Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21].[O:22]=[C:23]1[C:31]2[C:26](=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[CH:29][CH:30]=2)[CH2:25][N:24]1[CH:35]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][C:36]1=[O:42]>>[O:22]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[CH2:2][N:3]1[CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21].[O:1]=[C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:23][N:24]1[CH:35]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][C:36]1=[O:42]
Reactant: O=C1CCC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Reactant: O=C1CCC(N2Cc3cc([N+](=O)[O-])ccc3C2=O)C(=O)N1
Product: O=C1CCC(N2Cc3ccc([N+](=O)[O-])cc3C2=O)C(=O)N1
Product: O=C1CCC(N2Cc3cccc([N+](=O)[O-])c3C2=O)C(=O)N1

Procedure:
1-Oxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline, 1-oxo-2-(2,6-dioxopiperidin-3-yl )-4-nitroisoindoline. 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-nitroisoindoline, and 1-oxo-2-(2,6-dioxopiperidine-3-yl)-7-nitroisoindoline can be obtained by allowing 2,6-dioxopiperidin-3-ammonium chloride to react with methyl 2-bromomethyl-5-nitrobenzoate, methyl 2-bromomethyl-4-nitrobenzoate methyl 2-bromomethyl-6-nitrobenzoate, and methyl 2-bromomethyl-7-nitrobenzoate, respectively, in dimethylformamide in the presence of triethylamine. The methyl 2-(bromomethyl)nitrobenzoates in turn are obtained from the corresponding methyl esters of nitro-orthotoluic acids by conventional bromination with N-bromosuccinimide under the influence of light.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][C:12]=1[O:13]C)[CH:4]=[CH2:5]>CS(C)=O>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][C:12]=1[OH:13])[CH:4]=[CH2:5]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1O
Temperature: 65 °C

Procedure:
To one liter of dimethyl sulfoxide was added 750 mL of 2 N aqueous sodium hydroxide and the mixture was heated to 65° C. The pale yellow solid 3-allyloxy-4-methoxynitrobenzene prepared above was added in portions over a 30 minute period and then the temperature was raised to 95° C. and maintained for 3 hours, after which time the starting material had been consumed. The mixture was allowed to cool and poured into a mixture of 1 L ice and 1 L 2 N HCl. 73 Grams of crude but homogeneous (by tlc 1:1 CH2Cl2hexane) desired product was isolated as a light brown solid by filtration. This material was subsequently dissolved in 1:1 hexane/methylene chloride and filtered through silica gel to give 68 g of pale yellow solid, which, when recrystallized from ethyl/acetate/hexane, gave m.p. 61-62° C. The aqueous mother liquors from the initial crystallization above were extracted with 2 L of ethyl acetate. This was dried over sodium sulfate, filtered and evaporated to a dark oil. Column chromatography on silica with 1:1 CH2Cl2/hexane gave an additional 12 g of the title compound as a yellow solid. Elution with 2% MeOH in CHCl3 gave 12 g of a dark oil which slowly crystallized in vacuum. This proved to be the Claisen product, 3-allyl-4-nitrocatechol.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[N:6]([CH:9]2[CH2:11][CH2:10]2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:4]1.[N-:19]=[N+:20]=[N-:21].[Na+].[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])#[CH:24].C(OCC)(=O)C>C(#N)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[C:7](=[O:8])[N:3]([CH2:2][N:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:32])([F:33])[F:34])[N:21]=[N:20]3)[N:4]=2)=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1ccccc1C(F)(F)F
Reactant: O=c1n(CCl)nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=c1n(Cn2cc(-c3ccccc3C(F)(F)F)nn2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60 mg (0.21 mmol) of the compound from Example 122A were dissolved in 2 ml of acetonitrile, 14 mg (0.21 mmol) of sodium azide were added and the mixture was stirred at RT for 1 h. 0.4 mg (0.002 mmol) of copper(II) acetate monohydrate and 43 mg (0.25 mmol) of 1-ethynyl-2-(trifluoro-methyl)benzene were then added. The resulting mixture was stirred at RT for 20 h. For work-up, 10 ml of ethyl acetate were added and the mixture was washed twice with in each case 5 ml of water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 48 mg (45% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[NH:14]([CH2:16]C(O)=O)[CH3:15].O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:9])[CH2:15][N:14]([CH3:16])[C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Solvent: O
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccc(F)cc2C1=O
Temperature: 100 °C

