Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].[Cl:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17](Cl)=[O:18])(=[O:14])=[O:13].N1C=CC=CC=1>O1CCCC1>[C:1]([O:5][CH2:6][CH2:7][O:8][C:17](=[O:18])[CH2:16][CH2:15][S:12]([CH2:11][CH2:10][Cl:9])(=[O:14])=[O:13])(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCS(=O)(=O)CCCl
Reactant: C=CC(=O)OCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCOC(=O)CCS(=O)(=O)CCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Into a mixture of 600 ml. of tetrahydrofuran, 45.8 g. of hydroxyethyl acrylate, and 72 g. of 3-(2-chloroethylsulfonyl)propionyl chloride placed in a reaction vessel chilled with ice-water to maintain the temperature below 5° C., a solution of 31.2 g. of pyridine in 100 ml. of tetrahydrofuran was poured dropwise for 1.75 hours. The resulting mixture was stirred at room temperature for 2 hours, and poured into 2.5 l. of ice-water. The aqueous mixture was then extracted with 4 portions of 300 ml. of chloroform. The organic extract was dried over sodium sulfate, and concentrated to give 87 g. of 2-[3-(2-chloroethylsulfonyl)propionyloxy]ethyl acrylate (yield 88%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:32]>O1CCOCC1.CCOCC>[ClH:32].[ClH:32].[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)nc2)cc1
Yield: 94 %

Procedure:
5-[4-(Methylsulfonyl)phenyl]-2-[(4-piperidinylmethyl)oxy]pyridine dihydrochloride (0.32 g, 94%) was prepared as a light yellow solid from 1,1-dimethylethyl 4-[({5-[4-(methylsulfonyl)phenyl]-2-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (Example 70, 0.36 g, 0.81 mmol), 1,4-dioxane (16 mL), ether (12 mL), 4.0M HCl in 1,4-dioxane (12 mL) and 2M HCl in ether (12 mL) in a manner similar to Example 66, Step 1. 1H NMR (400 MHz, CD3OD): δ 8.48 (d, 1H, J=2.5 Hz), 8.06 (dd, 1H, Ja=8.6 Hz, Jb=2.5 Hz), 8.03 (d, 2H, J=8.5 Hz), 7.86 (d, 2H, J=8.4 Hz), 6.94 (d, 1H, J=8.6 Hz), 4.28 (d, 2H, J=6.1 Hz), 3.50-3.40 (m, 2H), 3.14 (s, 3H), 3.10-3.00 (m, 2H), 2.30-2.15 (m, 1H), 2.15-2.05 (m, 2H), 1.70-1.55 (m, 2H); LRMS (ESI), m/z 347 (M+H).
Reaction SMILES: N#N.[F:3][C:4]1[C:5]([NH:22][C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:35])[CH:31]([OH:34])[CH2:32][OH:33])[CH:26]=[CH:27][CH:28]=2)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)=[N:8][CH:9]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1.C(OCC)(=O)C>[CH3:36][S:37]([O:33][CH2:32][CH:31]([OH:34])[C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:5]2[C:4]([F:3])=[CH:9][N:8]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=3)[N:6]=2)[CH:24]=1)=[O:35])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C(O)CO)c3)n2)cc1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C(O)COS(C)(=O)=O)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
In a 25 mL 3-neck RBF equipped with N2-bubbler and thermo-pocket, N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-2,3-dihydroxypropanamide (I-4) (0.08 g) was dissolved in THF (5 mL), TEA (0.0212 g) was added at room temperature. The reaction mixture was cooled to 0° C. Methane sulphonyl chloride (0.021 g) was slowly added at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored on TLC by using ethyl acetate (100%) as mobile phase. (Only 50% of the reaction was complete on TLC). The reaction was diluted with ethyl acetate (20 mL), washed with saturated NaHCO3 (25 mL). The organic layer was separated and dried over sodium sulfate. Ethyl acetate was removed under reduced pressure at 40° C. Crude material was purified by Combiflash chromatography eluted with 7% ethyl acetate in hexane. The solvent was removed under vacuum to give 0.03 g of 3-((3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)amino)-2-hydroxy-3-oxopropyl methanesulfonate.
Reaction SMILES: NC1N=C(C)C2C(=NO)CC(C3C=CC=CC=3C3C=CC=CC=3)CC=2N=1.[H-].[Na+].[CH3:29][N:30]([CH3:61])[CH2:31][CH2:32][CH2:33][O:34][N:35]=[C:36]1[CH2:45][CH:44]([C:46]2[CH:51]=[C:50](F)[CH:49]=[CH:48][C:47]=2[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:43][C:42]2[N:41]=[C:40]([NH2:59])[N:39]=[C:38]([CH3:60])[C:37]1=2>>[CH3:61][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][O:34][N:35]=[C:36]1[CH2:45][CH:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:43][C:42]2[N:41]=[C:40]([NH2:59])[N:39]=[C:38]([CH3:60])[C:37]1=2
Reactant: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1ccccc1-c1ccccc1)C2

