3.0 mL) at ambient temperature was added a solution of lithium aluminum hydride in THF (1.31 mL, 1.31 mmol, 1.0M, 3.0 equiv) and the reaction mixture was heated to 65° C. for 2 h. The reaction was cooled to 0° C. and quenched with water (0.1 mL), 1M NaOH (0.2 mL), and water (0.3 mL). The reaction mixture was stirred a further 0.5 h, diluted with ethyl acetate (50 mL), dried over MgSO4, and concentrated to an oil. To a solution of the residual oil in dimethylacetamide (2.1 mL) was added triethylamine (0.24 mL, 1.72 mmol, ca. 4 equiv), and 2-chloro-6-fluoroquinazoline (0.094 g, 0.52 mmol, ca. 1.2 equiv) and the reaction was heated to 175° C. for 15 minutes in the microwave. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was dried over MgSO4 and concentrated. The residue was purified by column chromatography (0 to 60% ethyl acetate in hexanes) to afford E-5 as a yellow solid. ESI MS [M+H] for C22H23FN4O=379.2.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.[SH:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C[O-].[Na+].O>CN(C)C=O>[C:8]([C:7]1[C:2]([S:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:3][CH:4]=[CH:5][N:6]=1)#[N:9]
Reactant: N#Cc1nccnc1Cl
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCSc1nccnc1C#N
Temperature: 25 °C
Yield: 43.7 %

Procedure:
To a solution of 2-chloro-3-cyanopyrazine (9.9 g, 73.8 mmol) and methyl 3-mercaptopropionate (9.36 mL, 84.5 mmol) in anhydrous dimethylformamide (40 mL) cooled to 4° C. was added solid sodium methoxide (4.7 g, 87.0 mmol). The reaction mixture was allowed to warm to room temperature overnight. The mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed once saturated aqueous sodium bicarbonate solution, five times with brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 7:3 hexanes:ethyl acetate gave methyl 3-(3-cyanopyrazin-2-ylthio)propanoate (7.2 g) as a pale yellow liquid. 1H NMR (300 MHz, CDCl3): 8.51 (d, 1H), 8.32 (d, 1H), 3.72 (s, 3H), 3.50 (t, 2H), 2.79 ppm (t, 2H). MW=223 confirmed by LC-MS, tr=11.11 min (Method Y) MH+=221-225.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClC(Cl)C.Cl>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[CH:21][C:22]([C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:11])=[CH:23][CH:24]=1
Reactant: O=C1CCC(=O)O1
Reactant: Fc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
Aluminum trichloride (6.2 g, 46.5 mmol) was suspended in 50 ml of dichloroethane, and 3.02 g (30.2 mmol) of succinic anhydride and 4.0 g (23.2 mmol) of 2-fluorobiphenyl were added thereto, followed by stirring the mixture at room temperature for 4 hours. The reaction solution was poured in hydrochloric acid containing ice, and extracted with chloroform. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was recrystallized from chloroform to obtain 5.6 g of the above-mentioned compound (yield 89%).
Reaction SMILES: I.C[O:3][C:4]1[CH:24]=[CH:23][C:7]2[C:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=4)[CH:12]=3)=[N:9][O:10][C:6]=2[CH:5]=1.C(O)(=O)C.C(OC(=O)C)(=O)C>O>[OH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:8]1[C:7]3[CH:23]=[CH:24][C:4]([OH:3])=[CH:5][C:6]=3[O:10][N:9]=1)[CH:20]=[CH:19]2
Reactant: COc1ccc2cc(-c3noc4cc(OC)ccc34)ccc2c1
Agent: I
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Oc1ccc2cc(-c3noc4cc(O)ccc34)ccc2c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
Hydriotic acid (57% w/w aq., 10 mL) was added into a mixture of 6-methoxy-3-(6-methoxy-2-naphthyl)-1,2-benzisoxazole (1.0 g, 3.3 mmol), acetic acid (10 mL) and acetic anhydride (5 mL). The reaction mixture was stirred at 160° C. for 2 h, and then cooled to room temperature and poured into water. The precipitated solid was filtered off and dried to give a yellow solid (0.89 g, 91% yield, m.p. 280-282° C.); MS m/e 278 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.O>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Reactant: O=C1CCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(C(=C2CCCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a stirred suspension of zinc powder (0.71 g, 10.9 mmoL) in anhydrous THF (15 mL) was slowly added, via syringe, TiCl4 (0.58 mL, 1.0 g, 5.3 mmoL) at RT under a nitrogen atmosphere. The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 2.5 h. To the refluxing reaction mixture was added