Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].Br[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH2:14])=[CH:11][CH:10]=1>C(OCC)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl.[Fe]>[CH3:5][C:4]([CH3:7])([CH3:6])[CH2:3][C:12]1([CH:13]=[CH2:14])[CH:11]=[CH:10][CH:9]=[CH:16][CH2:15]1
Reactant: CC(C)(C)CBr
Reactant: C=Cc1ccc(Br)cc1
Agent: Cl[Ni]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: CCOCC
Product: C=CC1(CC(C)(C)C)C=CC=CC1
Yield: 127.2 %

Procedure:
To a solution of 0.8 g (33.10 mmol) of magnesium turnings and 2.0 g (13.2 mmol) of 1-bromo-2,2-dimethylpropane in 10 mL diethyl ether was added a solution of 1.42 g (7.76 mmol) of 4-bromostyrene and 69 mg (0.13 mmol) of Ni(dppf)Cl2 The resulting reaction mixture was heated at refluc for 8 h. The reaction was quenched with 50% saturated NH4Cl, and was extracted with MTBE (2×150 mL). The combined extractions were washed with water, dried and concentrated. Flash chromatography on a Biotage 40M cartridge with hexanes as the eluant afforded 1.74 g of the title compound: 1H NMR (500 Mhz) δ 0.93 (s, 9H), 2.49 (s, 2H), 5.20 (d, J=10.9, 1H), 5.73 (d, J=17.6, 1H), 6.72 (dd, J1=17.6, J2=10.8, 1H), 7.10 (d, J=8.2, 2H), 7.33 (d, J=8.0, 2H); ESI-MS 161 (M+H); LC-1: 4.4 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11](=[S:13])[NH2:12])=[CH:7]2.[C:25]([O:30][CH2:31][CH3:32])(=[O:29])[C:26]#[C:27][CH3:28].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:25](=[O:29])[CH2:26][CH:27]1[S:13][C:11]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:3][C:2]=3[CH3:1])=[N:12][CH2:28]1)[CH3:32]
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(C)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
To a mixed solution of 7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (2.6 g), ethyl 2-butynoate (1.7 mL), tetrahydrofuran (40 mL), and toluene (60 mL) was added tri-n-butylphosphine (2.2 mL) under an argon atmosphere at room temperature, and the mixture was stirred at 40° C. for 2.5 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=40:60 to 65:35, volume ratio) to give the title compound (2.59 g, yield 76%) as a pale-yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH:13]=[CH:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])=[CH:5][CH:4]=1>[Pd].C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(C=CN3C(=O)c4ccccc4C3=O)c2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc2cccc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reaction time: 8 h

Procedure:
In a reactor, 2 g of the compound obtained in Step B and 1 g of 5% palladium-on-carbon are introduced into a methano/THF 1/2 mixture under hydrogen pressure and at ambient temperature. After reacting for 8 hours, the reaction mixture is filtered. After evaporating off the solvents, the title product is obtained quantitatively with a chemical purity of 95%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:10]1[NH:11][C:12](=O)[C:13]2[NH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH2:7][CH2:8][CH3:9].[OH-].[Na+]>>[CH2:6]([C:10]1[N:11]=[C:12]([Cl:3])[C:13]2[NH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1nc2cc[nH]c2c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc(Cl)c2[nH]ccc2n1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Phosphorus oxychloride (20 mL, 21.46 mmol) was added to 2-butyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (1.69 g). The resultant mixture was heated at 100° C. After 4 hours the reaction mixture was cooled to room temperature then poured onto ice. The aqueous phase was treated with aqueous sodium hydroxide solution (5M) until the pH was 7. The resultant mixture was extracted with ethyl acetate (2×150 mL). The combined organic phase were washed with brine, dried (Na2SO4), filtered and evaporated to give the title compound (1.69 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[CH:19]=2)=[CH:4][CH:3]=1.Cl>[Pd].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH2:17][CH:16]([CH3:18])[CH2:15][CH2:14][N:13]3[CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccn2cc(CCc3ccc(N)cc3)nc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC1CCn2cc(CCc3ccc(N)cc3)nc2C1
Yield: 83.4 %

