Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[OH:4][CH:5]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([CH2:24]Cl)=[N:22][C:21]([C:26]([NH2:28])=[O:27])=[N:20]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-].[Na+]>CO>[OH:4][CH:5]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:23]([CH2:24][N:2]([CH3:3])[CH3:1])=[N:22][C:21]([C:26]([NH2:28])=[O:27])=[N:20]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(O)c2ccccc2)n1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(O)c1ccccc1

Procedure:
6.8 ml of 33% ethanolic dimethylamine solution is added to a solution of 5.6 g (about 0.015 mole) of 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxamide and 0.225 g of sodium iodide in 80 ml of methanol, and the whole is refluxed for 5 hours with stirring. The reaction mixtute is thereupon concentrated in vacuo. Water and saturated sodium carbonate solution are added to the residue until the pH-value has reached 10, and extraction is performed twice with ethyl acetate. The organic phase is washed with water, and is then extracted three times with 1N hydrochloric acid solution. Sodium carbonate is added to the aqueous acidified extracts until the pH-value of 10 is obtained. The base that has precipitated is taken up in ether; the ether solution is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo to yield amorphous 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]- 1H-1,2,4-triazole-3-carboxamide. This is converted as follows into the crystalline hydrochloride: the crude base is dissolved in ethyl acetate, and ethereal hydrogen chloride solution is added until the pH-value is 4. The precipitated hydrochloride is filtered off with suction and washed with ethyl acetate and ether. After drying in vacuum, there is obtained 1-[2-(α-hydroxybenzyl) 4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide-hydrochloride, m.p. 155°-157° (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[K].[CH3:26][S:27]([CH3:30])(=[NH:29])=[O:28]>COCCOC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([N:29]=[S:27]([CH3:30])([CH3:26])=[O:28])=[O:11]
Reactant: CS(C)(=N)=O
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [K]
Solvent: COCCOC
Product: CS(C)(=O)=NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 38.01 g of 5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrobenzoyl chloride in 125 ml of absolute 1,2-dimethoxyethane is added dropwise at 10°-15° C. while stirring during 30 minutes to a suspension of the dimethyl sulphoximine potassium salt in 250 ml of absolute 1,2-dimethoxyethane. The mixture is stirred at room temperature for 24 hours and subsequently evaporated to dryness under reduced pressure. The resinous residue is dissolved in 1.25 l of diethyl ether, the solution is filtered through Celite and the filtrate is evaporated to dryness. The residue is subsequently purified by chromatography on silica gel with methylene chloride. There is obtained N-[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrobenzoyl]-S,S-dimethyl-sulphoximine as colourless crystals, m.p. 126°-127° C.; 1H-NMR (CDCl3): 7.99 (d,1H), 7.80 (d,1H), 7.60 (q,1H), 7.23 (d,1H) 7.14 (d,1H), 7.02 (q,1H) and 3.40 (s,6H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([CH3:38])[CH:30]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1>C(O)C.C1COCC1.[Pd]>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:30][C:31]=1[CH3:38]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 12 h
Yield: 86 %

Procedure:
To 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-nitrophenyl)methylsulfonamido)benzofuran-3-carboxamide (2.0 g, 3.72 mmol) in Ethanol (10 mL) and THF (2 mL), Pd/C (0.396 g) was added and subjected to hydrogenation at RT for 12 h. The reaction mixture was filtered through Celite. The solvent was evaporated under reduced pressure to afford the title compound in 86% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.85-7.95 (m, 1H), 7.67-7.73 (m, 1H), 7.37-7.42 (m, 1H), 7.11-7.26 (m, 1H), 6.59-6.68 (m, 1H), 5.86 (br. s., 1H), 3.18 (s, 1H), 2.99 (s, 2H), 2.10-2.17 (m, 1H), 1.37-1.51 (m, 1H), 1.08-1.19 (m, 1H), 0.91-1.06 (m, 1H), 0.45-0.92 (m, 1H). LCMS (m/z, ES+)=508 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH:24]=[CH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CC(C)([O-])C.[K+:38]>O1CCOCC1.[OH-].[Na+].C(O)(C)(C)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH:24]=[CH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O-:21])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[K+:38]
Reactant: COC(=O)CCC(CC=Cc1cccnc1)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: O=C([O-])CCC(CC=Cc1cccnc1)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.097 g of methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-2-propenyl]octanoate in 1 mL dioxane and 0.45 mL 1N sodium hydroxide is stirred at room temperature for 18 hours. The mixture is acidified with 0.45 mL of 1N hydrochloric acid and then subjected to evaporation. The residue is triturated with methylene chloride and the organic phase is dried, filtered and evaporated to yield a light amber oil. The oil is dissolved in 1 mL t-butanol and one equivalent of potassium t-butoxide in tetrahydrofuran is added. The mixture is freeze-dried to obtain potassium 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-2-propenyl]octanoate as about a 1:1 mixture of cis and trans isomers.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:4](=[O:21])[C:3]=1[NH:22][C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](=[O:40])(=[O:39])[NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:27][CH:26]=1.[OH-].[Na+]>CO>[CH2:8]([N:7]1[C:2]2[N:1]=[C:23]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)(=[O:39])=[O:40])=[CH:29][CH:30]=3)[NH:22][C:3]=2[C:4](=[O:21])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:6]1=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1c(N)c(NC(=O)Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)c(=O)n(Cc2ccccc2F)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(S(=O)(=O)Nc4ccccn4)cc3)nc21
Yield: 3 %

