Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.[Na+].[Na+].[Na+].[Na+].C1(S([O-])(=O)=O)C2C3=C4C(=CC=2)C=CC=C4C=C(S([O-])(=O)=O)C3=C(S([O-])(=O)=O)C=1S([O-])(=O)=O>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=P(O)(O)O
Agent: O=S(=O)([O-])c1c(S(=O)(=O)[O-])c2ccc3cccc4cc(S(=O)(=O)[O-])c(c1S(=O)(=O)[O-])c2c34
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 88 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To 300 g of polyphosphoric acid (117% phosphoric acid) heated at 90° C. was added 6.8 g of pyrene tetrasulfonic acid tetrasodium salt (prepared by the method described in Justus Liebiffs Ann. Chem., 540, 189-210 (1939)) followed by 68.2 g of 2,5-dianilinoterephthalic acid. The mixture was heated at 120°-125° C. for two hours. After the melt was cooled to 88° C., the acid strength was adjusted to 112% by the dropwise addition of phosphoric acid. The resultant melt was slowly poured into 453 g of methanol at 24° C. During the drown, the temperature was allowed to increase to 55° C., with the temperature being controlled by external cooling and adjustment of melt addition rate. The slurry was heated at reflux (68°-72° C.) for one hour, diluted with water, and stirred at 60° C. for 30 minutes. The solid component was collected by filtration and washed with water until acid free. The resultant presscake was reslurried in water. After adjustment of the pH to greater than 7, 7.5 g of 50% sodium hydroxide was added and the resultant slurry was heated at 90° C. for one hour. The slurry was cooled, filtered, and washed with water until alkali free, then reslurried in water. After adjustment of the pH to greater than 8.5, 3.2 g of a cycloaliphatic carboxylic acid was added. The resultant slurry was heated at about 140°-145° C. for two hours in a closed system, cooled, acidified with phosphoric acid, and stirred. The solid component was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 52 g of quinacridone as a brilliant violet pigment.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:12]1[N:16]([CH2:17][CH2:18][OH:19])[C:15]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:14]=2[N:13]=1)(O)[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH3:10])[C:12]2=[N:13][C:14]3[C:15](=[C:20]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH:21]=[CH:22][CH:23]=3)[N:16]2[CH2:17][CH2:18][O:19]1
Reactant: CCN(CC)c1cccc2nc(C(C)(O)c3ccc(Cl)cc3Cl)n(CCO)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCN(CC)c1cccc2nc3n(c12)CCOC3(C)c1ccc(Cl)cc1Cl
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-(2,4-dichlorophenyl)-1-[7-(diethylamino)-1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]ethanol (Reference example 210, 63.8 mg, 0.151 mmol) and triphenylphosphine (59.4 mg, 0.227 mmol) in tetrahydrofuran (4 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 103 μL, 0.227 mmol) at room temperature. After 2.5 h, the reaction mixture was concentrated in vacuo, and purified by column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give a colorless amorphous (53.3 mg, 0.132 mmol, 87%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>CO.CC(N(C)C)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)c2cc(I)ccc21
Reactant: Nc1ccccc1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1c2ccc(I)cc2C(=O)N1c1ccccc1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
As described above, 4-iodophthalic anhydride (2.0 g, 7.3 mmol), aniline (665 μL, 7.3 mmol), pyridine (2.1 mL, 25.5 mmol) and DMAc (10 mL) were heated at 80° C. for 2 hours, followed by continued heating in the presence of acetic anhydride (2.75 mL, 29.2 mmol) for 16 hours. MeOH (5 mL) was added to the warm solution which was then cooled to room temperature. The crystalline solid was removed by filtration, washed with MeOH and dried in vacuo to give 1.96 g (77%) product. The filtrate was concentrated and cooled to 0° C. to afford another 300 mg (11%) product. Total yield 88% mp 178°-179° C., 1H NMR (CDCl3) δ8.27 (d, J=1.0 Hz, 1), 8.13 (dd, J=7.5, 1.0 Hz, 1), 7.65 (d, J=7.9 Hz, 1), 7.49 (m, 2), 7.40 (m, 3). 13C NMR (CDCl3) {1H} δ166.6, 165.7, 143.3, 133.1, 132.8, 131.5, 131.0, 129.1, 128.2, 126.4, 124.9, 101.1. Combustion analysis calculated for C14H8INO2 : C, 48.16; H, 2.31; N, 4.01. Found: C, 47.81; H, 2.39; N, 3.95.
Reaction SMILES: C(O[C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)=[O:10])C1C=CC=CC=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>>[CH2:20]([N:22]([CH2:23][CH2:24][NH:25][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1)=[O:10])[CH2:26][CH3:27])[CH3:21]
Reactant: O=C(O)c1ccc(C(=O)OCc2ccccc2)cc1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)c1ccc(C(=O)O)cc1

