Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:14][S:13][C@@H:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[S:11]1)(C(C)(C)C)(C)C>CO.C(Cl)(=O)C.[Cl-].[NH4+]>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([C@H:12]1[S:11][C@@H:10]([CH2:9][OH:8])[CH2:14][S:13]1)=[O:16])[CH3:19]
Reactant: CCOP(=O)(OCC)[C@@H]1SC[C@H](CO[Si](C)(C)C(C)(C)C)S1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)Cl
Solvent: CO
Product: CCOP(=O)(OCC)[C@@H]1SC[C@H](CO)S1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of cis-4-(t-butyldimethylsilyloxymethyl)-2-(diethyloxyphosphinoyl)-1,3-dithiolane (example 49) (3.70 g, 9.56 mmol) in anhydrous methanol (50 mL) was added acetyl chloride (6 drops) at 0° C. The solution was stirred at 0° C. for 30 min and then at room temperature for 4.5 hrs. A saturated solution of ammonium chloride (3 drops) was added and the solution was stirred for 15 min followed by evaporation of solvents. The crude material was purified by flash chromatography with a mixture of dichloromethane and methanol (95:5) to give the compound (2.02 g) in 77% yield. 1H NMR (300 MHz, CDCl3) δ: 1.34 (t, 6H, J=7.0 Hz, CH3), 3.30 (dd, 1H, J=5.5 Hz, 12.0 Hz, H-5a), 3.42 (dd, 1H, J=6.0 Hz, 12.1 Hz, H-5b), 3.80 (m, 2H, CH2OH and 1H, OH), 4.05 (m, 1H, H-4) , 4.19 (m, 4H, CH2) , 4.35 (d, 1H, 2JHP =4.1 Hz, H-2).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:8][Cl:9])([C:5](=[O:7])[CH3:6])[CH3:4].[Br:10]Br>>[Br:10][CH2:6][C:5](=[O:7])[C:3]([CH2:8][Cl:9])([CH2:2][Cl:1])[CH3:4]
Reactant: BrBr
Reactant: CC(=O)C(C)(CCl)CCl
Product: CC(CCl)(CCl)C(=O)CBr

Procedure:
Finally, the 2,2-bis-chloromethyl-butan-3-one was then reacted with bromine to give 1-bromo-3,3-bis-chloromethylbutan-2-one.
Reaction SMILES: [C:1]([C:3]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)([CH2:10][CH2:11][C:12]([O-])=[O:13])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2]>COCCO.[Ni]>[Cl:22][C:17]1[CH:16]=[C:15]([C:3]2([CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:1][NH:2][C:12](=[O:13])[CH2:11][CH2:10]2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)CCC(C#N)(CCC(=O)[O-])c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Solvent: COCCO
Product: COC(=O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1
Reaction time: 72 h

Procedure:
40 g of the compound prepared in step A are dissolved in 500 ml of 2-methoxyethanol, 2 g of Raney nickel are added and the mixture is hydrogenated at 40° C. under atmospheric pressure for 3 days. It is filtered and evaporated to give the expected product in the form of an oil (39 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=O)=[CH:4][C:3]=1[O:15][CH3:16].Br.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:22][NH2:23].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>>[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[OH:27])[CH2:22][NH:23][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:15][CH3:16])[CH:4]=1
Reactant: NCc1ccc(O)c(O)c1
Reactant: COc1cc(/C=C/C=C/C(=O)O)ccc1O
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/C=C/C(=O)NCc2ccc(O)c(O)c2)ccc1O

Procedure:
The compound was prepared as described in Example 5 using 11 mg (0.05 mmol) of 5-(4-hydroxy-3-methoxyphenyl)-penta-2E,4E-dienoic acid [Example 3], 22 mg (0.10 mmol) of 3,4 dihydroxybenzylamine hydrobromide, 50 μl (0.50 mmol) of triethylamine, and 33 mg (0.075 mmol) of BOP reagent.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].OC[C:16]([CH2:21][OH:22])([CH2:19][OH:20])CO>>[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:12][CH2:13][C:16]2([CH2:19][O:20][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])[O:22][CH2:21]2)[CH2:1][O:2]1)#[N:11]
Reactant: OCC(CO)(CO)CO
Reactant: COC(CCCCCCC#N)OC
Product: N#CCCCCCCC1OCC2(CO1)COC(CCCCCCC#N)OC2
Yield: 112.5 %