Procedure:
24 g (132.5 mmol) of 5-fluoroisatoic acid anhydride are dissolved in 140 ml of dimethyl sulphoxide and treated with 11.8 g (132.5 mmol) of sarcosine. The solution is stirred at 100° C. until the gas evolution ceases (duration: ca 1.5 hours) and subsequently poured into ca 1.2 liters of water. After stirring for 10 minutes, a solid crystallises out. The crystals are filtered off under suction, washed with 1 liter of water and dried. There is obtained 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 262°-263° C.
Reaction SMILES: [P:1]([OH:40])([OH:39])([O:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[O:8][C:7]2[CH:14]=[CH:15][C:16]([NH:18][C:19]3[C:24]([F:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=4)[N:20]=3)=[N:17][C:6]1=2)=[O:2].O.O.O.O.O.O.P([O-])([O-])(OCN1C(=O)C(C)(C)OC2C=CC(NC3C(F)=CN=C(NC4C=C(OC)C(OC)=C(OC)C=4)N=3)=NC1=2)=O.[Na+].[Na+].[CH2:89]([N:91]([CH2:94][CH3:95])[CH2:92][CH3:93])[CH3:90]>C(O)(C)C.O>[F:25][C:24]1[C:19]([NH:18][C:16]2[CH:15]=[CH:14][C:7]3[O:8][C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:5]([CH2:4][O:3][P:1]([O-:39])([O-:40])=[O:2])[C:6]=3[N:17]=2)=[N:20][C:21]([NH:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=2)=[N:22][CH:23]=1.[CH2:89]([NH+:91]([CH2:94][CH3:95])[CH2:92][CH3:93])[CH3:90].[CH2:89]([NH+:91]([CH2:94][CH3:95])[CH2:92][CH3:93])[CH3:90]
Reactant: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)N(COP(=O)(O)O)C(=O)C(C)(C)O4)n2)cc(OC)c1OC
Reactant: CCN(CC)CC
Agent: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)N(COP(=O)([O-])[O-])C(=O)C(C)(C)O4)n2)cc(OC)c1OC
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC[NH+](CC)CC
Temperature: 20 °C

Procedure:
To [6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate; N,N-dimethylformamide solvate (Step E) (1.00 kg, 1.00 mol eq) is added a solution of triethylamine (0.34 kg, 2.20 mol eq) in isopropanol (1.32 kg) and water (3.33 kg). This is stirred at about 20° C. to give a solution which is then filtered. The resulting solution of the sub-title compound is used directly in the next step.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.O[CH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH2:13][CH2:12]1.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([NH:28][CH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: COC(=O)c1ccc2c(c1)C(O)CC2
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(NC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of methanesulfonic acid anhydride (6.79 g, 39.062 mmol, 2.5 eq.) in DCM (20 ml) was added dropwise at −78° C. to a solution of methyl 3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (3.0 g, 15.625 mmol, 1.0 eq.) and TEA (11.0 ml, 78.125 mmol, 5.0 eq.) in DCM (60 ml) and stirred for 2 hours at the same temperature. tert-Butylamine (16 ml, 156.5 mmol, 10.0 eq.) was slowly added dropwise at −78° C., and the mixture was heated to RT and stirred for 14 hours. The reaction solution was diluted with DCM (100 ml), washed with water (2×50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 13% ethyl acetate in hexane). Yield: 32% (1.2 g, 4.858 mmol)
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][NH:8][C:6]=2[N:7]=1.C(OC(=O)C)(=O)C.C1(N(C)C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:33].Cl>CC#N>[Cl:33][C:4]1[C:5]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1c[nH]c2nc(N)[nH]c(=O)c12
Agent: Cl
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)c1ccccc1
Product: CC(C)c1c[nH]c2nc(N)nc(Cl)c12
Yield: 45 %