Procedure:
4-([2-(N,N-diethylamino)ethyl]aminocarbonyl)benzoic acid was prepared from 4-benzyloxycarbonylbenzoic acid by reaction with N,N-diethylethylene diamine to yield the mono amide derivative which was hydrogenolysed to give the acid (CI-MS: m/z 265 [M+b]+).
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)(C)(=O)=O.[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][N:26]([CH2:5][CH2:6][C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: Cc1cccc(C#CCCS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(C#CCCN2CCC(O)(Cc3ccccc3)CC2)c1
Yield: 20.7 %

Procedure:
A mixture of 1-mesyl-4-(3-methylphenyl)but-3-yne (344 mg, 1.45 mmol), 4-benzyl-4-hydroxy-piperidine (332 mg, 1.73 mmol) and K2CO3 (598 mg, 4.34 mmol) in 15 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×20 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a brown oil (100 mg, 20%) 1H NMR (CDCl3) 1.37 (s, 1 H) , 1.55 (m, 2 H) 1.75 (m, 2 H), 2.30 (s, 3 H), 2.41 (m, 2 H), 2.60 (m, 3 H), 2.75 (m, 5 H), 7.11-7.31 (m, 9 H)
Reaction SMILES: [O-]CC.[Na+].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:14])=[C:10]([CH:13]=1)[CH:11]=O.[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:16]=[N-:17]>C(O)C.C(O)C.O1CCCC1>[N:15](/[C:18](=[CH:11]\[C:10]1[CH:13]=[C:6]([Br:5])[CH:7]=[CH:8][C:9]=1[Cl:14])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:16]=[N-:17]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cc(Br)ccc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1cc(Br)ccc1Cl)N=[N+]=[N-]
Temperature: -10 °C
Reaction time: 3 h

Procedure:
To a solution of sodium ethoxide in ethanol (15 mL) cooled to −10° C. was added dropwise a solution of 5-bromo-2-chlorobenzaldehyde (1.0 g) and ethyl 2-azidoacetate (11 mL, 18 mmol) in ethanol-tetrahydrofuran (15 mL-3 mL). The reaction mixture was stirred at −10° C. for 3 hours, allowed to warm to 10° C. over 3 hours and poured onto crushed ice. The solid was collected by filtration and dried in a vacuum oven to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:19]=[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18].C(O)(C)C.[NH4+]=S>O>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:2]=2[Cl:1])=[C:10]([F:18])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 103.2 %

