Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([N:16]3[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]3)=[C:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:11]3[N:10]=[N:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1c(-c2ccc(F)cc2)nnc(N2CCN[C@H](C)C2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCN(c3nnc(-c4ccc(F)cc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 110 °C
Yield: 63.6 %

Procedure:
Combine 3-(4-fluoro-phenyl)-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (522 mg, 1.73 mmol), 5-chloro-pyrazine-2-carboxylic acid methyl ester (360 mg, 2.07 mmol), diisopropylethylamine (900 μl, 5.19 mmol) and dioxane (3 mL) in a round bottom flask. Heat to 110° C. for 18 h. Concentrate reaction mixture and purify by column chromatography (0-100% ethylacetate/heptane gradient). Triturate product with acetonitrile to give 480 mg of (R)-4-[6-(4-fluoro-phenyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (63%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3[N:60]=[CH:59][N:58](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:57]=3)=[CH:53][CH:54]=2)[C:49]([C:80]2[CH:81]=[C:82](O)[CH:83]=[CH:84][CH:85]=2)=[N:48]1.Cl>O1CCCC1>[NH:57]1[C:56]([C:52]2[CH:51]=[C:50]3[C:55](=[CH:54][CH:53]=2)[NH:47][N:48]=[C:49]3[C:80]2[CH:81]=[CH:82][CH:83]=[C:84]([O:28][CH2:27][CH2:26][N:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)[CH:85]=2)=[N:60][CH:59]=[N:58]1
Reactant: OCCN1CCOCC1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCOCC2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 29.9 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 2-morpholinoethanol (0.321 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel pretreated with 2% triethylamine/hexanes followed by 0–20% ethyl acetate/hexanes and gave the title compound (0.0774 g, 30% yield). 1H NMR (CD3OD) δ 8.72 (m, 1H), 8.36 (br s, 1H), 8.10 (dd, 1H), 7.68 (d, 1H), 7.62 (dt, 1H), 7.56 (t, 1H), 7.46 (t, 1H), 7.04 (m, 1H), 4.28 (t, 2H), 3.72 (t, 4H), 2.89 (t, 2H), 2.65 (t, 4H). ES-MS (m/z) 391 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4](S(C)=O)[N:3]=1.[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(Cl)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(Cl)nc(N)nc1OCc1ccccn1

Procedure:
From 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 261 (M+, 75), 184 (46), 108 (95), 92 (100), 65 (70), 39 (45).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][OH:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.P(Br)(Br)Br.Cl[C:25]1C=C(C=CC=1)NC1C2C=C(CBr)NC=2N=CN=1.C[O-].[Na+]>C(OCC)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][O:16][CH3:25])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Clc1cccc(Nc2ncnc3[nH]c(CBr)cc23)c1
Reactant: OCc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: BrP(Br)Br
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COCc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled suspension of 82.5 mg (0.30 mmol) of 4-(3-chloro-anilino)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin (cf. Example 49) in 5 ml of diethyl ether are added under argon 14 μl (0.15 mmol) of phosphorus tribromide. After stirring for 18 h at 0° C. and 18 h at RT (→4-(3-chloro-anilino)-6-bromomethyl-7H-pyrrolo[2,3-d]pyrimidin), 2 ml of methanol are added. The mixture is stirred for 2 h and then 1 ml of sodium methanolate (5.4 M in methanol) is added dropwise. After 18 h, the mixture is concentrated in vacuo; the residue is redissolved in methanol, silica gel is added and the mixture is evaporated to a dry powder. This powder is put on top of a chromatography column (SiO2 ; CH2Cl2 /ethanol [2:1]). Eluation with CH2Cl2 /ethanol [2:1], concentration and washing with ethyl acetate/diethyl ether/hexane affords the title compound; m.p. 226-230° C.; TLC-Rf =0.59 (CH2Cl2 /methanol [10:1]); HPLC: tRet (Grad20)=9.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:16][CH2:17][CH2:18][CH2:19]Br.[CH2:21]([C@:23]1([C:34]([O:36]C)=[O:35])[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([OH:33])=[CH:28][CH:29]=2)[O:24]1)[CH3:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:16][CH2:17][CH2:18][CH2:19][O:33][C:27]1[CH:26]=[C:25]2[C:30]([CH2:31][CH2:32][C@:23]([CH2:21][CH3:22])([C:34]([OH:36])=[O:35])[O:24]2)=[CH:29][CH:28]=1
Reactant: CC[C@]1(C(=O)OC)CCc2ccc(O)cc2O1
Reactant: Fc1ccc(Oc2ccc(OCCCBr)c(Cl)c2)cc1
Product: CC[C@]1(C(=O)O)CCc2ccc(OCCCOc3ccc(Oc4ccc(F)cc4)cc3Cl)cc2O1