a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.408 g, 1.47 mmol) and cyclopentanone (0.38 mL, 0.36 g, 4.3 mmol) in THF (15 mL) and heating continued an additional 2 h. The reaction mixture was allowed to cool to room temperature and water (10 mL) slowly added. The reaction mixture was then filtered through a pad of Celite and the Celite pad washed with EtOAc. The filtrate was transferred to a separatory funnel and the organic layer was separated. The organic phase was washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 60:40) to give 0.391 g (81%) of compound 3 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.59 (m, 4H), 2.27 (m, 4H), 6.66 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 9.32 (s, 1H). HRMS (EI) Calcd for C18H17BrO: 328.0463 (M+.). Found: 328.0469.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CCCCC[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>[Cu]>[C:1]1([N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:50]5[CH:49]=[CH:48][C:47]([CH3:46])=[CH:52][CH:51]=5)=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(Nc2ccccc2)cc1
Reactant: CCCCCCCCCCCC
Reactant: Ic1ccc(-c2ccc(-c3ccc(I)cc3)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccc(C)cc5)cc4)cc3)cc2)cc1
Temperature: 205 °C
Reaction time: 30 h
Yield: 76.4 %

Procedure:
Phenyl-p-tolylamine (11.5 g (0.063 mol)), 14.5 g (0.030 mol) of 4,4″-diiodo-p-terphenyl, 5.0 g (0.036 mol) of anhydrous potassium carbonate, 0.38 g (0.006 mol) of copper powder and 15 ml of n-dodecane were mixed, and heated up to 200 to 210° C. while introducing nitrogen gas, followed by stirring for 30 hours. After the termination of the reaction, the reaction product was extracted with 400 ml of toluene, and insoluble matter was removed by filtration. Then, the filtrate was concentrated to dryness. The resulting solid matter was purified by column chromatography (carrier: silica gel, eluent: toluene:hexane=1:4) to obtain 13.6 g of N,N′-diphenyl-N,N′-di-p-tolyl-4,4″-diamino-p-terphenyl (compound No. 17) (yield: 76.4%, melting point: 167.2 to 168.2° C.).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:9][C:8]([CH2:32][C:33]#[N:34])([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].[OH-].[NH4+]>C(#N)C.O>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([C:13]2[CH:12]=[N:11][N:10]([C:8]3([CH2:32][C:33]#[N:34])[CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:9]3)[CH:14]=2)=[N:20][CH:19]=1
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 75 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (6, 327 g, 655 mmol) in acetonitrile (3 L) and water (300 mL) was added LiBF4 (614 g, 6.55 mol, 10.0 equiv). The resulting reaction mixture was stirred at 75° C. for overnight. The reaction mixture was cooled to 0° C. before a solution of ammonium hydroxide (NH4OH, 570 mL) in water (2.2 L) was added slowly to keep the temperature below 10° C. (pH 9-10). The mixture was stirred at room temperature for overnight. When the reaction was deemed complete, water (10 L) was added and the resulting mixture was vigorously stirred for 3 h at room temperature. The solids were collected by filtration, washed with water (6.7 L) and heptane (6.7 L), and dried in vacuum oven at 45° C. over the weekend. The dried solid was then dissolved in 20% MeOH in dichloromethane (12 L), and was purified by column chromatography on 1.3 Kg of silica gel eluting with a 20% MeOH in dichloromethane solution (18 L) to afford 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (7, 204 g, 243.3 g theoretical, 83.8% yield) as an off-white solid. For 7: 1H NMR (300 MHz, d6-DMSO) 81.25 (t, 3H), 3.25 (q, 2H), 3.75 (s, 2H), 4.25 (d, 2H), 4.65 (d, 2H), 7.10 (d, 1H), 7.65 (dd, 1H), 8.50 (s, 1H), 8.70 (s, 1H), 8.95 (s, 1H), 12.2 (bs, 1H); MS: m/z calcd. 372.12. found: 372.0.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)#[N:18]>O1CCCC1>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1

Procedure:
13.1 g (0.13 moles) of triethylamine were added to a solution of 14.2 g (0.12 moles) of 4-aminobenzonitrile in 100 ml of tetrahydrofuran and the temperature was then kept at about 5° C. and 20 g (0.12 moles) of 4-cyanobenzoyl chloride were added dropwise. The mixture was left to react for 12 h under agitation. The solvent was evaporated, the residue was taken up with H2O and the precipitate formed was filtered. The precipitate was washed with dilute HC1, a 10% solution of bicarbonate and again with H2O.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([P:23]([O:29][CH:30]([CH3:32])[CH3:31])(=[O:28])[O:24][CH:25]([CH3:27])[CH3:26])[P:13]([O:19][CH:20]([CH3:22])[CH3:21])(=[O:18])[O:14][CH:15]([CH3:17])[CH3:16])[CH:6]=[C:7]([CH2:9]Br)[CH:8]=1.[C:33]([O-:36])(=[S:35])[CH3:34].[K+]>CN(C=O)C>[C:33]([S:35][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([P:23]([O:29][CH:30]([CH3:32])[CH3:31])(=[O:28])[O:24][CH:25]([CH3:27])[CH3:26])[P:13]([O:19][CH:20]([CH3:22])[CH3:21])(=[O:18])[O:14][CH:15]([CH3:17])[CH3:16])[CH:6]=[C:7]([CH2:9][S:35][C:33](=[O:36])[CH3:34])[CH:8]=1)(=[O:36])[CH3:34]
Reactant: CC(C)OP(=O)(OC(C)C)C(Cc1cc(CBr)cc(CBr)c1)P(=O)(OC(C)C)OC(C)C
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SCc1cc(CSC(C)=O)cc(CC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
To a solution of bisphosphonate 17 (2 g, 3.2 mmol) in 12 ml of anhydrous DMF under nitrogen is added at 0° C. via a cannula a solution of potassium thioacetate (1.1 g, 9.6 mmol) in 15 ml of anhydrous DMF. The mixture is stirred for 1.50 h at 0° C., quenched with water and extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography (silica gel, MeOH:CH2Cl2 /0:100-2:98) to give bisthioacetate 18 (1.38 g, 70%) as a light yellow oil. IR (neat) 2980, 2932, 2230, 1692, 1600 cm-1 ; 1H NMR (CDCl3): δ 1.16 (6H, d, J=6.2 Hz), 1.18 (6H, d, J=6.2 Hz), 1.23 (12H, d, J=6.2 Hz), 2.26 (6H, s), 2.40 (1H, tt, J=24, 6.3 Hz), 3.07 (2H, td, J=16.5, 6.3 Hz), 4.00 (4H, s), 4.67 (4H, m), 6.95 (1H, s), 6.99 (2H, s); 13C NMR (CDCl3): δ 23.72, 23.75, 23.78, 23.84, 23.87, 23.90, 24.14, 30.25, 31.35 (t, J=4.8 Hz), 33.17, 40.59 (t, J=134 Hz), 70.98 (d, J=3 Hz), 71.01 (d, J=3 Hz), 71.15 (d, J=3 Hz), 71.28 (d, J=3 Hz), 127.24, 128.55, 137.62, 140.99 (t, J=7.6 Hz), 194.77; MS (APCI) m/z (relative intensity) 611 (MH+, 100), 569 (63), 527 (58), 485 (37), 453 (31)); MS (FAB) m/z (relative intensity) 611 (MH+, 100); HRMS calcd for C26H45O8P2S2 (MH+) 611.2031, found 611.2029.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H].I[CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:33])[N:25]2[CH3:32].Cl>ClCCl.C1COCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:20]([CH2:19][CH2:18][CH2:17][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[C:21]2[C:26]=1[N:25]([CH3:32])[C:24](=[O:33])[CH:23]=[CH:22]2
Reactant: COc1ccc(CCCI)c2ccc(=O)n(C)c12
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(CCCc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Yield: 93 %

Procedure:
Sodium hydride (60% in oil) (0.39 g) was added under ice cooling to a THF solution (30 ml) of diethyl malonate (1.85 ml), and stirring was carried out until the generation of hydrogen stopped. 5-(3-Iodopropyl)-8-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline (2.89 g) was added, followed by stirring at room temperature for 4.5 hours. The reaction mixture was added to cold hydrochloric acid, and extraction with dichloromethane was performed. After drying over anhydrous sodium sulfate, the dry product was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The purified product was concentrated under reduced pressure to thereby obtain 2.94 g (yield: 93%) of diethyl 2-[3-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)propyl]malonate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[OH:23]OS([O-])=O.[K+].[OH2:29]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1)(=[O:23])=[O:29]
Reactant: O
Reactant: O=S([O-])OO
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(F)cc2F)CC1
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of tert-butyl 4-((2,4-difluorophenyl)thio)piperidine-1-carboxylate (2.141 g, 6.50 mmol) in THF/MeOH (3:1, 74 mL) at 0° C. was treated with a cold solution of Oxone® (9.99 g, 16.25 mmol) in water (56 mL). The reaction mixture was allowed to stir overnight, gradually warming to room temperature. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organics were washed with water and then saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a gradient of 10% to 40% EtOAc with 0.1% triethylamine in heptanes gave tert-butyl 4-((2,4-difluorophenyl)sulfonyl)piperidine-1-carboxylate (1.32 g, 56%) as a white solid. ESI-MS m/z [M+Na]+ 383.80.