Procedure:
The following materials were added to a 2-L CHEMGLASS® reactor: 3-chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (110.00 g, 221 mmol), isopropyl alcohol (990.00 mL), ammonium sulfide (˜40% in water, 297.00 mL, 2324 mmol). The mixture was allowed to stir at 20° C. for 3-4 h. 3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine was not detected by HPLC analysis. The reaction mixture was heated to 70° C. and allowed to stir for 3-4 h. Once the reaction was complete, water (14 mL/g·LR) was added. The reaction mixture was cooled to 20° C. (reaction temp) over 1 h. Upon cooling a solid precipitated and was filtered off and washed with water (12.5 mL/g·LR), followed by heptane:MTBE (4:1; 5 mL/g·LR). After LOD (˜25%), 95.3 g of crude 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine (90AP) was obtained. The crude 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine was dissolved into n-BuOAc (7 mL/g·LR) by heating to approximately 85° C. At 85° C., heptane (7 mL/g·LR) was added dropwise until the solution became cloudy. The solution was then allowed to cool to 20° C. with stirring. Once at 20° C., the slurry was aged for 8 h. The solid was filtered, washed with heptane (5 mL/g·LR), and then dried overnight in a vacuum oven at 60° C. to afford 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene)pyridin-2-amine (62.53 g; 67.69% yield) as a faint yellow solid. 1H NMR (CDCl3) δ 6.23 (dd, 1H, J=1.0, 5.6 Hz), 6.43 (m, 1H), 6.49 (dd, 1H, J=2.5, 12.1 Hz), 6.92 (t, 1H, J=8.6 Hz), 7.25-7.60 (m, 8H), 7.87 (m, 2H), 7.95 (d, 1H, J=6.1 Hz); MS (ESI+) m/z 418.6 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[C:4]([CH3:18])[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[CH3:9][O:8][C:7]1[C:2]([NH:1][C:20]2[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]([F:31])([F:29])[F:30])=[CH:22][N:21]=2)=[CH:3][C:4]([CH3:18])=[C:5]([C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])[CH:6]=1
Reactant: COc1cc(C(=O)N2CCOCC2)c(C)cc1N
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(Nc2cc(C)c(C(=O)N3CCOCC3)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 58.3 %

Procedure:
A mixture of (4-amino-5-methoxy-2-methylphenyl)(morpholino) methanone (2.12 g, 8.47 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (1.79 g, 8.47 mmol) and para-toluene sulfonic acid (1.62 g, 8.47 mmol) in dioxane (80 mL) was heated to 100° C. for 18 h. Saturated aqueous sodium bicarbonate solution (100 mL) and DCM (100 mL) were added, the organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) gave (5-methoxy-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone (2.1 g, 58%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=426 at 2.59 min. 1H NMR (400 MHz, CDCl3): δ 8.47 (s, 1H), 8.18 (s, 1H), 7.74 (s, 1H), 6.71 (s, 1H), 5.25 (br s, 1H), 3.88 (s, 3H), 3.80 (br d, 4H), 3.59 (br s, 2H), 3.31 (br s, 2H), 3.12 (d, 3H), 2.28 (s, 3H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:32])[C@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([S:19][C:20]2[N:24]4[CH:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]4=[N:22][N:21]=2)=[CH:14][CH:13]=3)[CH2:5]1.[NH2:33][O:34][CH2:35][CH2:36][OH:37]>CO.Cl>[ClH:1].[OH:37][CH2:36][CH2:35][O:34]/[N:33]=[C:29](/[C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([S:19][C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[N:11]=[CH:10][C:9]([N:6]3[CH2:7][CH2:8][C@H:4]([N:3]([CH3:32])[CH3:2])[CH2:5]3)=[CH:18]4)=[N:21][N:22]=2)[CH:25]=1)\[CH3:30]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
To a solution of (81.3) (12 mg, 0.026 mmol) and 2-(aminooxy)ethanol (9.86 mg, 0.128 mmol) in MeOH (5 ml) was added 2 drops of HCl (2 N) by a 1-ml syringe to reach pH about 3 and the mixture was stirred in a sealed tube at 85° C. for 16 h. The mixture was evaporated to dryness and the residue was purified by preparative acid HPLC (gradient eluent NB from 20/80 to 95/5. mobile phase A: TFA/CH3CN 0.05%; mobile phase B: TFA/H2O 0.05%). The desired fractions were collected, evaporated by BUCHI under 30 mbar at 35° C. to remove CH3CN. The remained solution was lyophilized to afford title compound (11.5 mg, yield 85%).
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2CC)=[CH:6][C:5]=1[Br:19].[CH3:21][CH:22](C[AlH]CC(C)C)C.Cl.CCOCC>C1(C)C=CC=CC=1>[Br:19][C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:21][CH3:22])=[CH:15][CH:16]=2)[CH:8]=[CH:9][C:4]=1[CH2:3][OH:20]
Reactant: CCc1ccccc1Oc1ccc(C(=O)OC)c(Br)c1
Reactant: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCc1ccc(Oc2ccc(CO)c(Br)c2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
Under a nitrogen stream, to a solution of 2-bromo-4-(ethylphenoxy)-benzoic acid methyl ester (90 mg, 0.269 mmol) in anhydrous toluene (2 ml), a toluene solution of DIBAL (1M, 0.537 ml, 0.537 mmol) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours and at room temperature for 1.5 hours. The reaction mixture was cooled again to −78° C., followed by addition of 1N hydrochloric acid (0.2 ml) and ether (3.5 ml). The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:5)) to give the titled compound (78 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[CH:16]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([O:43][CH3:44])=[C:31]([CH:42]=2)[CH2:32][N:33]([CH2:39][CH2:40][OH:41])C(NCC)=O)[C:23]([Cl:45])=[CH:22][N:21]=1>>[Cl:45][C:23]1[C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([O:43][CH3:44])=[C:31]([CH2:32][NH:33][CH2:39][CH2:40][OH:41])[CH:42]=2)=[N:25][C:20]([NH:1][C:2]2[C:3]([O:17][CH3:18])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH3:15])[C:6]=3[CH:16]=2)=[N:21][CH:22]=1
Reactant: CCN1CC(=O)N(C)c2cc(N)c(OC)cc2C1
Reactant: CCNC(=O)N(CCO)Cc1cc(Nc2nc(Cl)ncc2Cl)ccc1OC
Product: CCN1CC(=O)N(C)c2cc(Nc3ncc(Cl)c(Nc4ccc(OC)c(CNCCO)c4)n3)c(OC)cc2C1