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (30 mg, 0.087 mmol), 3-dimethyl-aminopropyl chloride hydrochloride (16 mg, 0.105 μmol) and sodium hydride (60% dispersion in oil) (11 mg, 0.278 mmol), following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[O:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccsc1C(N)=O
Product: Cc1ccsc1-c1nc(CCl)co1
Yield: 61 %

Procedure:
In substantially the same manner as in Reference Example 47, 3-methyl-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3-methyl-2-thienyl)oxazole. The yield was 61%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 95-96° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=2)[C:6](=O)[CH:7]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:6]1[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(=O)n2nc(-c3ccccc3)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
5-Methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (210 mg, 0.932 mmol) is heated in phosphoryl chloride (1.74 mL, 18.6 mmol) in a sealed vial at 100° C. for 2 hr. The reaction mixture is cooled to room temperature and slowly poured over ice. The resulting suspension is extracted with dichloromethane and washed with brine. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The crude material is purification by column chromatography (eluent 0-100% ethyl acetate:hexanes) to provide 7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine (123 mg, yield 54%). LCMS: (AA) M+1 244; 1H NMR (400 MHz, DMSO) δ 8.07-8.02 (m, 2H), 7.53-7.47 (m, 2H), 7.46-7.41 (m, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 2.53 (s, 3H).
Reaction SMILES: [N+:1](C1C=CC2C(C(O)=O)=CSC=2C=1)([O-])=O.[N+:16]([C:19]1[CH:30]=[CH:29][C:22]2[S:23][CH:24]=[C:25]([C:26](O)=[O:27])[C:21]=2[CH:20]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:30]=[CH:29][C:22]2[S:23][CH:24]=[C:25]([C:26]([NH2:1])=[O:27])[C:21]=2[CH:20]=1)([O-:18])=[O:17]
Reactant: O=C(O)c1csc2ccc([N+](=O)[O-])cc12
Reactant: O=C(O)c1csc2cc([N+](=O)[O-])ccc12
Product: NC(=O)c1csc2ccc([N+](=O)[O-])cc12

Procedure:
are obtained as a mixture during the reaction of a mixture of 6-nitro-benzo[b]-thiophene-3-carboxylic acid and 5-nitro-benzo[b]thiophene-3-carboxylic acid (Example XLV). The crude product is chromatographed on silica gel, while the two products are obtained as a mixture and further reacted directly in Example XII (30).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.S(Cl)(Cl)=O.Cl.[CH3:28][O:29][C:30]([C:32]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31].C(=O)([O-])O.[Na+]>CC(=O)OCC>[CH3:28][O:29][C:30]([C:32]1([NH:39][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:10][CH2:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[F:1])[CH:13]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)=[O:31]
Reactant: COC(=O)C1(N)CCCCCC1
Reactant: COc1ccc(C(=O)O)cc1OCCc1cc(C)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cc(C)ccc3F)c2)CCCCCC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 37.3 %