Procedure:
10% Palladium on carbon (1.0 g) was added to a mixture of 2-[2-(4-aminophenyl)ethyl]-7-methylimidazo[1,2-a]pyridine (4.0 g) in methanol (100 ml) and 1N-hydrochloric acid (60 ml) and the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. To the residue was added a mixture of ethyl acetate and water and the mixture was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated with a solution of diethyl ether and ethyl acetate. The precipitate was collected by filtration and dried to give 2-[2-(4-aminophenyl)ethyl]-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (3.39 g).
Reaction SMILES: C1(SC)C=CC=CC=1.C([O:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=1)[CH2:20][NH:21][C:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2)=[O:23])C1C=CC=CC=1.FC(F)(F)C(O)=O>>[OH:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=1)[CH2:20][NH:21][C:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2)=[O:23]
Reactant: O=C(NCc1cccc(OCc2ccccc2)c1)c1ccc2ncccc2c1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cccc(O)c1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.9 %

Procedure:
Thioanisole (1.7 mL, 14 mmol) was added to a mixture of quinoline-6-carboxylic acid 3-benzyloxybenzylamide (1.3 g, 3.6 mmol) and trifluoroacetic acid(8 mL) on an ice bath, and the solution was stirred for 4 hours at room temperature. The solvent was evaporated in vacuo, then water, an aqueous solution of saturated sodium bicarbonate, ethyl acetate and tetrahydrofuran were added to the residue for extraction, the organic layer was washed with brine, then, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, recrystallized from ethyl acetate-methanol, and the title compound (0.64 g, 2.3 mmol, 64%) was obtained as a white crystal.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:24][CH2:23][C@H:22]([OH:25])[C@H:21]([OH:26])[CH2:20]1.C1COCC1.CN(C=O)C>C(N(CC)CC)C>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[C@H:21]([OH:26])[CH2:20]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: O[C@@H]1CNCC[C@@H]1O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CC[C@H](O)[C@H](O)C3)s2)noc1C(F)(F)F
Yield: 81 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (3R,4S)-3,4-Piperidinediol (CAS [135501-61-0]) by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF/DMF (4 mL/1 mL) solution of triethylamine and (3R,4S)-3,4-Piperidinediol (2 mmol). After 30 min the reaction mixture was quenched with the addition of water. The resulting solids were then filtered and washed with a 1 N aqueous HCl solution followed by water. The material was air dried to afford product as a colorless solid (304 mg, 81%). 1H NMR (DMSO-d6) 1.53-1.60 (m, 1 H), 1.65-1.71 (m, 1 H), 2.34 (d, J=1.3, 3 H), 3.10-4.00 (br m, 6 H), 4.70 (d, J=4.4, 1 H), 4.81 (d, J=4.0, 1 H), 7.54 (br s, 1 H), 7.65 (d, J=4.0, 1 H). 19F NMR −62.2. LC/MS 5.44 min, [M+1]+ 377.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[F:38])=[O:28])[CH2:16][CH2:17][CH2:18][O:19][P:20]([O:24]C)([O:22]C)=[O:21])[N:2]=1.[Si](I)(C)(C)C>C(#N)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[F:38])=[O:28])[CH2:16][CH2:17][CH2:18][O:19][P:20]([OH:24])([OH:22])=[O:21])[N:2]=1
Reactant: COP(=O)(OC)OCCC[C@@H](COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)NCc1cccc(F)c1F
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCOP(=O)(O)O)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
(S)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-5-(dimethoxyphosphoryloxy)pentyl isoquinolin-3-ylcarbamate (531 mg, 0.91 mmol) in acetonitrile (18 mL) was added TMSI (0.50 mL, 3.66 mmol) at 0° C. After stirred at RT for 10 min, the reaction was quenched with MeOH. The solvent was removed and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O (0.1% HCOOH buffer) to give (S)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-5-(phosphonooxy)pentyl isoquinolin-3-ylcarbamate (261 mg, 52%). LRMS (M+H+) m/z 553.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:33][S:30]([C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([C:19]1[CH:20]=[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=[CH:17][N:18]=1)[CH2:22][CH2:23]2)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 131.3 %

