Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:8])[CH2:2]1.[Br:10]Br>C(Cl)Cl>[Br:10][CH:2]1[C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH2:7][C:1]1=[O:9]
Reactant: BrBr
Reactant: O=C1CCCCC(=O)C1
Solvent: ClCCl
Product: O=C1CCCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
Into the solution of 1,3-cycloheptanedione (252 mg, 2.0 mmol) in 5 mL of CH2Cl2 was added a solution of Br2 (320 mg, 2.0 mmol) in 2 mL of CH2Cl2. The mixture was stirred at room temperature for 15 minutes. The white solid was collected, washed with CH2Cl2, and dried to give 2-bromo-1,3-cycloheptanedione (330 mg), which was used for next step with no further purification. Into the solution of 2-bromo-1,3-cycloheptanedione (205 mg, 1 mmol) in 5 mL of MeOH was added thiourea (152 mg, 2 mmol) and K2CO3 (276 mg, 2 mmol). The mixture was stirred at 70° C. for 1 hour, cooled down to room temperature. The solution was concentrated, and the residue was partitioned between EtOAc and H2O. The aqueous layer was washed with EtOAc. The combined organic phases were dried (Na2SO4) and concentrated to give the crude thiazole 22a as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:9])=[O:8])=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1sccc1Br
Product: O=C(O)c1sccc1-c1ccc(F)cc1

Procedure:
prepared by reaction of 3-bromo-thiophene-2-carboxylic acid with 4-fluorophenyl-boronic acid. LC-MS (basic): tR=0.47 min; [M−H]−=221.1.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([O:18]C(C)(C)C)=[O:17])[CH2:3]1.Cl>O1CCOCC1>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[CH2:3]1
Reactant: CC(C)c1csc(COc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(O)C4)nc3c2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1csc(COc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCCC(O)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.9 %

Procedure:
tert-Butyl (E)-3-{2-(3-hydroxypiperidino)-8-[(4-isopropyl-1,3-thiazol-2-yl)-methoxy]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (24 mg, 0.046 mmol) was added with a mixture of 4 N hydrochloric acid and dioxane (1 ml) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (chloroform:methanol=15:1) to obtain 24 mg (100%) of the title compound as yellow crystals.
Reaction SMILES: [C:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[C:23]([CH3:26])[C:22]([F:27])=[C:21]([NH2:28])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:29])[CH2:5][CH2:6][CH3:7])(=[O:3])[CH3:2].[H-].[Na+].I[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C)C=O>[C:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[C:23]([CH3:26])[C:22]([F:27])=[C:21]([NH:28][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:29])[CH2:5][CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: CCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)c(C)c(F)c3o2)cc1F
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCNc1c(F)c(C)c(F)c2oc(-c3ccc(N(CCC)C(C)=O)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
299 mg (0.740mmol) of the above 2-[4-[N-acetyl-N-(1-propyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one was dissolved in 10 mL of dimethylformamide under argon atmosphere, 60 mg (1.5 mmol) of sodium hydride (60% oil dispersion) and 0.98 mL (7.4 mmol) of 1-iodopentane were added under ice-cooling and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give 91.2 mg of 2-[4-[N-acetyl-N-(1-propyl)amino]-3-fluorophenyl]-6,8-difluoro-7-methyl-5-(1-pentylamino)-4H-1-benzopyran-4-one (yield: 26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[CH2:12]([CH:14](OS(C)(=O)=O)[CH2:15][CH3:16])[CH3:13].CC([O-])(C)C.[K+].Cl>CS(C)=O.CC([O-])(C)C.[K+].C(OCC)(=O)C>[CH2:12]([CH:14]([O:11][C:4]1[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:15][CH3:16])[CH3:13]
Reactant: CCC(CC)OS(C)(=O)=O
Reactant: COc1cccc(OC)c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC(CC)Oc1c(OC)cccc1OC
Temperature: 50 °C
Yield: 100.2 %