Procedure:
The title compound was prepared from 8-Amino-4-ethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and 1-[5-(2,5-Dichloro-pyrimidin-4-ylamino)-2-methoxy-benzyl]-3-ethyl-1-(2-hydroxy-ethyl)-urea in an analogous manner to example 730 (0.010 g, 9%). Mp 65-70° C.; LCMS (m/e) 556 (M); 1H-NMR (DMSO, 400 MHz) δ 8.87 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 7.41 (m, 2H), 7.01 (s, 1H), 6.86-6.84 (d, 1H, J=9.35 Hz), 4.54 (m, 1H), 4.34-4.43 (d, 1H, J=4.04 Hz), 3.86 (s, 3H), 3.78 (s, 4H), 3.68 (s, 2H), 3.45 (s, 4H), 2.97 (s, 2H), 2.80 (s, 2H), 2.63-2.58 (m, 2H), 1.07-1.05 (t, 3H, J=7.07 Hz).
Reaction SMILES: C([Mg]Cl)(C)C.C1COCC1.C(O[C:14]([C:16]1[N:17]([S:29](=[O:34])(=[O:33])[N:30]([CH3:32])[CH3:31])[N:18]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)=[O:15])C.Cl.[CH3:36][NH:37][O:38][CH3:39]>C(Cl)Cl.[NH4+].[Cl-]>[CH3:39][O:38][N:37]([CH3:36])[C:14]([C:16]1[N:17]([S:29](=[O:33])(=[O:34])[N:30]([CH3:31])[CH3:32])[N:18]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=1)=[O:15]
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.7 %

Procedure:
A 2M solution of isopropylmagnesium chloride in THF (1.9 mL, 3.8 mmol) was added to a stirred suspension of 2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.45 g, 1.27 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.16 g, 1.65 mmol) in DCM (6.5 mL) under nitrogen at −78° C. The mixture was slowly allowed to warm to room temperature and stirred for 16 hours. The mixture was diluted with a saturated solution of NH4Cl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-dimethylsulfamoyl-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid methoxy-methyl-amide (0.2 g, 44% yield) as a colourless oil that solidified upon standing.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:49]=[CH:48][CH:47]=[C:41]2[C:42]([NH:44][C:45](=[O:46])[C:40]=12)=[O:43]>CS(C)=O>[C:7]([S:8][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:49]=[CH:48][CH:47]=[C:41]2[C:42]([NH:44][C:45](=[O:46])[C:40]=12)=[O:43])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)c2c(CCCCCCBr)cccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: O=C1NC(=O)c2c(CCCCCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cccc21

