Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=O)[CH2:30][C:31](OCC)=[O:32])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:38][NH2:39]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][C:29]3[NH:39][N:38]=[C:31]([OH:32])[CH:30]=3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Solvent: O
Solvent: CCO
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2cc(O)n[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 65 °C

Procedure:
To a solution of 42 mg (0.08 mmol) of ethyl 4-43R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-3-oxobutanoate (Example 79, Step B) in ethanol (4 mL) was added 36 μL (0.48 mmol) hydrazine monohydrate (64-65% weight percent hydrazine). The resulting colorless solution was heated at 65° C. for 3.5 h, and then was concentrated under reduced pressure. Purification of the residue by reversed phase prep. HPLC (Sunfire Prep C18 OBD 10 μm column, gradient elution of 45% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O>[Si:26]([O:1][CH2:2][C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A solution of 11.052 g of (1S,5R,6S,7R)-6-hydroxymethyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one (DOS No. 2,610,718) in 54.0 ml of absolute dimethylformamide is combined with 3.03 g of imidazole and 6.63 g of tert-butyldimethylsilyl chloride, and the mixture is stirred for 3 hours at room temperature. The solution is subsequently precipitated into 500 ml of ice water, the precipitate is suctioned off, and the residue is dissolved in methylene chloride. The organic solution is dried over magnesium sulfate and concentrated. The crude product is recrystallized from hexane, thus obtaining 15.30 g of the title compound, mp 75.8° C.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@@H:13]([N:16]([CH:30]3[CH2:32][CH2:31]3)[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)(=[O:19])=[O:18])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH:30]1([N:16]([C@@H:13]2[C@H:11]3[C@H:10]([CH2:9][NH:8][CH2:12]3)[CH2:15][CH2:14]2)[S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=2)(=[O:18])=[O:19])[CH2:31][CH2:32]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)[C@H]1CC[C@H]2CNC[C@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3aS*,4S*,6aR*)-2-benzyl-N-cyclopropyloctahydrocyclopenta[c]pyrrol-4-amine (0.308 g, 0.663 mmol) from Example 199 and methanol (2 mL) were added to 20% palladium hydroxide on carbon (wet, 4 mg) in a 50 mL pressure bottle. The reaction was stirred for 16 hours under hydrogen (30 psi) at room temperature. The mixture was filtered through a nylon membrane and the solvent removed in vacuo. The crude material was chromatographed on a silica gel cartridge (Analogix®, Burlington, Wis., RS15-24) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 8.14 (s, 1H), 8.07 (d, J=7.9, 1H), 7.87 (d, J=7.9, 1H), 7.70 (t, J=7.8, 1H), 3.80-3.69 (m, 1H), 3.25 (dd, J=7.8, 10.7, 1H), 3.06-2.88 (m, 2H), 2.79-2.71 (m, 1H), 2.63-2.51 (m, 1H), 2.46 (dd, J=5.9, 10.8, 1H), 2.05 (qd, J=7.0, 12.1, 1H), 1.79 (ddd, J=3.9, 6.8, 10.7, 1H), 1.72-1.63 (m, 2H), 1.56 (dd, J=4.8, 6.1, 1H), 1.48 (td, J=6.9, 12.8, 1H), 1.31 (ddd, J=2.7, 5.5, 8.8, 1H), 0.92-0.70 (m, 3H); MS (ESI+) m/z 375 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:19][CH2:20][CH3:21])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:7]1[CH2:19][CH2:20][CH3:21]
Reactant: Clc1ccccc1CBr
Reactant: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Yield: 84.5 %

Procedure:
Methyl 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxylate (533 mg) was prepare from methyl 3-isobutyryl-2-propylindole-6-carboxylate (440 mg) and 2-chlorobenzyl bromide (346 mg) in a similar manner to that of Example 1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[S:19](=[O:21])(=[O:20])[N:18](CC[Si](C)(C)C)[C:17](=[O:28])[CH2:16]2)=[C:11]([O:29]CC2C=CC=CC=2)[CH:10]=1.[CH2:37]([S:39](Cl)(=[O:41])=[O:40])[CH3:38]>>[OH:29][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[N:15]1[CH2:16][C:17](=[O:28])[NH:18][S:19]1(=[O:21])=[O:20])[CH2:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]1[NH:1][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40]
Reactant: CCS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3N)cc2OCc2ccccc2)S1(=O)=O
Product: CCS(=O)(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-[4-((1S*,2R*)-2-aminocyclohexylmethyl)-2-benzyloxy-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and ethanesulfonyl chloride analogous to Example 205, steps B, C and D. MS (M−1)−=430; HPLC retention time=0.91 min. (Method A).
Reaction SMILES: N1C=CN=C1.[CH2:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>ClCCl>[Si:17]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][OH:12])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCCCO)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 41.1 %

