Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=C[N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=N[N:38](CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.P(Br)(Br)Br>>[CH2:1]([O:8][C:9]1[CH:14]=[N:38][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Reactant: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Agent: BrP(Br)Br
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1

Procedure:
5-Benzyloxy-2-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 15c from 9.40 g (26.8 mmol) 5-benzyloxy-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 17a) and 2.52 mL (26.8 mmol) phosphorus tribromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.C[O-].[Na+].[CH:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=O>CO>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23](/[CH:21]=[CH:9]/[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(Cl)cc1Nc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A 2 L 3-necked round-bottomed flask equipped with a stirrer, a nitrogen bubbler, an addition funnel and a thermometer was charged with 1-(4-chloro-2-(phenylamino)phenyl)ethanone (79.3 g, 323 mmol) and methanol (628 g, 793 mL). The reaction was treated while stirring with a solution of sodium methoxide (25 wt % in methanol, 119 mL, 520 mmol) followed by addition of methyl 4-formylbenzoate (53.0 g, 323 mmol). The reaction mixture was allowed to stir overnight. At this time, the reaction was cooled in an ice bath. The resulting solids were collected by filtration, washed with cold methanol and dried to afford 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-benzoic acid methyl ester (115 g, 90.9%) as a red solid. This material was used without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:58])[C:32]([CH3:57])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][CH2:50][C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:58])[C:32]([CH3:57])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][CH2:50][C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)=[C:44]([CH:48]=2)[C:45]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.4 %

Procedure:
4-Trifluoromethylaniline (0.242 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.215 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.035 g, 0.0618 mmol, 12%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([Si](C)(C)C)([F:19])[F:18]>CN(C)C=O>[CH3:1][C:2]1[S:3][C:4]([CH:8]([OH:9])[C:17]([F:19])([F:18])[F:16])=[C:5]([CH3:7])[N:6]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1nc(C)c(C=O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(O)C(F)(F)F)s1
Yield: 74.8 %

Procedure:
According to Reference Example 8-2, by use of 2,4-dimethylthiazole-5-carbaldehyde (300 mg, 2.12 mmol) dissolved in N,N-dimethylformamide (4 mL), potassium carbonate (59 mg, 0.42 mmol) and (trifluoromethyl)trimethylsilane (0.376 mL, 2.54 mmol), the mixture was stirred and reacted at room temperature for 1.5 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 1-(2,4-dimethylthiazol-5-yl)-2,2,2-trifluoroethanol (Compound DS) (335 mg, yield: 75%).
Reaction SMILES: [F:1][CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:12].[Se](=O)=[O:14]>O1CCOCC1>[F:1][CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH:12]=[O:14]
Reactant: O=[Se]=O
Reactant: Cc1nc2ccccc2n1CF
Solvent: C1COCCO1
Product: O=Cc1nc2ccccc2n1CF
Yield: 82.8 %

Procedure:
Using the procedure of Example 10B and starting with 2.87 g of 1-fluoromethyl-2-methylbenzimidazole and 1.94 g of selenium dioxide in 50 ml of dioxane, 2.58 g of the desired product was isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:3]=12.[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[N:10]=[C:9]2[CH2:11][CH2:12][CH3:13])=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCCc1nc2nccc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A suspension of 7-methyl-2-propylimidazo[4,5-b]pyridine (1.00 g, 5.71 mmol) and NaH (189 mg, 1.1 eq) in DMF (25 mL) was stirred for 1 hour and then cooled to 0° C. 4-Benzyloxybenzyl chloride (1.46 g; 1.1 eq) was then added and the ice bath removed. The reaction mixture was stirred for 2.5 hours and was then concentrated in vacuo. The residue was chromatographed on a silica gel flash chromatography column (30×200 mm) eluted with 30% ethyl acetate/hexane to yield 1.07 g (50%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH:15]([CH3:17])[CH3:16])[C:13](=[O:18])[C:12]([CH3:20])([CH3:19])[C:11]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH:15]([CH3:17])[CH3:16])[C@H:13]([OH:18])[C:12]([CH3:19])([CH3:20])[C:11]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)C1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 2-chloro-4-(5-isopropyl-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (300 mg) and lithium tri(sec-butyl)borohydride-THF solution (1.48 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as a colorless solid (yield: 209 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:19][C:20]([O:22]CC)=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=[C:10]2[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=[C:10]2[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1CCCCc2nc(C(C)(C)C)n(Cc3ccc(Cl)cc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CC(=O)O)CCCC2
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Intermediate 16 (22 mg) was dissolved in Methanol (1 ml) and treated with sodium hydroxide, 2M aq. (1 mL). The RM was left in solution for 1 hour. The residue was purified by MDAP (Method A). The desired fractions were combined and concentrated under nitrogen blowdown to give the title compound (17 mg). LC/MS MH+ 375, Rt 1.72 min (5 minute run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)[CH2:22][CH3:23]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH:27]2[CH2:28][CH2:29][N:24]([CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CCCN1CCC(N)CC1
Product: CCCN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-propylpiperidin-4-amine (14.2 mg, 0.12 mmol). The title compound was obtained as a solid (10 mg, 21% yield). MS m/z: 474.98, 476.97 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:38]([O:40][CH3:41])=[O:39])=[N:14][C:15]([N:18]([CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)C(OCC3C=CC=CC=3)=O)=[CH:16][CH:17]=2)[N:4]=1>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:38]([O:40][CH3:41])=[O:39])=[N:14][C:15]([NH:18][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:16][CH:17]=2)[N:4]=1
Reactant: COC(=O)c1nc(N(CCOc2ccccc2)C(=O)OCc2ccccc2)ccc1Oc1nc(OC)cc(OC)n1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nc(NCCOc2ccccc2)ccc1Oc1nc(OC)cc(OC)n1
Yield: 70.4 %