Procedure:
The condensation reaction of 11.9 g of 7-cyanoheptanal dimethylacetal and 4.35 g of pentaerythritol was carried out to obtain 13.6 g of 3,9-bis(6-cyanohexyl)-2,4,8,10-tetraoxaspiro[5.5]undecane, which was then subjected to catalytic reduction to form 8.6 g of 3,9-bis(7-aminoheptyl)-2,4,8,10-tetraoxaspiro[5.5]undecane.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1.[CH2:13](Br)[CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1
Reactant: CCCn1c(=O)cc(Cl)[nH]c1=O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(Cl)cc(=O)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 7 g of 6-chloro-3-propyluracil, 10.28 g of butyl bromide, 10.28 g of potassium carbonate, 6 g of potassium iodide and 80 ml of dimethylformamide was stirred at room temperature for 23 hours. After the reaction solution was concentrated to dryness under reduced pressure, 300 ml each of chloroform and water were added to the residue, and the mixture was shaken. The chloroform layer was washed with water and then concentrated to dryness under reduced pressure to give 6-chloro-1-butyl-3-propyluracil as a brown oily substance. This product, without being purified, was dissolved in 20 ml of ethanol, and 20 ml of 100% hydrazine hydrate was added to the solution, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure and the residue was washed with water and recrystallized from a mixture of ethanol, ethyl acetate and isopropyl ether to give 7 g of yellow prisms of 6-hydrazino-1-butyl-3-propyluracil melting at 146°-147° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.N1C=CC=CC=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:21]([O:13][CH:10]([C@H:8]1[O:7][C@@H:5]2[O:6][C:2]([CH3:1])([CH3:14])[O:3][C@@H:4]2[CH2:9]1)[CH2:11][CH3:12])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCC(O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a stirred solution of crude 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 1e, 8.08 g, 40.0 mmol) and pyridine (16.1 mL, 200 mmol) in DCM was added benzoyl chloride (5.0 mL, 43.0 mmol) dropwise at 0° C. After the addition, the mixture was warmed to room temperature and stirred at room temperature overnight. The resulting mixture was washed with 1N hydrochloric acid, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:3 EtOAc in petroleum ether) to afford 6.86 g of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl benzoate (compound 26a).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([OH:20])[C:17]3[C:12](=[CH:13][C:14]([OH:21])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].[CH3:22][CH:23]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH3:24].N1C=CN=C1>CN(C=O)C>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([OH:20])[C:17]3[C:12](=[CH:13][C:14]([O:21][Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:24])[CH3:22])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)Nc1nc(-c2cc(O)c3ccc(O)cc3n2)cs1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)Nc1nc(-c2cc(O)c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3n2)cs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a solution of 2-(2-Isopropylamino-thiazol-4-yl)-quinoline-4,7-diol (1.27 g, 4.2 mmol) in 4 mL of DMF was added TIPSCl (2.67 mL, 12.6 mmol) followed by imidazole (2.86 g, 42 mmol). The solution was stirred for 5 min at rt, dissolved in 20 mL EtOAC, quenched by saturated solution of NH4Cl in H2O. The solution was extracted and evaporated under vacuo. The crude product was purified by silica gel chromatography using SiO2 (eluted with 5% to 20% MeOH/DCM) to give 2-(2-Isopropylamino-thiazol-4-yl)-7-triisopropylsilanyloxy-quinolin-4-ol as a dark orange solid (1.9 g, 99%). 1H-NMR (300 MHz, DMSO): δ 11.0 (bs, 1H), 7.93 (d, 1H), 7.70 (bs, 1H), 7.42 (s, 1H), 7.25 (s, 1H), 6.81 (dd, 1H), 6.49 (s, 1H), 3.97-3.87 (m, 1H), 1.38-1.25 (m, 1H), 1.22 (d, 6H), 1.07 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[CH2:13][NH2:14].[CH3:15][CH:16]([CH3:20])[CH2:17][CH:18]=O.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[CH2:13][NH:14][CH2:18][CH2:17][CH:16]([CH3:20])[CH3:15]
Reactant: CC(C)CC=O
Reactant: COc1cccc2c(CN)cccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc2c(CNCCC(C)C)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-methoxynaphthalen-1-ylmethylamine (Preparation 12) (389 mg, 2.08 mmol) in MeOH (15 mL), was added 3-methylbutyraldehyde (223 μL, 2.08 mmol). The mixture was stirred for 16 h at rt under nitrogen before adding NaBH4 (236 mg, 6.24 mmol). After stirring for 1 h water (0.5 mL) was added and the solvent removed in vacuo. The mixture was partitioned between EtOAc (100 mL) and NaHCO3 (25 mL), the organic phase was washed with water (25 mL), brine (25 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (DCM: MeOH: NH4OH, 97:3:0.3 to 95:5:0.5) to give the title compound: RT=2.46 min; m/z (ES+)=258.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH2:24][NH:23][CH2:22][CH2:21]2)[S:9]([C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:28]([N:23]1[CH2:22][CH2:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[S:9]([C:12]3[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=3)(=[O:11])=[O:10])[CH:19]=2)[CH2:24]1)(=[O:30])[CH3:29]
Reactant: CC(=O)O
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccccc2)c2ccc3c(c2)CCNC3)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2cc(N(Cc3ccccc3)S(=O)(=O)c3ccn(C)n3)ccc2C1
Yield: 66.7 %

