Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN[O:4][CH3:5].[CH:6]([N:9](C(C)C)CC)(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([C:26]([OH:28])=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH:24]([C:26](=[O:28])[NH:9][CH2:6][O:4][CH3:5])[CH2:25]1)=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COCNC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
A mixture of N,O-dimethylhydroxylamine hydrochloride (773 mg, 7.93 mmol) and diisopropylethylamine (1.38 mL, 7.93 mmol) in dichloromethane (5 mL) was added to a mixture of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 5.30 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.27 g, 6.63 mmol) in dichloromethane (10 mL). The resulting reaction mixture was stirred at RT under nitrogen atmosphere for 16 h. The organic phase was washed with water (1×25 mL), 10% aqueous citric acid solution (2×25 mL), brine (1×30 mL), and dried over sodium sulphate. The solvents were reduced in vacuo to afford the title compound as pale yellow oil (1.06 g, 82%). 1H NMR (400 MHz, CDCl3): δ 4.14 (2 H, m), 4.05 (2 H, t, J=8.72 Hz), 3.66 (4 H, s), 3.20 (3 H, s), 1.43 (9 H, s).
Reaction SMILES: [CH:1]([CH:3]([CH2:9][C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)[C:4](OCC)=O)=[O:2].[N+:15]([NH:18][C:19]([NH2:21])=[NH:20])([O-:17])=[O:16].C[O-].[Na+]>CO>[N+:15]([NH:18][C:19]1[NH:21][C:1](=[O:2])[C:3]([CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][N:20]=1)([O-:17])=[O:16]
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: CCOC(=O)C(C=O)Cc1ccco1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccco1
Yield: 59.3 %

Procedure:
Ethyl 2-formyl-3-(2-furyl)propionate (24.0 g, 0.122 mol) was added to a mixture of nitroguanidine (12.69 g, 0.122 mol) and sodium methoxide (from 3.09 g, 0.134 mol, sodium) in methanol and the mixture was stirred and heated under reflux for 18 hours and evaporated to dryness. The residue was dissolved in water and the solution was adjusted to pH 4 with acetic acid. The solid which separated was filtered off to give 2-nitroamino-5-(2-furylmethyl)-4-pyrimidone (17.1 g, 59%). A sample recrystallised from methanol-acetic acid and from acetic acid had m.p. 183°-184°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])[C:8]([C:10]1[CH:40]=[CH:39][C:13]2[N:14]([CH3:38])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:37])[NH:26][C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[OH-].[Na+]>ClCCl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])[C:8]([C:10]1[CH:40]=[CH:39][C:13]2[N:14]([CH3:38])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:37])[NH:26][C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)n2C)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cn1c(CNc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Yield: 62 %

Procedure:
Prepared analogously to Example 104 from 1-methyl-2-[N-[4-(N-benzyloxycarbonylamidino)phenyl]-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and sodium hydroxide solution. Yield: 62% of theory, C33H31N7O5 (605.7) Rf value: 0.26 (silica gel; dichloromethane/methanol=9:1) ##EQU133##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[C:7](\[CH3:10])/[CH2:8]Br)[CH3:2].[Cl:15][CH2:16][CH2:17][O:18][P:19]([O:24]CCCl)[O:20][CH2:21][CH2:22][Cl:23]>>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH:11][CH:12]=[O:13])/[CH:6]=[C:7](\[CH3:10])/[CH2:8][P:19]([O:20][CH2:21][CH2:22][Cl:23])([O:18][CH2:17][CH2:16][Cl:15])=[O:24])[CH3:2]
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: CCOC(=O)C(/C=C(\C)CBr)NC=O
Product: CCOC(=O)C(/C=C(\C)CP(=O)(OCCCl)OCCCl)NC=O