Procedure:
A solution of crude N-[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[4-(pyridin-2-ylsulfamoyl)-phenyl]-acetamide (50 mg, 0.86 mmol) in methanol (5 mL) was treated with a 10% w/v aqueous sodium hydroxide solution (0.1 mL, 0.25 mmol). The resulting solution was heated to reflux for until all of the starting material had been consumed. At this time, the reaction mixture was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 5/95 methanol/methylene chloride) followed by trituration with cold methanol afforded 4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-N-pyridin-2-yl-benzenesulfonamide (14.7 mg, 26% from [4-(pyridin-2-ylsulfamoyl)-phenyl]-acetic acid) as a colorless solid; 1H NMR(DMSO-d6, 300 MHz) δH 13.50 (broad s, 1H), 7.90 (broad s, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.63 (t, J=7.3 Hz, 1H), 7.37 (d, J=7.7 Hz, 2H), 7.30–6.95 (m, 5H), 6.77 (broad s, 1H), 5.02 (s, 2H), 4.06 (s, 2H), 3.87 (t, J=7.1 Hz, 2H), 1.54 (t, J=7.0 Hz, 2H), 1.17 (q, J=7.5 Hz, 2H), 0.77 (t, J=7.3 Hz, 3H); FAB-HRMS m/e calculated for C28H27FN6O4S (M+H)+ 563.1877, found 563.1860.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu]>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([O:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: Oc1ccccc1
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(Nc3nc(Oc4ccccc4)nc4c3CCC4)cc2)CCC1
Temperature: 27.5 °C
Reaction time: 13 h

Procedure:
The title compound was prepared following a published procedure in the literature (D'Angelo, N. D. et al. Tetrahedron Letters, 2006, 47, 5045-5048). A mixture of 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]cyclobutane carboxylic acid methyl ester (0.45 g, 1.26 mmol), phenol (0.23 g, 2.5 mmol), copper powder (0.010 g) and cesium carbonate (1.25 g, 3.8 mmol) in anhydrous dimethylformamide (3 mL) was stirred at a temperature in the range of 10° C. to 100° C. for 6 to 20 hours. The mixture was cooled to about 20 to 35° C. and diluted with water. The organics were extracted with EtOAc and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel) to afford white solid (43% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:17]Br>ClCCl>[Br:17][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N:8]2[CH2:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[N:4][CH:5]=1
Reactant: BrBr
Reactant: O=C(O)C1=CCN(c2ncccc2F)CC1
Solvent: ClCCl
Product: O=C(O)C1=CCN(c2ncc(Br)cc2F)CC1
Reaction time: 18 h

Procedure:
A 500 mL round bottom flask fitted with a rubber septum was charged with 10 grams of 1-(3-fluoropyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid 21 (45 mMol) and dissolved in 170 mL dichloromethane (DCM). With a syringe, 1.1 equivalents bromine (49.5 mMol) was added slowly to the solution. The reaction was allowed to progress at room temperature for 18 hours. The precipitate was collected by vacuum filtration and washed with 2×100 mL DCM. The filter cake was transferred to a 2 L beaker and covered with 300 mL 1N aq. sodium hydroxide, and stirred with a magnetic stir bar until all solids dissolved. The solution was transferred to a 1000 mL extraction funnel and shaken with 2×100 mL ethyl acetate (EtOAc). The organic layer was discarded and the aqueous layer was acidified with 50 mL 2N aq.HCl. The crude compound 23 was extracted with 2×100 mL EtOAc. The organic layer was dried over sodium sulfate, concentrated under vacuum, and crystallized as white needles from hot EtOAc. 23: (55% white solid): m/z 301, 1H NMR (DMSO) δ 12.42 (s, 1H), 8.14-8.11 (m, 1H), 7.93-7.87 (m, 1H), 6.94-6.89 (m, 1H), 4.13-4.07 (m, 2H), 3.58-3.52 (m, 2H), 2.40-2.33 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O>CO.O1CCCC1.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(N)c(N)c1
Yield: 98 %

