Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:20])[C:8]=1[CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[NH2:5].[N:21]([O-])=O.[Na+]>C(O)(=O)C.O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:21])[CH:6]=[C:7]([Cl:20])[C:8]=1[CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1
Reactant: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(N)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(NN)cc1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 96 %

Procedure:
In 40 ml of acetic acid was dissolved 3.0 g of 3,5-dichloro-4-(3,4-dichloro-α-cyanobenzyl)aniline. To the solution was then added 3 ml of 35% hydrochloric acid. To the mixture was added dropwise, while cooling at temperatures ranging from 10 to 12° C., a solution of 0.8 g of 98.5% sodium nitrite in 3 ml of water. The reaction mixture was stirred for 40 minutes under the same conditions, to which was then added 7.0 g of stannous chloride dissolved in 10 ml of 35% hydrochloric acid. The reaction mixture was poured into ice-water, which was then made into alkaline, followed by extraction with 200 ml of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to afford the titled compound in a yield of 96%, m.p. 183-185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][N:8]3[C:7](=[O:24])[C:6]=2[CH:25]=1.O[CH2:27][CH:28]1[CH2:30][CH2:29]1>CCO.CCO.CCO.CCO.[Ti]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:27][CH:28]4[CH2:30][CH2:29]4)=[O:16])=[C:10]3[C@@H:9]3[CH2:22][CH2:23][N:8]3[C:7](=[O:24])[C:6]=2[CH:25]=1
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OCC1CC1)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Reaction time: 24 h

Procedure:
A mixture of 2.95 g (8.6 mmol) of tert.butyl (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 10 g of hydroxymethyl-cyclopropane and 1.6 g (6.8 mmol) of tetraethyl orthotitanate is stirred at 120° for 24 hours, about 3 ml of solvent being distilled off in vacuo after 1 hour. The mixture is subsequently evaporated in vacuo, the residue is dissolved in 40 ml of chloroform, the chloroform solution is treated with 30 ml of water and stirred for 1.25 hours. The mixture is filtered through siliceous earth, washed with chloroform, the chloroform phase is dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate/n-hexane, there is obtained cyclopropylmethyl (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 171°-172°.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)[O:5]CC)[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[CH2:1]([O:3][P:4]([Cl:20])([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCc1ccccc1)OCC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOP(=O)(Cl)CCCCc1ccccc1

Procedure:
A mixture of diethyl(4-phenylbutyl)phosphonate (0.73 g., 2.6 mmole), benzene (10 ml.) and phosphorus pentachloride (1.0 eq.) is refluxed under argon for 30 minutes. The benzene and phosphorus oxychloride are removed in vacuo to give ethoxy(4-phenylbutyl)phosphinyl chloride.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([C:26]4[N:27]=[CH:28][C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:20]=3)=[N:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.C(Cl)(=O)OC(Cl)C>ClC(Cl)C>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([C:21]2[CH:20]=[C:19]([NH:18][C:14]3[C:15]4[CH2:16][CH2:17][NH:8][CH2:9][C:10]=4[CH:11]=[CH:12][N:13]=3)[CH:24]=[CH:23][C:22]=2[CH3:25])[N:27]=1
Reactant: Cc1ccc(Nc2nccc3c2CCN(Cc2ccccc2)C3)cc1-c1cc2ccccc2cn1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: Cc1ccc(Nc2nccc3c2CCNC3)cc1-c1cc2ccccc2cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 6-benzyl-N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (320 mg, 0.7 mmol) in dichloroethane is added DIEA (225 mg, 1.75 mmol) and 1-chloroethyl carbonochloridate (200 mg, 1.4 mmol). The reaction mixture is stirred at 90° C. for 12 hours. After cooling, the solvent is removed by rotary evaporation. The residue is redissolved in 20 ml of methanol and stirred at room temperature for 15 hours. After removing solvent, the crude product is purified by silica gel flash chromatography, eluted with 5% methanol in ethyl acetate to afford N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine as a light yellow solid. MS m/z 367.2 (M+1).
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:20])[NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1.[CH3:32][CH2:33]N=C=NCCCN(C)C.BrCC.C([O-])([O-])=O.[K+].[K+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH2:32]([O:31][C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][NH:13][C:12]([NH:11][C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[O:20])=[CH:23][CH:24]=1)=[O:30])[CH3:33]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCCNC(=O)NC12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OC(=O)CCCNC(=O)NC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 12 h
Yield: 19.7 %