Procedure:
Imidazole (0.65 g, 9.60 mmol) was added to a stirring solution of pentan-1,5-diol (1.00 g, 9.60 mmol) in dry dichloromethane (10 mL) at 0° C. under an argon atmosphere followed by the dropwise addition of tert-butylchlorodiphenylsilane (3.85 mL, 9.60 mmol) in CH2Cl2 (2 mL). The reaction was allowed to slowly reach room temperature. After 12 hours, the reaction mixture was washed with water (2×30 mL), brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue which was purified by SiO2 flash chromatography using 30% ethyl acetate/hexane as eluent to furnish 2 (1.35 g, 46%), recovered SM and di-protected compound. TLC: 30% EtOAc/hexanes, Rf˜0.38; 1H NMR (CDCl3, 400 MHz) δ 7.67-7.62 (m, 4H), 7.45-7.35 (m, 6H), 3.67 (t, 2H, J=6.0 Hz), 3.52 (t, 2H, J=6.7 Hz), 2.03-1.93 (m, 2H), 1.72-1.64 (m, 4H), 1.04 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(O[C:36](=O)[N:37]([CH2:39][CH2:40][NH2:41])C)(C)(C)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:41][CH2:40][CH2:39][NH:37][CH3:36])=[O:14])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCCNC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, after treatment with HCl, the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C([O-])([O-])=O.[K+].[K+].C(N1C2C(=CC=CC=2)C=C1C1C=COC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.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:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:22]2[CH:23]=[CH:24][O:20][CH:21]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccccc21
Reactant: OB(O)c1ccco1
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: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1c(-c2ccoc2)cc2ccccc21
Yield: 69 %

Procedure:
N-Benzenesulfonyl-3-iodoindole (11), 2-furanboronic acid, Pd(PPh3)4 and K2CO3 in toluene are allowed to react in the same manner as described in the preparation of compound 3 to give 0.29 g (69%) of 12: 1H NMR (CDCl3): δ8.04 (d, 1H, J=7.53 Hz), 7.87–7.93 (m, 3H), 7.26–7.57 (m, 7H), 6.66 (d, 1H, J=3.23 Hz), 6.50–6.52 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(c1ccc(Cl)cc1)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 4-chlorobenzoyl chloride (2 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5])[CH:19]=[CH:18]2
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1-n1ccc2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 14 h
Yield: 98.1 %

Procedure:
A mixture of 2-fluoro-5-(trifluoromethyl)benzonitrile (1000 mg), 5-chloro-1H-indole (800 mg), potassium carbonate (1.8 g), and DMSO (10 ml) was stirred at 100° C. for 14 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzonitrile (1.66 g).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][CH:9]=2)=[N:6][N:7]=1)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1)[CH3:2]
Reactant: CCc1nnc(-c2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)o1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnc(-c2ccc(S)cc2)o1
Reaction time: 0.17 h

Procedure:
2-Ethyl-5-(4-(tritylthio)phenyl)-1,3,4-oxadiazole was dissolved in trifluoroacetic acid (5 ml) and a large excess of triethyl silane (500 μl) was added. The solution was stirred for 10 minutes then the solvent was removed under a stream of nitrogen to leave 4-(5-ethyl-1,3,4-oxadiazol-2-yl)benzenethiol-Compound F 98 mg (99%).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8](Cl)=[O:9])#[N:2].C[Si]([C:15]([Si](C)(C)C)(C([O-])=O)[C:16]([O-:18])=[O:17])(C)C.CCN(CC)CC.[Li+].[Br-].OS(O)(=O)=O>CC#N.C(OC(C)=C)(=O)C>[C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8](=[O:9])[CH2:15][C:16]([OH:18])=[O:17])#[N:2]
Reactant: N#Cc1ccsc1C(=O)Cl
Reactant: C[Si](C)(C)C(C(=O)[O-])(C(=O)[O-])[Si](C)(C)C
Agent: C=C(C)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccsc1C(=O)CC(=O)O

