Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][C:9]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20]P(Br)Br.O>C(Cl)Cl>[Br:20][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(CC2CCCCC2)c(C(F)(F)F)c1
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1cc(CBr)ccc1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 198.9 %

Procedure:
To a stirred solution of (4-(cyclohexylmethyl)-3-(trifluoromethyl)phenyl)methanol (80 mg, 0.29 mmol) in dry DCM (1 mL) was added tribromophosphine (11 μL, 0.12 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h, poured into water, extracted with DCM. The combined organics were washed with saturated NaHCO3 solution and brine, dried and concentrated. The residue was purified by column chromatography to give the title compound (80 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 0.96-1.06 (m, 2H), 1.14-1.22 (m, 3H), 1.55-1.72 (m, 6H), 2.65 (d, J=6.5 Hz, 2H), 4.49 (s, 2H), 7.28 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.0 and 1.7 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH:21]1([NH2:24])[CH2:23][CH2:22]1>>[CH:21]1([NH:24][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])[CH2:23][CH2:22]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and cyclopropylamine (19 mg, 0.32 mmol). The title compound was obtained as a solid (39 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.82 (1H, m), 8.37 (1H, s), 2.74 (1H, m), 0.69 (2H, m), 0.52 (2H, m). MS m/z: 388.02, 390.02 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:20])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH2:4][C@H:3]1[NH:21]C(=O)OCC1C=CC=CC=1>CO.[Pd]>[NH2:21][C@H:3]1[C@H:2]([OH:1])[CH2:6][N:5]([C:7](=[O:20])[CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[CH2:4]1
Reactant: O=C(N[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1O
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Benzyl ((3R,4R)-4-hydroxy-1-(2-(4-trifluoromethoxyphenyl)ethanoyl)pyrrolidin-3-yl)carbamate (14 g) was dissolved in methanol (140 mL), followed by addition of 5% Pd—C (2.4 g), and the mixture was stirred overnight under hydrogen atmosphere. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. The precipitated solids were washed with a mixed solvent of isopropyl ether and hexane to obtain the title compound (8.6 g).
Reaction SMILES: Cl[CH:2]([C:6]1[C:7]([O:12][CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][CH:4]=[CH2:5]>CO.[Zn]>[CH2:2]([C:6]1[C:7]([O:12][CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCC(Cl)c1cccnc1OC
Agent: [Zn]
Solvent: CO
Product: C=CCCc1cccnc1OC
Yield: 22.7 %

Procedure:
A total of 71.4 g of zinc (copper-activated) are added to 118.5 g (0.54 mol) of the compound from Example II in 1000 ml of anhydrous methanol, and the mixture is refluxed for 2 hours. The precipitate is filtered off, and the filtrate is subsequently evaporated in vacuo. Fractional distillation of the residue produces 20.0 g of the title compound having b.p. 96° C./20 mmHg.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[NH:8][CH:7]=[N:6][C:5]=2[C:4](=S)[NH:3]1.[CH3:12][NH:13][NH2:14]>>[CH3:12][N:13]([C:4]1[C:5]2[N:6]=[CH:7][NH:8][C:9]=2[NH:10][C:2](=[O:1])[N:3]=1)[NH2:14]
Reactant: O=c1[nH]c(=S)c2nc[nH]c2[nH]1
Reactant: CNN
Product: CN(N)c1nc(=O)[nH]c2[nH]cnc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
2-Oxo-6-thioxo-1,2,3,6-tetrahydro-9H-purine (1.0 g, 5.9 mmol) were added to methylhydrazine (20 ml), and the mixture was stirred in a sealed tube for 30 minutes at 120° C. After completion of reaction, the mixture was concentrated under reduced pressure. The residual crystals were washed with 50% ethanol, and crystals collected by filtration were recrystallized from ethanol to obtain 0.64 g (yield 60%) of colorless powdery crystals (m.p.=247° C. (decomposed)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH2:22])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[C:26]([F:33])[CH:25]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(N(C(C)C)C(C)C)C>CO.CCOC(C)=O>[NH2:21][C:17]1[O:18][CH2:19][CH2:20][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([NH:22][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][C:26]=2[F:33])=[CH:11][CH:10]=3)[N:16]=1
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncc(Br)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cc3F)ccc1Oc1ncc(Br)cc12
Reaction time: 0.58 h
Yield: 19.6 %

