Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]([CH:23]1[CH2:25][CH2:24]1)#[CH:22]>C(NCC)C.CS(C)=O.C(OCC)(=O)C.[Cu]I>[CH:23]1([C:21]#[C:22][C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: C#CC1CC1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCNCC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C#CC3CC3)cn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
In a sealed tube, the mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (1.0 g, 2.9 mmol), ethynylcyclopropane (482 mg, 7.3 mmol), tetrakis(triphenyl-phosphine)palladium (335 mg, 0.29 mmol) and copper(I) iodide (28 mg, 0.15 mmol) in diethylamine (10 mL) and dimethyl sulfoxide (10 mL) was stirred at 100° C. for 3 hours under nitrogen atmosphere. The mixture was then diluted with ethyl acetate (100 mL) and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate=15:1 to afford tert-butyl 4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazine-1-carboxylate (930 mg, 98%) as a yellow solid. MS (ES+) C18H24N4O2 requires: 328, found: 329 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:3]([N:5]1[CH2:9][C@@H:8]([CH3:10])[CH2:7][C@H:6]1[C:11]1[NH:12][C:13]([C:16]2[CH:29]=[C:28]3[O:30][CH2:31][C:25]4[C:26]5[C:27]3=[C:18]([CH2:19][O:20][C:21]=5[CH:22]=[C:23]([C:32]3[NH:36][C:35]([C@@H:37]5[CH2:41][C@H:40]([CH3:42])[CH2:39][N:38]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49](=[O:52])[O:50][CH3:51])[CH:45]([CH3:47])[CH3:46])=[N:34][CH:33]=3)[CH:24]=4)[CH:17]=2)=[CH:14][N:15]=1)=[O:4].[CH3:60][C:61]1([CH3:69])[C:63]([CH3:65])([CH3:64])[CH:62]1[C:66](O)=[O:67].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C.CN(C=O)C.O.C(O)=O.CO>[CH3:47][CH:45]([CH3:46])[C@H:44]([NH:48][C:49](=[O:52])[O:50][CH3:51])[C:43]([N:38]1[CH2:39][C@@H:40]([CH3:42])[CH2:41][C@H:37]1[C:35]1[NH:36][C:32]([C:23]2[CH:24]=[C:25]3[CH2:31][O:30][C:28]4[C:27]5=[C:18]([CH:17]=[C:16]([C:13]6[NH:12][C:11]([C@@H:6]7[CH2:7][C@H:8]([CH3:10])[CH2:9][N:5]7[C:3](=[O:4])[C@@H:2]([C:54]7[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=7)[NH:1][C:66]([CH:62]7[C:63]([CH3:65])([CH3:64])[C:61]7([CH3:69])[CH3:60])=[O:67])=[N:15][CH:14]=6)[CH:29]=4)[CH2:19][O:20][C:21]([CH:22]=2)=[C:26]35)=[CH:33][N:34]=1)=[O:53]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc([C@@H]6C[C@H](C)CN6C(=O)[C@H](N)c6ccccc6)[nH]5)cc(c2-4)OC3)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=CO
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc([C@@H]6C[C@H](C)CN6C(=O)[C@H](NC(=O)C6C(C)(C)C6(C)C)c6ccccc6)[nH]5)cc(c2-4)OC3)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Methyl (S)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-amino-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (45 mg, 0.049 mmol) in 0.5 mL 10% DIPEA in DMF was added to a mixture of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (8.4 mg, 0.059 mmol) and HATU (22 mg, 0.059 mmol) in 0.2 mL 10% DIPEA in DMF. After 20 minutes stirring at room temperature, the reaction mixture was diluted with 0.2 mL water, 5 drops formic acid, and methanol to a total volume of 2.4 mL and purified by reverse phase HPLC to give 22.6 mg product as a trifluoroacetate salt.
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=O>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[CH2:17][CH2:18][N:20]([CH2:21][CH3:22])[CH2:23][CH3:24]
Reactant: CCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: B
Solvent: C1CCOC1
Product: CCN(CC)CCc1ccc([N+](=O)[O-])cc1Cl
Reaction time: 4 h