Procedure:
The compound of step 2 (285 mg, 0.937 mmol) was dissolved in an excess of thionyl chloride (0.7 ml) and stirred for 20 min at 60° C. The solution was evaporated to dryness in vacuo. The residue was dissolved in a little DCM and added to a well-stirred mixture of 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (195 mg, 0.937 mmol), EA and an excess of a saturated aqueous sodium hydrogencarbonate solution. The mixture was stirred for 30 min at room temperature. The layers were separated, the aqueous phase was extracted with EA, the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. This residue was purified by preparative RP HPLC (water/ACN gradient) to give 160 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH2:20])=[O:19])=[CH:13][CH:12]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1.[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1.C1(C)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]2[N:6]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][C:18]([NH:20][C:34]([NH:33][S:30]([C:27]4[CH:28]=[CH:29][C:24]([CH3:36])=[CH:25][CH:26]=4)(=[O:32])=[O:31])=[O:35])=[O:19])=[CH:15][CH:16]=3)[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CC(N)=O)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CC(=O)NC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 6 h
Yield: 91.7 %

Procedure:
A mixture of 2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]acetamide (step 5, 105 mg, 0.30 mmol), p-toluenesulfonyl isocyanate (0.07 mL, 0.45 mmol), toluene (10 mL) and THF (5 mL) was heated at reflux temperature. After 6 h, an additional 0.1 mL of p-toluenesulfonyl isocyanate was added and the mixture was heated for 3 h. The mixture was cooled and left at room temperature for 2 days. The mixture was concentrated and the residue was purified by preparative TLC (ethyl acetate) to afford 150 mg (92%) of the title compound as colorless amorphous solids: 1H-NMR (CDCl3) δ 9.78 (1H, s), 7.95 (2H, d, J=8.3 Hz), 7.84 (1H, s), 7.54 (2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.0 Hz), 7.32 (2H, d, J=8.4 Hz), 7.18 (1H, s), 3.78 (2H, s), 2.77 (2H, q, J=7.5 Hz), 2.41 (3H, s), 1.35 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]1([CH2:20][CH2:21][C:22](O)=O)[CH2:19]CCCC1>>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH:19]2[CH2:14][CH2:20][CH2:21][CH2:22]2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCCC1CCCCC1
Reactant: O=C(O)CCC1CCCCC1
Product: O=C(CCCCC1CCCCC1)C1CCCC1

Procedure:
The title compound was prepared analogously to Example A(44), where cyclohexanepentanoic acid was substituted in place of 3-cyclohexylpropionic acid in Step 1 of that example.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([Cl:19])=[N:16]3)=[CH:11][CH:10]=2)[C:4]1=[O:20].[S:21]1[C:25]([S:26](Cl)(=[O:28])=[O:27])=[CH:24][C:23]2[CH:30]=[CH:31][CH:32]=[CH:33][C:22]1=2.COC1C=C2C(C=CC(S(Cl)(=O)=O)=C2)=CC=1>C(Cl)(Cl)Cl>[Cl:19][C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:26]([C:25]4[S:21][C:22]5[CH:33]=[CH:32][CH:31]=[CH:30][C:23]=5[CH:24]=4)(=[O:27])=[O:28])[C:4]3=[O:20])=[CH:10][CH:11]=2)[N:16]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: N[C@H]1CCN(Cc2ccc3ccc(Cl)nc3c2)C1=O
Agent: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccccc3s2)CCN1Cc1ccc2ccc(Cl)nc2c1

Procedure:
The title compound is prepared in CHCl3 instead of CH3CN from 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline hydrochloride as described in EXAMPLE 1, Part K using benzo[b]thiophene-2-sulfonyl chloride as prepared in EXAMPLE 8, Part A in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is triturated from CH2Cl2 to afford the title compound as a beige solid.
Reaction SMILES: [C:1]1([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH3:19].[H-].[Na+].O>CN(C)C=O.CCOCC>[CH3:19][O:17][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1
Reactant: OC1(c2ccccc2)CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 7.5 h