Procedure:
To a solution of 4a (0.55 g) in 8 mL of DCM, was added trifluoroacetic acid (3 mL, 33 eq) at room temperature. The reaction mixture was stirred at room temperature for 3 h then the solvent and excess trifluoroacetic acid were removed under a stream of nitrogen to give 0.57 g of 4b.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.Cl.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(CC)CC)C.O>CC#N.CCOC(C)=O>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:6]2[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc(Cl)nc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
A mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (0.221 g, 1.00 mmol), 1-Boc-4-aminomethylpiperidine hydrochloride (0.251 g, 1.00 mmol) and triethylamine (0.556 mL, 4.00 mmol) in CH3CN (10 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-2-chloropyrimidine-5-carboxylate (0.390 g).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][OH:18])=[CH:6]1.Cl.[CH3:25][O:26][NH2:27]>>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:27][O:26][CH3:25])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][OH:18])=[CH:6]1
Reactant: CON
Reactant: O=C(O)c1cc2c(CO)cn(Cc3ccc(F)cc3F)c2cn1
Agent: Cl
Product: CONC(=O)c1cc2c(CO)cn(Cc3ccc(F)cc3F)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluoro-benzyl)-3-hydroxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and O-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) δ; 8.76 (s, 1H), 8.41 (s, 1H), 7.58 (s, 1H), 7.23–7.29 (m, 1H), 6.88–7.00 (m, 2H), 5.54 (s, 2H), 4.80 (s, 2H), 3.82 (s, 3H). LCMS (APCI, M+H+): 348.0. HRMS calcd for C17H16F2N3O3 (M+H) 348.1160. found 348.1148. HPLC: 100% purity.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:12][N:13]([CH2:15]N(C)C)[CH3:14]>O1CCOCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][N:13]([CH3:15])[CH3:14]
Reactant: Oc1ccc2ccccc2c1
Reactant: CN(C)CN(C)C
Solvent: C1COCCO1
Product: CN(C)Cc1c(O)ccc2ccccc12

Procedure:
A mixture of 2-hydroxynaphthalene (20.18 g), N,N,N',N'-tetramethyldiaminomethane (19.10 ml) and 1,4-dioxane (200 ml) was heated on a steam bath for 24 hours and then evaporated to dryness under reduced pressure. The residue was dissolved in 2M hydrochloric acid and washed with ethyl acetate, neutralised with concentrated sodium hydroxide solution and extracted with dichloromethane to give a solid which was recrystallised from petroleum ether, b.p. 60°-80° C. to give 2-hydroxy-1-(dimethylaminomethyl)naphthalene, m.p. 79°-80° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Br)[C:3]=1[CH:10]=[N:11][NH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]2[C:3]=1[CH:10]=[N:11][N:12]2[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17]
Reactant: Cc1cc(Br)c(C=NNc2cccc(C(=O)O)c2)c(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)c2cnn(-c3cccc(C(=O)O)c3)c2c1
Temperature: 70 °C
Reaction time: 0.57 h
Yield: 88 %

Procedure:
A solution of 3-{2-[(2,6-dibromo-4-methylphenyl)methylidene]hydrazino}benzoic acid (1050 g) in DMF (3.46 L) was cooled to 10° C. under nitrogen. Lithium bis(trimethylsilyl)amide solution (1M in THF, 6.34 L) was then added while maintaining the temperature below 15° C. The stirred solution was heated at 70±3° C. for 64 hrs and then the reaction mixture was cooled to 5° C. and quenched sequentially with the slow addition of water (4.2 L), 5M hydrochloric acid (2.62 L) and water (3.68 L). The resulting slurry was stirred at 5° C. for 1 hr 34 min, filtered and washed successively with purified water (1 L and then 2.1 L at 5±5° C.) and methanol (2×1 L at 5±5° C.). The solid was dried in vacuo at 50° C. to afford the title compound (742.9 g).
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4])[NH2:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[O:22][CH2:23][C:24](O)=[O:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[O:22][CH2:23][C:24]([NH:2][NH:1][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4])=[O:25]
Reactant: COc1ccc(OCC(=O)O)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: COc1ccc(OCC(=O)NNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a solution of (S)-t-butyl 2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (50.0 g) and 2-(3,4-dimethoxyphenoxy)acetic acid (47.8 g) in chloroform (1000 ml), HOBt (35.3 g) and WSC hydrochloride (50.0 g) were added and the mixture was stirred at room temperature for 4 hours. After distilling off the solvent under reduced pressure, water was added, followed by extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine and dried over MgSO4 before it was filtered. The solvent was distilled off under reduced pressure to give a crude form of the titled compound (61.0 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[N:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C([O:27][CH2:28][C:29]1[C:34]([N:35]2[N:44]=[CH:43][C:42]3[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=3)[C:36]2=[O:50])=[CH:33][CH:32]=[CH:31][C:30]=1[B-](F)(F)F)(=O)C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[Na+]>C(O)CCC.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.[Pd]>[C:45]([C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([F:49])[CH:39]=1)[C:36](=[O:50])[N:35]([C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[N:12]=[CH:13][C:14]([N:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[N:15][CH:16]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:29]=1[CH2:28][OH:27])[N:44]=[CH:43]2)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(=O)OCc1c(-n2ncc3cc(C(C)(C)C)cc(F)c3c2=O)cccc1[B-](F)(F)F
Reactant: CN1CCN(c2cnc(Nc3cc(Cl)nn(C)c3=O)cn2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Solvent: O
Product: CN1CCN(c2cnc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)cn2)CC1
Temperature: 110 °C
Reaction time: 72 h

