Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=[CH:19][C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([Cl:37])[CH:27]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:33]([O:32][C:30](=[O:31])[C:29]1[CH:35]=[CH:36][C:26]([NH:25][C:20]([C:17]2[CH:18]=[CH:19][C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:23][CH3:24])(=[O:9])=[O:10])[C:15]=3[CH:16]=2)=[O:22])=[CH:27][C:28]=1[Cl:37])[CH3:34]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CO3)cc1Cl
Temperature: 60 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
A solution of 3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid (1.00 g, 2.70 mmol), ethyl 4-amino-2-chlorobenzoate (1.08 g, 5.41 mmol), 4-methylmorpholine (1.37 g, 13.5 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluoro-phosphate (1.54 g, 4.06 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (337 mg, 2.70 mmol) were added, and the solution was stirred at 60° C. for 18 h. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 2-chloro-4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester (849 mg, 57%). Off-white solid, MS (ISP)=551.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18]I>CN(C=O)C>[CH3:18][O:15][C@@H:10]([CH2:11][CH2:12][CH:13]=[CH2:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC[C@H](O)COCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC[C@@H](COCc1ccccc1)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of (2S)-1-(benzyloxy)hex-5-en-2-ol (71 g, 344 mmol) in DMF (500 mL) at 0° C. was added sodium hydride (16.52 g, 413 mmol) in portions over 30 minutes. The resulting suspension was stirred at 0° C. for 15 minutes and then at ambient temperature for 15 minutes. The mixture was cooled to 0° C. and methyl iodide (43 mL, 688 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The mixture was cooled to 0° C. and quenched with water. The mixture was extracted with DCM (3×). The organic layers were combined and washed with water (2×), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl2): δ 7.34 (s, 5 H); 5.85-5.74 (m, 1 H); 5.06-4.89 (m, 2 H); 4.55 (s, 2 H); 3.49 (d, J=4.7 Hz, 2 H); 3.41 (s, 3 H); 3.37 (m, 1 H); 2.16-2.04 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][N:5]2[C:6](=[O:15])[C:7]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=[C:4]2[CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)#[CH:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]#[C:19][C:2]2[CH:17]=[CH:16][N:5]3[C:6](=[O:15])[C:7]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[N:9]=[C:4]3[CH:3]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: O=c1c2c(nc3cc(Br)ccn13)CCCCC2
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1c2c(nc3cc(C#Cc4ccc(F)cc4)ccn13)CCCCC2
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A solution of 3-bromo-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one (250 mg, 0.85 mmol), 1-ethynyl-4-fluorobenzene (255 mg, 2.12 mmol), Pd(OAc)2 (38.2 mg, 0.17 mmol), PPh3 (200 mg, 0.76 mmol), CuI (16.2 mg, 0.085 mmol), and Et3N (0.7 mL) in DMF (8 mL) was stirred in a sealed tube at 70° C. for 3.5 hours. After it was cooled to room temperature, the reaction mixture was diluted with H2O and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel to produce 185 mg of desired product. MS (ESI): 333 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.97-8.94 (dd, J=7.44, 0.66 Hz, 1H), 7.65-7.56 (m, 3H), 7.15-7.06 (m, 3H), 3.00-2.97 (m, 4H), 1.94-1.88 (m, 2H), 1.80-1.64 (m, 4H). mGluR5 PAM EC50: +++++. Fold shift at 10 μM: +.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])/[CH:11]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A 250 mL round-bottomed flask was charged sequentially aq. NaOH solution (NaOH 7.1 g/H2O 50 mL) and EtOH (40 mL). The solution was maintained below 10° C. in an ice bath. 1-(3-hydroxyphenyl)ethanone (20.0 g, 147 mmol) was added and stirred for 30 min at 10° C. To the resulting mixture was then added benzaldehyde (15 mL, 1.0 eq). After being stirred for additional 1 h at 10° C., the reaction mixture was stirred at room temperature for further 26 h. The solution was concentrated by rotary evaporation under reduced pressure. The residue was dissolved in EtOAc. The organic layer was washed with 3N HCl and H2O, dried over MgSO4, and concentrated in vacuo to obtain the desired product (32.5 g, 98%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]3[C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][C@@H:34]([CH2:43][S:44]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)(=O)=O)[CH2:35][CH2:36][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[C:29]([S:53]([C:56]([F:59])([F:58])[F:57])(=[O:55])=[O:54])[CH:28]=4)(=[O:26])=[O:25])=[N:21][N:22]=[C:16]3[CH2:15]2)[CH2:10][CH:9]1[CH3:60])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:60][CH:9]1[CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][N:17]3[C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][C@@H:34]([CH2:43][S:44][C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[CH2:35][CH2:36][N:37]5[CH2:38][CH2:39][O:40][CH2:41][CH2:42]5)=[C:29]([S:53]([C:56]([F:59])([F:57])[F:58])(=[O:55])=[O:54])[CH:28]=4)(=[O:26])=[O:25])=[N:21][N:22]=[C:16]3[CH2:15]2)[CH2:12][CH2:13][NH:8]1
Reactant: CC1CC(N2CCn3c(nnc3NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CS(=O)(=O)c4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)C2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CC(N2CCn3c(nnc3NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)C2)CCN1
Reaction time: 2.5 h
Yield: 59.3 %

