Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH2:36][NH:37][CH2:38][CH2:39][CH2:40][OH:41]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:37]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:36][C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]=2)=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: OCCCNCc1ccc2ccccc2n1
Product: Cc1ccc(N(CC(=O)N(CCCO)Cc2ccc3ccccc3n2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-[(quinolin-2-ylmethyl)-amino]-propan-1-ol
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[Br:11]Br>C(Cl)(Cl)Cl.C(O)(=O)C.Br>[BrH:1].[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH2:9][Br:11])[CH:5]=[N:6][CH:7]=1
Reactant: BrBr
Reactant: CC(=O)c1cncc(Br)c1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)c1cncc(Br)c1
Temperature: 25 °C

Procedure:
4 g (0.02 mol) of 5-bromo-3-acetyl-pyridine are dissolved in 50 ml of chloroform, 5 drops of glacial acetic acid/hydrobromic acid (35%) are added and the mixture is heated to boiling. To this boiling solution, 3.2 g (0.02 mol) of bromine in 30 ml of chloroform are added dropwise over a period of 5 hours with stirring. After cooling to ambient temperature the yellow solid product is suction filtered.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:54][N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:68]=[CH:67][C:65]([NH2:66])=[CH:64][CH:63]=2)[CH2:57][CH2:56]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:66][C:65]3[CH:64]=[CH:63][C:62]([O:61][CH:58]4[CH2:59][CH2:60][N:55]([CH3:54])[CH2:56][CH2:57]4)=[CH:68][CH:67]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: CN1CCC(Oc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(Oc2ccc(NC(=O)c3cccc(N4CCc5nc(N)ncc5C4)c3)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (63 mg, 0.165 mmol) in 1.5 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 10 minutes 4-((1-methylpiperidin-4-yl)oxy)aniline (46 mg, 0.225 mmol) was added and the reaction continued at room temperature for 3 hours. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with EtOAc to give the title compound as an off-white solid (48 mg, 70%). 1H NMR (DMSO-d6) δ: 10.02 (s, 1H), 8.13 (s, 1H), 7.60-7.67 (m, 2H), 7.49 (s, 1H), 7.30-7.40 (m, 2H), 7.20 (dt, J=7.7, 2.0 Hz, 1H), 6.90-6.96 (m, 2H), 6.40 (s, 2H), 4.28 (s, 2H), 4.26-4.35 (m, 1H), 3.64 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 2.56-2.66 (m, 2H), 2.17 (s, 3H), 2.10-2.21 (m, 2H), 1.86-1.97 (m, 2H), 1.55-1.69 (m, 2H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[CH3:18])[O:14][CH2:13][C:12]1[N:7]2[CH:8]([CH3:20])[C:9](=[O:19])[NH:10][N:11]=1.Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[CH3:18])[O:14][CH2:13][C:12]1[N:7]2[CH:8]([CH3:20])[C:9](=[O:19])[N:10]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:11]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cc2c(cc1Br)N1C(=NNC(=O)C1C)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1Br)N1C(=NN(COCC[Si](C)(C)C)C(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a suspension of NaH (60%, 0.387 g, 9.67 mmol) in DMF (15 mL) was added 6-bromo-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.0 g, 6.45 mmol) in portions and the reaction mixture was stirred at 0° C. for 0.5 h. (2-(Chloromethoxy)ethyl)trimethylsilane (1.613 g, 9.67 mmol) was added and the reaction mixture was warmed to ambient temperature and stirred for 2 h. Water (100 mL) was added and the aqueous solution was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 30% EtOAc in petroleum ether) to give 6-bromo-4,7-dimethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as solid (2.24 g, 79%). 1H NMR (DMSO-d6, 400 MHz): δ 7.52 (s, 1H), 7.12 (s, 1H), 5.01 (m, 2H), 4.95 (m, 1H), 4.68 (s, 2H), 3.60 (m, 2H), 2.28 (s, 3H), 1.32 (m, 3H), 0.89 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].CN(C)CCN(C)C.C([Li])CCC.[I:27]I>O.O1CCCC1>[I:27][C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ncccc1I
