Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[CH2:19]([N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([C:34]([CH3:37])([CH3:36])[CH3:35])=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[C:30]([C:31]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:32])=[CH:29][C:28]([C:34]([CH3:37])([CH3:36])[CH3:35])=[N:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: CC(C)(C)c1cc(C(=O)Cl)n(Cc2ccccc2)n1
Product: CC(C)(C)c1cc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)n(Cc2ccccc2)n1
Yield: 39 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1-benzyl-3-tert-butyl-1H-pyrazole-5-carbonyl chloride to afford the title compound (40 mg, 39%). 1H-NMR (δ, ppm, DMSO-d6): 1.29 (s, 9H, t-Bu), 5.67 (s, 2H, CH2), 6.47 (d, 1H, HPy,5, J=6.0 Hz), 6.89 (d, 1H, Harom, J=8.0 Hz), 7.00 (s, 1H, Hpyrrazole), 7.11 (d, 2H, Harom, J=8.0 Hz), 7.22 (t, 1H, Harom, J=7.0 Hz), 7.11 (t, 2H, Harom, J=8.0 Hz), 7.40 (t, 1H, Harom, J=8.0 Hz), 7.48-7.51 (m, 1H, Harom), 7.60 (d, 1H, Harom, J=8.0 Hz), 7.79 (d, 1H, HPy,6, J=6.0 Hz), 10.23 (s, 1H, NHamide), 11.18 (s, 1H, NHPy3), 11.38 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C27H27N6O3: 483.2145; found: 483.2145.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH2:17][CH2:18][C:19](OCC)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.O>CCOCC>[C:7]1([CH2:17][CH2:18][CH2:19][OH:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CCc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of LiAlH4 (1.91 g, 50.4 mmol) in anhydrous ether (50 mL) was added dropwise a solution of 8 (11.5 g, 50.4 mmol) in ether (50 mL) over 30 minutes at 0° C. under argon and then the mixture was stirred at room temperature (overnight). The reaction mixture was cooled to 0° C. and quenched by slow (30 minutes addition of H2O (7.2 mL, 0.4 mol), then the mixture was stirred at 0° C. (1 h). Solid was removed by filtration washed with ether, then the combined ether solution was dried (Na2SO4) and taken to dryness, yielding 9 as an oil70 (9.36 g, 100%). 1H NMR (CDCl3) δ 8.08 (1H, dd, J=2.4, 7.4 Hz), 7.88 (1H, m), 7.74 (1H, d, J=7.6 Hz), 7.34˜7.57 (4H, m), 3.76 (2H, t, J=6.4 Hz), 3.20 (2H, t, J=7.5 Hz), 2.05 (2H, m), 1.75 (1H, brs).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O>O>[C:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)OCCCCCCCCCCCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)c1ccc(NCCCCCCCCCCCc2ccccc2)cc1

Procedure:
A mixture of 16.5 g. of ethyl p-aminobenzoate, 16.3 g. of 11-phenylundecanol O-methanesulfonate (prepared as described in Example 7) and 50 ml. of hexamethylphosphoramide are heated in an oil bath at 120° C. for 20 hours. The mixture is poured into ice and water and extracted with chloroform. The extracts are washed with water, 0.1 N NaOH, saturated sodium chloride solution and water. After drying over magnesium sulfate the extract is filtered through silica gel and the silica gel is washed with chloroform. The filtrate is concentrated in vacuo to an oil which is combined with 200 ml. of ethanol-water (9:1), 15 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with 50 ml. of water and chilled. Dilution with 100 ml. of ethanol and 25 ml. of water and filtration gives a gummy solid which is washed with water. The solid is dissolved in hexane:ether:ethyl acetate:acetic acid (40:5:5:2) and filtered through silica gel G. The support is washed with the same solvent (2 fractions). The first fraction is concentrated in vacuo to an oil which is crystallized from hexane to give pale yellow crystals, m.p. 50°-52° C. Recrystallization from ether-hexane (1:1) gives white crystals, m.p. 53°-55° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH3:2].[C:29](=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH3:29][CH:18]1[CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]2[CH:26]=[C:10]([O:9][CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)[CH:11]=[CH:12][C:13]=2[S:19]1(=[O:20])=[O:21]
Reactant: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CC(C)S3(=O)=O)cc1
Temperature: 70 °C
Reaction time: 16.5 h
Yield: 73.5 %