Procedure:
1.12 g (2 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-[N-(2-phenoxy)ethyl-N-benzyloxycarbonylamino]picolinate was catalytically reduced in 30 ml of methanol in the presence of 1 g of palladium carbon (10%). The catalyst was filtered off, and the filtrate was distilled under reduced pressure at a low temperature of not higher than 40° C., and the residual oily product was purified by column chromatography to obtain the desired product as colorless transparent oily product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[N+:24]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.C(Cl)Cl>[NH2:24][C:10]1[CH:11]=[C:12]([O:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)c1ccccc1
Reactant: [H][H]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(OC(=O)c2ccccc2)ccc1OCc1ccccc1
Yield: 79.3 %

Procedure:
A Parr hydrogenator was charged with platinum(IV) oxide(PtO2) (0.3 g) and a solution of benzoic acid 4-benzyloxy-3-nitro-phenyl ester (5.23 g, 15 mmol) (which was obtained in Example 15) in methanol (80 mL) and CH2Cl2(40 mL). This mixture was then hydrogenated at 5 psi of hydrogen at 0˜10° C. for 2 hours. The reaction mixture was filtered through a short pad of celite and concentrated. Recrystallization from CH2Cl2/hexanes gave the title compound as a white solid (3.80 g, 79%); 1H NMR (300 MHz, CDCl3) δ 5.09 (s, 2H), 6.57 (dd, J=10.1, 2.7 Hz, 1H), 7.10 (d, J=2.7 Hz, 1H), 7.30-7.50 (m, 8H), 7.55-7.65 (m, 1H), 8.15-8.25 (m, 2H); MS (ES) m/z: 320.0 (MH+, 100%); HRMS Calcd. for C20H18NO3 (MH+): 320.1281. Found: 320.1278.
Reaction SMILES: [O:1]([C:8]1[C:9]([CH2:14][O:15]C(=O)C)=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[O:1]([C:8]1[C:9]([CH2:14][OH:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCc1ncccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1ncccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of acetic acid 3-phenoxy-pyridin-2-ylmethyl ester (0.234 g, 0.96 mmol) in MeOH (10 mL) was added K2CO3 (0.264 g, 1.92 mmol) and the mixture stirred at room temperature for 2 h. The mixture was concentrated and the resultant residue was diluted with CH2Cl2 (30 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4), and concentrated to give (3-phenoxy-pyridin-2-yl)-methanol as a clear oil (0.130 g, 68%), which was used without further purification. 1H NMR (CDCl3) δ 4.26 (t, 1H, J=4.8 Hz), 4.84 (d, 2H, J=4.3 Hz), 6.97 (m, 2H), 7.18 (m, 3H), 7.37 (m, 2H), 8.32 (dd, 1H, J=2.9, 1.4 Hz).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[S:29][C:28]2=[N:30][C:31]([CH3:36])=[C:32]([C:33](O)=[O:34])[N:27]2[CH:26]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[N:27]3[C:28]([S:29][C:25]([CH3:24])=[CH:26]3)=[N:30][C:31]=2[CH3:36])=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cn2c(C(=O)O)c(C)nc2s1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sc(C)cn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,6-Dimethyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=506.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([SH:11])[CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[S:11][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2cc(F)ccc12
Temperature: 135 °C
Yield: 1.2 %