Procedure:
To a solution of 2-methyl-4-{3-[4-((R)-3-morpholin-4-yl-1-phenylsulfonylmethylpropyl-amino)-3-trifluoromethanesulfonyl-benzenesulfonylamino]-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl}-piperidine-1-carboxylic acid tert-butyl ester (42 mg, 0.048 mmol) in CH2Cl2 (1 mL) under nitrogen was added trifluoroacetic acid (0.093 mL, 1.203 mmol) and the reaction was stirred for 2.5 hours. The reaction mixture was then concentrated and diluted with water and CH2Cl2. It was then basified to pH approximately 8 with saturated Na2CO3. The aqueous layer was extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N-[7-(2-methyl-piperidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonamide (22 mg, 59% yield). MS [m/z; (M+1)+]: 773.6
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1.CN(C=O)C.S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([Cl:18])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)s1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)s1

Procedure:
15.0 g (94.8 mmol) 5-methoxy-2-thiophenecarboxylic acid were heated in 100 ml thionyl chloride and 1 ml abs. DMF for 30 minutes under reflux. The excess thionyl chloride was then distilled off under vacuum. The crude product (ca. 18 g brownish oil) was quickly distilled.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[OH:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1[CH:22]=O.C(O)(=O)C>O1CCCC1>[OH:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1/[CH:22]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C=C/c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
Sodium hydride (content: 62%, 3.3 g) was suspended in tetrahydrofuran (30 ml). The suspension was ice-cooled in an atmosphere of argon gas. A solution of t-butyl diethylphosphonoacetate (20.9 g) in tetrahydrofuran (20 ml) was room temperature. A solution of 2-hydroxy-5-nitrobenzaldehyde (6.6 g) in tetrahydrofuran (20 ml) was gradually added to the mixture often with ice-cooling. The mixture was stirred for 10 min. at room temperature. Acetic acid was gradually added to the mixture until pH of the mixture was down to 5.0. The reaction mixture was gel-filtered with using YMC gel. Moreover the gel was washed with ethyl acetate. A mixture of the filtrate and washings was evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→3:2) to give the title compound (10.0 g) having the following physical data.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3].Br[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:1][CH2:2][CH3:3])[CH3:16])[CH3:15]
Reactant: CCOC(=O)C(C)Br
Reactant: CCCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1nccn1C(C)C(=O)OCC

Procedure:
2-Propylimidazole (5.5 g), ethyl 2-bromopropionate (9.95 g) and potassium carbonate (12.4 g) were stirred in refluxing acetonitrile (100 ml) for 72 hours. The suspension was allowed to cool, filtered and the solvent removed under reduced pressure, yielding the title compound as an off-white foam, 9.2 g [88%].
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]Br)=[CH:8][CH:7]=1)=[O:4].[C-:23]#[N:24].[Na+].O>CS(C)=O>[F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:23]#[N:24])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Nc1ccc(CCBr)cc1)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 18 h
Yield: 49.1 %