Procedure:
65 mL (65 mmol) of a 1M borane-THF solution is added dropwise to a solution of 3.7 g (13.67 mmol) of 2-(2-chloro-4-nitrophenyl)-N,N-diethylacetamide in 130 mL of THF at ambient temperature and stirred for 4 hours. Then the reaction mixture is evaporated down and the residue is combined with 15 mL of methanol and 15 mL of dilute hydrochloric acid. The mixture is then stirred for 15 minutes at 100° C., cooled, and diluted with water. Then the mixture is made alkaline with sodium carbonate solution and extracted twice with ethyl acetate. The combined organic phases are extracted twice with water and once with saturated saline solution and dried over sodium sulfate. The purification is carried out by column chromatography on Alox, neutral, act. II-III (eluant: petroleum ether/ethyl acetate (4:1)). Yield: 2.1 g (59.8% of theory); C12H17ClN2O2 (M=256.73); Rf value: 0.63 (Alox, petroleum ether/ethyl acetate (3:1)).
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:30][CH:31]=1
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.065 g, 0.23 mmol), methyl-4-iodophenylacetate (0.063 g, 0.23 mmol), triethyl amine (8 mL), copper(I)iodide (0.018 g, 0.093 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.065 g, 0.093 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.09 g, 90%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[N:31]1([CH2:36][CH2:37][NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[O:30]=[C:4]1[C:3](=[CH:2][NH:46][C:43]2[CH:44]=[CH:45][C:40]([CH2:39][NH:38][CH2:37][CH2:36][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:41][CH:42]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(CNCCN2CCCC2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CNCCN4CCCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 30.5 %

Procedure:
small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 200 mg, 0.498 mmol) and THF (4 mL). To the resulting solution was added 4-[(2-Pyrrolidin-1-yl-ethylamino)-methyl]-phenylamine (prepared below; 109.2 mg, 0.498 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜5 mL of EtOAc. Hexanes were added causing a yellow precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 31% (0.092 g, 0.152 mmol) of the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([O-])(O)=O.[Na+].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH3:30])[CH:21]=1>C1(C)C=CC=CC=1.CCO.[Cl-].[Na+].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>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)=[C:22]([O:29][CH3:30])[CH:21]=1
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: COc1cc(F)ccc1B(O)O
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: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(F)ccc1-c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 95 °C
Yield: 80.5 %

Procedure:
In a round bottom flask under argon, 4-bromo-2-trifluoromethylbenzonitrile (1 g, 4 mmol) was solubilized in a mixture of toluene (55 mL) and EtOH (20 mL). Aq. NaHCO3 (20 ml, 5 eq., 0.8 M solution) and 4-fluoro-2-methoxyphenylboronic acid (816 mg, 4.8 mmol) were added. The mixture was degassed under the stream of argon for 10 min. Then Pd(PPh3)4 (462 mg, 0.4 mmol) was added and the mixture was heated at 95° C. for 2 hr. After it was cooled, the mixture was poured in brine and extracted with CH2Cl2. This organic layer was dried (MgSO4), filtered and evaporated. Chromatography on a silica gel (250 ml, EtOAc:hexanes, 1:9), gave a white solid (951 mg, 81%), 1H NM (300 MHz, acetone-d6)δ: 8.02-8.14 (m, 3H, C2,5,6—H), 7.53 (dd, 1H, J=8, 7 Hz, C6′—H), 7.03 (dd, 1H, J=11, 2 Hz, C3′—H), 6.89 (td, 1H, J=8, 2Hz, C5′—H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Si:39]([O:46][C:47]1[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])=[CH:53][C:52]([Br:63])=[CH:51][C:48]=1[CH:49]=O)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>O1CCCC1.CCCCCC.C(OC)(C)(C)C>[Br:63][C:52]1[CH:51]=[C:48](/[CH:49]=[CH:7]\[C:6]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:4]([O:3][CH3:2])[CH:5]=2)[C:47]([O:46][Si:39]([C:42]([CH3:45])([CH3:43])[CH3:44])([CH3:41])[CH3:40])=[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:57])[CH3:58])[CH:53]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(C=O)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(/C=C\c2cc(Br)cc(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.9 %