Procedure:
4-Amino-3-nitrobenzonitrile (25 g) was dissolved in methanol (200 mL) and tetrahydrofuran (200 mL). The mixture was stirred in the presence of 10% palladium/carbon (3.0 g) under a hydrogen atomosphere (1 atm) for 20 hr. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure to give 3,4-diaminobenzonitrile (20 g) as a charcoal brown solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.Cl.O[N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[N:30]1([O:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18](=[O:27])[N:19]([CH3:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: On1ccnc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCOn2ccnc2)cc1)c1ccccc1
Yield: 79 %

Procedure:
The title compound was prepared as its TFA salt in 79% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 1-hydroxyimidazole hydrochlorid.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Oc2ccccc2)nc2nc(-c3ccco3)nn12
Product: CC(=O)Nc1nc(Oc2ccccc2)nc2nc(-c3ccco3)nn12

Procedure:
A solution of 7-amino-2-(2-furyl)-5-phenoxy-[1,2,4]triazolo[1,5-a][1,3,5]triazine (950 mg) in acetic anhydride was heated under reflux for 1.5 hours. The solvent was then evaporated in vacuo and the residue was purified by chromatography on silica eluting with dichloromethane containing ethyl acetate (5% v/v). The amorphous solid thereby obtained was crystallised from toluene to give 7-acetylamino-2-(2-furyl)-5-phenoxy-[1,2,4]-triazolo[1,5-a][1,3,5]triazine as colourless prisms, m.p. 168°-170° C.; microanalysis, found; C, 60.9; H, 4.2; N, 22.6%; C16H12N6O3 0.45 C7H8 requires: C, 60.9; H, 4.1; N, 22.3%; NMR 2.3 (s, 3H equivalent, toluene CH3), 2.35 (s, 3H, CH3CO), 6.7 (q, 1H, furyl-4H), 7.1-7.6 (complex, 6H, furyl-3H+ phenyl-H+toluene), 7.95(d, 1H, furyl-5H), 11.5 (broad s, 1H, NH); m/e 336 (M+).
Reaction SMILES: [CH:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])([CH3:3])[CH3:2].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH:1]([CH3:3])[CH3:2])=[O:5])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CC(C)S(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)C(C)C)n1

Procedure:
A mixture of 6.4 g. 3-isopropylsulphinyl-1,2,4-triazole, 8.0 ml. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate was distilled under reduced pressure to give an oily residue which subsequently solidified. This solid residue was recrystallized from petroleum ether (b.p. 60° - 80°C.) to give 1-diallylcarbamoyl-3-isopropylsulphinyl-1,2,4-triazole, m.p. 32° - 34°C. Elemental analysis satisfactory. EXAMPLE 19
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([CH2:23][CH2:24][CH:25]3OCC[O:26]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:3]1.S(=O)(=O)(O)O>O.C(O)(=O)C>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([CH2:23][CH2:24][CH:25]=[O:26])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc2n1CCC1OCCO1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=CCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Temperature: 60 °C
Yield: 761.4 %

Procedure:
A stirred suspension of the product of Example 69B (0.65 g, 0.15 mmol) in water (3 mL) and glacial acetic acid (12 mL) at ambient temperature was treated dropwise with sulfuric acid (1 mL). The mixture was heated to 60° C. for 1 hour, and then diluted with water. The mixture was filtered and the filter cake was washed with water and dried to produce the title compound (0.455 g, 78%). MS (DCI/NH3) m/z 399 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.72 (m, 2H), 4.59 (t, J=6.62 Hz, 2H), 7.17 (dd, J=7.72, 4.78 Hz, 1H), 7.28 (m, 1H), 7.55 (m, 1H), 7.67 (d, J=7.72 Hz, 1H), 8.39 (dd, J=7.72, 1.84 Hz, 1H), 8.52 (dd, J=4.78, 1.84 Hz, 1H), 9.76 (t, J=2.21 Hz, 1H), 9.76 (t, J=2.21 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[P:14]([O:19]C)([O:17][CH3:18])[O:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:16][O:15][P:14]([CH2:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O:17][CH3:18])=[O:19]
Reactant: COP(OC)OC
Reactant: Cc1nc2ccccc2cc1CBr
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1cc2ccccc2nc1C)OC
Yield: 105.6 %