Procedure:
A mixture of 2-amino-5-isopropyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one and acetic anhydride (20 mL) was heated to reflux for 3 h and evaporated. The residue was treated with BnNEt3Cl (8.99 g, 40 mmol), PhNMe2 (4.9 mL) and POCl3 (17 mL, 120 mmol) in CH3CN (100 mL) at 100° C. for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (80 mL×3), and evaporated to give an oil which was digested with methanolic 4N HCl (50 mL) at 50° C. for 2 h. After cooling, and neutralization to pH 7 with 2N NaOH, the solid was collected by filtration and dried to give 4-chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (1.88 g, 45%). HPLC Rt: 5.796 min. 1H-NMR (DMSO-d6): δ 11.170 (s, 1H), 6.82 (s, 1H), 6.42 (s, 2H), 3.24 (7, 1H), 1.25 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH3:24][N:25]([CH3:37])[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([C:26](=[O:27])[N:25]([CH3:24])[CH3:37])[CH:29]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccc(C(=O)N(C)C)c4)c(C(=O)O)s3)c2cc1OC
Yield: 4 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-dimethylcarbamoylphenylboronic acid (29 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-dimethylcarbamoyl-phenyl)-thiazole-5-carboxylic acid (1.8 mg, 4%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (s, 1 H); 7.84 (s, 1 H); 7.73-7.79 (m, 2H); 7.44-7.59 (m, 3 H); 7.40 (s, 1 H); 3.91 (s, 3 H, NCH3), 3.86 (s, 3 H); 3.01 (s, 3 H); 2.74 (s, 3 H). MS 453 m/z (M+1).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9]Br)[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([NH:25][C:26]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]([CH2:9][CH2:8][CH2:7][C:6]([O:5][CH2:3][CH3:4])=[O:11])[C:26]1[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(C)cc(C)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C(=O)OC(C)(C)C)c1c(C)cc(C)cc1C(=O)OC
Temperature: 55 °C
Reaction time: 48 h
Yield: 113.6 %

Procedure:
Charge a 22 L flask, equipped with overhead agitation, heating mantle, condenser and a N2 purge, with DMF (10 L), ethyl-4-bromobutyrate (1.07 kg, 787.8 mL, 5.32 moles), cesium carbonate (2.92 kg, 22.5 moles), and methyl 2-(tert-butoxy carbonylamino)-3,5-dimethylbenzoate (1,000.0 g, 3.54 moles). Heat the resulting mixture to about 55° C. and stir for about 48 hours. Cool; filter off the solid; and wash the solid with MTBE (2×4 L). Combine the filtrate and the MTBE washings into a 50 L flask and cool to less than about 5° C. Add water (6 L) to quench the reaction. Separate the layers. Wash the aqueous layer with MTBE (3 L); combine the organic layers; and wash the resulting organic solution with brine (2×3 L). Dry the organic solution over Na2SO4; filter; and wash the collected solids with MTBE to yield 1.582 kg of the title compound.
Reaction SMILES: [C:1]1(NN)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Te:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=O)=[CH:13][CH:12]=1>C1C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([Te:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:24][CH:23]=1.[C:1]1([C:15]2[CH:16]=[C:11]([O:10][CH3:9])[CH:12]=[CH:13][C:14]=2[Te:17][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Reactant: NNc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc([Te]c2ccc(OC)cc2)cc1
Product: COc1ccc([Te]c2ccc(OC)cc2-c2ccccc2)c(-c2ccccc2)c1
Yield: 29 %
Yield: 68 %