Procedure:
A suspension of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (1.69 g, 3.23 mmol) in tetrahydrofuran (30 mL) was cooled to 0° C. and butyllithium (2 mL of a 1.6 N solution in hexane, 3.23 mmol) was added dropwise. The brick red solution was stirred at 0° C. for 20 min, then a solution of 19 (0.96 g, ca 2.2 mmol) in tetrahydrofuran (12 mL) was added dropwise. The temperature was allowed to rise to room temperature overnight, than the reaction was diluted with tert-butylmethyl ether (ca 100 mL) and washed with water (ca 50 mL, containing 1 mL 2N HCl) then brine (30 mL). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give a crude which was purified by column (elution with cyclohexane:AcOEt 10:1) to give 0.75 g of 20 still impure with 20% of the E isomer.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:20].[N:21]1([CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:37][C:34]4[CH:35]=[CH:36][C:31]([O:30][CH2:29][CH2:28][CH2:27][N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:32][CH:33]=4)[C:4](=[O:20])[NH:5]3)=[CH:10][CH:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=CNc2ccc(OCCCN3CCCCC3)cc2)c1
Temperature: 25 °C

Procedure:
The named compound is prepared by refluxing 0.020 gms E & Z 3-hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (see example 268) with 0.0375 gms 4-(3-piperidin-1-yl-propoxy)-phenylamine (used in the preparation of Example 218) in tetrahydrofuran (0.33 mL) for 36 h. Following cooling to room temperature, solvent evaporation in vacuo, trituration with isopropanol and filtration the reaction yields the named compound as a solid in the amount of 16.8 mg.
Reaction SMILES: C([O:4][C:5]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8])(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:20]([C:17]1[CH:18]=[CH:19][C:5]([OH:4])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:8])#[CH:21]
Reactant: CC(=O)Oc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(O)c(C(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 100 mg (0.3 mmol) of 2-acetoxy-5-trimethylsilanylethynyl-4'-methylbenzophenone (Compound X) in 5 mL of tetrahydrofuran (under a blanket of argon) was added 0.86 mL (0.86 mmol) of tetrabutylammonium fluoride (1M in tetrahydrofuran). The resultant yellow solution was stirred at ambient temperature for 30 minutes, diluted with water (1 mL), extracted between ethyl ether and 10% HCl (aq.) solution, the layers separated and the aqueous phase washed with ethyl ether. The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica, 3% ethyl acetate in hexane) gave the title compound as an oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[N:27]=4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9](=[O:44])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:7][CH2:8]1)#[N:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C4CC4)c3n2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
In a round-bottomed flask, 2-(1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.158 g, 0.193 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.6 ml, 7.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was redissolved in dichloromethane (1 ml) and ethylenediamine (0.8 ml, 11.7 mmol) was added. The solution was stirred at room temperature for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with MeOH/CH2Cl2 (0.5% NH4OH) (gradient 0-4% MeOH) followed by trituration with ethyl acetate to afford 31 mg (32%) of 2-(1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a light yellow powder. MS: (M+H)+=483; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.89 (br. s., 1H), 9.17 (s, 1H), 8.79 (d, J=7.9 Hz, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.45 (d, J=9.4 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.13-7.33 (m, 1H), 4.88 (t, J=7.9 Hz, 1H), 4.19 (s, 3H), 3.68-4.05 (m, 2H), 3.34-3.66 (m, 2H), 3.14 (br. s., 1H), 1.47-2.07 (m, 4H), 1.34 (br. s., 1H), 0.37-0.65 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32].O>O1CCCC1.C(OCC)(=O)C>[C:31]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: Nc1nc2ccc(Oc3cccc(NC(=O)C(F)(F)F)c3)cc2s1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)C(F)(F)F)c3)cc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-2,2,2-trifluoroacetamide (10.0 g, 28.3 mmol) and pyridine (3.36 g, 42.5 mmol) in tetrahydrofuran (150 mL) was added acetyl chloride (2.44 g, 31.1 mmol), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture were added water (300 mL) and ethyl acetate (500 mL), and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was triturated with ethyl acetate/diisopropyl ether to give the title compound (10.6 g, 95%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[S:18][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:19]([O:21]CC)=O.[NH3:24].C(Cl)Cl>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[S:18][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:19]([NH2:24])=[O:21]
Reactant: CCOC(=O)c1c(Nc2ccc(I)cc2F)sc2ncccc12
Reactant: N
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc(I)cc2F)sc2ncccc12
Temperature: 95 °C