Procedure:
A solution of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-bromoethyl)phenyl]butanamide (9.9 g), and sodium cyanide (1.72 g) in dimethylsulfoxide (50 mL) was stirred at room temperature under a nitrogen atmosphere for 24 hours. The mixture was treated with additional sodium cyanide (0.8 g) and the reaction was stirred for another 18 hours. The reaction mixture was poured into water (1 L) and extracted with diethyl ether. The extracts were washed with water and with saturated brine solution, dried over sodium sulfate, filtered and concentrated with a rotary evaporator. The crude orange residue was chromatographed on silica gel, eluted with a hexane-ethylacetate (7:3) mixture to give 4.2 g of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-cyanoethyl)phenyl]butanamide as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:13]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:14]=1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=[CH:5]2.C1(C)C=CC=CC=1.C(OCC)(=O)C.[CH3:42][N:43](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:42]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:13]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:14]=1[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH:6]=[CH:5]2)#[N:43]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Oc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Oc1ccc2cc(C#N)ccc2c1
Temperature: 25 °C

Procedure:
The compound (t-butyl 2-(6-bromo-2-naphthyloxy)-4-nitrobenzoate) (1.78 g) obtained in a previous production example, zinc cyanide (0.33 g) and tetrakis(triphenylphosphine)palladium (0) (690 mg) were reacted for 12 hours at 100° C. in N,N-dimethylformamide. After cooling to room temperature, toluene and ethyl acetate were added, the organic layer was washed with 2 N ammonia water and saturated saline and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (300 g, hexane:ethyl acetate=6:1) to obtain 1.14 g of t-butyl 2-(6-cyano-2-naphthyloxy)-4-nitrobenzoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=1[N+:25]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1-n1cccc1C(C)(C)C
Agent: [Pd]
Product: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1-n1cccc1C(C)(C)C

Procedure:
The title compound was prepared from [4-(2-tert.-butyl-pyrrol-1-yl)-5-methoxy-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example A5) (513 mg, 1.32 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light brown gum (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:11])=[CH:4][CH:3]=1.CO.NN>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH:10]([NH2:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(C#Cc1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: ClCCl
Product: CC(N)C#Cc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a solution of 2-[3-(4-chloro-phenyl)-1-methyl-prop-2-ynyl]-isoindole-1,3-dione (4.1 g, 13.2 mmol) in 20 mL of dichloromethane was added 30 mL of methanol followed by hydrazine (4.2 mL, 133 mmol, 10 eq.). The mixture was stirred for 1 hr, filtered, concentrated and chromatographed with 3% methanol-dichloromethane to provide 1.5 g of 3-(4-chloro-phenyl)-1-methyl-prop-2-ynylamine.
Reaction SMILES: FC(F)(F)C1C=CC(COC2C=CC=CC=2CO)=CC=1.C[O:22][C:23](=[O:55])[CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)=[C:31]2[C:27]=1[CH2:28][CH2:29][CH2:30]2>>[F:53][C:51]([F:52])([F:54])[C:48]1[CH:49]=[CH:50][C:45]([CH2:44][O:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[CH2:36][S:35][C:32]2[CH:33]=[CH:34][C:26]([O:25][CH2:24][C:23]([OH:55])=[O:22])=[C:27]3[C:31]=2[CH2:30][CH2:29][CH2:28]3)=[CH:46][CH:47]=1
Reactant: COC(=O)COc1ccc(SCc2ccccc2OCc2ccc(C(F)(F)F)cc2)c2c1CCC2
Agent: OCc1ccccc1OCc1ccc(C(F)(F)F)cc1
Product: O=C(O)COc1ccc(SCc2ccccc2OCc2ccc(C(F)(F)F)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 81A. MS m/z 265 (M-Cl). Step 3. Preparation of {7-[2-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (Compound 81C)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)=[CH:27][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)=[CH:27][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@:9]([CH2:12][CH2:13][N:54]2[CH2:55][CH2:56][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:52][CH2:53]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CC[C@]3(c4ccc(Cl)c(Cl)c4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.Br[CH2:37][CH:38]1[CH2:41][CH2:40][CH2:39]1>>[CH:38]1([CH2:37][N:34]2[CH:35]=[C:31]([C:9]3[C:8]4[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][C:7]=4[NH:11][N:10]=3)[CH:32]=[N:33]2)[CH2:41][CH2:40][CH2:39]1
Reactant: BrCC1CCC1
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1nccc2[nH]nc(-c3cnn(CC4CCC4)c3)c12
Yield: 64 %