Procedure:
To a solution of 4-(3-adamantan-1-yl-ureido)butyric acid 822 (0.15 g, 0.54 mmol), DMAP (0.07 g, 0.54 mmol), and 4-hydroxyphenylacetic acid (0.09 g, 0.59 mmol) in methylene chloride (20 mL) was added EDCI (0.11 g, 0.59 mmol) at room temperature. After stirring for 12 h, the reaction mixture was washed with water (20 mL), and the methylene chloride solution dissolving the product was dried over Na2SO4 and concentrated to give conjugated product. This crude mixture in DMF (30 mL) was treated with bromoethane (0.15 g, 1.34 mmol) and K2CO3 (0.18 g, 1.34 mmol) at room temperature and stirred for 12 h at room temperature. The ethyl ester product was extracted with ether (30 mL), and the ether solution was washed with 1 N NaOH aqueous solution (20 mL) and water (30 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting hexane and ethyl acetate (5:1) to give 852 (47 mg, 20%) as a white solid: 1H NMR (CDCl3) 1.40 (3H, t, J=6.9 Hz), 1.66-1.68 (6H, m), 1.89-1.95 (8H, m), 2.05-2.07 (3H, m), 2.62 (2H, t, J=6.9 Hz), 3.25 (2H, q, J=6.9 Hz), 3.60 (2H, s), 4.07 (1H, s), 4.16 (2H, q, J=6.9 Hz), 4.29 (1H, s), 7.08-7.10 (2H, m), 7.28-7.30 (2H, m); LC-MS (ESI) m/z calcd for C25H34N2O5 [M+H]+ 443.25. found [M+H]+ 443.25; mp 95-97 C. Anal. (C25H34N2O5) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8](=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl.O>[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:24][CH:25]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of N-(4-Amino-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide (0.105 grams, 0.31 mmole) and triethyl amine (0.047 grams, 0.46 mmole) in methylene chloride was cooled to 0° C., and Acetyl chloride (0.029 grams, 0.37 mmole) was added. The mixture was stirred for 10 minutes and then allowed to warm to room temperature for 30 minutes. The mixture was diluted with water and extracted with methylene chloride. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give a solid . Recrystalization from ethyl acetate/hexane gave a white solid. (0.082 g). M.P. 128-130° C.; Anal. calcd. for C21H18N3O3F: C, 66.48; H, 4.78; N, 11.08. Found: C, 66.14; H, 4.47; N, 11.08.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15](Cl)=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:18]1([NH2:27])[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[N:18]1([NH:27][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: Nn1ccc2ncccc21
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride (0.45 mmol) in EtOAc (8 mL) is added to a stirred solution of pyrrolo[3,2-b]pyridin-1-ylamine (0.45 mmol) and potassium carbonate (0.45 mmol) in EtOAc (4 mL) and H2O (8 mL) at rt and the reaction mixture is stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is purified by silica gel chromatography eluting with 20-80% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid pyrrolo[3,2-b]pyridin-1-ylamide (38 mg, 24%) as a solid. MS: 348 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.76 (s, 3H), 6.59 (m, H) 7.07-7.64 (m, 4H), 7.96 (m, H), 8.23 (m, H), 8.32 (m, 2H), 9.12 (s, H), 10.01 (br, N—H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:20][C:2]2[C:3]3[N:4]([CH:12]=[CH:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCC1
Reactant: Clc1nc2ccccc2n2ccnc12