Procedure:
The title compound was prepared following the procedures described in Example 1, Steps B-C employing 3-bromopropyl 2-chloro-4-(4-fluorophenoxy)phenyl ether (Example 20, Step A) instead of 4-(3-bromopropoxy)-3-propylphenyl phenyl ether, and (2R)-methyl 2-ethyl-7-hydroxychromane-2-carboxylate (Example 25, Step E) instead of ethyl 7-hydroxychromane-2-carboxylate.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19].Cl>C(OCC)C.O>[CH3:15][O:16][CH2:17][C:18]([NH:1][C@@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:19]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COCC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.7 %

Procedure:
(S)-2-amino-3,3-dimethylbutanoic acid (0.50 g, 3.8 mmol) and sodium bicarbonate (0.80 g, 9.5 mmol) were dissolved into water (20 mL) then cooled in an ice bath. Methoxyacetyl chloride (0.38 mL, 4.2 mmol) was dissolved in diethyl ether (5 mL) and added dropwise with vigorous stirring. The solution was stirred at ambient temperature for 5 hours then adjusted to pH 3 with concentrated hydrochloric acid and extracted into ethyl acetate. The organic solution was dried over sodium sulfate, filtered, and concentrated to give 0.16 g (21%) of the title compound as a waxy solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([C:18]#N)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[O:31]1CCCC1>>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:17])([CH:18]=[O:31])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C#N)O2
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C=O)O2

Procedure:
(±)-6-acetoxy-2-cyano-2,5,7,8-tetramethylchroman was reduced with diisobutylaluminum hydride as described in Example 101, with tetrahydrofuran as reaction solvent. TLC of the crude product indicated that it was partially deacetylated. The material was thus reacetylated by the process described in Example 2 to give (±)-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxaldehyde as a white solid, m.p. 88°-90°, from 30°-60° petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[NH:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)(O)[O-].[Na+].Br[CH2:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[CH2:29][C:30]([OH:35])([C:31]([F:34])([F:33])[F:32])[N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(CBr)C(F)(F)F
Reactant: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1F
Yield: 63.5 %

Procedure:
To a mixture of 3-fluoro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (4.15 g, 12.9 mmol) and sodium bicarbonate (2.16 g, 25.8 mmol) in isopropanol (150 mL), 3-bromo-1,1,1-trifluoroacetone (4.8 mL, 45 mmol) was added. After heating the reaction mixture at 70–75° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.8 g) was purified by chromatography (silica gel, toluene/ethyl acetate, 7/3) to give 2-(3-fluoro-4-methoxyphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (3.54 g, 64%) as a white solid: mp (DSC) 210° C. Anal. Calc'd. for C18H16N2SO4F4.0.1 PhCH3: C, 50.86; H, 3.83; N, 6.34. Found: C, 50.61; H. 3.64; N, 6.16.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:16]([Br:17])=[C:15]([N:18](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:14]3[N:35]=[CH:36][C:37]([C:38]4[CH:39]=[N:40][C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4].CO.[OH-].[Na+].Cl>O>[NH2:18][C:15]1[N:14]2[N:35]=[CH:36][C:37]([C:38]3[CH:39]=[N:40][C:41]4[C:46]([CH:47]=3)=[CH:45][CH:44]=[CH:43][CH:42]=4)=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)[C:16]=1[Br:17]
Reactant: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1c(Br)c(C2CCC(C(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
4-{7-[Bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-6-bromo-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexanecarboxylic acid methyl ester (100 mg, 0.135 mmol) in 2:1 MeOH:H2O (3 mL) was treated with 2N NaOH(aq) (0.5 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with 1N hydrochloride solution (2 ml) at 65° C. for 4 h. The reaction mixture was concentrated and purified by prep-LC to afford the title compound (21.8 mg): LC/MS RT=3.57 min. Mass calculated for, M+H 466.08, observed 466.08.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:12][NH2:13])=[C:7]([Cl:14])[N:6]=1)=[O:4].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18](Cl)[N:17]=1>C(O)CC(C)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:12][NH:13][C:18]2[N:17]=[C:16]([NH2:15])[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=2)=[C:7]([Cl:14])[N:6]=1)=[O:4]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: COC(=O)c1nc(Cl)c(NN)nc1N
Solvent: CC(C)CCO
Product: COC(=O)c1nc(Cl)c(NNc2nc(N)c3cc(OC)c(OC)cc3n2)nc1N
Temperature: 120 °C
Reaction time: 12 h
Yield: 96.2 %