Procedure:
To a yellow solution of 38.5 g 2,6-dimethoxy phenol (0.25 mol) and 83.1 g methanesulfonic acid 1-ethyl-propyl ester (0.50 mol) in 500 ml dimethylsulfoxide was added under stirring at 50° C. a solution of 56,1 g potassium tert-butylate (0.50 mol) in 500 ml dimethylsulfoxide over 4 h. After additional 2.8 g potassium tert-butylate (0.025 mol) were added, stirring at 50° C. was continued for lh. The reaction mixture was distributed between 500 ml ethyl acetate and 600 ml 1N HCl. The organic layer was washed twice with 250 ml, a total of 500 ml deionized water and the aqueous layers were extracted sequentially with 250 ml ethyl acetate. The combined organic layers were dried over ca. 25 Na2SO4, filtered and the solvent was evaporated by rotary evaporation (50° C./≧1 mbar) affording 56.2 g (100.2%) of the title product as an orange oil, which was used without purification in the next step (bp. 90° C./0.03 mbar).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:37])[C:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=1)=[C:13]2[CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([CH3:9])[CH3:8])C>>[C:33]([O:32][C:30]([NH:29][CH2:28][CH2:27][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:7]([CH3:9])([CH3:8])[C:6]([OH:37])=[O:5])[CH:11]=2)[NH:15][C:14]=1[C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNC(=O)OC(C)(C)C)c2c1
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2CCNC(=O)OC(C)(C)C)c1
Temperature: 94 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a stirred solution of 2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester (665 mg in 20 mL methanol) was added 7 mL of 2.0N potassium hydroxide and the mixture heated to 94° C. on an oil bath. After 6 hours the mixture was acidified to pH5 and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (620 mg).
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=2)=O)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(#N)C>[CH:1]1([C:4]2[O:16][C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=3)=[N:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: O=C(NNC(=O)C1CC1)c1cccc(I)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Ic1cccc(-c2nnc(C3CC3)o2)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
N′-Cyclopropanecarbonyl-3-iodobenzoic hydrazide (535 mg, 1.62 mmol) obtained in Step 1 was suspended in acetonitrile (20 mL), and the mixture was stirred at 60° C. for 6 hours after adding triphenylphosphine (850 mg, 3.24 mmol), carbon tetrachloride (0.63 mL, 6.48 mmol), and triethylamine (0.45 mL, 3.24 mmol). The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give 2-cyclopropyl-5-(3-iodophenyl)-1,3,4-oxadiazole (499 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:17][C:18]1[C:23]([CH2:24][C:25](O)=[O:26])=[CH:22][CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[N:19]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.BrC1C(C2C=CC(Cl)=CC=2)=CC(NNC(=O)CC2C=NC(C(F)(F)F)=CC=2)=NC=1>CC#N>[Br:1][C:2]1[C:3]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:4][C:5]([NH:8][NH:9][C:25](=[O:26])[CH2:24][C:23]2[C:18]([CH3:17])=[N:19][C:20]([C:28]([F:29])([F:31])[F:30])=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CC(=O)O
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)ccc1CC(=O)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Yield: 97 %

Procedure:
The title compound (160 mg, 97%) as a beige powder was prepared from 5-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine (100 mg, 0.33 mmol), 2-(2-methyl -6-(trifluoromethyl)pyridin-3-yl)acetic acid (75 mg, 0.33 mmol), (i-Pr)2EtN (86 mg, 0.66 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBop, 190 mg, 0.37 mmol) in CH3CN (2.5 mL) by the procedures analogous to those described for N′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide (Example 56C). LC/MS (method B): retention time=1.92 min, [M+H]+=499.0.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[C@H:15]([CH2:19][CH2:20][C:21]1([CH3:26])[O:25][CH2:24][CH2:23][O:22]1)[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:28]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]([CH2:19][CH2:20][C:21]1([CH3:26])[O:25][CH2:24][CH2:23][O:22]1)[CH2:16][CH:17]=[O:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](CCC1(C)OCCO1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(CC[C@H](CC=O)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)OCCO1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-10 (16.0 g, 42.8 mmol) and Sudan III dye (10 mg) in dichloromethane (500 mL) at −78° C. was bubble ozone until the color of the dye was discharged (45 min.), after which time the solution was purged with argon for 0.5 h. Triphenylphosphine (16.9 g, 64.3 mmol) was added and the solution was allowed to warm to ambient temperature for 3 h. The reaction mixture was concentrated at reduced pressure and the resulting oil was purified by flash column chromatography (silica gel, 10 to 20% ethyl acetate/dichloromethane) to give 1-11 as an oil which crystallized on standing.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19](O)=[O:20])[C:14]=1[CH3:22].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C:60](=[O:73])[C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH2:68][CH2:69][CH2:70][CH2:71][NH2:72])=[N:63][CH:62]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][C:60](=[O:73])[C:61]1[CH:66]=[CH:65][C:64]([NH:67][CH2:68][CH2:69][CH2:70][CH2:71][NH:72][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:20])=[N:63][CH:62]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Reactant: NCCCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (300 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(4-aminobutylamino)nicotinamide (314 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (447 mg, 77%) as a yellow solid. 1H NMR (DMSO-d6)δ1.59 (m, 4H, CH2CH2), 2.39 (s, 3H, pyrrole-CH3), 2.41 (s, 3H, pyrrole-CH3), 3.25 (m, 4H, 2×CH2), 4.85 (s, 2H, benzene-NH2), 6.49 (m, 1H), 6.57 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.83 (m, 1H), 6.91 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 7.67˜7.76 (m, 3H), 7.90 (d, J=8.0 Hz, 1H), 8.63 (s, 1H), 9.35 (s, 1H, benzene-NH), 10.88 (s, 1H, indolinone-NH), 13.66 (s, 1H, pyrrole-NH). LC-MS (m/z) 582 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][C:9]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].F[C:20]1[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][CH:25]=1>CN(C)C=O>[C:3]([N:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([O:18][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: CC(=O)N1CCC(O)(c2ccccc2)CC1
Reactant: Fc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 20.9 %