Procedure:
Phenylhydrazine (121 mg, 1.12 mmol) was reacted with bis-(p-methoxyphenyl)-telluroxide for 0.2 h. to yield benzene (53%), p.l.c. (benzene-petroleum ether 2.8) afforded bis-(p-methoxyphenyl)-telluride (262 mg, 68%) and phenyl-p-methoxyphenyl-telluride (101 mg, 29%) m.p. 59°-62°. The latter on recrystallisation from methanol gave white needles, m.p. 61°-62° (lit., 60.5-61.5), δ(CDCl3) 7.63 (d, J 8 Hz), 7.72-7.00 (m), 6.70 (d, j 8 Hz) combined integral 9H and 3.73 (3H, S), m/e 314(+), 184(100%) 169, 141 and 77 (Found: C, 50.03; H, 3.86 Calc. for C13H12O Te: C, 50.07; H, 3.88%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].O.[C:6]([C:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7].C(N(CC)CC)C>C(Cl)Cl>[N:14]([C:8]1([CH2:6][CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[C:1]=[S:2]
Reactant: C#CC1(N)CCCCC1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(N=C=S)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thiophosgene (140 g) was dissolved in 250 ml methylene chloride and 250 ml water was added. To the two-phase system was added dropwise a solution of 1-ethynyl-1-amino-cyclohexane (123 g) and triethylamine (101 g) in 250 ml methylene chloride. The mixture was cooled to prevent refluxing. The mixture was stirred at room temperature for two hours, phase separated, and the organic phase was collected. This layer was dried (MgSO4) and stripped, and the residue was dissolved in diethyl ether, filtered and stripped to yield a dark brown oil. A small portion of the oil was purified on a silica gel column (3×10 cm) with hexane elution to yield 1-isothiocyano-1-ethyl-cyclohexane (A), 5.9 g.
Reaction SMILES: CC1C=[CH:4][C:5]([NH:9][C:10](N(C)C)=O)=CC=1[Cl:8].CN([C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24](Cl)=[C:25]([Cl:27])[CH:26]=1)=O)C.[CH3:29][CH:30](C1C=CC(NC(N(C)C)=O)=CC=1)C.CN(OC)C(NC1C=CC(Cl)=C(Cl)C=1)=O>>[CH3:10][N+:9]1[CH:26]=[CH:25][C:24]([C:23]2[CH:22]=[CH:21][N+:20]([CH3:18])=[CH:30][CH:29]=2)=[CH:4][CH:5]=1.[Cl-:8].[Cl-:27]
Reactant: CN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(NC(=O)N(C)C)cc1Cl
Reactant: CC(C)c1ccc(NC(=O)N(C)C)cc1
Agent: CON(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Product: C[n+]1ccc(-c2cc[n+](C)cc2)cc1
Product: [Cl-]

Procedure:
chlorotoluron, diuron, isoproturon or linuron;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][CH3:22])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: CC=O
Reactant: CCc1c(NC2CCOCC2)cc(Cl)cc1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CCc1c(C(=O)O)cc(Cl)cc1N(CC)C1CCOCC1
Yield: 86.2 %

Procedure:
To a solution of methyl 5-chloro-2-ethyl-3-[(oxan-4-yl)amino]benzoate (350 mg, 1.18 mmol) in DCE (10 ml) at room temperature and under nitrogen was added acetaldehyde (0.66 ml, 11.75 mmol) followed by acetic acid (0.4 ml, 7.05 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (2.49 g, 11.75 mmol) at room temperature. After stirring for 23 h further acetaldehyde (0.66 ml, 11.75 mmol) was added followed sodium triacetoxyborohydride (2.49 g, 11.75 mmol). After stirring for a further 3 hours deionized water (15 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×15 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 85:15 Heptane:EtOAc) to afford the title compound (317 mg) as a 2:1 mixture of methyl and ethyl esters that were used in the next stage.
Reaction SMILES: [N:1]1([C:7](=[O:20])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[N:18][N:17]=[N:16]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:21]1[CH2:23][CH:22]1[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[O:29][CH2:28][CH2:27]2>C(O)C>[OH:21][CH:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[O:29][CH2:28][CH2:27]2)[CH2:23][N:4]1[CH2:5][CH2:6][N:1]([C:7](=[O:20])[CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH:19]=[N:18][N:17]=[N:16]3)=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: O=C1OCCc2cc(C3CO3)ccc21
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Solvent: CCO
Product: O=C1OCCc2cc(C(O)CN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4)CC3)ccc21