Procedure:
A mixture of 4-fluoro-2-mercaptobenzoic acid (5.00 g, 29.0 mmol), 2-cyanopyridine (3.05 g, 29.3 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 48 hrs as described in Example 9. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The resultant product was recrystallized from ethanol to give the titled compound (0.09 g, 1%).
Reaction SMILES: CO[CH:3]([O:13]C)[C:4]1[C:5]([O:11][CH3:12])=[N:6][CH:7]=[C:8](Br)[CH:9]=1.[C-:15]#[N:16].[Na+].N.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)CC.CC(C)=O.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:15]([C:8]1[CH:9]=[C:4]([CH:3]=[O:13])[C:5]([O:11][CH3:12])=[N:6][CH:7]=1)#[N:16]
Reactant: COc1ncc(Br)cc1C(OC)OC
Reactant: [C-]#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: N
Solvent: CC(C)=O
Solvent: CCC#N
Product: COc1ncc(C#N)cc1C=O
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 68.1 %

Procedure:
2.00 g of 5-bromo-2-methoxy-3-pyridinecarboxaldehyde dimethyl acetal was dissolved in 25 ml of propionitrile. To the mixture were added 449 mg of sodium cyanide, 152 mg of cuprous iodide and 462 mg of tetrakis(triphenylphosphine)palladium, followed by stirring at 100° C. for 45 minutes in nitrogen atmosphere. A diluted ammonia was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give an oil. The oil was dissolved in 16 ml of acetone, 4 ml of 5N-hydrochloric acid was added thereto, and the mixture was left for 30 minutes at room temperature. An aqueous sodium carbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (toluene:ethyl acetate=1:1), to give 843 mg of the title compound as white crystals.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO>[I:1][C:2]1[C:7]([C:8]([O:10][CH3:13])=[O:9])=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1nccc(I)c1C(=O)O
Solvent: CO
Product: COC(=O)c1c(I)ccnc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-Iodo-2-methoxynicotinic acid (800 mg, 2.87 mmol) is dissolved in MeOH (7 mL) and cooled at 0° C. Trimethylsilyldiazomethane (9 mL, 2M in hexane, 4.5 mmol) is added slowly over 20 minutes. The reaction mixture is brought to room temperature and stirred for 16 hours. The reaction mixture is concentrated and purified by silica gel column chromatography using hexane:ethyl acetate as eluent to afford the desired compound. 1H NMR 400 MHz (DMSO-d6) δ 7.88 (d, 1H, J=5.6 Hz), 7.34 (d, 1H, J=5.6 Hz), 4.12 (s, 3H), 3.84 (s, 1H); MS m/z 294.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:16])=[O:15])[C:11]([CH3:17])=[CH:10][C:9]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].ClCC(=O)C.[I-].[K+]>CC(C)=O.[I-].[K+]>[CH3:6][O:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:16])=[O:15])[C:11]([CH3:17])=[CH:10][C:9]=1[O:18][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: COc1cc(S(C)=O)c(C)cc1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(S(C)=O)c(C)cc1OCC(C)=O
Reaction time: 16 h