Procedure:
Into a suspension of methyl 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (200 mg) in THF/methanol (6/3 ml) was added at room temperature an aqueous solution (0.7 ml) of potassium carbonate (137 mg), and the resulting mixture was stirred at 70° C. for 16.5 hours. After cooling to room temperature, 1 N hydrochloric acid was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain methyl 7-[(4-ethoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (147 mg) as colorless crystals.
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4]CSC.[P:8]([O-])([O:18][CH2:19][C:20]1C=CC=[CH:22][CH:21]=1)([O:10][CH2:11][C:12]1C=CC=[CH:14][CH:13]=1)=[O:9].IN1C(=O)CCC1=O>C1COCC1.C(OCC)(=O)C>[CH3:1][S:2][CH2:3][O:4][P:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:9]
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: CSCOCSC
Agent: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCOP(=O)(OCCCC)OCSC
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of bis(methylthiomethyl)ether (30 mg, 2.34 mmol) and molecular sieves (300 mg) in THF (100 ml) at room temperature was added dibenzyl phosphate (2.74 g, 9.85 mmol) followed by N-iodosuccinimide (608 mg, 2.71 mmol) and the solution was stirred for 4 h. The reaction mixture was then diluted with ethyl acetate and filtered through a pad of celite. The filtrate was treated with a 1:1 (v:v) solution of saturated aqueous sodium bicarbonate and 5% aqueous sodium thiosulfate. The colorless organic extract was then washed with brine, dried over sodium sulfate and concentrated in vacuo to provide 600 mg (69%) of the title compound:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([N+:15]#[C-:16])=[C:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])[CH3:2].C(N(CC)CC)C.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[N:15]=[CH:16][N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])=[O:17])[CH3:2]
Reactant: CC(C)CN
Reactant: [C-]#[N+]C(C(=O)OCC)=C(Br)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(CC(C)C)c1-c1ccccc1Br
Yield: 71 %

Procedure:
A 0.5 M solution of 3-bromo-3-(2-bromophenyl)-2-isocyano-acrylic acid ethyl ester (2.55 g; 7.11 mM) and triethylamine (990 μl; 7.11 mM) in dimethylformamide (DMF) is added drop by drop at room temperature with isobutylamine (850 μl; 8.53 mM). The reaction mixture is kept at room temperature until complete reaction, then is quenched with a NaHCO3 saturated solution, extracted with ethyl acetate, washed with water, dried over Na2SO4, and evaporated under reduced pressure. The crude is purified by flash chromatography, eluting with ethyl acetate, to obtain 1.77 g of 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-carboxylic acid ethyl ester. (Yield: 71%).
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[OH:5][CH2:6][CH:7]([CH2:9]O)[OH:8]>>[B:1]([O:4][CH2:9][CH:7]([CH2:6][OH:5])[OH:8])([OH:3])[OH:2]
Reactant: OB(O)O
Reactant: OCC(O)CO
Product: OCC(O)COB(O)O

