Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(C)[CH:26]=CC(S(Cl)(=O)=O)=C[CH:22]=1.COC(OC)(C)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[O:12][C:21]([CH3:26])([CH3:22])[O:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(COCc1ccccc1)C(O)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: CC1(C)OC(COCc2ccccc2)C(c2ccccc2Cl)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8262.7 %

Procedure:
To a solution of (±)-3-(benzyloxy)-1-(2-chlorophenyl)propane-1,2-diol (Preparation example 370, 2.4 g, 8.2 mmole) in CH2Cl2 (40 mL) was added p-toluenesulfonyl chloride (15.2 g, 0.08 mmole), and dimethoxypropan (8.4 mL, 9.84 mmole) at 0° C. sequently. The mixture was stirred for 1.5 hr at room temperature. The TLC showed complete consumption of SM. The reaction mixture was quenched with H2O then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H2O, then dried over MgSO4 and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (2.2 g, 75˜90%).
Reaction SMILES: C[CH:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:3]1S.[CH3:21][O-:22].[Na+].C(N(CC)CC)C>CO>[CH3:21][O:22][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:3]=1
Reactant: C[O-]
Reactant: CCNC1=NC(C)N(S)C(NC(CC)CC)=C1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCNc1nc(OC)nc(NC(CC)CC)c1[N+](=O)[O-]
Yield: 74.5 %

Procedure:
30 g (0.1 mol) of 2-methyl-mercapto-4-ethylamino-5-nitro-6-(3-pentyl-amino)-pyrimidine are dissolved in 400 ml of methanol. A solution of 8.1 g (0.15 mol) of sodium methylate in 100 ml of methanol is added together with 20 ml of triethylamine to the previously prepared solution. The mixture is refluxed for 16 hours, evaporated, and the residue is treated with 200 ml of water. After extracting 3 times with ether, the extracts are dried over MgSO4, dried, filtered, and the ethereal solution is evaporated, to leave as residue 21.1 g of 2-methyoxy-4-ethylamino-5-nitro-6-(3-pentylamino)-pyrimidine with a boiling point of 162° C/0.001 Torr (74.5% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.Cl>CC(O)C>[ClH:11].[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc2c(c1)NCC2
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(C)cc43)c2cc1OC
Yield: 88 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 88% yield from 6-methyl-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The HCl salt was generated from the purified free base according to the procedure given in Example 2 (M.P. 231°-232° C.; LC-MS: 322 (MH+); anal. RP18-HPLC RT: 4.32 min.).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:22][CH:23]([SH:26])[CH2:24][CH3:25].O>C(#N)C>[CH3:22][CH:23]([S:26][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH2:24][CH3:25]
Reactant: CCC(C)S
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCC(C)Sc1cc(C(F)(F)F)ccc1C#N
Yield: 74.9 %

Procedure:
2-Nitro-4-trifluoromethylbenzonitrile (10.8 g) and potassium carbonate (8.3 g) were heated to reflux in acetonitrile. A solution of 1-methylpropanethiol (5 g) in acetonitrile was added. The resultant suspension was heated at reflux for 4.5 hours. After cooling water was added and the mixture extracted with ethyl acetate. The organic extracts were washed with water. The organic extracts were washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue purified by column chromatography eluting with ethyl acetate in cyclohexane to give 2-(1-methylpropylsulphenyl)-4-trifluoromethylbenzonitrile (9.7 g) as a yellow oil, NMR (CDCl3) 1.0(t,3H), 1.2(d,3H), 1.5(m,2H), 3.4(m,1H), 7.3(m,1H), 7.6(m,2H).
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[CH2:6]([O:13][C:14]([NH:16][C@@H:17]([CH2:21][C:22]([F:31])([F:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]([OH:20])=[O:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[CH2:6]([O:13][C:14]([NH:16][C@@H:17]([CH2:21][C:22]([F:30])([F:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]([O:20][CH3:1])=[O:19])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(N[C@@H](CC(F)(F)Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trimethylsilyl chloride (0.61 g, 5.61 mmol, 2 eq) was added dropwise to a solution of (S)-2-benzyloxycarbonylamino-4,4-difluoro-5-phenylpentanoic acid (1.02 g, 2.81 mmol) in 40 ml of methanol. After the addition had ended, the mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the residue was used crude in the reaction which followed.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][CH:14]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: Cc1ccccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Agent: Cl
Product: Cc1ccccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Yield: 28 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2-methylbenzyl)pyrrolidine-2-carboxamide, gave Compound 55, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2-methylbenzyl)pyrrolidine-2-carboxamide (36 mg, 28%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.55 (d, 2H), 7.26-7.08 (m, 6H), 7.05-6.91 (m, 4H), 5.24 (q, 2H), 4.56-4.49 (m, 1H), 3.88-3.80 (m, 1H), 2.82-2.64 (m, 3H), 2.30 (s, 3H), 2.28-1.89 (m, 2H). MS (EI) for C29H28FN5O3. found 514.0 (MH+).
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[I:12][C:13]1[CH:14]=C2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=C2O>ClCCCl>[Cl:11][C:6]1[C:7]2[C:20](=[CH:21][CH:22]=[C:13]([I:12])[CH:14]=2)[N:19]=[CH:18][N:17]=1
Reactant: Oc1ncnc2ccc(I)cc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.4 %