Procedure:
To a 15 mL microwave reaction vial was added 6-chloro-2-methyl-4-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino)-2H-pyridazin-3-one (71 mg, 211 μmol, Eq: 1.00) in 7 mL n-butanol and 1.4 mL water. Argon was bubbled through the suspension. To the slurry was added potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (149 mg, 211 μmol, Eq: 1.00), then X-PHOS (15.1 mg, 31.7 μmol, Eq: 0.15) with stirring. To this mixture was added bis(dibenzylideneacetone)palladium (9.12 mg, 15.9 μmol, Eq: 0.075). The tube was sealed and heated at 110° C. (bath temp) for 3 hrs then cooled to room temperature. A solution of NaOH (84 mg, 2.11 mmol, 10 eq) in water (1.5 mL) was added and the reaction was stirred for 3 days.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O=[C:15]([CH3:22])[CH2:16][C:17](OCC)=[O:18].C(=O)([O-])[O-].[K+].[K+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[C:11]3[C:10](=[CH:9][CH:8]=2)[NH:13][C:15]([CH3:22])=[CH:16][C:17]3=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(Cn2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(=O)c2cc(Cn3ccnc3)ccc2[nH]1
Yield: 14.4 %

Procedure:
To a stirred and heated (100° C.) solution of 10 parts of 4-(1H-imidazol-1-ylmethyl)-benzenamine in 50 parts of poly phosphoric acid were added 15 parts of ethyl 3-oxobutanoate. The whole was stirred for 4 hours at 140° C. 100 Parts of water were added to the mixture and the whole was neutralized with potassium carbonate. The product was extracted with a mixture of ethyl acetate and methanol. The extract was dried, filtered and concentrated. The concentrate was crystallized from a mixture of 2-propanone and methanol. The product was filtered off and dried, yielding 2 parts (14.4%) of 6-(1H-imidazol-1-ylmethyl)-2-methyl-4(1H)quinolinone; mp. 245.5° C. (decomp.) (compound 77).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1C)=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH:10]12[CH2:14][CH:13]([NH:8][CH2:9]1)[CH2:12][N:11]2[CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Product: Oc1ccc(CCNc2nccc(-c3cccc(CN4CC5CC4CN5)c3)n2)cc1

Procedure:
Intermediate 142 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 402. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.43 (s, 1H) 8.37 (d, 1H) 8.34 (d, 1H) 8.04 (d, 1H) 7.73 (t 1H) 7.65 (d, 1H) 7.17 (d, 2H) 6.69 (d, 2H) 4.62 (s, 2H) 4.19 (d, 2H) 3.92 (d, 2H) 3.63 (t, 2H) 3.23 (d, 2H) 2.94 (t, 2H) 2.61 (d, 1H) 2.37 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:69]=[CH:68][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:69]=[CH:68][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:65])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.1 %

Procedure:
To a solution of 185 mg (0.87 mmol) 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 278 mg of TBTU (0.87 mmol) in 13 ml DMF, were added 0.74 ml (4.33 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 290 mg (0.87 mmol) (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 140 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by two successive column chromatographies (90 g silica gel; diethylether/heptane 1:1; then 8 g silica gel; DCM/heptane 70:30 to 90:10) to give 125 mg white foam (27%). M (EI) 530.2 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5]Br.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:9]=[C:8]([CH3:10])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(CNc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of 3,5-dimethylbenzyl bromide (1.59 g, 7.986 mmol), 4-bromoaniline (1.374 g, 7.986 mmol), potassium carbonate (5.519 g, 39.93 mmol) and N,N-dimethylformamide (6.5 ml) was stirred at 80° for 2 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=15:1) to give the title compound (2.106 g, 57.2%) as a pale yellow oil.