Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:38])[C:15]=1[OH:39].[C:40]([O:49][CH3:50])(=[O:48])[C@H:41]([CH2:43][C:44]([O:46][CH3:47])=[O:45])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C(Cl)Cl>[CH3:47][O:46][C:44](=[O:45])[CH:43]([O:39][C:15]1[C:16]([Br:38])=[CH:17][C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:19][C:14]=1[Br:13])[CH2:41][C:40]([O:49][CH3:50])=[O:48]
Reactant: COC(=O)C[C@H](O)C(=O)OC
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)CC(Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)OC
Temperature: 79 °C
Yield: 50 %

Procedure:
Diethylazodicarboxylate (0.254 mL, 1.61 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenol (0.600 g, 1.10 mmol), dimethyl (S)-(-)-malate (0.213 mL, 1.61 mmol) and triphenylphosphine (0.421 g, 1.61 mmol) in benzene (7.5 mL) under a dry nitrogen atmosphere. The solution was heated in an 79° C. oil bath for 23 h. Additional Dimethyl (S)-(-)-malate (0.043 mL, 0.321 mmol) and triphenylphosphine (0.084 g, 0.321 mmol) and diethylazodicarboxylate (0.050 mL, 0.321 mmol) were added and the reaction mixture was heated for an additional 10 hours. The reaction mixture was cooled to room temperature, diluted with methylene chloride combined with silica gel (20 mL) and concentrated. The silica adsorbate was flash chromatographed (92:8 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.389 g, 51%): mp 118-121° C.: NMR (CDCl3); δ8.36 (dd, J=8, 0.5 Hz, 1 H), 7.83 (dd, J=8, 0.5 Hz, 1 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.61 - 7.59 (m, 3 H), 7.55 -7.43 (m, 2 H), 7.26 - 7.21 (m, 1 H), 6.79 (d, J=8 Hz, 1 H), 5.46 (t, J=6 Hz, 1 H), 3.90 (s, 3 H), 3.77 (s, 3 H), 3.32 - 3.30 (m, 1 H); MS (EI): [M+], 3 bromine isotope pattern, 704 (5%), 706 (15%), 708 (15%), 710 (4%); Anal. Calc. for C28H19Br3O5S: C, 47.55, H, 2.71, N, 0.00. Found: C, 47.93, H, 2.65, N, 0.14.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[CH2:11]([N:3]1[CH:4]=[C:5]([CH:7]=[O:8])[N:6]=[C:2]1[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(C=O)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C=O)cn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 2-methyl-1H-imidazole-4-carbaldehyde (5.50 g) in N,N-dimethylformamide (100 mL) was slowly added sodium hydride (60%, oily, 2.4 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Benzylbromide (7.1 mL) was slowly added to the reaction mixture, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give 1-benzyl-2-methyl-1H-imidazole-4-carbaldehyde (3.8 g, yield 38%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 61° C.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-:16].[Na+].C(Cl)Cl.Cl>O>[OH:16][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Sc2cccc(F)n2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Sc2cccc(O)n2)cc1

Procedure:
A solution of 5 grams (0.023 mole) of 4-((6-fluoro-2-pyridyl)thio)phenol and 2.72 grams (0.68 mole) of sodium hydroxide in 15 milliliters of water was heated at reflux for 21/2 hours. The resulting solution was poured over a mixture of ice and methylene chloride and the resulting mixture was vigorously stirred. The mixture was acidified by the dropwise addition of concentrated hydrochloric acid. The white crystalline solid 4-((6-hydroxy-2-pyridyl)thio)phenol product which precipitated out was recovered by filtration and washed with methylene chloride. The product was recovered in a yield of 4.35 grams (88 percent of theoretical) and melted at 234°-238° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])N)=[CH:5][CH:4]=1.[C:19]([OH:22])(=[O:21])[CH3:20].C([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=O)C>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:27]([CH2:20][C:19]([OH:22])=[O:21])[CH2:28][CH2:29][CH2:30][C:25]=3[C:15]3[C:10]2=[C:11]([CH3:16])[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1N(N)Cc1ccc(Cl)cc1
Reactant: CCC1CCCCC1=O
Reactant: CC(=O)O
Agent: Cl
Product: Cc1cccc2c3c(n(Cc4ccc(Cl)cc4)c12)C(CC(=O)O)CCC3