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethyl-N-pyridin-2-yl-propionamide described in Preparation Example 1-1-1 (3.0 g, 17 mmol), N,N,N′,N′-tetramethyl ethylenediamine (6.3 mL, 42 mmol) and tetrahydrofuran (60 mL) was added n-butyl lithium (1.6M n-hexane solution, 30 mL, 47 mmol) dropwise at −78° C, which was stirred overnight at 0° C. To the reaction mixture was added iodine (6.8 g, 27 mmol) at −78° C, which was stirred at 0° C for 1.5 hours. To the reaction mixture were added water and a saturated aqueous solution of sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride water, and the solvent thereof was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (2.9 g).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[Br:15][C:16]1[N:17]=[C:18]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)c1ccn2c(-c3cccc(Br)n3)cnc2c1F
Yield: 60 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (194 mg, 1.0 mmol) was coupled with 2,6-dibromopyridine (403 mg, 1.7 mmol) using Cs2CO3 (652 mg, 2.0 mmol), as described in Example 4, affording 2-[3-(6-bromopyridin-2-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as a white amorphous solid (210 mg, 60%): m/z (ES+) 350, 352 (100%, [MH]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([N:16]([CH2:28][CH3:29])[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]([CH3:27])[NH:22][CH2:21][CH2:20]2)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[C:17]([N:16]([CH2:28][CH3:29])[CH2:14][CH3:15])[CH:18]=4)[CH:23]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCN(CC)c1ccc2c(c1)CCNC2C
Product: CCN(CC)c1ccc2c(c1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-amine to provide the title compound in moderate yield.
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([OH:15])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[P:17]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.FC(F)(F)C(O)=O>O1CCCC1>[CH:24]1([P:17]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:12]([OH:15])(=[O:14])=[O:13])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(O)c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
n-Butyllithium (manufactured by Kanto Chemical Co., Inc., 1.65 M hexane solution, 5.1 ml, 8.4 mmol) was added to a tetrahydrofuran (THF) solution (20 ml) of benzenesulfonic acid (manufactured by Tokyo Chemical Industry Co., Ltd., 0.66 g, 4.2 mmol) at 0° C. under argon atmosphere and the mixture was stirred for 2.5 hours at room temperature. After cooling the reaction container to −78° C., chlorodicyclohexylphosphine (manufactured by Sigma-Aldrich, 0.89 mg, 3.8 mmol) was added thereto at −78° C. and stirred for 24 hours at room temperature. After ceasing the reaction with trifluoroacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd., 0.50 M THF solution, 8.4 ml, 4.2 mmol), the precipitate formed was collected by filtration and dried under reduced pressure to obtain 2-(dicyclohexylphosphino)benzenesulfonic acid (compound 1a). The yield was 0.66 g (85%).
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].[F:14][C:15]([F:30])([F:29])[C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]([CH2:25][C:26](O)=[O:27])[N:17]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C>[F:30][C:15]([F:14])([F:29])[C:16]1[C:24]2[CH2:23][CH2:22][CH:21]=[CH:20][C:19]=2[N:18]([CH2:25][C:26]([NH:1][C:2]2[S:10][C:5]3[CH2:6][O:7][CH2:8][CH2:9][C:4]=3[C:3]=2[C:11]([NH2:13])=[O:12])=[O:27])[N:17]=1
Reactant: NC(=O)c1c(N)sc2c1CCOC2
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2C=CCC3)sc2c1CCOC2
Temperature: 120 °C
Yield: 9 %