Procedure:
A stirred suspension of sodium hydride (60% in oil, 1.8 g) in 35 ml of dimethylformamide was treated with a solution of 9.00 g of 1-acetyl-4-hydroxy-4-phenylpiperidine in 100 ml of dimethylformamide and heated at 70° C. until evolution of gas had ceased. A solution of 7.38 g of 3-fluorobenzotrifluoride in 20 ml of dimethylformamide was added, dropwise, and the reaction allowed to proceed at 70° C. for 20 hours. The reaction mixture was then poured into an ice/water mixture and the aqueous suspension extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. High pressure liquid chromatography of the oil (silica gel; elution with 50% ethyl acetate/dichloromethane) afforded 3.11 g (20.90%) of 1-acetyl-4-phenyl-4-(3-trifluoromethylphenoxy)piperidine, m.p. 100°-103° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[S:16][C:17]([CH:20]=O)=[CH:18][N:19]=1>ClCCl>[Cl:14][C:15]1[S:16][C:17]([CH:20]=[N:1][C:2]2[C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:18][N:19]=1
Reactant: O=Cc1cnc(Cl)s1
Reactant: Nc1ncccc1-c1ccccc1
Solvent: ClCCl
Product: Clc1ncc(C=Nc2ncccc2-c2ccccc2)s1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
2-Amino-3-phenylpyridine (i.e. the product of Step A, 0.342 g, 2.01 mmol) was added to 2-chloro-1,3-thiazole-5-carbaldehyde (0.296 g, 2.01 mmol) in dichloromethane (10 mL) at room temperature. The suspension was stirred for 10 min and then concentrated to dryness under vacuum. The resulting residue was heated to 90° C. for 20 min on a rotory evaporator with a non-returning bump trap to facilitate water removal. The residual yellow solid was again dissolved in dichloromethane (10 mL) and heated to 90° C. on a rotory evaporator for an additional 20 min. At this time the yellow solid was checked by NMR to verify reaction completion. The title compound was obtained as a yellow solid and used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25])#[N:15].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[NH2:8][C:6]1[N:7]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[C:17]([F:25])[CH:18]=2)[CH:3]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)Nc1cc(Cl)nc(N)n1
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: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Into a 25 mL sealable tube under nitrogen were combined 6-chloro-N4-(1,1-dimethylethyl)-2,4-pyrimidinediamine (440 mg, 2.19 mmol) and (4-cyano-3-fluorophenyl)boronic acid (0.416 g, 2.52 mmol) in 1,4-dioxane (8 mL). Saturated aqueous NaHCO3 (4 mL) was added, and the resulting mixture was degassed with nitrogen for 10 minutes. Pd(Ph3P)4 (0.127 g, 0.11 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 95° C. overnight. The reaction was cooled to room temperature, solids and other insoluble impurities formed during the reaction were filtered, and the orange filtrate was concentrated. The resulting solid was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated. The resulting solid was dissolved in DMSO and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA). Fractions were evaporated and solids were triturated in Et2O and filtered to afford the title compound (553 mg). LC-MS (ES) m/z=286 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:19])[C:15](=[CH:17][CH3:18])[CH3:16])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]>S(=O)(=O)(O)O>[O:19]=[C:14]1[C:11]2[C:10](=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([Cl:1])[C:12]=2[Cl:13])[CH:17]([CH3:18])[CH:15]1[CH3:16]
Reactant: CC=C(C)C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: CC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1C