Procedure:
A solution of 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone (200 mg, 0.734 mmol), 6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (140 mg, 0.734 mmol) in ethanol was heated in a microwave reactor at 130° C. for 1 h. The reaction mixture was concentrated and the residue was purified by preparative TLC to afford the title compound. LC/MS: [(M+1]+=463.
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:7])([N+:8]([O-:10])=[O:9])[CH3:1])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCCO)[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCCOS(C)(=O)=O)[N+](=O)[O-]
Reaction time: 1 h
Yield: 93.8 %

Procedure:
4-Methyl-4-nitropentanol (4.3 g, 29.2 mmol) was dissolved in methylene chloride (100 ml) and triethylamine (6.1 ml, 43.8 mmol) was added, which was followed by ice-cooling. Methanesulfonyl chloride (2.94 ml, 38.0 mmol) was added and the mixture was stirred for 1 h under ice-cooling. The mixture was washed with water (50 ml), 0.5 mol/L hydrochloric acid (50 ml), 5% aqueous sodium hydrogencarbonate solution (50 ml) and saturated brine (50 ml). Methylene chloride was evaporated by concentration under reduced pressure and the residue was subjected to crystallization with ethyl acetate (4 ml) and n-hexane (20 ml). After filtration, the residue was dried under reduced pressure at 40° C. to give the objective compound (6.17 g, yield 93.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[NH:12][C:13]3[C:14](I)=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][OH:34]>C(Cl)Cl.[Cu]I>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][O:34][C:14]1[C:13]2[NH:12][C:11]3[CH2:20][CH2:21][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=3[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)CCO
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(I)cccc3c2C1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C)CCOc1cccc2c3c([nH]c12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 150 °C
Yield: 67.1 %

Procedure:
tert-Butyl-6-iodo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (500 mg, 1.26 mmol), copper(I) iodide (71.7 mg, 0.38 mmol) and tri-potassium orthophosphate (533 mg, 2.51 mmol) were suspended in 2-dimethylaminoethanol (10 ml, 99.40 mmol) and sealed into a microwave tube. The reaction was heated to 150° C. for 1 hour in the microwave reactor and cooled to RT. The reaction mixture was diluted with DCM (100 mL), and washed with 2N NaOH (3×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (0.1% NH3, CH3CN/H2O gradient) to afford tert-butyl 6-(2-(dimethylamino)ethoxy)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (304 mg, 67%) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=4)[NH2:25])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:29]([N:32]([CH:35](C)C)CC)(C)[CH3:30].ClC(Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.C(N)C>ClCCl>[CH2:29]([NH:32][C:35]([NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][O:17][C:15]2[C:16]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][S:10][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:23]=1)=[O:41])[CH3:30]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Agent: CCN
Solvent: ClCCl
Product: CCNC(=O)Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 139.8 %

Procedure:
A mixture of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline (25 mg, 0.063 mmol) and diisopropylethylamine (9.0 mg, 0.069 mmol) in dichloromethane (1.5 mL) was added in three portions over a period of 30 minutes to a solution of triphosgene (7.0 mg, 0.023 mmol) in dichloromethane (0.5 mL) while stirring at ambient temperature. Stirring continued for 15 minutes followed by the addition of ethylamine (0.075 mL, 2M in tetrahydrofuran). The reaction was stirred for 2 hours, then diluted with dichloromethane (30 mL) and washed with sodium bicarbonate (2×20 mL). The organic layer was dried (Na2SO4), concentrated, and purified by column chromatography over silica gel using 40% ethyl acetate in hexanes as eluant to give 15 mg (51%) of N-ethyl-N′-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)phenyl]urea as a white solid. MS [M+H] 467.3. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.64 (s, 1H), 7.45-7.38 (m, 2H), 7.21 (s, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.06-7.01 (m, 2H), 6.82 (t, J=2.4 Hz, 1H), 6.79 (m, 1H), 6.50 (m, 1H), 4.58 (t, J=6.0 Hz, 2H), 3.72 (t, J=6.0 Hz, 2H), 3.30 (q, J=7.2 Hz, 2H), 2.06 (m, 2H), 1.16 (t, J=7.2 Hz, 3H).