Procedure:
8.2 g of E-5-bromo-2-formylamino-4-methyl-3-pentenoic acid ethyl ester and 19 ml of tris-(2-chloroethyl)-phosphite are stirred at a bath temperature of 70° for 20 hours. The resulting mixture is chromatographed on silica gel using ethyl acetate and ethyl acetate/isopropanol (7:1) as eluant, and the product is crystallised from ethyl acetate/diethyl ether. In this manner there is obtained E-2-formylamino-4-methyl-5-di(2-chloroethyl)phosphono-3-pentenoic acid ethyl ester, m.p. 47°-49°.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:21]=1[CH2:22][NH:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]#[C:36][Si](C)(C)C)=[CH:31][N:30]=2)[CH2:25]1>O1CCCC1.O.ClCCl>[Cl:19][C:20]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:21]=1[CH2:22][NH:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[CH:31][C:32]([C:35]#[CH:36])=[CH:33][N:34]=2)[CH2:25]1
Reactant: C[Si](C)(C)C#Cc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C#Cc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Add tetrabutylammonium fluoride (1.0 mL, 1.0 mmol, 1.0 M solution in tetrahydrofuran) to a stirred solution of (S)-(2,4-dichlorobenzyl)-[1-(5-trimethylsilanylethynylpyrimidin-2-yl)-pyrrolidin-3-yl]-amine (327 mg, 0.78 mmol) in tetrahydrofuran (10 mL) at 0° C. Warm to room temperature and stir for 1 hour and concentrate to give a residue. Dilute the residue with water (10 mL), extract with ethyl acetate (3×25 mL). Extract the combined organic layers with saturated aqueous sodium chloride (10 mL), concentrate to give a residue. Dissolve the residue in dichloromethane, filter, concentrate to give a residue, and chromatograph the residue on silica gel followed by chromatography on SCX-2 to give the title compound as a yellow gum (194 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C1CNC([CH2:28][OH:29])C1.Cl.CC[N:33]([CH:37]([CH3:39])C)[CH:34]([CH3:36])C>CC(O)C>[Br:1][C:2]1[C:3]([N:33]2[CH2:34][CH2:36][C@@H:39]([CH2:28][OH:29])[CH2:37]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: OCC1CCCN1
Agent: Cl
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](CO)C2)c(Br)c1
Temperature: 140 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 500 mg, 1.264 mmol), (R)-beta-prolinol hydrochloride (191 mg, 1.39 mmol) and DIPEA (442 μL, 2.53 mmol) in iPrOH (1945 μL) were added to a MW vial and subjected to MW irradiation at 140° C. for 30 min. Additional (R)-beta-prolinol hydrochloride (34.8 mg, 0.253 mmol) and DIPEA (221 μL, 1.264 mmol) were added to the mixture which was heated at 140° C. for a further 30 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure treated with 0.5 M HCl (20 mL) and extracted with EtOAc. The combined extracts were washed with 0.5 M HCl (10 mL), water, dried over MgSO4 and evaporated to dryness under reduced pressure. Trituration in a cyclohexane/EtOAc mixture and filtration of the solid afforded the title compound as a white solid. UPLC-MS (condition 1) tR=2.76 min, m/z=460.0-462.0 [M+H]+, m/z=458.0-460.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.77 (m, 1H) 1.91-2.06 (m, 1H) 2.28-2.42 (m, 1H) 3.35-3.51 (m, 2H) 3.56 (dd, J=11.00, 7.34 Hz, 1H) 3.63-3.86 (m, 3H) 4.71 (br. s, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.34 (d, J=1.96 Hz, 1H) 8.68 (d, J=1.96 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[N:16]=[C:17]([N:20]=[C:21]([NH2:23])[NH2:22])[S:18][CH:19]=2)[N:14]=1.[CH3:24][N:25]=[C:26]=[O:27]>CO>[NH2:22][C:21](=[N:20][C:17]1[S:18][CH:19]=[C:15]([C:13]2[N:14]=[C:10]([CH2:9][NH:8][C:26]([NH:25][CH3:24])=[O:27])[S:11][CH:12]=2)[N:16]=1)[NH2:23]
Reactant: CN=C=O
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.6 %