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2-methylphenyl)hydrazine hydrochloride and ethyl-2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=O)[C:20]12[O:31]CCCO1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:33][C:34]1([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:25]=[CH:24][C:23]2[N:22]3[CH2:33][C:34]4([CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:39][N:40]=[C:21]3[C:20](=[O:31])[C:19]=2[CH:18]=1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(CCl)CCCC1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C12OCCCO2
Product: O=C1C2=NCC3(CCCC3)CN2c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc21

Procedure:
The title compound was prepared as a yellow solid from 5′-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one and 1-chloromethyl-cyclopentanecarbonitrile (Syn. Comm. 20(12) 1757, 1990) using a procedure similar to that of steps 3-5 of Example 12. NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 478 [M−H]. m.p.: 142.9.8-144.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12].[H][H].C(OCC)(=O)C>CO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12]
Reactant: CC(O)c1cc([N+](=O)[O-])ccc1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1cc(N)ccc1N
Yield: 100 %

Procedure:
Catalytic hydrogenation of 6 (27.0 g, 150 mmole) under 60 psi hydrogen pressure with 10% Pd/C (2.7 g) in anhydrous MeOH (150 mL)/ethyl acetate (150 mL) was completed in 2.5 h. The catalyst was removed by filtration over Celite. The filtrate was evaporated under vacuum to afford 1-(2,5-diamino-phenyl)-ethanol 1 (22.83 g, 100 % yield). Mp 124° C.; 1HNMR (400 MHz, DMSO-d6) δ1.26 (d, 3H, J=6.4 Hz), 4.15 (d, 4H, J=10.7 Hz), 4.61-4.65 (m, 1H), 4.94 (d, 1H, J=3.6 Hz), 6.24 (dd, 1H, J=2.5, 8.2 Hz), 6.36 (d, 1H, J=8.2 Hz), 6.45 (d, 1H, J=2.5 Hz); MS m/z 152 (M+); Anal. Calcd. for C8H12N2O: C, 63.13. H, 7.95. N, 18.41.O, 10.51. Found: C, 62.83. H, 7.90. N, 18.46. O, 10.17.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=O.O.[NH2:13][NH2:14]>CO>[NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[N:13][NH2:14]
Reactant: NN
Reactant: O=C1Nc2ccccc2C1=O
Solvent: O
Solvent: CO
Product: NN=C1Nc2ccccc2C1=O

Procedure:
Chem. Educ. 1993, 70 (4), p. 332 discloses that 2-oxindoles are prepared by a two-step reaction, the first step of which comprises reacting isatin with hydrazine hydrate in anhydrous methanol to give the intermediate isatin hydrazone and isolating and purifying the intermediate. In the second step, the purified and dried intermediate is subjected to a Wolf-Kishner reduction in an anhydrous ethanol solution in the presence of a strong base such as sodium ethoxide. The yields achieved by this preparation method are up to about 69%. However, the disadvantage of this variant is the necessity of isolating, purifying and drying the intermediate before the reduction step can take place. A further disadvantage is the use of expensive, anhydrous ethanol as solvent because of the readiness of sodium ethoxide to react with water. A further preparation variant is described by Synth. Commun. 1994, 24 (20), p. 2835-41. In this variant, isatin is first dissolved in pure hydrazine and then reacted with pure hydrazine under reflux to give 2-oxindole in yields of up to 76%. However, this method requires a large quantity of pure hydrazine which serves as solvent and as reagent. When pure hydrazine is used, there is known to be a risk of explosion on heating or on reaction with oxidizing agents, so that particular safety measures have to be taken. An improvement suggested by U.S. Pat. No. 5,973,165 comprises preparing 2-oxindoles by reacting isatin with hydrazine hydrate in the presence of a weak base as catalyst and in a polar solvent. In order to obtain the desired end product in pure form, after the end of the reaction, 2-oxindole (purity about 97%) is first extracted, the extract is dried and then dissolved in a suitable solvent, and activated carbon is then added to the solution to decolorize it. After filtering off the activated carbon, 2-oxindole is crystallized out of the solution and obtained in a purity of 99.5%. The yields which are obtained by this process according to Example 1 are around 85%, but otherwise from 52 to 72%.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=[O:20].Cl.[CH3:23]N(C=O)C>[Cu]Cl.CO.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([S:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][C:19]([O:21][CH3:23])=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(S)c1
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccccc1Br
Agent: Cl[Cu]
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccccc1Sc1cccc(OC)c1
Yield: 91 %