Product: c1ccc2c(c1)nc(NC1CCCC1)c1nccn12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with cyclopentylamine according to a procedure that is similar to that followed in example 3 there is obtained 4-cyclopentylaminoimidazo[1,2-a] quinoxaline. m.p. (DSC)=114.3° C. (onset); IR (KBr): 3419, 2962, 1543 cm-1 ; 1H-NMR (CDCl3):δ7.9 (1H,s), 7.8÷7.0 (5H,m), 6.2 (1H,d), 4.7 (1H, m), 2.3÷2.05 (4H,m), 2.0÷1.3 (4H,m); UV (EtOH): δmax =228, 244, 285, 297, 319, 333 nm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[OH:18]O>ClCCl.O.C[Re](=O)(=O)=O.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N+:11]([O-:18])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: OO
Reactant: Fc1ccc(-c2ccncc2)cc1C(F)(F)F
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Then, 4-(4-fluoro-3-trifluoromethyl-phenyl)-pyridine-1-oxide 74 was prepared as follows. To a solution of compound 73 (2.49 g, 10.3 mmol) in dichloromethane (10 mL) was added methyltrioxorhenium(VII) (0.128 g, 0.515 mmol), followed by hydrogen peroxide in water (30%, 5.15 mL). The reaction mixture was stirred at room temperature for 16 hours. Manganese (IV) oxide (0.050 g) was added. The mixture was stirred for another 30 minutes. The organic layer was separated. The aqueous layer was extracted with more dichloromethane (2×10 mL). The combined organic phase was washed with brine (3×30 mL), dried over MgSO4 and filtered. After evaporating the solvent, the crude material was loaded to a silica gel column, eluting with 10% methanol in ethyl acetate to give a white solid 74 (2.51 g, 94%). 1H-NMR (CDCl3, 400 MHz) δ 7.35 (t, J=9.3 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.74-7.82 (m, 2H), 8.30 (d, J=7.1 Hz, 2H); MS (DCI) m/z 258, 259 (M+H)+.
Reaction SMILES: [NH2:1]/[C:2](=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.O.[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32](=[CH2:35])[CH:33]=O)=[CH:29][CH:28]=1>CCCCO>[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32]2[CH:35]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:1][CH:33]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)/C=C(\N)C(=O)OCC
Reactant: C=C(C=O)Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Product: CCOC(=O)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of diethyl 2-aminofumarate (153 g, 0.81 mol) and p-TsOH.H2O (1.5 g, 8.1 mmol) in n-BuOH (325 mL) was added 2-(4-fluorobenzyl)propenal (162 g, 0.98 mol) dropwise at 120° C. The mixture was stirred for 17 h at 120° C. and at rt for ca. 24 h. The mixture was filtered and concentrated under vacuum to yield the crude diethyl 5-(4-fluorobenzyl)-2,3-pyridinedicarboxylate. This material was dissolved in EtOH (400 mL) and an ice-cold solution of NaOH (88 g, 2.2 mol) in water (300 mL) was added. The mixture was stirred for 2 h at rt. After removal of EtOH in vacuo, water (400 mL) and 6N HCl (200 mL) were added and the mixture was extracted with EtOAc. The EtOAc layer was washed with water and the combined aqueous layers adjusted to pH 2 with 6N HCl (175 mL). The mixture was stirred for 1 h at ice-bath temperature and the product was collected by filtration: 1H NMR (d6-DMSO) δ 8.64 (1H, d, J=2 Hz), 8.01 (1H, d, J=2 Hz), 7.32 (2H, dd, J˜9, 6 Hz), 7.12 (2H, t, J˜9 Hz), 4.05 (2H, s); ES+ MS: 276 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.C(O)(=[O:35])C>Cl.C(O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:35])[NH2:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C#N)c1
Reactant: CC(=O)O
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(N)=O)c1
Temperature: 50 °C