Procedure:
Compound (51) (5 mmol) was added to a solution of 4-amino-2-chloro-6,7-dimethoxy quinazoline (0.96 g, 4 mmol) in isoamyl alcohol (10 mL) at 25° C. The mixture was then stirred at 120° C. for 12 h. After cooling to room temperature, the desired product was filtered and rinsed with acetone to give 1.62 g (96%) of the title compound: TLC (Rf =0.30; 10% CH3OH/CH2Cl2); 1H NMR (DMSO) δ 11.90 (br, 1H), 10.30 (br, 1H), 9.80 (br, 1H), 9.00 (br, 1H), 8.80 (br, 1H), 7.80 (s, 1H), 7.69 (d, 1H, J=2.0), 7.41 (s, 1H), 7.19 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H); HRMS (FAB) m/z 421.1152 (M+H)+ (C16H18N8O4Cl requires 421.1110); Anal. (C16H18N8O4Cl·1/4CH3OH) C, H, N.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[N:17]=[N:18][N:19]([C:21]([CH3:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[N:20]=2)=[CH:6][CH:5]=1.Cl.O>CO>[CH3:29][C:21]([N:19]1[N:18]=[N:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][CH:8]=2)=[N:20]1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: COC(OC)c1ccc(-c2ccccc2-c2nnn(C(C)(C)c3ccccc3)n2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(C=O)cc2)n1
Yield: 97.3 %

Procedure:
A solution of 4-dimethoxymethyl-2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl (2.9 g, 7.0 mmol) and 15 mL of 4M hydrochloric acid in 50 mL of methanol was stirred at room temperature for 18 hours. The mixture was diluted with 200 mL of diethyl acetate and poured into 300 mL of water. The ethyl acetate layer was washed 3 times with water, dried over magnesium sulfate and concentrated giving a white, waxy solid (2.51 g). A portion of the solid (1.53 g) was crystallized from diethyl ether and isolated. Drying gave 2'-[2-(1-methyl-1-phenylethyl)biphenyl-2H-tetrazolebiphenyl-4-carbaldehyde (1.2 g, 3.2 mmol), m.p. 98.5°-97° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C(I)=C(C=CC=1)C(O)=O.FC1C=CC(I)=C(C=1)C(O)=O>>[F:16][C:4]1[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=[CH:2][CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1cccc(F)c1I
Agent: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1cccc(F)c1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 1, substituting for 3-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 7.93 (s, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.63-7.58 (m, 1H), 7.29 (td, J=8.9, 0.9 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH2:17][CH:18](O)[CH3:19]>O1CCCC1>[CH2:18]([C:17]1[C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][C:11]=2[NH:15][CH:16]=1)[CH3:19]
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: CC(O)CCN
Solvent: C1CCOC1
Product: CCc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Temperature: 150 °C
Reaction time: 5 h
Yield: 51.1 %

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (4.0 g), 4-aminobutan-2-ol (2.5 g), molecular sieves 4A (24 g) and tetrahydrofuran (60 ml) was refluxed for 13 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (100 ml). To the solution were 2-bromomesitylene(4.2 g), tetrakistriphenylphosphine palladium (0.6 g) and potassium carbonate (5.9 g), and the mixture was stirred at 150° C. for 5 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 3-ethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (2.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:23][C:25]([CH2:26][OH:27])=[CH:28][N:22]=1)[NH:6]2
Reactant: CN(c1ccc(Cl)c2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(c1ccc(Cl)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 90 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
A mixture of 4-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.51 g), bromomalonaldehyde (0.30 g) and N,N-dimethylacetamide (15 mL) was stirred at 90° C. for 4 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. To a mixture of the obtained crystals, tetrahydrofuran (5 mL) and methanol (5 mL) was added sodium borohydride (55 mg) at 0° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added 10% aqueous citric acid solution, 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 and the title compound (0.30 g, yield 52%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). melting point 225-226° C.
Reaction SMILES: Cl[CH:2]([C:4]1[C:5]([CH3:20])=[N:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:3].[C:21]([O:25][C:26](=[O:40])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]C(=O)C)=[CH:31][C:30]=1[CH3:39])([CH3:24])([CH3:23])[CH3:22].C(OC(=O)COC1C=CC(S)=CC=1C)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.CO>[C:21]([O:25][C:26](=[O:40])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35][CH:2]([C:4]2[C:5]([CH3:20])=[N:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)[CH3:3])=[CH:31][C:30]=1[CH3:39])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Agent: Cc1cc(S)ccc1OCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CO
Product: Cc1cc(SC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)OC(C)(C)C
Yield: 54.1 %