Procedure:
The glycerol borate acid salt of TEDA was prepared according to U.S. Pat. No. 3,113,515. Boric acid was combined with 2 molar equivalents of glycerol and hested to 180° F. to afford a glycerol borate acid. The reaction mixture was then cooled to 100° F. and treated with 1 molar equivalent of TEDA. Further cooling afforded a viscous material containing 30 wt % TEDA which had a measured Brookfield viscosity of 14,800 centipoise at 25° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([C:41]([CH3:48])([CH2:45][CH:46]=[CH2:47])[C:42](Cl)=[O:43])[CH:39]=[CH2:40]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:42](=[O:43])[C:41]([CH2:45][CH:46]=[CH2:47])([CH3:48])[CH2:38][CH:39]=[CH2:40])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=CCC(C)(CC=C)C(=O)Cl
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C=CCC(C)(CC=C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 86.1 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 2.0 g (3.6 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1, 1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 1.26 g (7.3 mmol) of 2-allyl-2-methyl-4-pentenoyl chloride, to provide 2.13 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9](Cl)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15]CC)=O)[N:6]2[CH3:12].[CH3:18][NH2:19].CO>>[CH3:18][NH:19][C:13]([C:5]1[N:6]([CH3:12])[C:7]2[C:3]([CH:4]=1)=[CH:2][CH:10]=[CH:9][CH:8]=2)=[O:15]
Reactant: CN
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2n1C
Solvent: CO
Product: CNC(=O)c1cc2ccccc2n1C
Temperature: 50 °C
Reaction time: 17.5 h
Yield: 99 %

Procedure:
A suspension of ethyl 4,6-dichloro-1-methyl-1H-indole-2-carboxylate (1.06 g, 3.90 mmole) in 2.0 M CH3NH2/CH3OH (40 mL) in a sealed pressure bottle was heated in an oil bath preset at 50° C. A homogeneous solution formed within 2.5 hr. The reaction was kept at 50° C. for 17.5 hr, during which time a solid precipitated. The mixture was cooled to RT and poured into H2O (40 mL). The resulting mixture was concentrated on the rotavap to remove the methanol, and the solid was collected by suction filtration. This was washed with plenty of H2O and dried in high vacuum at 45–50° C. to afford the title compound (0.99 g, 99%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1 H), 7.16 (d, J=1.5 Hz, 1 H), 6.86 (s, 1 H), 6.21 (br s, 1 H), 4.02 (s, 3 H), 3.02 (d, J=4.9 Hz, 3 H); MS (ES) m/e257 and 259 (M+H)+.
Reaction SMILES: CC(P(C(C)(C)C)[C:6]1[C:11]([C:12]2C=CC=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.[C:22]1([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(C1C=CC=CC=1)C#C>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:14]=[C:13]([CH2:12][C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:35]1)[CH3:33]
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Agent: [Au]
Agent: C#CCc1ccccc1
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccccc2)C=C(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
Method 2—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, prop-2-ynylbenzene (70 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-phenyl-6-benzyl-1,2-oxaphosphorin 2-oxide (68.5 mg, 70%) which is a title compound.
Reaction SMILES: [BrH:1].O.Br.C([O:8][C:9]([CH2:11][CH2:12][C:13]([NH:15][CH2:16][C:17]1[O:21][C:20]([C:22]([O:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:35](=[NH:37])[NH2:36])[CH:31]=3)[CH:26]=2)=[O:23])=[CH:19][CH:18]=1)=[O:14])=[O:10])(C)(C)C>C(O)(=O)C>[BrH:1].[C:9]([CH2:11][CH2:12][C:13]([NH:15][CH2:16][C:17]1[O:21][C:20]([C:22]([O:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:35](=[NH:36])[NH2:37])[CH:31]=3)[CH:26]=2)=[O:23])=[CH:19][CH:18]=1)=[O:14])([OH:10])=[O:8]
Reactant: CC(C)(C)OC(=O)CCC(=O)NCc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CCC(=O)O)o3)ccc2c1
Reaction time: 3 h