Procedure:
A mixture of the sodium salt of 3-methoxythiophenol [prepared by treatment of 3-methoxythiophenol (2.8 g) with sodium hydroxide (0.8 g) in methanol (20 ml) followed by evaporation to dryness], 2-bromophenylacetic acid (4.3 g) and copper(I) chloride (0.4 g) in dry DMF (25 ml) was heated overnight at reflux. The reaction mixture was cooled, poured into water and acidified with dilute hydrochloric acid. The aqueous mixture was extracted with ether (×3) and the combined ether extracts were extracted in turn with dilute sodium hydroxide solution (×2). The combined aqueous hydroxide extracts were acidified with dilute hydrochloric acid and re-extracted with ether (×3). These combined ether extracts were washed with water (×3), dried and evaporated to give an orange oil (3.5 g, 96.8% by GC). The oil was treated with acidic methanol overnight at room temperature. Normal work-up afforded methyl 2-(3-methoxyphenylthio)phenylacetate (2.9 g, 91% by GC) as a yellow liquid which was used in the next stage without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:21]([OH:24])(=[O:23])=[O:22])[C:5]([CH:8]=[CH:9][C:10]2[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1.[N:25]1[C:32]([Cl:33])=[N:31][C:29]([Cl:30])=[N:28][C:26]=1Cl.[OH-].[Na+:35]>CC(C)=O>[Cl:30][C:29]1[N:31]=[C:32]([Cl:33])[N:25]=[C:26]([NH:1][C:2]2[CH:3]=[C:4]([S:21]([O-:24])(=[O:23])=[O:22])[C:5]([CH:8]=[CH:9][C:10]3[C:11]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:12][C:13]([NH:16][C:26]4[N:25]=[C:32]([Cl:33])[N:31]=[C:29]([Cl:30])[N:28]=4)=[CH:14][CH:15]=3)=[CH:6][CH:7]=2)[N:28]=1.[Na+:35].[Na+:35]
Reactant: Nc1ccc(C=Cc2ccc(N)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=S(=O)([O-])c1cc(Nc2nc(Cl)nc(Cl)n2)ccc1C=Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1S(=O)(=O)[O-]
Temperature: 0 °C

Procedure:
Disodium 4,4'-bis(4,6-dichloro-s-triazin-2-ylamino)-2,2'-stilbenedisulfonate was prepared by interaction of 500 pounds of 4,4'-diamino-2,2'-stilbenedisulfonic acid with a solution of 500 pounds of cyanuric chloride in 2100 pounds of acetone in an aqueous reaction medium at pH 7-8 prepared by mixing 3200 pounds of crushed ice and approximately 2100 pounds of 10 percent aqueous sodium hydroxide solution. The disodium 4,4'-bis(4,6-dichloro-s-triazin-2-ylamino)-2,2'-stilbenedisulfonate thus obtained was mixed with 270 pounds of disodium phosphate and interacted at 15°-50° C. with 625 pounds of aniline for thrity minutes and then the pH of the reaction mixture was adjusted to 6.7-6.8 by adding approximately 600 pounds of 10 percent aqueous sodium hydroxide solution during a period of one hour.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:27]2[C:32]([Cl:33])=[N:31][CH:30]=[CH:29][N:28]=2)[N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>CCO>[ClH:33].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH2:16])[C:27]2[C:32]([Cl:33])=[N:31][CH:30]=[CH:29][N:28]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Solvent: CCO
Solvent: ClCCl
Product: Cl
Product: NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl

Procedure:
2-[(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-isoindole-1,3-dione (2.76 g, 6.05 mmol) was dissolved in EtOH (12 mL) and CH2Cl2 (4 mL) charged with N2H4 (0.57 mL, 18.16 mmol) and allowed to react for 16 h at rt. The white precipitate was filtered and washed with EtOAc. The filtrate and organic washings were concentrated in vacuo, and purified via HPFC using a 100 g Jones silica gel column (50% EtOAc: Hex to 5% MeOH: CH2Cl2) to yield the desired product as a reddish oil; 1H NMR (CDCl3, 400 MHz) δ 5.04 (s, 2H), 5.52 (s, 1H), 6.85-6.98 (m, 2H), 7.21-7.26 (m, 2H), 7.30-7.41 (m, 5H), 8.26 (d, 1H, J=2.5 Hz), 8.52 (d, 1H, J=2.5 Hz); MS (ES) 326.25 (M+1), 328.23 (M+3), 329.24 (M+4).
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.Cl.C(N(CC)CC)C.C1(C)C(C)=CC=CC=1.Cl[C:22]1[N:23]=[N:24][C:25]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=12>O>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:25]2[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[C:22]3[N:23]([CH:1]=[N:3][N:4]=3)[N:24]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(-c2nnc(Cl)c3cnccc23)cc1
Reactant: NNC=O
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(-c2nn3cnnc3c3cnccc23)cc1
Yield: 75.2 %