Procedure:
The (S)-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.035 g, 0.097 mmol) was dissolved in MeOH (2 mL) and 4-chloro-2-fluorobenzoic acid (0.019 g, 0.107 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride hydrate (0.031 g, 0.107 mmol) were added, followed by N-ethyl-N-isopropylpropan-2-amine (0.019 mL, 0.107 mmol). After 35 min, additional 4-chloro-2-fluorobenzoic acid (0.0095 g, 0.053 mmol) and additional 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride hydrate (0.015 g, 0.053 mmol) were added. After 2 h, the reaction was taken up in EtOAc (75 mL), and the organic layer was washed with half-saturated NaHCO3 (2×10 mL), then with saturated brine (10 mL), dried over MgSO4 and concentrated. The material was purified by preparative tlc (85% EtOAc-hexane) to afford (S)—N-(2′-amino-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-4-chloro-2-fluorobenzamide (9.7 mg, 0.019 mmol). MS (m/z) 517/519 (M+H)+. 1H NMR (400 MHz, CDCl3): 8.40 (d, 1H, J=14.7 Hz), 8.31 (d, 1H, J=2.4 Hz), 8.12 (t, 1H, J=8.5 Hz), 7.91 (d, 1H, J=2.4 Hz), 7.62 (m, 2H), 7.31 (m, 1H), 7.27 (m, 1H), 7.23 (m, 1H), 4.21 (m, 1H), 4.11 (m, 1H), 1.94 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:35][NH2:36]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4cccc(C)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3cccc(C)c3)c2O1

Procedure:
The title compound was prepared (0.055 g, 70%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-methylphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp 230-234° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[O:28]=[C:29]1[NH:33][C:32](=[O:34])[CH:31]([CH2:35][C:36]2[CH:46]=[CH:45][C:39]([O:40][CH2:41][C:42](O)=[O:43])=[CH:38][CH:37]=2)[S:30]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:28]=[C:29]1[NH:33][C:32](=[O:34])[CH:31]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:40][CH2:41][C:42]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:43])=[CH:45][CH:46]=2)[S:30]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 84.5 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-trifluoromethylphenoxy)phenyl]-N-methylcarbamate (0.68 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.73 g), diethyl cyanophosphonate (0.49 g), triethylamine (0.30 g) and anhydrous tetrahydrofuran (50 ml) and the reaction mixture was purified to give the desired product (0.97 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:3])[CH3:2].[K].[CH3:15][S:16]([CH3:19])(=[NH:18])=[O:17]>O1CCCC1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([N:18]=[S:16]([CH3:19])([CH3:15])=[O:17])=[O:9])(=[O:3])[CH3:2]
Reactant: CS(C)(=N)=O
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Agent: [K]
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc(C(=O)N=S(C)(C)=O)c1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
A solution of 99.3 g of m-acetoxybenzoyl chloride in 150 ml of absolute tetrahydrofuran is added dropwise at -35° C. during 20 minutes while stirring to the dimethyl sulphoximine potassium salt suspension and the mixture is then stirred at -35° C. for 30 minutes. N-(m-Acetoxybenzoyl)-S,S-dimethyl-sulphoximine is thus formed in suspension.
Reaction SMILES: Cl.[CH2:2]([NH:9][NH2:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>C(O)C>[CH2:2]([NH:9][N:10]=[C:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCNN
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCNN=C(C)C(=O)OCC
Reaction time: 0.33 h

Procedure:
4.0 g. Heptylhydrazine hydrochloride are dissolved in 40 ml. ethanol and 2.3 g. ethyl pyruvate added thereto. The solution is left to stand for 20 minutes at ambient temperature, then mixed with 160 ml. water and the oil which separates out is extracted with diethyl ether. The ethereal solution is washed several times with a 2 N aqueous sodium carbonate solution and then with water, dried over anhydrous sodium sulphate and evaporated. The ethyl 2-(heptylhydrazono)-propionate obtained as residue does not crystallize. The yield is 3.7 g. (82.4% of theory).
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH:11]=[CH:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1CCCC=C[CH:22]=1>>[C:1]1([CH:7]([N:9]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]3[CH:12]=[CH:11][CH:10]2[CH2:20][CH2:21][CH2:22]3)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C[C@@H](C2)N1[C@@H](C)c1ccccc1
Reactant: C1=CCCCC=C1
Product: CCOC(=O)C1C2C=CC(CCC2)N1C(C)c1ccccc1