Procedure:
A solution of Example 1 (250 mg, 0.56 mmol) in ethanol (5 mL) was added to liquid ammonia (15 mL) and the mixture heated in a Parr apparatus to 95° C. at 800 psi for 18 hours. The volatiles were removed in vacuo to give an oily brown residue. Repeated trituration with ethanol and DCM afforded the title compound as a white solid (18 mg). δH (DMSO-d6) 11.20 (1H, bs), 8.34 (1H, d, J 3.4 Hz), 8.20 (1H, dd, J 8.2, 1.3 Hz), 7.76 (1H, dd, J 10.4, 1.8 Hz), 7.62 (1H, d, J 8.2 Hz), 7.57 (2H, br s), 7.49-7.39 (2H, m). LCMS (ES+) RT 3.11 minutes, 412 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([NH:5][CH2:6][CH2:7]2)[CH2:3]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:5]2[CH2:6][CH2:7][C@@H:8]3[CH2:9][N:2]([CH3:1])[CH2:3][C@H:4]23)=[CH:13][CH:12]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Temperature: 70 °C

Procedure:
The product of Example 7B (2.30 g, 18.2 mmole), 1,4-dibromobenzene (5.16 g, 20.9 mmole), tris(dibenzylideneacetone)dipalladium (340 mg, 0.36 mmole), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (460 mg, 0.73 mmole) and sodium tert-butoxide (2.63 g, 27.3 mmole) were dissolved in 20 ml of toluene and heated to 70° C. under N2 for 16 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (5×). The combined organics were dried over sodium sulfate, filtered and concentrated and purified by chromatography (eluting with a mixture of 5% methanol in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.25-7.30 (m, 2H) 6.41-6.46 (m, 2H) 4.07 (m, 1H) 3.47 (ddd, J=9.1, 7.7, 5.9 Hz, 1H) 3.19 (dt, J=8.9, 7.3 Hz, 1H) 2.95 (m, 1H) 2.68 (dd, J=9.0, 3.0 Hz, 1H) 2.55-2.60 (m, 3H) 2.32 (s, 3H) 2.13-2.22 (m, 1H) 1.88-1.98 (m, 1H). MS: (M+H)+=281/283.
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.Br[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=2)[CH:30]=[C:29]([CH3:44])[CH:28]=1.[S:45]1[CH:49]=[CH:48][N:47]=[CH:46]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C(C)(C)C>CC(N(C)C)=O.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[CH3:44][C:29]1[CH:28]=[C:27]([C:49]2[S:45][CH:46]=[N:47][CH:48]=2)[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=2)[CH:30]=1
Reactant: c1cscn1
Reactant: Cc1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC(C)(C)C(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cncs2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
In a dry flask, allylpalladium(II) chloride dimer (1.333 g, 3.64 mmol) and butyldiadamantylphosphine (5.23 g, 14.57 mmol) were taken-up in degassed dimethylacetamide (50 mL). The vessel was evacuated and backfilled with argon (3 times), and then stirred at rt for 10 minutes. Additional degassed dimethylacetamide (50 mL), 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (12.1 g, 36.4 mmol), thiazole (10.36 mL, 146 mmol), potassium carbonate (15.11 g, 109 mmol), and pivalic acid (6.34 mL, 54.6 mmol) were added. The vessel was evacuated and backfilled with argon (3 times) and stirred under argon at 130° C. overnight. The reaction mixture was then diluted with EtOAc (500 mL), cooled to rt, filtered through Celite®, and concentrated. Water was added to the crude product mixture and the resulting precipitate was collected via filtration and subjected to silica gel flash chromatography (ethyl acetate-hexanes). Purification yielded 4-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (5.29 g, 15.72 mmol, 43% yield) as a yellow solid. MS ESI calcd for C15H11F3N4S [M+H]+ 337, found 337. 1H NMR (600 MHz, DMSO) δ 10.21 (s, 1H), 9.14 (s, 1H), 8.59 (s, 1H), 8.52 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 7.43 (s, 1H), 7.20 (d, J=5.1 Hz, 1H), 7.11 (s, 1H), 2.30 (s, 3H) ppm.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[CH:12][CH:11]=1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C2Cc3ccccc3O2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C2Cc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of tert-butyl 4-(2,3-dihydrobenzofuran-2-yl)benzoate (0.03 g, 0.1 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was removed in vacuo, and the mixture was dissolved in dichloromethane (50 mL), washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give pure product 4-(2,3-dihydrobenzofuran-2-yl)benzoic acid as a white solid (0.02 g, 80%).