Procedure:
To 250 g of a 30% hydrobromic acid solution in acetic acid was added with water-cooling 8.0 g of 6-amidino-2-naphthyl 5-(3-t-butoxycarbonylpropionylaminomethyl)furan-2-carboxylate hydrobromide, and the mixture was stirred for 3 hours. The precipitate was filtered off, and the filtrate was poured into 2 l of ether. The mixture was stirred for 3 hours at room temperature and the precipitate was collected by filtration to obtain 5 g of the intended product.
Reaction SMILES: ClC(Cl)C(O)=O.N[C:8]1[N:9]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([CH:39]3[CH2:41][CH2:40]3)=[CH:31][CH:30]=2)[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][C:19]=2[Cl:28])=[O:16])=[N:11][N:12]=1.N([O-])=O.[Na+].[Br:46]CBr>>[Br:46][C:8]1[N:9]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([CH:39]3[CH2:41][CH2:40]3)=[CH:31][CH:30]=2)[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][C:19]=2[Cl:28])=[O:16])=[N:11][N:12]=1
Reactant: Nc1nnc(SCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)n1-c1ccc(C2CC2)c2ccccc12
Reactant: BrCBr
Agent: O=C(O)C(Cl)Cl
Agent: O=N[O-]
Agent: [Na+]
Product: NS(=O)(=O)c1ccc(NC(=O)CSc2nnc(Br)n2-c2ccc(C3CC3)c3ccccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
Dichloroacetic acid (180 uL, 2.2 mmol) was added to a suspension of 2-[5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-chloro-4-sulfamoylphenyl)acetamide (0.59 g, 1.1 mmol), sodium nitrite (1.5 g, 22 mmol) and BTEABr (0.91 g, 3.3 mmol) in dibromomethane (30 mL). The reaction mixture was stirred at room temperature for 4 hours, then extracted with dichloromethane and sodium bicarbonate in water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield 2-[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-chloro-4-sulfamoylphenyl)acetamide (224 mg, 31%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Cl:11][CH2:12][C:13](O)=[O:14]>O>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:13](=[O:14])[CH2:12][Cl:11])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(O)CCl
Solvent: O
Product: O=C(CCl)Nc1ccccc1[N+](=O)[O-]

Procedure:
30 Grams of o-nitroaniline and 55.7 g of anhydrous chloroacetic acid were mixed together and the mixture was heated at 70° to 80° C. for 30 minutes with stirring, then water was added to the reaction mixture, the crystals thus formed were collected by filtration and recrystallized from isopropyl ether to obtain 49.42 g of o-nitro-α-chloroacetanilide in the form of light yellow flake-like crystals. Melting point: 85.5°-87.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.BrCC1C=CC=C(F)C=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:10][C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: Fc1cccc(CBr)c1
Product: Nc1cccc(OCc2ccc(F)cc2)c1

Procedure:
3-Nitro-phenol was reacted with 1-bromomethyl-4-fluoro-benzene according to the procedure from Example 199A substituting 1-bromomethyl-4-fluoro-benzene for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: Cl[CH:2]=[C:3]([CH2:9][CH2:10][CH3:11])[C:4](=O)[CH:5]([CH3:7])[CH3:6].C([O:14][C:15](=[O:18])[CH2:16][SH:17])C>>[CH:5]([C:4]1[C:3]([CH2:9][CH2:10][CH3:11])=[CH:2][S:17][C:16]=1[C:15]([OH:18])=[O:14])([CH3:7])[CH3:6]
Reactant: CCOC(=O)CS
Reactant: CCCC(=CCl)C(=O)C(C)C
Product: CCCc1csc(C(=O)O)c1C(C)C
Yield: 30.5 %