Procedure:
In the reaction (a) of Example 1, 1,3-cycloheptadiene is used in place of cyclopentadiene, to give ethyl 6-(1-phenylethyl)-6-azabicyclo[3.2.2]non-8-ene-7-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1cnccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cnccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
A suspension of 1B (1 g, 2.33 mmol) and platinium 5% wt on activated carbon (600 mg) in THF (30 mL) and MeOH (30 mL) was stirred at RT under H2 at 75 psi for 2 days. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel (40 g) column chromatography eluting with a gradient of methanol (0-6%) in EtOAc/hexane (1:1) to give the title compound as a white foam (360 mg, 36%). LC/MS (method A): retention time=2.77 min, (M+H)+=430.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.Br[CH:12]1[CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:12]2[CH2:14][CH2:13]2)[CH:3]=1
Reactant: BrC1CC1
Reactant: N#Cc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1OC1CC1
Temperature: 170 °C

Procedure:
A mixture of 4-bromo-2-hydroxybenzonitrile (300 mg, 1.5 mmol), bromo-cyclopropane (480 mg, 4.0 mmol) and Cs2CO3 (300 mg, 1.6 mmol) in 2 mL of anhydrous DMF were heated to 170° C. for 2 hours by microwave. The solid was filtered off, and the filtrate was poured to water, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified with prep-TLC to give 4-bromo-2-(cyclopropyloxy)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.46˜7.48 (m, 1H), 7.36˜7.38 (m, 1H), 7.14˜7.16 (m, 1H), 3.79˜3.84 (m, 1H), 0.86˜0.87 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:38])[O:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=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>[CH3:22][N:19]1[CH2:18][CH2:10][C:9]2[N:8]([C:4]3[CH:3]=[C:2]([C:28]4[C:24]([CH3:23])=[N:25][O:26][C:27]=4[CH3:38])[CH:7]=[CH:6][CH:5]=3)[C:16]3[CH:11]=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=3[C:21]=2[CH2:20]1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3c(C)noc3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (125 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 4-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-3,5-dimethylisoxazole. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.7 (t, 1H), 7.41-7.5 (m, 2H), 7.4 (s, 1H), 7.37 (s, 1H), 7.18 (d, 1H), 7.03 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (m, 4H), 3.01 (m, 1H), 3.43 (m, 6H), 2.31 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=1[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CS(C)=O.C(O)C.C(OCC)(=O)C.O1CCCC1.O>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[N:10]=3)[CH:7]=2)=[C:19]([CH3:27])[CH:20]=1
Reactant: O=C(Nc1cn2cc(O)ccc2n1)C1CC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1Oc1ccc2nc(NC(=O)C3CC3)cn2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
To a solution of N-(6-hydroxyimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (300 mg, 1.38 mmol) and 4-fluoro-3-methyl-1-nitrobenzene (279 mg, 1.80 mmol) in dimethyl sulfoxide (3 mL) was added cesium carbonate (67.4 mg, 2.07 mmol), and the mixture was stirred at room temperature for 24 hr. Ethyl acetate, tetrahydrofuran and water were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration. A mixed solution of the obtained solid, reduced iron (406 mg, 6.9 mmol) and ammonium chloride (738 mg, 13.8 mmol) in ethanol (5 mL)/tetrahydrofuran (3 mL)/water (2 mL) was stirred at 80° C. for 6 hr. The reaction mixture was diluted with ethyl acetate and tetrahydrofuran, and filtered through celite. Water was added to the filtrate, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1→ethyl acetate alone) to give the title compound (190 mg, 43%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]([Br:19])[CH:16]=[N:17][CH:18]=1>COCCOC>[Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([CH3:9])=[N:6][C:7]=1[NH:11][CH2:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([Br:19])[CH:14]=1
Reactant: Cc1nc(O)c(Br)c(Cl)n1
Reactant: NCc1cncc(Br)c1
Solvent: COCCOC
Product: Cc1nc(NCc2cncc(Br)c2)c(Br)c(=O)[nH]1
Temperature: 23 °C