Procedure:
240 mg (4.0 mmol) of formohydrazide and 551 mg (4.0 mmol) of triethylamine hydrochloride were added to a xylene solution (10 ml) of 543 mg (2.0 mmol) of 4-chloro-1-(4-methoxyphenyl)-pyrido[3,4-d]pyridazine, and then stirred under reflux for 2 hours. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 417 mg of a crude product of 6-(4-methoxyphenyl)-pyrido[3,4-d][1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:3])=[O:2].Br[CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Si:26]([O:25][CH2:24][CH2:23][CH2:22][N:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:9]2[CH:8]=[CH:7][C:6]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:12][CH2:13]1)([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27]
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 70 °C

Procedure:
A mixture of EXAMPLE 157B (300 mg), (3-bromopropoxy)(tert-butyl)dimethylsilane (304 mg) and cesium carbonate (967 mg) was suspended in anhydrous N,N-dimethylformamide (5 mL). The reaction mixture was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified using flash column purification with 3-10% methanol/dichloromethane to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH3:22])O)#[N:2].[N:23]1C=CC=CC=1.O=S(Cl)Cl>C(Cl)Cl.O>[NH2:23][C:6]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH3:22])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][C:7]1=[O:12]
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOc1ccccc1C1(N)C(=O)Nc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
8.0 g (27.2 mMol) of intermediate 1b and 43 ml (54.4 mMol) of pyridine were dissolved in 70 ml of methylene chloride. Then, at 0° C., 3 ml (40.8 mMol) of SOCl2 were slowly added dropwise. The reaction mixture was then stirred for a further 30 minutes. The reaction solution was subsequently poured into ice-water, and the organic phase was separated off, washed with water, dried and concentrated in vacuo. This residue was added at 0° C. to a solution of 300 ml of 0.5M NH3 solution in dioxane and 150 ml of methylene chloride. The mixture was stirred at room temperature for 16 h. The reaction solution was concentrated in vacuo, and the residue obtained in this way was suspended in water. The precipitate was separated off and recrystallized from a little methanol. 4.7 g of the product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][C:11]1[C:12]([N:20]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][S:28][C:22]=3[CH:21]2[CH3:29])=[N:13][C:14]([Cl:19])=[N:15][C:16]=1[CH2:17][CH3:18]>CN(C)C=O>[ClH:19].[CH3:10][C:11]1[C:12]([N:20]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][S:28][C:22]=3[CH:21]2[CH3:29])=[N:13][C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[CH3:9])=[N:15][C:16]=1[CH2:17][CH3:18]
Reactant: Cc1cc(F)ccc1N
Reactant: CCc1nc(Cl)nc(N2CCc3ccsc3C2C)c1C
Solvent: CN(C)C=O
Product: CCc1nc(Nc2ccc(F)cc2C)nc(N2CCc3ccsc3C2C)c1C
Product: Cl
Yield: 14.4 %