Procedure:
To a stirred solution of 1-methyl-1H-pyrazole-3-sulfonic acid benzyl-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide (24 mg, 0.06 mmol) and acetic acid (3.6 μl, 0.06 mmol) in dry acetonitrile (2 ml) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (24 mg, 0.06 mmol), then diisopropylethylamine (33 μl, 0.20 mmol) and the solution was stirred at 50° C. for 16 hrs. The reaction mixture was concentrated in vacuo and the residue purified using preparative HPLC to afford the title compound as a white solid (17 mg, 67% yield), HPLC retention time 3.97 min. Mass spectrum (ES+) m/z 425 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29](O)(=[O:33])[CH2:30][CH:31]=[CH2:32].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][CH:31]=[CH2:32])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(=O)O
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Reaction time: 27 h

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. 3-Butenoic acid (0.27 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 27 hr. at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography with gradient elution (70%→90% ethyl acetate in hexanes) affording the desired product (27) as a solid. CIMS (NH3Cl): 447 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:28]2[CH2:27][CH2:26][N:25]([CH:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[CH2:30][CH2:29]2)=[O:17])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CC(C)(C)OC(=O)Nc1nc(CC(=O)O)cs1
Product: CN1CCC(N2CCN(C(=O)Cc3csc(NC(=O)OC(C)(C)C)n3)CC2)CC1