Procedure:
A stirred mixture of 5-bromo-6-chloro-2-methyl-4-pyrimidinol (4.54 g, 20.3 mmol) and 5-aminomethyl-3-bromopyridine (11.4 g, 61.0 mmol) in 1,2-dimethoxyethane (40 mL) was heated at reflux for 18 hours. The mixture was cooled to 23° C. The precipitate which formed was isolated, rinsed with 1,2-dimethoxyethane and water, and then recrystallized from methanol to provide the title compound as a white, analytically pure product (5.16 g, 13.8 mmol, 68% of theory): mp 241-242 C.; Rf 0.62 (20% MeOH in EtOAc); 1H NMR (DMSO-D6, 400 MHz)δ8.56 (d, J=2 Hz, 1H), 8.49 (d, J=2 Hz, 1H), 7.92 (m, 1H), 7.33 (t, J=6 Hz, 1H), 4.55 (d, J=6 Hz, 2H), 2.16 (s, 3H); IR (KBr) 3400 (NH), 2700-3000 (CH), 1640 (C=O) cm-1 ; UV (MeOH)λ278 (ε12,400); mass spectrum m/e 372 (M+, 54%), 374 (M+, 100%), 376 (M+, 52%), 185 (C6H6BrN2, 78%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:17]([O:21][C:22]([NH:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: COCCOc1ccc(C(=O)OC)c(O)c1
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Product: COCCOc1ccc(C(=O)OC)c(OCC(C)(C)CNC(=O)OC(C)(C)C)c1
Yield: 85.6 %

Procedure:
Using a procedure similar to that of Example 26-B, methyl 2-hydroxy-4-(2-methoxyethoxy)benzoate (3.2 g, 14.14 mmol) is alkylated with 3-tert-butoxycarbonylamino-2,2-dimethylpropanol (2.88 g, 14.14 mmol) to afford methyl 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-(2-methoxyethoxy)benzoate (4.982 g) after purification over silica gel, eluting with a gradient of 0-40% ethyl acetate in hexane.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]3[CH:15]=[C:16]([C:19]([O:21]CC)=O)[C:17]([OH:18])=[C:11]3[C:10]2=[O:24])=[CH:6][CH:5]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[F:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]3[CH:15]=[C:16]([C:19]([NH:2][CH3:1])=[O:21])[C:17]([OH:18])=[C:11]3[C:10]2=[O:24])=[CH:6][CH:5]=1
Reactant: CN
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
Anhydrous methylamine gas was bubbled through a mixture of ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (3.0 g, 9.0 mmol) and anhydrous aluminum chloride (3.0 g, 22.5 mmol) in anhydrous chloroform (45 mL) at 0° C. for 5 minutes. The resultant mixture was heated in a seal tube at 70° C. overnight and concentrated under vacuum. The residue partitioned between aqueous HCl and chloroform. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([CH:21]4[CH2:24][O:23][CH2:22]4)[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([F:45])=[CH:32][C:31]=1[N:46]1[CH2:57][CH2:56][C:55]2[C:54]3[CH2:53][C:52]([CH3:59])([CH3:58])[CH2:51][C:50]=3[S:49][C:48]=2[C:47]1=[O:60])(=[O:27])[CH3:26].CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]([O:28][CH2:29][C:30]1[C:35]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:20]=[CH:19][C:18]4[CH2:17][N:16]([CH:21]5[CH2:24][O:23][CH2:22]5)[CH2:15][CH2:14][C:13]=4[N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:34][C:33]([F:45])=[CH:32][C:31]=1[N:46]1[CH2:57][CH2:56][C:55]2[C:54]3[CH2:53][C:52]([CH3:59])([CH3:58])[CH2:51][C:50]=3[S:49][C:48]=2[C:47]1=[O:60])(=[O:27])[CH3:26]
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCN(C2COC2)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(n3)CCN(C3COC3)C4)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Yield: 57.3 %

Procedure:
A 25 mL sealed tube was charged with 5-bromo-1-methyl-3-(6-(oxetan-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyridin-2(1H)-one 219a (400 mg, 1.0 mmol), (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 247b (493 mg, 1.0 mmol), CH3COONa (168 mg, 2.0 mmol), K3PO4 (546 mg, 2.0 mmol), PdCl2(dppf) (84 mg, 0.1 mmol) suspended in CH3CN (25 mL) and H2O (1 mL). The mixture was heated at 110° C. for 2 hours. It was then evaporated and the residue was purified by column chromatography eluting with 20:1 methylene chloride/methanol (20:1) to give 280a as a brown solid (400 mg, 56%). MS: (M+H)+ 698.