Procedure:
1-Chloro-4-methyl-2-propyl-pent-1-en-3-one (29.7 g, 170 mmol) is reacted with mercaptoacetic acid ethyl ester (40.9 g, 340 mmol) in analogy to the procedure given for Intermediate A7 to give 3-isopropyl-4-propyl-thiophene-2-carboxylic acid (11.0 g) as colourless crystals; 1H NMR (CD3OD): δ 7.21 (s, 1H), 3.83 (hept, J=7.0 Hz, 1H), 2.60 (t, J=7.6 Hz, 2H), 1.70-1.56 (m, 2H), 1.33 (d, J=7.6 Hz, 6H), 0.99 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCOCC3)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). Morpholine (0.04 ml; 0.46 mmol; 1.40 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is purified by preparative HPLC, affording Compound (13) is obtained as white-off solid (15 mg; 19%). 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.46 (s, 3H), 2.96 (m, 4H), 3.67 (m, 4H), 7.33 (d, J=3.8 Hz, 1H), 7.61 (d, J=3.8 Hz, 1H), 12.35 (s, 1H). M−(ESI): 386.17; M+(ESI): 388.46. HPLC, Rt: 3.21 min (purity: 99.7%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][NH2:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12](=S)=[S:13].OO.Cl>C(#N)C.O>[Cl:1][C:2]1[C:3]2[N:4]([C:12](=[S:13])[NH:11][N:10]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: S=C=S
Reactant: COc1ncc(Cl)c(NN)n1
Agent: Cl
Agent: OO
Solvent: CC#N
Solvent: O
Product: COc1ncc(Cl)c2n[nH]c(=S)n12
Yield: 142 %

Procedure:
5-Chloro-4-hydrazino-2-methoxypyrimidine (17.45 g, 0.10 mol) and 25 g (0.033 mol) of carbon disulfide were combined in 120 mL of acetonitrile and 30 mL of water at ambient temperature with stirring and 11.4 g (0.10 mol) of 30 percent hydrogen peroxide was added to the resulting mixture with stirring over a 2-hour period. The temperature rose from 20° C. to 48° C. Analysis of the mixture by high pressure liquid chromatography (HPLC) indicated that the reaction was complete. A 79.8 g (47.2 percent of the total) portion of the reaction mixture was diluted with 50 mL of water and the mixture was acidified with hydrochloric acid. The solids present were then recovered by vacuum filtration and dried to obtain 10.15 g of a mixture of the title compound and sulfur. The sulfur was then removed by extracting the solids with 45 g of carbon disulfide to obtain 8.08 g (80 percent of theory) of the title compound as a tan powder. This material was 92 percent pure by HPLC analysis; it decomposed on heating.
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C>O1CCOCC1>[CH:17]1([C:3]2[C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: c1ccc(-c2nnc3cc(C4CCC4)c(N4CCOCC4)nn23)cc1

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.35 mmol), morpholine (154 mg, 1.8 mmol) and triethylamine (178 mg, 1.8 mmol) were heated in 1,4 dioxane (6 ml) in a sealed tube at 90° C. for 24 h. The reaction mixture was partitioned (ethyl acetate/water). The organic layer was washed (water, brine), dried (MgSO4) and was evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate to give the title compound. 1H NMR (250 MHz, CDCl3) δ 1.96-2.88 (1H, m), 2.48 (2H, m), 3.25-3.28 (4H, m), 3.70-3.76 (1H, m), 3.90-3.94 (4H, m), 7.52-7.55 (3H, m), 7.98 (1H, s), 8.49 (2H, s); MS (ES+) m/e 336 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:13])[CH2:10][CH2:11][CH3:12].CO>C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:9](=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCC(=O)Nc1ccccc1C
Temperature: 90 °C
Yield: 89.3 %

Procedure:
1128.6 g of o-toluidine were initially charged in 500 ml of toluene and heated to 90° C. 134.3 g of butyryl chloride were added dropwise within 2 hours. After completed addition, the mixture was heated to reflux and stirring continued at this temperature until the end of gas formation. The mixture was cooled to 70° C., 12 ml of methanol were added and stirring was continued for an hour. To remove the methanol, the mixture was heated and 70 ml were distilled off. 300 ml of toluene were then distilled off and 400 ml of cyclohexane were added. The mixture was cooled to 10° C. and filtration gave 199.5 g (92% yield) of the product in 98% purity after drying.