Procedure:
Triethylamine (0.7 g) was added to a suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (1.0 g) in methanol (20 ml). To the mixture was added methylisocyanate (0.21 g). The mixture was stirred at room temperature for 1.5 hours. The solvent was removed under the reduced pressure and the residue was chromatographed on a Silica gel column eluting with a mixture of chloroform and methanol (10:1). Recrystallization from a mixture of water and methanol afforded 2-(diaminomethyleneamino)-4-[2-(3-methylureido)methylthiazol-4-yl]thiazole (0.5 g).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:13][CH3:14])[C:10]([F:12])=[CH:11][C:5]=2[CH:4]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>ClC1C=CC=CC=1.CCOC(C)=O>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:4]2[C:5]3[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:6]=3[S:7][C:3]=2[N:2]([CH3:15])[CH3:1])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2sc(N(C)C)cc2cc1F
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2sc(N(C)C)c(C(=O)c3ccc([N+](=O)[O-])cc3)c2cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 116.4 %

Procedure:
A solution of 1.08 g (4.82 mmol) of 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene (Part B) in 15 mL of chlorobenzene was treated with 0.99 g (5.31 mmol) of 4-nitrobenzoyl chloride. The reaction was stirred at room temperature for 17 h and was diluted with 100 mL of EtOAc. The solution was washed sequentially with 2 N aqueous NaOH (2×50 mL), H2O (50 mL) and brine (50 mL), then dried over Na2SO4, and filtered. Evaporation of the solvent in vacuo afforded 2.1 g of a dark solid which was purified by flash chromatography (SiO2; gradient of 10% then 20% then 40% EtOAc in hexanes) to give 0.27 g of starting material and 1.25 g (3.34 mmol; 93% based on consumed starting material) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[SH2:9].[K].C(O)C.C[O-].[Na+].CO.[Cl:19][C:20]1[N:24]2[N:25]=[C:26](Cl)[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1>CO>[Cl:19][C:20]1[N:24]2[N:25]=[C:26]([S:9][CH2:2][CH2:3][CH2:4][S:5](=[O:7])(=[O:6])[NH2:8])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1
Reactant: NS(=O)(=O)CCCCl
Reactant: Clc1ccc2ncc(Cl)n2n1
Reactant: S
Agent: C[O-]
Agent: [K]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: NS(=O)(=O)CCCSc1ccc2ncc(Cl)n2n1
Temperature: 70 °C

Procedure:
To a solution of 1.57 g of 3-chloro-1-propanesulfonamide in 20 ml of methanol was added 20ml of 2N-potassium hydrogensulfide-ethanol solution, followed by heating at 70° C. for 50 minutes. Then, 1.48 g of 28% sodium methoxide-methanol solution and 1.32g of 3,6-dichloroimidazo[1,2-b]pyridazine were added to the reaction mixture and refluxed at 100° C. for 3 hours. The mixture was concentrated under reduced pressure, and to the residue was added 20 ml of water, which was adjusted to pH 7.0 with 1N-hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from methanol and ethyl ether to obtain 1.12 g of the title compound.
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.[F:15][C:16]1[CH:17]=[C:18]([P:22](Cl)(Cl)=[O:23])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([P:22]2(=[O:23])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=P(Cl)(Cl)c1cccc(F)c1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: O=P1(c2cccc(F)c2)c2ccccc2CN1c1ccccc1
Yield: 13 %

Procedure:
The procedure of Example 38 was employed utilizing N-benzylaniline and 3-fluorophenyl phosphonic dichloride to yield 1-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.3 g, 13% yield) as a white solid having a melting point of 209°-210° C. and the following analysis:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:22])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:10]=2[C:9](=O)[CH2:8]1.[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].Cl.CS(O)(=O)=O.C1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[S:3][C:4]([Cl:22])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:10]=2[C:9](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:8]1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2cc(Cl)sc2Cl)Cc2nncc(C(F)(F)F)c21
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: N=C(N)NN=C1CC(c2cc(Cl)sc2Cl)Cc2nncc(C(F)(F)F)c21
Yield: 31.3 %