Procedure:
2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide (40 mg, 0.20 mmol) and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydroindazole-1-yl)acetic acid (50 mg, 0.20 mmol) were dissolved in DCM/DMF (3 mL/50 μL) and polymer supported carbonyldiimidazole (330 mg, 1.2 mmol/g, 0.396 mmol) added. The reaction mixture was heated at 120° C. for 10 min in the microwave. The reaction mixture was filtered washing with MeOH (10 mL), EtOAc (10 mL), and MeCN (10 mL). The filtrate was concentrated in vacuo to give a yellow gum. Purification by preparative reverse phase HPLC gave desired product as a white solid (7.6 mg, 0.018 mmol, 9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][OH:6].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][O:6][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.5 %

Procedure:
A solution of 3-bromo-5-nitrobenzyl alcohol (5 g, 21.5 mmol), in N,N-dimethylformamide (5 mL) was treated with tert-butyldimethylsilyl chloride (4.9 g, 32.3 mmol) and imidazole (2.5 g, 36.6 mmol) and stirred at room temperature for 14 h. The reaction was quenched with water and extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica (0-75% ethyl acetate in hexanes) afforded [(3-bromo-5-nitrobenzyl)oxy](tert-butyl)dimethylsilane (7.32 g, 20.1 mmol, 93% yield) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.Cl.[N:17]1([CH2:23][CH2:24][C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([C:34](Cl)=[O:35])[N:26]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([C:27]2[N:26]=[C:25]([CH2:24][CH2:23][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=23)=[O:35])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Reactant: Nc1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To a solution of 3-fluoroaniline (0.052 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (30 mg, 18%). 1H NMR (DMSO-d6) δ 10.02 (1H), 8.45 (1H), 8.15 (1H), 7.88 (1H), 7.70 (1H), 7.43 (1H), 7.20 (1H), 6.95 (1H), 6.85 (1H), 3.58 (4H), 3.25 (2H), 2.80 (2H), 2.44 (4H); m/z (M+H)=369.22.
Reaction SMILES: Br.[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]=2[CH2:9][O:8]1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH2:6][CH2:5][CH2:4][N:3]([CH3:25])[CH3:2])([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[O:8][CH2:9][C:10]=2[CH:15]=1)=[NH:17])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: Br
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C(=N)NCc3ccccc3)ccc21
Temperature: 80 °C
Yield: 19 %

Procedure:
Using 250 mg of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile hydrobromide (citalopram HBr) and benzylamine (1.2 equiv) gave, after heating at 80° C. for 14 h, title product (72 mg, 19% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1)#[CH:2].I[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.C(OCC)(=O)C>C(N(CC)CC)C.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.[Cu]I>[C:19]([C:18]1[CH:22]=[CH:23][C:15]([C:2]#[C:1][C:3]2[C:4]3[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=3[S:6][CH:7]=2)=[CH:16][CH:17]=1)([OH:21])=[O:20]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#Cc1csc2cccc(OC)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cccc2scc(C#Cc3ccc(C(=O)O)cc3)c12
Yield: 97.7 %

Procedure:
3-Ethynyl-4-methoxybenzo[b]thiophene (0.2 g) was dissolved in triethylamine (4mL). To the solution were added 4-iodobenzoic acid (0.29 g), tetrakis(triphenylphosphine)palladium (0) (0.12 g) and copper (I) iodide (41 mg), and the mixture was heated for ref lux under an argon atmosphere overnight. The reaction mixture was poured into ethyl acetate-1 mol/L hydrochloric acid, and the insoluble material was removed by filtration. The organic layer was separated from the filtrate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-1/2) to give 3-[2-(4-carboxyphenyl)ethynyl]-4-methoxybenzo[b]thiophene (0.32 g). This material was dissolved in N,N-dimethylformamide (10 mL). To the solution were added potassium carbonate (0.29 g) and benzyl bromide (0.16 mL), and the mixture was stirred at room temperature for three hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give the title compound (0.2 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH3:8].[F:9][C:10]1[CH:11]=[C:12]([C:16]2[N:31]=[C:19]3[N:20]=[C:21]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:22]=[C:23]([NH2:24])[N:18]3[N:17]=2)[CH:13]=[CH:14][CH:15]=1.CCN(CC)CC>CC#N>[F:9][C:10]1[CH:11]=[C:12]([C:16]2[N:31]=[C:19]3[N:20]=[C:21]([N:25]4[CH2:26][CH2:27][N:28]([CH2:2][C:3]5[CH:4]=[N:5][O:6][C:7]=5[CH3:8])[CH2:29][CH2:30]4)[N:22]=[C:23]([NH2:24])[N:18]3[N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1oncc1CCl
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3cccc(F)c3)nn12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1oncc1CN1CCN(c2nc(N)n3nc(-c4cccc(F)c4)nc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 2-(3-fluoro-phenyl)-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see Example 10(a) above) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=3)[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][N:17]=1.O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.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>[CH3:30][N:28]1[CH:29]=[C:25]([CH2:24][N:21]2[CH2:20][CH2:19][N:18]([C:13]3[C:12]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:17][CH:16]=[CH:15][N:14]=3)[CH2:23][CH2:22]2)[C:26]([CH3:31])=[N:27]1
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)CC1
Reactant: OB(O)c1ccccc1F
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: O
Solvent: CC(=O)N(C)C
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2-c2ccccc2F)CC1
Temperature: 110 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
Add 2-fluorobenzeneboronic acid (215 mg, 1.5 mmol) to a nitrogen purged solution of 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (200 mg, 0.65 mmol) in dry N,N-dimethylacetamide (4 mL), deoxygenated water (2 mL), potassium carbonate (215 mg, 1.72 mmol), tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.0035 mmol) and stir at 110° C. for 16 hr. Cool to room temperature, add water (10 mL) and extract with DCM (3×20 mL). Concentrate the combined DCM extracts and purify by reverse phase HPLC to give the title compound (0.130 g, 54%). MS (ES): m/z=367 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:10][C:11]([CH3:17])=[CH:12][C:13]([O:15][CH3:16])=[O:14].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:10][C:11]([N:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]1)([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C=C(C)C
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(C)(C)n1cc([N+](=O)[O-])c(C)n1
Yield: 6.8 %