Procedure:
The 3-(3-cyano-thiophen-2-yl)-3-oxo-propionic acid was prepared from 3-cyano-thiophene-2-carbonyl chloride (24.33 g, 140.6 mmol) and bis(trimethylsilyl)malonate (38.0 mL, 147.7 mmol) with Et3N (41 mL, 295.4 mmol) and LiBr (13.5 g, 154.7 mmol) in CH3CN at 0° C. according to general procedure H (method c1). The crude material (24.8 g) was transformed into the tide compound by stirring in isopropenyl acetate and conc. H2SO4 according to general procedure J (method a). Obtained as an orange solid (5.6 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:12]([CH3:22])[C:13]=2[S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)#[N:2].[N:29]([Sn](C)(C)C)=[N+:30]=[N-:31]>C1(C)C(C)=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:14][C:13]2[N:12]([CH3:22])[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:1]3[N:29]=[N:30][NH:31][N:2]=3)=[CH:8][CH:7]=2)=[CH:16][CH:17]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nn[nH]n3)cc2)c1Sc1ccc(Cl)cc1

Procedure:
A solution of 2-{4-(4-cyanophenyl)-5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-2-yl}pyridine (Example 23, 160 mg, 0.41 mmol) and azidotrimethyltin (420 mg, 2.0 mmol) in xylene (1.5 mL) was heated at 140° C. under nitrogen for 2 hrs. After cooling, the reaction mixture was filtered through a pad of Celite and silica, and the filtrate was concentrated to afford 2-{5-[(4-Chlorophenyl)thio]-1-methyl-4-[4-(2H-tetrazol-5-yl)phenyl]-1H-imidazol-2-yl}pyridine, which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1>CCCCCC.[Pd]>[C:9]([O:11][CH2:12][CH3:13])(=[O:10])/[CH:8]=[CH:7]\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C#Cc1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)/C=C\c1ccccc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
Ethyl phenylpropiolate (10.8 g, 0.062 mol) was dissolved in hexane (540 ml), followed by addition of quinoline (11.2 g) and palladium on calcium carbonate (Lindlax catalyst, 3.6 g). The resulting reaction mixture was stirred under hydrogen (1 atm) at room temperature, and the progress of the reaction was monitored closely by GC analysis. The reaction was stopped by displacement of the hydrogen atmosphere with nitrogen once the rate of absorption of hydrogen was observed to decrease abruptly. The resulting mixture was filtered through a pad of diatomaceous earth and the filtrate was dried over Na2SO4. Solvent was removed under reduced pressure. Then the residue was distilled under vacuum (2.5 mm Hg, at 98°-100° C.) to provide 10.08 g of cis-ethyl cinnamate, for a yield of nearly 95%. By GC analysis, this product mixture was found to contain 5.7% over-reduced alkane and 3.5% trans-ethyl cinnamate, but was used without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>O>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:20][C:2]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(OC)ccc1Br
Reactant: C=Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(OC)ccc1C=Cc1ccc(F)cc1
Yield: 132.1 %

Procedure:
A mixture of methyl 2-bromo-5-methoxybenzoate (28.3 g, 115 mmol), 4-fluorostyrene (20.6 ml, 173.3 mmol), tert-n-butylamine (2.7 ml, 11.5 mmol), Pd[(o-tolyl)3 P]2 Cl2 (0.9 g, 1.15 mmol), and NaHCO3 (14.6 g, 173.3 mmol), and water (220 ml) was stirred and heated at reflux for 16 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (2×400 ml). The extracts were washed with 2M HCl (100 ml), water (100 ml), brine (100 ml), dried (MgSO4), filtered and evaporated to dryness. The brown gum obtained was purified by chromatography on silica (90 g, Biotage column), eluting with a gradient of ethyl acetate in iso-hexane (0%-20% ethyl acetate). The relevant fractions were combined and evaporated to give methyl 2-[2-(4-fluorophenyl)ethenyl]-5-methoxybenzoate, (43.5 g)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]\[C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CN(C)C=O.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1ncc(/C=C\c2ccc([N+](=O)[O-])cc2)s1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ncc(CCc2ccc(N)cc2)s1
Yield: 26.7 %