Procedure:
47.1 Using general method C, (2-tert-butoxycarbonylamino-thiazol-4-yl)-acetic acid (example 37.2) was coupled with 1-(N-methylpiperidin-4-yl)piperazine to give (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-carbamic acid tert-butyl ester. Off-white powder. MS 424.0 ([M+H]+)
Reaction SMILES: C[O:2][C:3](=[O:37])[CH:4]([N:11]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:13]=2[CH:12]1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCOCC1>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH:12]1[C:13]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:14]=2[CH2:15][CH2:16][CH2:17][N:11]1[CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]([OH:37])=[O:2]
Reactant: COC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid methyl ester (1.17 g, 2.31 mmol), in MeOH (9 ml) and dioxane (12 ml), was added dropwise aqueous NaOH 2N (11 ml, 22 mmol). The resulting yellow homogeneous mixture was then stirred at 45° C. for 8 h. The reaction mixture was then concentrated in vacuo and washed with Et2O (5 ml). The aqueous phase was acidified (pH=1) with HCl 2N and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give the titled carboxylic acid (1.14 g, 2.31 mmol, 100%) as a beige solid (mixture of diastereoisomers).
Reaction SMILES: C(O[C:4](=[NH:20])[C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:19])(=[O:18])[NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)C.[NH2:21][NH2:22]>C(O)C>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[NH:12][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]([NH:21][NH2:22])=[NH:20])=[CH:10][CH:9]=1)(=[O:19])=[O:18]
Reactant: CCOC(=N)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: NN
Solvent: CCO
Product: N=C(NN)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4-(thiazol-2-ylsulfamoyl)-benzimidic acid ethyl ester (0.18 mmol) in ethanol (5 mL) was added hydrazine (0.1 mL) and the resulting mixture was stirred for 10 min. After the reaction mixture was concentrated in vacuo, it gave 4-(thiazol-2-ylsulfamoyl)-N-aminobenzamidine, which was used in next step without further purification. The crude 4-(thiazol-2-ylsulfamoyl)-N-aminobenzamidine was dissolved in THF and dichloromethane (10 mL, 1:1), and (3-chloro-phenyl)-acetyl chloride (0.36 mmol) and triethyl amine (0.9 mmol) were added. The mixture was stirred for 24 h before it was concentrated in vacuo. The mixture was diluted with AcOEt (30 mL) and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The solution of the residue in DMF and acetic acid (10 mL, 1:1) of was stirred at 80° C. for 24 h. After cooled to room temperature, the acetic acid was removed in vacuo and the residue was diluted with AcOEt (30 mL) and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by reverse phase HPLC to give 4-[5-(3-chloro-benzyl)-4H-[1,2,4]triazol-3-yl]-N-thiazol-2-yl-benzenesulfonamide (0.05 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2nc[nH]c2c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3ncc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a solution of 6-bromo-1H-imidazo[4,5-b]pyridine (500 mg, 2.52 mmol) and 1-chloromethyl-4-methoxy-benzene (394.6 mg, 2.52 mmol) in DMF (10 mL) was added Cs2CO3 (902 mg, 2.77 mmol). The reaction mixture was stirred at room temperature for 2 hours, and then partitioned between EtOAc and water. The organic layer was dried over MgSO4, and concentrated. The residue was purified on a silica gel column eluting with EtOAc-Hexane to provide 6-bromo-1-(4-methoxy-benzyl)-1H-imidazo[4,5-b]pyridine (450 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][C:29]([CH3:31])=O>>[CH2:31]([O:1][C:2]1[C:7]2[C:8]([CH3:20])=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][C:6]=2[C:5]([Cl:21])=[CH:4][CH:3]=1)[CH:29]=[CH2:28]
Reactant: COc1ccc(Cc2oc3c(Cl)ccc(O)c3c2C)cc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c12
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran (164) (Example 44) (1.5 g, 5 mmol) in 30 mL acetone was added potassium carbonate (690 mg, 5 mmol) amd allyl bromide (605 mg, 5 mmol). The mixture was refluxed for 20 h, then filtered through celite after cooling to room temperature. Concentration of the filtrate gave 1.94 g of the 4-allyloxy-7-chloro-2-(4'-methoxyphenylmethyl)-3-methylbenzofuran as a light brown oil. The crude material was refluxed in 8 mL o-dichlorobenzene for 6 h. Evaporation of the solvent followed by chromatography gave the title compound as a white solid, mp 90°-93° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([OH:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Oc1cccc(N2CCNCC2)c1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc(O)c2)CC1
Yield: 75 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:3]=1.Cl.[NH:21]1[C:26]2[N:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:23][C:22]1=[O:36].CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([C:8]([C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:33]3[CH2:32][CH2:31][C:24]4([O:23][C:22](=[O:36])[NH:21][C:26]5[N:27]=[CH:28][CH:29]=[CH:30][C:25]4=5)[CH2:35][CH2:34]3)[CH:3]=1)=[O:9])[CH2:11][CH2:12]2
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Nc2ncccc2C2(CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)ncn3)CC2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.10 g (0.36 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone were added to 92 mg (0.36 mmol) spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one-hydrochloride and 146 μL (0.84 mmol) DIPEA in 1.8 mL DMF. The reaction mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product fractions were combined and lyophilised.
Reaction SMILES: C([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([Br:15])[CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)(=O)C.C1C=C(Cl)C=[C:19]([C:24]([O:26]O)=[O:25])C=1>ClCCl>[C:24]([O:26][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[C:8]([Br:15])[CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)(=[O:25])[CH3:19]
Reactant: CC(=O)c1cn(C)c2c(Br)cccc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)Oc1cn(C)c2c(Br)cccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3-acetyl-8-bromo-1-methylquinolin-4(1H)-one (3.4 g, 12.14 mmol) in dichloromethane (60 mL) at room temperature was added portionwise with stirring m-CPBA (4.08 g, 18.21 mmol). The resulting mixture was stirred at room temperature for 1 h. The excess m-CPBA was quenched via addition of 15% aqueous Na2SO3 (30 mL), and the resulting mixture was stirred at room temperature for 0.5 h. The layers were separated, and the organic layer was washed sequentially with water (100 mL), 5% aqueous NaHCO3 (100 mL), and brine (100 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford crude 8-bromo-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl acetate (3.68 g, 10.56 mmol, 87% yield) as brown solid, which was used in the next hydrolysis step without further purification. LCMS: (M+H)+: 295.9.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:7]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)[P:8](=[O:11])([OH:10])[OH:9])(=[O:6])[OH:5])[CH3:2].[CH3:19][Mg]Br>O1CCCC1>[CH2:1]([O:3][P:4]([CH:7]([N:12]1[CH2:13][CH2:14][C:15]([OH:18])([CH3:19])[CH2:16][CH2:17]1)[P:8](=[O:9])([OH:10])[OH:11])(=[O:5])[OH:6])[CH3:2]
Reactant: CCOP(=O)(O)C(N1CCC(=O)CC1)P(=O)(O)O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCOP(=O)(O)C(N1CCC(C)(O)CC1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
43 g (0.11 mol) of 4-oxopiperidinomethylene bisphosphonic acid ethyl ester was dissolved in 500 mt of dried tetrahydrofuran, and 250 ml (0.25 mol) of a methyl magnesium bromide solution in tetrahydrofuran (concentration: 1 mol/) was added thereto. The mixture was stirred at 25° C. for 2 hours, then subjected to post treatment and purified by column chromatography (SiO2, cyclohexane/CHCl3 =1/1) to give 30.7 g (68.5%) of 4-hydroxy-4-methylpiperidinomethylene bisphosphonic acid ethyl ester as an oily substance. To 15.8 g (39.5 mmol) of this ester, 7.6 g (47.2 mmol) of diethylaminosulfur trifluoride was added at -78° C. in CH2Cl2, and the mixture was stirred at room temperature for 5 hours. The reaction solution was purified by column chromatography (SiO2, hexane/isopropylether=5/1) to give 6.3 (40%) of the above identified compound.