Procedure:
Triphenylmethanethiol (11.90 g, 43.08 mmol) was suspended in DMSO (40 mL). DBU (7.41 mL, 49.55 mmol) and 6-bromohexylphthalimide (13.32 g, 42.94 mmol) were added, and the mixture was allowed to react for approximately 15 min. The reaction mixture was partitioned between ethyl acetate (700 mL) and 0.1 M HCl (200 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL), and the combined organic fractions were washed with NaHCO3 sat. (80 mL) and brine (80 mL), dried over MgSO4, filtered and concentrated. The crude yellow oil was recrystallized from n-heptane/ethyl acetate. The intermediate 6-(S-Trityl-)mercaptohexylphthalimide was obtained as a white solid (13.3 g, 26.4 mmol, 62%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CCO>O>[NH2:6][C:5]1[C:4]([N+:12]([O-:14])=[O:13])=[CH:3][C:2]([F:1])=[CH:8][C:7]=1[NH2:9]
Reactant: Nc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)cc([N+](=O)[O-])c1N
Yield: 50 %

Procedure:
A solution of 4-fluoro-2,6-dinitroaniline (125 mg, 0.62 mmole) in freshly prepared 6% (NH4)2S (5 mL) and EtOH (5 mL) was refluxed for 30 min, diluted with water (10 mL,) and kept at 4° C. for several hours. The precipitate was collected and washed with cold water (2×1 mL), affording 53 mg (50%) of 1,2-diamino-4-fluoro-6-nitrobenzene as red crystals. 1H NMR (CDCl3: δ 3.619 (s, 2H), 5.724 (s, 2H), 6.732 (dd, 1H, J1=2.4 Hz, J2=8.4 Hz), 7.403 (dd, 1H, J1=2.4 Hz, J2=8.4 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:6]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:25][CH3:24])[S:6]1(=[O:23])=[O:22]
Reactant: CN
Reactant: O=S1(=O)N(CCCBr)Cc2ccccc2N1c1ccccc1F
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to Example 11 step 5, 3-(3-bromopropyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.23 mmol) was reacted to methylamine and then treated with HCl to provide 3-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine as a white solid:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](I)[CH3:8].[F:10][C:11]([F:21])([F:20])[C:12]1[N:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1>CN(C=O)C.CCOC(C)=O.O>[CH2:7]([NH:18][C:15]1[CH:16]=[N:17][C:12]([C:11]([F:10])([F:20])[F:21])=[CH:13][C:14]=1[NH2:19])[CH3:8]
Reactant: CCI
Reactant: Nc1cnc(C(F)(F)F)cc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCNc1cnc(C(F)(F)F)cc1N
Temperature: 25 °C

Procedure:
Cesium carbonate (3.1 g, 26.88 mmol) and ethyl iodide (1.76 g, 10.75 mmol) is added to a solution of 6-trifluoromethyl-pyridine-3,4-diamine (1.05 g, 8.96 mmol) in anhydrous DMF (12 mL). The mixture is heated in a sealed tube for 18 h, then cooled to room temperature, and diluted with EtOAc and water. Usual work up and purification by column chromatography, eluting with EtOAc-hexanes provides pure N3-Ethyl-6-trifluoromethyl-pyridine-3,4-diamine. 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H); 6.95 (s, 1H) 3.21 (q, J=5.4 Hz, 2H), 1.35 (t, J=5.4 Hz, 3H)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[C:18](=[O:19])[CH:17]([CH3:20])[C:16](=O)[NH:15][C:14]1=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([Cl:3])[NH:15][C:14]1=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1C(=O)NC(=O)N(Cc2ccccc2)C1=O
Solvent: CCO
Product: Cc1c(Cl)[nH]c(=O)n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 16.8 ml of 50% ethanol, 78.7 ml (844 mmol) of phosphorus oxychloride was added dropwise, with stirring under ice cooling conditions. To this solution, 23.22 g (100 mmol) of 3-benzyl-5-methylpyrimidine-2,4,6(1H,3H)-trione was added little by little. This mixture was stirred at 50° C. for 30 minutes and then at 100° C. for 90 minutes. After cooling, the reaction mixture was poured into ice water and stirred for 1 hour. The resulting precipitate was collected by filtration, washed with water and n-hexane and dried to yield 27.50 g (quant, light white crystal) of the desired product.