Procedure:
Potassium iodide (0.075 g) was added to a stirred solution of chloroacetone (3 ml) in dry acetone (3.5 ml) and the mixture was stirred for 16 hours. 2-Methoxy-5-methyl-4-methylsulphinylphenol (5.0 g) and potassium carbonate (0.85 g) were heated at reflux with stirring in dry acetone (25 ml). The chloroacetone/potassium iodide solution and potassium carbonate (3.4 g) were then added in four equal portions over 2 hours. The mixture was heated at reflux for a further 2 hours, cooled and filtered, the filter cake being washed well with acetone. The acetone was removed under reduced pressure and the residue chromatographed on a column of silica gel eluting with methylene chloride/methanol mixtures (gradient I to 3% v/v methanol). Trituration with diethyl ether gave the ketone (4.6 g) as colourless crystals, m.p. 104°-106°.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)C.O[C:25]1[CH:38]=[CH:37][C:28]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1>C1COCC1>[C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=3)=[CH:14][CH:15]=2)=[CH:33][CH:32]=1)(=[O:30])[C:28]1[CH:37]=[CH:38][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccc(CO)cc2)cc1)OC
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(-c2ccc(COc3ccc(C(=O)c4ccccc4)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-(4′-Hydroxymethyl-biphenyl-4-yl)-2-methoxy-propionic acid ethyl ester from Step A, was treated with 4-hydroxybenzophenone under the standard Mitsunobu coupling procedure B (THF). The product obtained after chromatography was hydrolyzed using the Standard Procedure C to get the title compound. 1H-NMR (CDCl3, 200.15 MHz): 7.86–7.73 (m, 4H), 7.63–7.43 (m, 9H), 7.34–7.29 (m, 2H), 7.05 (d, 2H, J=9.1), 5.18 (s, 2H), 4.06 (dd, 1H, J=7.3, 4.0), 3.42 (s, 3H), 3.20 (dd, 1H, J=14.5, 4.0), 3.06 (dd, 1H, J=14.5, 7.3). MS (ES) for C30H26O5 [M+H]+: 467.2, [M+Na]+: 489.2.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].C(N(CC)CCN[C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[CH:25]=2)[CH:20]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:18])C>>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH:7][C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[CH:25]=2)[CH:20]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:18])([CH3:3])[CH3:2]
Reactant: CCN(CC)CCNC(=O)N1CCc2cc(OC)c(OC)cc2C1c1ccccc1
Reactant: CC(C)N(CCN)C(C)C
Product: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)NCCN(C(C)C)C(C)C)CC2

Procedure:
Substitution of an equivalent quantity of 2-diisopropylaminoethylamine for the 2-diethylaminoethylamine used above and substantial repetition of the foregoing procedure affords N-(2-diisopropylaminoethyl)-6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide, melting at about 109°-110°C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:30][CH3:31])[C:20]3=[O:37])[CH:13]=[C:14]([Br:17])[CH:15]=2)[CH:10]=[C:9]1[O:38]C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:36][O:35][C:33](=[O:34])[CH2:32][CH:28]([N:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:19]([CH2:18][C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[C:16]3[C:11]=2[CH2:10][C:9](=[O:38])[NH:8]3)[C:20]1=[O:37])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC(CC(=O)OC)n1c(=O)n(Cc2cc(Br)cc3c2cc(OC(=O)OC(C)(C)C)n3C(=O)OC(C)(C)C)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(CC(=O)OC)n1c(=O)n(Cc2cc(Br)cc3c2CC(=O)N3)c2ccccc21
Reaction time: 1 h
Yield: 46.4 %

Procedure:
6-Bromo-2-tert-butoxycarbonyloxy-4-[3-(1-methoxycarbonylmethyl-butyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-indole-1-carboxylic acid tert-butyl ester (200 mg, 0.28 mmol) is dissolved in dichloromethane (5 mL) and then trifluoroacetic acid is added (2 mL). The reaction is stirred for 1 hour then evaporated in vacuo to give an oil that is purified by preparative reverse phase LC to give the title compound (63 mg 0.13 mmol 44%). LCMS (ESMS): m/z 487.6 (M+H+).
Reaction SMILES: [Cl:1][CH:2]([Cl:4])[CH3:3].[B:5](OC)([O:8][CH3:9])[O:6][CH3:7].C(NC(C)C)(C)C.C([Li])CCC.ClC(B(OC(C)C)OC(C)C)Cl>C1COCC1>[Cl:1][C:2]([B:5]([O:8][CH3:9])[O:6][CH3:7])([Cl:4])[CH3:3]
Reactant: CC(Cl)Cl
Reactant: COB(OC)OC
Agent: CC(C)OB(OC(C)C)C(Cl)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COB(OC)C(C)(Cl)Cl
Temperature: -78 °C

Procedure:
A modification of the procedure of Example 1 was followed. 1,1-Dichloroethane (25 ml, 0.30 mol) was used in place of dichloromethane and trimethyl borate (30 ml, 0.265 mol) was used in place of triisopropyl borate. The quantity of diisopropylamine was 40 ml and that of butyllithium was 0.25 mol. A -78° C. cooling bath was used. The yield of (I) (R3 =R7 =R8 =methyl), bp 48° C. (40 Torr), was 27 g, 55% taking into account the 14% THF indicated by NMR analysis.