Procedure:
To a stirred solution of anhydrous dimethyl foramide (DMF) (3.20 ml) in 1,2-dichloroethane (DCE) (10 ml), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (5.2 ml, 60 mmol) in DCE (25 ml). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 minutes. 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice-water mixture (approximately 300 ml) and extracted with DCM (approximately 500 ml). The aqueous layer is further extracted with DCM (2×50 ml). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 5.2 g (99%) of desired product as a tan solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[CH:9]=[O:10])=[CH:3][CH:2]=1.[CH:11]([O:13][CH2:14][CH3:15])=[CH2:12]>>[CH2:11]([O:13][CH:14]1[CH2:15][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:8]=[CH:9][O:10]1)[CH3:12]
Reactant: C=COCC
Reactant: O=C/C=C/c1ccccc1
Product: CCOC1CC(c2ccccc2)C=CO1

Procedure:
treating cinnamic aldehyde with ethyl vinyl ether to afford 2-ethoxy-4-phenyl-3,4-dihydro-2H-pyran, hydrogenating the resulting product to afford 3-cyclohexylpentane-1,5-diol and finally heating the above diol in the presence of a dehydrogenation catalyst to afford 3-cyclohexyl-pentanolide; or
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[O:8]=[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25]1>>[O:8]=[C:9]1[N:18]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7])[C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([O:30][CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][CH2:25]1
Reactant: O=c1[nH]c(=O)n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Reactant: N#CCCCCBr
Product: N#CCCCCn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Yield: 66.3 %

Procedure:
Using the method similar to that in Example 61 and 5-bromovaleronitrile (1.09 ml, 9.31 mmol) instead of benzyl bromide and starting from 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline (3.00 g, 6.20 mmol) obtained in Example 2, a free salt of the title compound (2.32 g, 66%) was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[O:5][C:6]1[C:7]2[CH:25]=[CH:24][N:23](CO)[C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:17]=2)[N:11]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[O:5][C:6]1[C:7]2[CH:25]=[CH:24][NH:23][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH:17]=2)[N:11]=1
Reactant: CN(C)CCn1cc(Nc2nc(Oc3cccc(N)c3)c3ccn(CO)c3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)CCn1cc(Nc2nc(Oc3cccc(N)c3)c3cc[nH]c3n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(3-aminophenoxy)-2-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methanol in MeOH (10 mL) and water (2 mL) was added K2CO3 until the pH of the reaction mixture was about 12. The reaction mixture was then stirred at rt for 2 hrs. Water was added and extracted with EtOAc (three×20 mL), dried with MgSO4, filtered and stripped to a dark oil to give the title compound as a dark oil that was taken on to the next step with no purification. m/z (ESI+) for C19H22N8O 379.15 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CO.[Pd]>[O:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CN2CCC(Oc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(OC2CCNCC2)cc1
Reaction time: 20 h

Procedure:
A mixture of 1-benzyl-4-phenoxy-piperidine (420 mg, 1.6 mmol), Pd—C 10% (10 mg) and TFA (0.18 mL, 1,6 mmol) in MeOH (5 mL) is hydrogenated at room temperature and atmospheric pressure for 20 h. The mixture is filtered over Celite and the filtrate is concentrated under reduced pressure. The residue is dissolved in CH2Cl2, washed with sat. NaHCO3, filtered and concentrated to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4N=N[NH:25][N:26]=4)[CH:17]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>N1C=CC=CC=1>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:36][C:35]([C:34]5[CH:38]=[CH:39][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=5)=[N:25][N:26]=4)[CH:17]=3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2-c1cccc(-c2nn[nH]n2)c1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(-c2nnc(-c3cccc(-n4c5ccc(Br)cc5c5cc(Br)ccc54)c3)o2)cc1
Yield: 69.1 %