Procedure:
A mixture of 4.5 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine in 50 cm3 of acetic acid and 50 cm3 of concentrated hydrochloric acid (d=1.18) is heated at 50° C. for 20 hours. The reaction medium is cooled to room temperature and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is taken up in 100 cm3 of ethanol and then the solution is concentrated to dryness under reduced pressure (2.7 kPa). The residue is precipitated in 60 cm3 of ethyl ether. The solid obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 25 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with dichloromethane and then a dichloromethane and ethanol mixture (99.5/0.5 by volume) as eluent and collecting 30 cm3 fractions. Fractions 35 to 46 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 15 cm3 of ethyl ether. 0.2 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a solid melting at 192° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 7.35 (4H, d, J=7 Hz, 4CH arom.), 7.45 (5H, d, J=7 Hz, 4CH arom. and 2 CONH2), 7.50 (2H, m, 2CH arom.), 7.85 (2H, m, 2CH arom.)].
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[NH3:20]>C(N)=O>[NH2:1][C:4]1[C:17]2[C:16](=[NH:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: NC=O
Product: N=C1c2ccccc2C(=O)c2cccc(N)c21
Reaction time: 4 h

Procedure:
26.3 g of 1-nitro-anthraquinone (96%) is suspended in 110 g of formamide. If ammonia gas is introduced at 155° C, no more starting material may be detected by thin layer chromatography after 4 hours. After complete removal of the solvent by distillation under vacuum, 22.5 g of an 80% 1-amino-anthraquinone (80% of the theoretical yield) which contains 4%, by weight of 1-amino-anthraquinone imine are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1.[Li+].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([CH3:24])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of Ethyl 3-(2,6-dimethylbenzyloxy)phenylacetate (Step B, 4 g, 13.6 mmol) in dry THF (30 ml) at −68° C. under a dry argon atmosphere was added LiHMDS drop wise (1 M solution in THF, 17.45 ml, 17.4 mmol), and the resulting orange solution was stirred at low temperature for 30 minutes before CH3I (5.71 g, 40.26 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 15 hours. The reaction was quenched with ice, and the product was extracted with EtOAc (2×), the organic phase washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ether 5:1) to give the title compound.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[C:6]([O:10][CH:11]([F:13])[F:12])=[C:5]([Cl:14])[N:4]=1>O1CCCC1>[NH2:1][C:3]1[N:4]=[C:5]([Cl:14])[C:6]([O:10][CH:11]([F:13])[F:12])=[C:7]([F:9])[N:8]=1
Reactant: Fc1nc(F)c(OC(F)F)c(Cl)n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nc(F)c(OC(F)F)c(Cl)n1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
9.8 g (0.578 mol) of gaseous ammonia were passed over the course of one hour into a stirred mixture of 62.5 g (0.289 mol) of 2,4-difluoro-6-chlorodifluoromethoxypyrimidine and 300 ml of tetrahydrofuran at -75° to -70° C. The mixture was stirred at -70° C. for one hour and then warmed to room temperature. The precipitate was filtered off with suction and partitioned between ethyl acetate and water, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate, chromatographed on silica gel with 5:1 petroleum ether/ether and concentrated. 46.5 g (75.3% of theory) of the title compound were obtained as colorless crystals of melting point 77°-80° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[C:5]([NH:7][C@H:8]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1)[CH2:9][CH2:10][S:11][CH3:12])=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:38].C(O)(=O)C.ClCl>ClCCl.ClCCl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[C:26]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:27])[C:5]([NH:7][C@H:8]([C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=2[N:14]=1)[CH2:9][CH2:10][S:11]([CH3:12])=[O:38])=[O:6]
Reactant: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: ClCl
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 81 %

Procedure:
Prepared analogously to Example 85 from 3-bromo-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropyl]-4-(pyrrolidin-1-ylcarbonyl)benzamide, 1 equivalent of 3-chloroperoxybenzoic acid, and glacial acetic acid in dichloromethane. Yield: 81%; Rf value: 0.20 (silica gel; dichloromethane/ethanol=9:1); C23H24BrClN4O3S (551.89); mass spectrum: (M+H)+=551/553/555 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16](CP(=O)(OCC)OCC)=[CH:15][CH:14]=2)[N:3]=1.C([P:30]([CH2:33][CH2:34]C1C=CC(N)=CC=1)(=[O:32])[O-:31])C.ClC1N=C(Cl)[C:46](C(F)(F)F)=[CH:45]N=1>>[CH2:45]([O:31][PH:30]([CH2:33][CH2:34][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:4]2[N:3]=[C:2]([Cl:1])[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=2)=[CH:27][CH:26]=1)=[O:32])[CH3:46]
Reactant: CCP(=O)([O-])CCc1ccc(N)cc1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Product: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Yield: 61 %

Procedure:
The title compound was prepared according to the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using ethyl(4-aminobenzyl)methylphosphinate (Compound 174B, 1.08 g, 5.07 mmol) and 2,4-dichloro-5-trifluoromethylpyrimidine. (1.0 g, 4.6 mmol). The compound was purified on an Isco Combiflash eluting with 0 to 10% MeOH in EtOAc. The compound was re-crystallized in EtOAc (˜20 mL) to afford 1.1 g, 61% yield, of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.79 (d, J=0.51 Hz, 1H), 7.62 (d, J=8.34 Hz, 2H), 7.25 (dd, J=2.27, 8.59 Hz, 2H), 3.86-4.01 (m, 2H), 3.15 (d, J=17.68 Hz, 2H), 1.31 (d, J=13.64 Hz, 3H), 1.19 (t, J=6.95 Hz, 3H); MS (ES+): m/z: 396.0708 [MH+]. HPLC: tR=1.41 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](S)=[N:12][C:11]=2[CH:16]=1>>[Cl:4][C:13]1[S:14][C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:16][C:11]=2[N:12]=1
Reactant: Fc1ccc2sc(S)nc2c1
Reactant: O=S(=O)(Cl)Cl
Product: Fc1ccc2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
Sulfuryl chloride (0.3 mL, 4.41 mmol) was added neat to 5-fluoro-benzothiazole-2-thiol (680 mg, 3.67 mmol). The mixture was stirred at RT for 1 hour, and then heated to 60° C. for 40 mins. The resulting solution was cooled to room temperature, and poured onto ice, extracted with EtOAc (3×50 mL), washed with brine and dried over Na2SO4. The dried organic layers were concentrated to give 2-chloro-5-fluorobenzo[d]thiazole (520 mg, 2.75 mmol, 75%). ESI-MS (M+1): 187 calc. for C7H5ClFN4S 186.