Procedure:
A mixture of N-{5-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (1 g) and 10% palladium carbon (1.04 g) in ethyl acetate (100 ml) and N,N-dimethylformamide (20 ml) was stirred under 4 atm hydrogen at ambient temperature for 4 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/methanol (30:1→20:1) as an eluent, and triturated with ethyl ether to give N-{5-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (240.9 mg) as an off-white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C>[F:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=1[F:3]
Reactant: OCCCCOc1cccc(F)c1F
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOCCCCOc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium hydride (1 equi.) was added to the solution of 4-(2,3-difluorophenoxy)-butan-1-ol (22), (1 equi.) and 1-bromopentane (1 equi.) in DMF (1 mL/mmole) and the reaction mixture was stirred at room temperature for 12 h,. quenched with water, extracted with ethyl acetate:hexane (1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) and recrystallization from acetonitrile gave 1,2-difluoro-3-(4-pentyloxybutoxy)-benzene (24), as a white solid (84%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Cl:14])=[C:9]([N+:15]([O-:17])=[O:16])[C:8]=1[Cl:18])[CH3:2].[CH:21](OCC)(OCC)[O:22][CH2:23][CH3:24].C(OC(=O)C)(=O)C>>[Cl:18][C:8]1[C:9]([N+:15]([O-:17])=[O:16])=[C:10]([Cl:14])[C:11]([F:13])=[CH:12][C:7]=1[C:6]([C:5](=[CH:21][O:22][CH2:23][CH3:24])[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[O:19]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl

Procedure:
244.8 g of ethyl(2,4-dichloro-5-fluoro-3-nitrobenzoyl)acetate are heated with 166 g of triethyl orthoformate and 185 g of acetic anhydride at 150°-160° C. for 3 hours. The mixture is then concentrated in vacuo, and 270 g of ethyl benzoylethoxyacrylate are obtained as an oily residue.
Reaction SMILES: [C:1]1(=[O:16])[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][C:2]1=O.[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)C=O>>[F:17][C:18]([F:28])([F:29])[O:19][C:20]1[CH:27]=[C:26]([CH:13]2[C:14]3[C:1](=[O:16])[CH2:2][CH2:3][CH2:4][C:5]=3[NH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]2=3)[CH:25]=[CH:22][CH:21]=1
Reactant: O=C1C=Cc2nc3ccccc3cc2C1=O
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Product: O=C1CCCC2=C1C(c1cccc(OC(F)(F)F)c1)C1=C(CCCC1)N2

Procedure:
The necessary acridinedione starting material may be prepared following the method described in Example 28 hereinbelow, but using 3-trifluoromethoxybenzaldehyde in place of 3-trifluoromethylbenzaldehyde. M.p. 273°-275° C. Found for C20H18FNO3: . C,63.55; H,4.71; N,3.67.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2].CC(O)=[O:28]>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:28])[C:8]=2[S:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1c(NC(C)=O)sc2c1CCC(Cc1ccccc1)C2
Solvent: O
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCC(Cc1ccccc1)C2=O
Temperature: 65 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
Compound 02-3 (22.1 g, 62 mmol) was dissolved in AcOH (200 mL). The mixture was heated to 65° C. and a solution of Na2Cr2O7-2H2O (27.2 g, 93 mmol) in hot H2O (200 mL) was added over a period of 2 min. After complete addition the mixture was stirred for 3 h at 65-67° C. and 2 h at 75° C. The mixture was allowed to cool to RT and then quenched with saturated aqueous Na2SO3 (100 mL) and diluted with H2O (1.5 L). The aqueous mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with H2O (3×400 mL), brine (400 mL) and dried over Na2SO4. After removal of the solvent in vacuo the crude product was treated with Et2O (50 mL) and filtered off to give 02-4 (9.5 g, 25 mmol, 41%) as yellow powder containing about 8% of starting material 02-3 (HPLC).