Procedure:
To a solution of 7-(2,5-dichlorothiophen-3-yl)-4-trifluoromethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.443 g) and aminoguanidine hydrochloride (167 mg) in ethanol (10 ml) were added methanesulfonic acid (0.2 ml) and benzene (10 ml), and the mixture was refluxed for 1.5 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was washed with isopropylether and diethylether and dried to give 7-(2,5-dichlorothiophen-3-yl)-5-guanidinoimino-4-trifluoromethyl-5,6,7,8-tetrahydrocinnoline (Compound 135) (0.160 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:15])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Cl)cc1
Temperature: 65 °C
Yield: 88 %

Procedure:
Thionyl chloride (200 ml) was added to 4-methoxyphenylacetic acid (78 g, 0.47 mole) followed by one drop of dimethylformamide. The reaction was heated at 65° C. for 4 hours and the solvent was removed under vacuum. The residue was distilled in vacuo (water aspirator) at 135° C. to give the product as a red oil (75.9 g, 88%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=3)=[CH:8][C:7]=2[CH:20]=1.C(Cl)Cl.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=3)=[CH:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2oc(-c3ccc(C(N)=O)nc3)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccc(-c2cc3cc(O)ccc3o2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
5-(5-Methoxy-benzofuran-2-yl)-pyridine-2-carboxylic acid amide (0.21 mmol) was mixed with CH2Cl2 (3 mL) at 0° C. under argon atmosphere. BBr3 (1M in CH2Cl2) (1.0 mL) was added dropwise and the mixture was stirred for 2 h at rt. The mixture was hydrolysed with H2O followed by NaHCO3 (sat. aq.). The resulting mixture was filtered, and the obtained precipitate was washed with H2O and EtOAc. The solid was dried at 40° C. for 15 h under vacuum to give the title compound (20 mg). 1H NMR δ ppm 9.08 (d, 1 H) 8.33 (dd, 1 H) 8.20 (br. s., 1 H) 7.97 (d, 1 H) 7.61 (br. s., 1 H) 7.54 (s, 1 H) 7.47 (d, 1 H) 7.02 (d, 1 H) 6.85 (none, 1 H); MS m/z 255 (M+H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:30])[CH2:24][C:25](OCC)=[O:26])[CH2:19][CH2:18]2)[N:4]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[OH2:13].[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:30])[CH2:24][C:25]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:26])[CH2:21][CH2:22]2)[N:4]=1.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:30])[CH2:24][C:25]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:26])[CH2:21][CH2:22]2)[N:4]=1.[ClH:1]
Reactant: CCOC(=O)CC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nc(N3CCN(C(=O)CC(=O)Nc4ccccc4)CC3)nc(N)c2cc1OC
Product: O
Temperature: 155 °C

Procedure:
A mixture of 4 g of the compound obtained in Example 18 and 14 ml aniline in 6 ml DMF is warmed at 155° C. for 5.5 h.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][CH2:11][CH:12]([CH2:14]O)[OH:13].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[OH:13][CH:12]1[CH2:11][O:10][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)[O:6][CH2:14]1
Reactant: OCC(O)CO
Reactant: O=Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: OC1COC(c2cccc(F)c2)OC1
Yield: 73.2 %

Procedure:
A mixture of 3-fluorobenzaldehyde (24.8 g, 0.2 mole), glycerol (18.4 g, 0.2 mole) and 40% sulfuric acid (2.0 ml) in benzene (200 ml) was heated with stirring under a Dean-Stark apparatus until water ceased to collect (approximately 2.5 hours). The mixture was cooled, neutralized with potassium carbonate and, after adding 200 ml of ether, washed with water (3 × 100 ml). The washed solution was dried over magnesium sulfate and concentrated under reduced pressure to give 29.0 g of colorless oil which was distilled under 0.025 mm using a short path distillation apparatus to give 18.9 g, nD24 1.5160, of 5-hydroxy-2-(3-fluorophenyl)-1,3-dioxane which distilled at a bath temperature of 86°-105° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[Br:14][C:15]1[C:27]([OH:28])=[CH:26][C:18]2[O:19][C:20]([CH3:25])([CH3:24])[O:21][C:22](=[O:23])[C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:28][C:27]1[C:15]([Br:14])=[CH:16][C:17]2[C:22](=[O:23])[O:21][C:20]([CH3:24])([CH3:25])[O:19][C:18]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)c2cc(Br)c(O)cc2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2cc(Br)c(OCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzyl bromide (4.88 mL) was added to a DMF (50 mL) suspension of 6-bromo-7-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one (9.34 g) and potassium carbonate (7.09 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then, water was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained solid was washed with diethyl ether to obtain the title compound (9.95 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[F:19])C1C=CC=CC=1>CO.[Pd]>[NH2:16][C:12]1[C:13]([F:15])=[CH:14][C:9]([OH:8])=[C:10]([F:19])[CH:11]=1
Reactant: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(O)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.4 %