Procedure:
[2,3-Dichloro-4-(2-ethylidenepropionyl)phenoxy]acetic acid (18.4 g., 0.061 mole) in concentrated sulfuric acid (110 ml.) is cyclized in the manner of Example 1, Step A, to afford 5.8 g. of (1-oxo-2,3-dimethyl-6,7-dichloro-5-indanyloxy)acetic acid, m.p. 174°-176° C., after recrystallization from ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[C:24]([Si:21]([CH3:23])([CH3:22])[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1cc2c(cc1O)C(C)(C)CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of 6-hydroxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 171, 2.04 g, 10 mmol) in anhydrous N,N-dimethyl formamide (10 mL) under argon was treated with imidazole (1 g, 14.7 mmol) followed by tert-butyldimethylsilyl chloride (1.5 g, 10 mmol). After stirring the reaction mixture at ambient temperature overnight, it was poured into water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to a residue that was purified by flash column chromatography on silica gel (230–400 mesh) usng 8–14% ethyl acetate in hexane as the eluent to afford the title compound (2.5 g, 79%).
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)[CH:24]=[CH:25][CH:26]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:18][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:37])([F:19])[F:36])[CH:22]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:17]
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)c3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)c3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-leucine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[3-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 605 Step B for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.34 (d, J=7.4, 1H), 7.34 (t, J=7.9, 1H), 7.06 (d, J=7.6, 1H), 6.94 (s, 1H), 6.78 (dd, J=8.3, 2.2, 1H), 4.46-4.38 (m, 1H), 3.55 (dd, J=9.9, 2.8, 1H), 3.37-3.32 (m, 1H), 3.27 (dd, J=8.3, 5.8, 1H), 3.17 (dd, J=9.5, 7.9, 1H), 3.01 (dd, J=9.7, 3.3, 1H), 2.79-2.70 (m, 2H), 2.46 (s, 3H), 0.2-1.86 (br s, 1H), 2.13 (dt, J=12.5, 6.7, 1H), 2.01-1.87 (m, 2H), 1.79-1.65 (m, 2H), 1.65-1.57 (m, 1H), 1.46-1.38 (m, 1H), 0.94 (d, J=6.6, 3H), 0.88 (d, J=6.6, 3H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)C>[CH2:29]([N:28]([CH3:27])[C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)[NH:10][C:4]=12)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CNCc1ccccc1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Solvent: CCOCC
Product: CN(Cc1ccccc1)c1c(Cl)cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c12
Yield: 42 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.10 g, 0.25 mmol) and N-methylbenzylamine (0.7 ml) were heated to 180° C. for 3 h. The reaction mixture was diluted with diethyl ether (15 ml) and extracted with 2M HCl (40 ml). The aqueous phase was basified with 10M NaOH and extracted with EtOAc. The organic phase was evaporated in vacuo and the oily residue became crystalline. The crystals were washed with tert-butyl methyl ether to afford the pure product (42%).
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn]([C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)(CCCC)CCCC)CCC>O1CCOCC1.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>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)([O-:9])=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1csc([N+](=O)[O-])c1-c1cnccn1
Temperature: 140 °C
Yield: 53.3 %

Procedure:
To a solution of 4-bromo-5-nitrothiophene-3-carbonitrile (312 mg, 1.34 mmol) in dioxane (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (154 mg, 0.133 mmol) and tributylstannylpyrazine (794 mg, 2.15 mmol). This was heated by microwave irradiation to 140° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue purified by flash chromatography to afford the titled compound (166 mg, 53%): Rf=0.33 (20% EtOAc/hexanes; silica); HPLC method [4], retention time=1.45 min; MS (ESI) 233.0 (MH+).