Procedure:
In a 50 ml two-neck flask, 2.5 g (5.33 mmol) of 3,6-dibromo-9-(3-2H-tetraazol-5-yl-phenyl)-9H-carbazole, 4.19 ml (21.45 mmol) of 4-tert-butylbenzoyl chloride, 3.5 ml of pyridine, and a stir bar were added. After the reaction was carried out with reflux under a nitrogen atmosphere for 8 hours, an extraction was conducted. The crude product was purified by column chromatography to obtain a white solid product of 3,6-dibromo-9-(3-(5-(4-tert-butyl-phenyl)-1,3,4-oxadiazol-2-yl)phenyl)-9H-carbazole (yield: 69.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[C:27]([CH2:26][CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[CH:28]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN1CCN(CCc2cccc(N)c2)CC1
Product: CN1CCN(CCc2cccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)c2)CC1
Yield: 55.8 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (240 mg, 0.77 mmol) was reacted with 3-(2-(4-methylpiperazin-1-yl)ethyl)aniline (170 mg, 0.77 mmol) to afford the desired product (212 mg, 55%) as a yellow solid: ESI MS m/z 493 [C26H29BrN4O+H]+.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8](S(C)(=O)=O)[C:7]1=[O:17])[CH2:4][CH3:5])[CH3:2].Cl.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([CH3:30])[CH:29]=1)[NH:26][CH2:25][CH2:24]2>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([CH3:30])[CH:29]=1)[N:26]([C:8]1[C:7](=[O:17])[N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH:11]=[C:10]([CH3:12])[N:9]=1)[CH2:25][CH2:24]2
Reactant: CCC(CC)n1cc(C)nc(S(C)(=O)=O)c1=O
Reactant: COc1cc(C)c2c(c1)CCN2
Agent: Cl
Product: CCC(CC)n1cc(C)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Example 481 was prepared in a similar fashion as described for Example 413 using XXXIII and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 138–140° C.; 1H NMR (300 MHz, CDCl3): δ 6.68 (d, J=2.2 Hz, 1 H), 6.56 (d, J=2.2 Hz, 1 H), 6.44 (s, 1 H), 4.90–4.79 (brs, 1 H), 4.34 (t, J=7.9 Hz, 2 H), 3.78 (s, 3 H), 3.05 (t, J=7.9 Hz, 2 H), 2.11 (s, 3 H), 2.00 (s, 3 H), 1.82–1.71 (m, 2 H), 1.67–1.60 (m, 2 H), 0.87 (t, J=7.4 Hz, 6 H); HRMS (ESI) calcd for C20H28N3O2 (M+H)+: 342.2182; found m/z 342.2196.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(Cl)(=O)C([Cl:16])=O.CCCCCC>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]([Cl:16])=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2[nH]ccc12
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(Cl)c1cccc2[nH]ccc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
32.2 g (0.2 M) dry indol-4-yl carboxylic acid are suspended in 150 ml absolute methylene chloride, 26 ml (0.3 M) oxalyl chloride are added to the stirred mixture at 20° over 30 minutes. Gas evolution results. The mixture is stirred for 31/2 hours at 20° C. 150 ml Hexane are added. The mixture is stirred for another 20 minutes and the resultant heading compound filtered off, washed with methylene chloride/hexane 1:1 dried at 20° in a vacuum to give beige crystals, which are used further without purification.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[C:8]([C:10]1[C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:9].[F:28][C:29]([F:66])([F:65])[C:30]1[CH:31]=[C:32]([CH:58]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:60]=1)[CH2:33][N:34]1[C:38]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[C:37]([Sn](CCCC)(CCCC)CCCC)[N:36]=[N:35]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:64][C:61]([F:62])([F:63])[C:59]1[CH:58]=[C:32]([CH:31]=[C:30]([C:29]([F:28])([F:65])[F:66])[CH:60]=1)[CH2:33][N:34]1[C:38]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[C:37]([C:15]2[C:10]([C:8]([C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[Cl:5])=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=2)[N:36]=[N:35]1
Reactant: O=C(c1ccccc1Cl)c1ncccc1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1Cl)c1ncccc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 120 °C
Yield: 10.8 %