Procedure:
To a solution of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (9.21 g) in methanol (300 ml) was added 10% palladium on carbon (921 mg), followed by stirring under a hydrogen atmosphere at room temperature for 24 hr and 20 min. The atmosphere in the reaction vessel was replaced with nitrogen to stop the reaction, and the catalyst was filtered through Celite. The filtrate was removed under reduced pressure to provide the titled compound as a brown solid (4.96 g, 99%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:8]=1>C1COCC1>[CH2:1]([NH:5][S:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:15])=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Reactant: CCCCN
Solvent: C1CCOC1
Product: CCCCNS(=O)(=O)Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
n-Butylamine (3.25 g, 44.43 mmol) was dissolved in THF (25 mL) and it was then cooled in an ice-bath. ((4-Chlorophenyl)methyl)sulfonyl chloride (5.0 g, 22.21 mmol) in THF (25 mL) was dropped in. The cooling-bath was removed after the addition. The mixture was stirred for 2 h and then evaporated to dryness. DCM (50 mL) was added to the residue. It was washed with HCl (5%, 10 mL), water (30 mL×3) and brine (20 mL), dried (MgSO4) and evaporated to give the title compound (5.43 g, 93%) as a solid; 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 2H), 7.32 (d, 2H), 4.19 (s, 2H), 4.11 (bt, 1H), 2.99 (dd, 2H), 1.50-1.43 (m, 2H), 1.36-1.26 (m, 2H), 0.90 (t, 3H); Mass Spectrum: M−H+ 260.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30]>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:34]3[CH:35]=[CH:36][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C

Procedure:
1-methylethyl[(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 61) (1.6 g, 4.33 mmol), potassium carbonate (1.198 g, 8.67 mmol), tetrakis(triphenylphosphine)palladium(0) (0.250 g, 0.217 mmol) and (4-formylphenyl)boronic acid (0.780 g, 5.20 mmol) were dissolved in Ethanol (10 mL) and Toluene (10 mL). The reaction mixture was degassed for 30 min then stirred and heated under nitrogen for 1 hr at 100° C. The reaction mixture was filtered and the solvent evaporated under vacuum. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was dried through a hydrophobic frit and concentrated in vacuo. The residue was dissolved with dichloromethane and purified by SP4 on a 40+M silica cartridge using a gradient 20-75% ethyl acetate in cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the required product (1.4 g) as a yellow solid. LCMS (Method B): Rt 0.99, MH+=395
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([O:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Oc1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(Br)cc(F)c1OCc1ccccc1

Procedure:
A stirred mixture of 4-bromo-2,6-difluorophenol (36 g, 0.172 mole), benzylchloride (21.77 g, 0.172 mole), and potassium carbonate (25 g, 0.18 mole) in demethylformamide (300 ml) was heated at 80°-90° for four hours. After cooling, the solvent was evaporated and ether added to the residue. The insoluble inorganic salts were removed by filtration, and solvent evaporated from the filtrate. The oily residue was subjected to bulb-to-bulb vacuum distillation on Kugelrohr apparatus to give the desired product as a nearly colorless oil (41 g, 80 percent): R.I.=1.5602 @ 25° C.; NMR (CDCl3) was consistent with the assigned structure.