Procedure:
To a solution of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-ol (5.76 g) and iodomethane (4.59 ml) in N,N-dimethylformamide (58 ml) was added sodium hydride (60% dispersion in mineral oil) (1.97 g) at 0° C. The solution was stirred for 2 hours at 0° C. and at room temperature for 7.5 hours. The reaction mixture was added to a mixture of water and ether. The organic layer was washed with brine and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (5:1 hexane-ethyl acetate elution) to give 8-methoxy-8-phenyl-1,4-dioxaspiro[4.5]decane (5.968 g).
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([F:25])[C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)C.C1(C)C=CC=CC=1.O>[CH3:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([F:25])[C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Separately, two drops of carbon tetrachloride are added to a solution of metallic magnesium (0.4 g) in absolute ethanol (0.9 ml). When the reaction starts, a mixture of diethyl malonate (2.6 ml), absolute ethanol (1.6 ml) and anhydrous toluene (6 ml) is added dropwise below 60° C. After stirring at 60° C. for 1 hour, the reaction mixture is cooled to 0° C. and thereto a solution of 2-methyl-3,4,6-trifluorobenzoyl chloride prepared above in toluene (5 ml) is added dropwise. After stirring for 30 minutes, a mixture of conc. sulfuric acid (0.4 ml) and water (6 ml) is added and the mixture is extracted with diethyl ether, and the extract is dried over magnesium sulfate and concentrated to give diethyl 2-methyl-3,4,6-trifluorobenzoylmalonate (5.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-])=O)=[C:16]([CH3:17])[C:11]=2[N:10]=[C:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]([CH3:21])=[N:10][C:11]=2[C:16]=1[CH3:17]
Reactant: Cc1c([N+](=O)[O-])ccc2c1nc(C)n2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(N)ccc2c1nc(C)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-t-butoxycarbonyl-2,4-dimethyl-5-nitrobenzimidazole (1.26 g, 4.32 mmol) in methanol (15 mL)/ethyl acetate (100 mL) are added 10% palladium-on-carbon (0.1 g) and ammonium formate (1.09 g, 17.3 mmol). The mixture is stirred at room temperature for 3 hours, then filtered on Celite with a methanol wash of the solids. The filtrate is rotary evaporated and the residue is purified by flash chromatography on silica gel, eluting with 20% ethyl acetate in hexane to afford 5-amino-1-t-butoxycarbonyl-2,4-dimethylbenzimidazole as a white solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:11](I)([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)([CH3:13])[CH3:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)N1CCCc2ccccc21
Temperature: 60 °C
Yield: 72.1 %