Procedure:
Add Pd2(dba)3.CHCl3 (42 mg, 0.04 mmol) to a degassed solution of trifluoro-methanesulfonic acid 2-(2-chloro-benzoyl)-pyridin-3-yl ester (149 mg, 0.41 mmol) and 4-[3-(3,5-bis-trifluoromethyl-benzyl)-5-tributylstannanyl-3H-[1,2,3]triazol-4-yl]-pyridine (296 mg, 0.45 mmol) in toluene (2 mL). Seal the mixture under N2 and heat at 120° C. for 2 hours. Add Pd(PPh3)4 (94 mg, 0.08 mmol), seal and heat at 120° C. for another 48 hours. Concentrate, dissolve in ACN, wash with hexanes (×3), dry over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-10% ACN/Et2O to afford the title compound (26 mg, 11%) as tan solid. MS(IS) 588 (M+1). TLC: Rf=0.33 (10% ACN/Et2O).
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17](C)([C:23]([O-])=O)[C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=1)=[O:10]>[OH-].[Na+].C(O)C.O>[S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)C(C)(C(=O)[O-])c1ccc(C(=O)c2cc3ccsc3s2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(C(=O)c2cc3ccsc3s2)cc1
Yield: 74.7 %

Procedure:
Ethyl 2-{4-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}-2-methyl-malonate (16.23 g) is suspended in a mixture of 5% (w/v) aqueous sodium hydroxide solution (90 cc) and ethanol (90 cc), and the suspension is heated at the boiling point for 3 hours. After cooling, the reaction mixture is diluted with distilled water (1000 cc), and then extracted three times with diethyl ether (total 600 cc). The aqueous phase is filtered off, acidified to pH 1 by the addition of a 5N aqueous hydrochloric acid solution and extracted three times with diethyl ether (total 600 cc). The combined ether solutions are washed three times with distilled water (total 300 cc), dried over anhydrous sodium sulphate, decolourizing charcoal (1 g) is added, and the solutions are filtered and evaporated. Crude 2-{4-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (9.9 g), melting at 150° C., is thus obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][C:21]=1B(O)O.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH:26]=[O:27])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC)cc21
Temperature: 80 °C
Yield: 98.8 %

Procedure:
A round bottom flask was charged with 6.0 g of Compound 1A (20.3 mmol), 5.5 g of 2-methoxy-5-formylphenylboronic acid (30.4 mmol) and tetrakis(triphenylphosphine)palladium(0), (1.17 g, 0.10 mmol). The flask was sealed and 100 mL of toluene and 30 mL of ethanol was added. The resulting solution was stirred to dissolve the reactants and then 21 mL of 2M K2CO3 was added via syringe. The reaction mixture was heated to 80° C. for 4 hours. After cooling, the reaction mixture was partitioned between ethyl acetate (200 mL) and water (75 mL). The water layer was further extracted (2×100 mL) and the combined organic layers were washed with water (50 mL) followed by brine (50 mL), dried over magnesium sulfate, filtered and excess solvent removed on the rotary evaporator. The crude product was purified by flash chromatography (EtOAc/Hexanes; gradient 20% to 40%) to give 7.05 g (99%) of product Compound 1B as a foamy solid. MS (electrospray): mass calculated for C22H25NO3, 351.18; m/z found 352.4, [M+H]+. 1HNMR (300 MHz, CDCl3): 9.94 (s, 1H), 7.93 (dd, J=2.1, 8.6 Hz, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.85 (s, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.90 (s, 3H), 2.52 (s, 2H), 2.10 (s, 3H), 1.33 (s, 6H), 1.23 (t, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[Cl:14][C:15]1[C:16]([O:25][CH3:26])=[C:17]([C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH:18]=O>>[Cl:14][CH:15]1[CH2:22][CH:18]([C:17]2[C:20]([O:23][CH3:24])=[CH:21][CH:22]=[C:15]([Cl:14])[C:16]=2[O:25][CH3:26])[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=2)[C:16]1=[O:25]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(Cl)c(OC)c1C=O
Product: COc1ccc(Cl)c(OC)c1C1CC(Cl)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10D (GP10D) using commercially available (4-(trifluoromethoxy)phenyl)methanamine and synthesized 3-chloro-2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 463.84 g/mol.