Procedure:
A mixture of the obtained 3-bromomethyl-2-methylquinoline (0.25 g, 1.0 mmol) and trimethyl phosphite (0.4 ml, 3.2 mmol) was refluxed in toluene (10 ml) for 16 hours. The reaction mixture was then concentrated in vacuo and the residue was flash chromatographed on silica gel. Elution with ethyl acetate afforded 0.28 g of 3-(dimethylphosphonomethyl)-2-methylquinoline.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].C(O)(C)(C)C.COC(=O)[CH2:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27](=[O:32])[NH:26]2)=[CH:20][C:19]=1[O:33]CC1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[OH:33][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[N:17]1[CH2:16][C:6](=[O:7])[NH:5][S:2]1(=[O:4])=[O:3])[CH2:24][CH:25]1[NH:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)CNc1ccc(CC2CCCCC(=O)N2)cc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: O=C1CCCCC(Cc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)N1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a cooled solution of chlorosulfonyl isocyanate (315 mg, 2.22 mmol) in CH2Cl2 (8 mL) is added dropwise a solution of t-butanol (165 mg, 2.22 mmol) in CH2Cl2 (1 mL). The solution is stirred at RT for 45 min and re-cooled, then a solution of [2-benzyloxy-4-(7-oxo-azepan-2-ylmethyl)-phenylamino]-acetic acid methyl ester (600 mg, 1.48 mmol) and triethylamine (252 mg, 2.52 mmol) in CH2Cl2 (2 mL) is added dropwise. The mixture is stirred at RT for 3 h then washed with water. The organic phase is dried over Na2SO4 and the solvent is removed under reduced pressure. The residual oil is purified by flash chromatography using EtOAc/CH2Cl2 (1:1) as eluent to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[O:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:23][CH2:24]1
Reactant: NC1CCOCC1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(NC4CCOCC4)n3)cc2s1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 23.2 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.200 g, 0.7 mmol), 4-aminotetrahydropyran (0.07 ml, 0.7 mmol), N-ethyl-N-isopropylpropan-2-amine (0.2 g, 1 mmol) in DMSO (1 g, 13 mmol) was heated under microwave (CEM) at 150° C. and 130 W (Powermax®& off) for 40 min. Then, the mixture was diluted with 1 ml of DMSO and purified by HPLC (5-50% CH3CN in water) to give a light yellow solid (60 mg) as a TFA salt. MS (ESI pos. ion) Found m/z: 370, (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([Cl:13])[CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1.[Cl-].[Na+].O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([Cl:13])[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C#N)c1ccc(Br)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(C(C)(C)C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
To a stirred solution of 2-(4-bromo-2-chlorophenyl)-2-methylpropanenitrile (2.85 g, 11.0 mmol) in anhydrous THF (60 mL) at −78° C. is added n-butyllithium (2 M in c-hexane) (60.1 mL, 12.1 mmol). The reaction mixture is stirred at this temperature 10 min., then N-methoxy-N-methyl-acetamide (2.34 mL, 22.0 mmol) is added neat and the solution is stirred 10 min. at −78° C. and then warmed up to room temperature for another hour. Acidic brine (60 mL) is then slowly added and the solution is extracted with EtOAc (3×60 mL). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (eluent: Hex/EtOAc 1:0 to 7:3) to provide the expected product 2-(4-acetyl-2-chlorophenyl)-2-methylpropanenitrile (1.57 g, 64%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.96 (1H, d, J=1.9 Hz), 7.81 (1H, dd, J=8.3, 1.9 Hz), 7.55 (1H, d, J=8.3 Hz), 2.56 (3H, s), 1.85 (6H, s).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([CH3:7])[N:6]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Br)sc1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(Br)sc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of (2-bromo-4-methylthiazol-5-yl)methanol of preparation 97 (3.8 g, 18.4 mmol) and MnO2 (16.5 g, 0.18 mmol) in CHCl3 (180 mL) was stirred at room temperature overnight. TLC (petroleum ether/EtOAc=3:1) showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by a Biotage silica gel cartridge (EA/PE=30%, Rf=0.5) to give the title compound as a white solid (1.8 g, 47%) as a white solid, and as well as impure 2-bromo-4-methylthiazole-5-carbaldehyde (1.3 g, 34%) as an off-white solid.