Procedure:
Prepared according to the general procedure described in Example 86 by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with (bromomethyl)cyclobutane to give the title compound (39.6 mg, 64% over two steps). LC-MS (Method G): m/z=284.1 [M+H]+; 3.72 min. 1H-NMR (400 MHz, DMSO): δ 13.73 (s, 1H), 8.13 (s, J=1.4, 1H), 8.04 (dd, J=8.0, J=1.4, 1H), 7.94 (d, J=6.0, 1H), 7.50 (d, J=8.0, 1H), 7.19 (d, J=6.0, 1H), 4.02 (s, 3H), 3.68 (s, 5H), 3.61-3.54 (m, 3H), 3.26-3.20 (m, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:1]1([CH2:7][O:8][C:9]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])=[CH:17][CH:18]=2)=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(CCNC(=O)OCc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1ccc(NS(=O)(=O)c2ccccc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
A solution of 868 mg (3.22. mmol) of Cbz amine from Example 3 in 15 mL of dichloromethane was cooled to 0° C. and treated with 0.286 mL (3.54 mmol) of pyridine followed by 569 mg (0.41 mL, 3.22 mmol) of benzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 2 h and then partitioned between chloroform and water. The organic phase was washed sequentially with 5% aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated. Purification by recrystallization from ethyl acetate/hexane gave 630 mg (48%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) 7.72 (d, 2H, J=7.2 Hz), 7.48 (m, 1H), 7.39 (m, 2H), 7.33 (m, 5H), 7.02 (d, 2H, J=8.3 Hz), 6.95 (d, 2H, J=8.3 Hz), 6.55 (s, 1H), 5.06 (s, 2H), 4.68 (broad s, 1H), 3.37 (m, 2H), 2.72 (t, 2H, J=6.9 Hz). FAB MS m/z 411 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:5]=1>C(#N)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:2][CH3:1])[CH:7]=[C:6]([CH2:11][O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:5]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: CN
Solvent: CC#N
Product: CNc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methylamine (0.382 mL of 33% solution in absolute ethanol, 3.06 mmol) was added to a solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (200 mg, 0.77 mmol) in acetonitrile (3 mL). The mixture was stirred at ambient temperature for 30 minutes. The solvents was removed in vacuum, and the residue was purified by preparative HPLC to yield the title compound, 135 mg, (69%).
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][O:6][C:7]([C:9]1[C:17]2[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([C@@H:24]([NH2:26])[CH3:25])=[N:14][C:13]=2[CH:12]=[CH:11][C:10]=1[F:27])=[O:8].Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][N:33]2[CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:5][O:6][C:7]([C:9]1[C:17]2[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([C@@H:24]([NH:26][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][N:33]4[CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[CH3:25])=[N:14][C:13]=2[CH:12]=[CH:11][C:10]=1[F:27])=[O:8]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c12
Temperature: 90 °C
Yield: 68.4 %

Procedure:
To a solution of 2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carboxylic acid methyl ester dihydrochloride dihydrochloride (1.4 g, 3.8 mmol) in IPA (20 mL) was added 6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (1.18 mg, 4.94 mmol) and DIPEA (2.6 mL, 15.2 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give the title compound as a white solid (1.34 g, 67%). LCMS (Method C): RT=3.11 min, [M+H]+=516.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:29])[CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:15]=1.C(N(CC)CC)C>C(O)CC(C)C>[O:13]=[C:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[C:3]([N:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:21]([NH:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)=[O:29])[CH2:24][CH2:25]2)[NH:12]1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: O=C(CN1CCNCC1)Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: O=C(CN1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1)Nc1cccnc1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), N-(3-pyridyl)-2-(piperazin-1-yl)acetamide * 3HCl (251.9 mg; 0.76 mmol) and triethylamine (282.5 μl; 2.04 mmol) are reacted in isoamyl alcohol (2 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up.