Procedure:
After 4-fluoro-2-methylaniline(0.51 ml, 4.59 mmol) was added to a mixture solution of 5-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl)-6-ethyl-2-chloropyrimidine(0.74 g, 2.4 mmol) and dimethylformamide(5 ml), 0.15 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: C([O-])(C)(C)C.[K+].ClC1C=CC(O[CH2:13][C:14]#[N:15])=CC=1.[N+:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)([O-:20])=[O:19].Cl>CN(C)C=O.O>[N+:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH2:13][C:14]#[N:15])([O-:20])=[O:19]
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c([N+](=O)[O-])ccc2ccccc12
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Prepare a solution of 53.5 g (0.477 mol) of potassium tert.-butanolate in 400 ml of dimethylformamide. Cool the resulting solution to −10° C. and add thereto, over the course of about 1 hour, a solution of 40 g of 4-chlorophenoxyacetonitrile (0.24 mol) and 37 g of 2-nitronaphthalene (0.213 mol) in 200 ml of dimethylformamide. After 2 hours at −5° C., pour the mixture into 4 litres of water containing 1 litre of concentrated hydrochloric acid and extract the aqueous phase with 3×500 ml of dichloromethane. Wash the organic phase with 300 ml of water, dry it over magnesium sulphate, filter and then evaporate off the solvent.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:4]=[C:3]1[C:23]([O:25]CC)=[O:24].Cl>C(O)C.O1CCCC1.[OH-].[Na+]>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:20])[F:21])[CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:4]=[C:3]1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCCn3cccc3)c2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(C(=O)O)cc2c(C(F)(F)F)ccc(OCCn3cccc3)c21
Temperature: 25 °C
Yield: 60.7 %

Procedure:
After 1.94 g (5.10 mmol) of ethyl 1-methyl-7-[2-(1H-pyrrol-1-yl)ethoxy]-4-trifluoromethyl-2-indolecarboxylate was dissolved in a mixture of 100 ml of ethanol and 50 ml of tetrahydrofuran, 10 ml of 3.75 N sodium hydroxide was added thereto. The mixture was stirred at room temperature for an hour. After completion of the reaction, the mixture was rendered acidic with 2 N hydrochloric acid and concentrated under reduced pressure. To the concentrate was added 100 ml of water. The mixture was then extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. Crystallization of the resulting residue from chloroform/ethyl acetate gave 1.09 g of 1-methyl-7-[2-(1H-pyrrol-1-yl)ethoxy]-4-trifluoromethyl-2-indolecarboxylic acid.
Reaction SMILES: [CH3:1][Li].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](C#N)=[C:13](C)[N:12]=[C:11]2[CH3:18])=[CH:6][C:5]=1[CH3:19].CC[O:22][CH2:23][CH3:24]>>[C:23]([C:24]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[C:5]([CH3:19])[CH:6]=2)[C:11]([CH3:18])=[N:12][C:13]=1[CH3:14])(=[O:22])[CH3:1]
Reactant: Cc1cc(-n2c(C)nc(C)c2C#N)ccc1N
Reactant: [Li]C
Reactant: CCOCC
Product: CC(=O)c1c(C)nc(C)n1-c1ccc(N)c(C)c1
Temperature: 25 °C

Procedure:
Methyllithium (219 cm3 of a 1.5M solution in ether) was added dropwise to a stirred suspension of 1-(4-amino-3-methylphenyl)-5-cyano-2,4-dimethylimidazole (9.3 g) in ether (100 cm3) at -70° under nitrogen. The mixture was allowed to warm to room temperature over 1 hour and then heated under reflux for 5 hours. The mixture was quenched by the dropwise addition of water (50 cm3), acidified with 2M hydrochloric acid (50 cm3), and warmed on a steam bath for 5 minutes. The mixture was basified with 10% sodium carbonate solution to pH9 and extracted with dichloromethane (3×200 cm3). The combined and dried (MgSO4) organic extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]). Elution of the column with hexane:ethyl acetate, 1:1, gave firstly fractions containing recovered starting material (2.9 g). Further elution with hexane:ethyl acetate, 1:4, followed by combination and evaporation of the appropriate fractions, afforded the title compound as an oil (5.6 g), which was used (Preparation 11) without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[Br:18]NC(=O)CCC(N)=O>S(=O)(=O)(O)O>[Br:18][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([NH:8][C:9](=[O:11])[CH3:10])=[C:5]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:4]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCCS(=O)(=O)c1ccc(C)cc1NC(C)=O
Agent: O=S(=O)(O)O
Product: CCCS(=O)(=O)c1cc(Br)c(C)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-[5-methyl-2-(propylsulfonyl)phenyl]acetamide (Intermediate 229; 5.0 g, 20 mmol) in conc. sulphuric acid (25 ml) was treated in portions with N-bromosuccinamide (3.8 g, 22 mmol). Reaction mixture was stirred at RT for 18 hrs, carefully quenched on ice and extracted to DCM (100 ml). The organic layer was washed with water and brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography (silica) eluting with petroleum ether/ethyl acetate to afford the title compound as a white solid.