Procedure:
In 60 ml of N,N-dimethylformamide were dissolved 13.8 g of 1,2,3,4-tetrahydroquinoline. To the resulting solution were added 21.1 g of isopropyl iodide and 20.6 g of potassium carbonate, followed by stirring under heat at 60° C. for 5 hours. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 3% ethyl acetate/n-hexane), whereby 13.1 g of the title compound were obtained in the form of a colorless oil.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([OH:8])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:24]([NH2:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>ClCCl>[C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([NH:32][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:8])(=[O:3])[CH3:2]
Reactant: CCCCCCCCN
Reactant: CSCCC(OC(C)=O)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)C(CCSC)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-acetoxy-4-(methylthio)butanoic acid (6.10 g, 31.7 mmol) in dichloromethane (100 mL) at 0° C. was added thionyl chloride (11.53 mL, 158.5 mmol) slowly over 30 min. The reaction was allowed to warm to room temperature with stirring overnight. The solvent was evaporated and the resulting oil was dried on the high vacuum for 3 hrs. To a solution of the resulting oil in dichloromethane (100 mL) at 0° C. was added triethylamine (8.84 mL, 63.4 mmol) and then octylamine (5.24 mL, 31.7 mmol) and the reaction was allowed to warm to room temperature with stirring overnight. The reaction was evaporated, redissolved in EtOAc (150 mL) and washed with 1N HCl (3×100 mL), saturated sodium bicarbonate (3×100 mL), and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography with 0-30% EtOAc/heptane to give a yellow oil. (6.61 g, 69%). m/z 304 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)[C:19]([OH:21])=[O:20])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1cc(C)cc(C=C(C(=O)O)c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
To a mixture of 43 (3.23 g, 24 mmol), 4-hydroxyphenylacetic acid (3.66 g, 24 mmol) and potassium acetate (2.83 g, 28 mmol) was added acetic anhydride (100 mL). The mixture was heated to reflux for 4 h, cooled to room temperature, and then poured over water (400 mL). After stirring for 1.5 h, a solid gum settled to the bottom and the supernatant was decanted. To the residue was added THF (100 mL) and 1N NaOH (150 mL) and the mixture was stirred for 30 min. The mixture was acidified with 1N HCl (200 mL) and the product was extracted into ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude solid was crystallized in toluene to yield 2.65 g (42%) of a pale yellow solid 44.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[H+].[B-](F)(F)(F)F.N([O-])=O.[Na+].[CH2:22]([O:24][P:25]([CH:30]=[CH2:31])(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]>O.CC([O-])=O.CC([O-])=O.[Pd+2].CO>[CH2:22]([O:24][P:25](/[CH:30]=[CH:31]/[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]
Reactant: Cc1cc(N)cc(C)c1C=O
Reactant: C=CP(=O)(OCC)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Product: CCOP(=O)(/C=C/c1cc(C)c(C=O)c(C)c1)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Amino-2,6-dimethylbenzaldehyde (149 mg, 1.0 mmol)) was taken up in enough 42% HBF4 until the suspension stirred well and then was cooled to 0° C. To this was added a solution of NaNO2 (69 mg, 1.0 mmol) in water (0.5 mL) slowly. After 30 minutes at 0° C., MeOH (3 mL) was added and followed by Pd(OAc)2 (7.5 mg) and vinylphosphonic acid diethyl ester (197 mg, 1.2 mmol). The reaction mixture was heated at 80° C. for 30 min and the suspension was filtered through Celite, washed with CH2Cl2, and the filtrate was extracted with CH2Cl2. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (4:1 then followed by 100% EtOAc) to give [(E)-2-(4-formyl-3,5-dimethylphenyl)-vinyl]-phosphonic acid diethyl ester as a colorless oil.
Reaction SMILES: I[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:10]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=4)[N:23]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:22]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:17][CH:16]=2)[CH2:12][CH2:11]1>CN(C=O)C.C(OCC)(=O)C>[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:2][CH3:3])[CH:28]=4)[N:23]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:22]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:19][CH:20]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(O)ccc2n1Cc1cccc(OC)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(OCC3CC3)cc2)c2cc(OCC)ccc2n1Cc1cccc(OC)c1
Temperature: 50 °C
Yield: 41.6 %

Procedure:
Iodoethane (468 mg, 3.0 mmol) and powdered potassium carbonate (138 mg, 1.0 mmol) was added to a solution of ethyl 3-[4-(cyclopropylmethoxy)phenyl]-5-hydroxy-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 66, 120 mg, 0.25 mmol) in DMF (5 mL). The mixture was heated (50° C.) for 16 h and then cooled. The resulting mixture was diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC using 4:1 ethyl acetate/hexane as the eluant, to afford 52 mg (42%) of the desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.42 (d, 1 H), 7.37 (d, 2 H), 7.19 (t, 1 H), 6.92-7.01 (m 4 H), 6.74-6.77 (m, 1 H), 6.64-6.68 (m, 2 H), 5.80 (s, 2 H), 4.13 (q, 2 H), 3.88-3.98 (m, 4 H), 3.69 (s, 3 H), 1.34-1.45 (m, 4 H), 1.04 (t, 3 H), 0.56-0.66 (m, 2 H), 0.34-0.44 (m, 2 H).