Procedure:
A solution of 3-methyl-4-nitro-1H-pyrazole (1.00 g, 7.87 mmol), methyl 3-methylbut-2-enoate (2.20 g, 18.9 mmol), and DBU (3.10 g, 20.5 mmol) in DMF (5.0 mL) was stirred overnight. The mixture was purified by reverse phase Combiflash to afford the title compound (130 mg, 7%) as yellow oil. LC-MS (ESI): m/z=242 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:16][N:17]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[O:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>>[O:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([C:15]3[O:14][C:13]([C:6]4[CH:7]=[CH:8][C:9]5[NH:10][C:40]([C:39]6[CH:38]=[CH:37][C:36]([N:33]7[CH2:34][CH2:35][O:30][CH2:31][CH2:32]7)=[CH:43][CH:42]=6)=[N:1][C:4]=5[CH:5]=4)=[N:17][N:16]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=[N+]([O-])c1ccc(-c2nnc(-c3ccc(N4CCOCC4)cc3)o2)cc1[N+](=O)[O-]
Product: c1cc(N2CCOCC2)ccc1-c1nc2cc(-c3nnc(-c4ccc(N5CCOCC5)cc4)o3)ccc2[nH]1

Procedure:
Compound 428 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-1-(5-(4-morpholinophenyl)-1,3,4-oxadiazol-2-yl)benzene and 4-morpholinobenzaldehyde. [M+H]+ calcd for C29H28N6O3: 590.23; found: 508.98.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1>>[F:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Fc1cccc(N=C=S)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(F)c4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol) and 3-fluorophenyl isothiocyanate (9.9 μL, 0.0824 mmol) were used. Purification on silica yielded compound 25 in Table 1, below (22 mg, 59%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.66 (s, 1H), 7.41 (s, 1H), 7.37-7.27 (m, 1H), 6.96 (t, J=7.39, 2H), 6.88 (t, J=7.67 Hz, 1H), 4.38-4.27 (m, 2H), 4.27-3.91 (m, 8H), 1.54-1.43 (m, 3H) ppm.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=4[F:43])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]3[CH2:28][CH2:27]3)[N:21]=2)[CH:16]1[CH3:44])C1C=CC=CC=1.[H][H]>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:26]1([NH:25][C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH:16]([CH3:44])[C:17]3=[N:18][C:19]=2[N:29]2[CH2:30][CH2:31][CH:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH2:33][CH2:34]2)[CH2:28][CH2:27]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: [H][H]
Reactant: CC1c2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC3CC3)nc2CCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC1NCCc2nc(NC3CC3)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc21
Reaction time: 8 h

Procedure:
Combined 6-benzyl-N-cyclopropyl-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (110 mg, 0.178 mmol) and Pd(OH)2 (20 wt %, 12.5 mg, 0.018 mmol) in THF (888 μL) was purged with hydrogen and allowed to stir under hydrogen (balloon) overnight. The reaction mixture was filtered through Celite™, washed with EtOAc, and concentrated under reduced pressure to give the title compound as a TFA salt (78 mg).