Procedure:
0.224 g (0.75 mmol) of [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine and 0.222 g (0.75 mmol) of (4-acetylsulfanyl-2-methyl-phenoxy)-acetic acid tert-butyl ester (prepared by standard acetylation of (4-mercapto-2-methyl-phenoxy)-acetic acid tert-butyl ester, described below in example 28A)-C]) were dissolved in 3.9 ml of acetonitrile and 0.2 ml of MeOH and treated with 0.292 g (1.2 eq.) of Cs2CO3. The reaction was then allowed to proceed over night. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1), afforded in the less polar fractions 0.210 g of pure title compound and in the more polar fractions 0.112 g of the corresponding methyl ester as waxy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(P(Cl)([Cl:25])=O)C=CC=CC=1>>[Cl:25][C:12]1[C:11]([C:15]#[N:16])=[CH:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: O=P(Cl)(Cl)c1ccccc1
Product: N#Cc1ccc(-c2ccc(Cl)cc2)nc1Cl

Procedure:
6-(4-Chlorophenyl)-3-cyano-2-pyridone (42 grams) and phenylphosphonic dichloride were heated for 2.5 hours at 175°-180° C. taking precautions to keep the reaction dry. Upon cooling, the reaction mixture was poured into 500 ml of ice water and was made slightly alkaline by the addition of concentrated NH4OH. A solid product formed which was thoroughly washed with water and recrystallized from ethanol/DMF, yield 42 grams, m.p. 179°-181° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[Br:23]Br>C1COCC1.CC(OC)(C)C>[Br:23][C:15]1[S:14][C:13]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:2]([F:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCCCCc1ccc(-c2cccs2)cc1F
Reactant: BrBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCCCc1ccc(-c2ccc(Br)s2)cc1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
20.0 g (80.5 mmol) of 2-(3-fluoro-4-pentylphenyl)thiophene are initially introduced in 200 ml of THF, and 50.0 ml of n-BuLi (79.6 mmol, 15% solution in hexane) are added dropwise to the solution at a temperature in the range 0-5° C. After 1 h at 0° C., the batch is cooled to −70° C., and 4.1 ml (80.0 mmol) of bromine are metered in. When the addition is complete, the mixture is stirred at 0° C. for 1 h. The batch is diluted with MTBE and washed successively with 2 N HCl, 10% sodium hydrogensulfite solution, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane). 2-Bromo-5-(3-fluoro-4-pentylphenyl)thiophene is obtained as a yellowish liquid.
Reaction SMILES: [C:1]([C:6]1(C(OCC)=O)[CH2:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]3[O:19][CH2:18][O:17][C:11]=3[CH:12]=2)[CH:7]1[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)([O:3]CC)=[O:2].[OH-].[Na+]>CO.O>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([C@@H:7]2[C:8]3[C:13](=[CH:12][C:11]4[O:17][CH2:18][O:19][C:10]=4[CH:9]=3)[C:14](=[O:16])[CH2:15][C@H:6]2[C:1]([OH:3])=[O:2])[CH:21]=[C:22]([O:30][CH3:31])[C:23]=1[O:28][CH3:29]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)c2cc3c(cc2C1c1cc(OC)c(OC)c(OC)c1)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc([C@@H]2c3cc4c(cc3C(=O)C[C@H]2C(=O)O)OCO4)cc(OC)c1OC
Temperature: 110 °C
Yield: 66.7 %

Procedure:
2,2-Dicarbethoxy-1-(3',4',5'-trimethoxyphenyl)-6,7-methylenedioxy-4-tetralone (XV; R2 = ethyl) (45 mg) was suspended in 10 ml of methanol. Aqueous NaOH (10 ml of 5%) was added and the mixture was refluxed for 3.5 hr. Then the mixture was cooled, diluted with water and washed one time with ether. The base layer was acidified to pH 2 with dilute sulfuric acid and extracted four times with chloroform. The organic layer was washed twice with water and once with saturated brine, and was dried over sodium sulfate. Filtration and evaporation gave a white solid which was heated briefly at 110° C. under nitrogen. Recrystallization of the white solid from methanol gave 24 mg (66%) of the title product, m.p. 221°-223° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1.O>CN(C=O)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[CH:18][N:17]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: COc1ccc(N)cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)N=C2NC(=O)CN2C)cn1

Procedure:
A mixture of 2.33 g (10.0 mM) of phenyl carbamate 8 and 1.24 g. (10.0 mM) of 5-amino-2-methoxypyridine in 9 ml of anhydrous DMF was heated at 70° C. for 6 hrs., cooled, and poured into 40 ml of water. On cooling in ice, crystals precipitated from the aqueous solution and these were collected and recrystallized from methanol to give 0.5 g of the above urea as pale yellow needles, m.p. 175°-176° C.