Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[N:20]=1>CN(C=O)C>[NH2:25][C:21]1[N:22]=[C:23]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[C:6]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7]2)[CH:24]=[CH:19][N:20]=1
Reactant: CN(C)C(=O)c1n[nH]c2cc(Br)ccc12
Reactant: Nc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-N,N-dimethyl-1H-indazole-3-carboxamide (95%, 450 mg, 1.59 mmol) in DMF (10 mL) was added NaH (60% dispension in mineral oil) (60 mg, 1.02 mmol) at 0° C. Mixture was stirred at rt for 10 mins before addition of 4-chloropyrimidin-2-amine (413 mg, 3.19 mmol). The mixture was stirred at 65° C. overnight. The mixture was quenched by addition of water (10 mL). The mixture was extracted with EtOAc (2×15 mL). The combined organics washed with water (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. Trituration with DCM:heptane (4:1) gave the desired product. The filtrate was re-filtered. The solids were combined to give the title compound; 1H NMR (250 MHz, DMSO) delta 3.11 (3H, s), 3.32 (3H, s), 7.08 (1H, d, J=5.48 Hz), 7.19 (1H, d, J=3.35 Hz), 7.58 (1H, dd, J=8.68, 1.68 Hz), 7.95 (1H, d, J=8.53 Hz), 8.34 (1H, d, J=5.63 Hz), 9.18 (1H, d, J=1.22 Hz); LC-MS: m/z=+362.8 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:41][CH3:42])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:29][CH2:30]CCCCCC)[C:21]=3[CH3:37])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[C:12](=[O:13])[O:11]2)=[C:6]([O:38][CH2:39][CH3:40])[CH:5]=1)[CH3:2].C1(CCNC2C=CC(C3(C4C5C(=CC=CC=5)N(CC)C=4C)C4C(=CC=CN=4)C(=O)O3)=C(OC)C=2)CCCCC1.C(N1C2C(=CC=CC=2)C(C2(C3C4C(=CC=CC=4)N(CC)C=3C)C3C(=CC=CC=3)C(=O)O2)=C1C)C>>[CH2:41]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:29][CH3:30])[C:21]=3[CH3:37])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[C:12](=[O:13])[O:11]2)=[C:6]([O:38][CH2:39][CH3:40])[CH:5]=1)[CH3:42]
Reactant: CCCCCCCCn1c(C)c(C2(c3ccc(N(CC)CC)cc3OCC)OC(=O)c3cccnc32)c2ccccc21
Agent: CCn1c(C)c(C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3ccccc32)c2ccccc21
Agent: CCn1c(C)c(C2(c3ccc(NCCC4CCCCC4)cc3OC)OC(=O)c3cccnc32)c2ccccc21
Product: CCOc1cc(N(CC)CC)ccc1C1(c2c(C)n(CC)c3ccccc23)OC(=O)c2cccnc21

Procedure:
3-(4-diethylamino-2-ethoxyphenyl)-3-(1-octyl-2-methylindol-3-yl)-4-azaphthalide; 3-(4-cyclohexylethylamino-2-methoxyphenyl)-3-(1-ethyl-2-methylindol-3-yl)-4-azaphthalide; 3,3-bis(1-ethyl-2-methylindol-3-yl)phthalide; 3,6-bis(diethylamino)fluoran-γ-(3′-nitro)anilinolactam; 3,6-bis(diethylamino)fluoran-γ-(4′-nitro)anilinolactam; 1,1-bis[2′,2′,2″,2″-tetrakis(p-dimethylaminophenyl)-ethenyl]-2,2-dinitrileethane; 1,1-bis[2′,2′,2″,2″-tetrakis(p-dimethylaminophenyl)-ethenyl]-2-β-naphthoylethane; 1,1-bis[2′,2′,2″,2″-tetrakis(p-dimethylaminophenyl)ethenyl]-2,2-diacetylethane; bis[2,2,2′,2′-tetrakis(p-dimethylaminophenyl)ethenyl]-methylmalonic acid dimethyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][OH:18].[H-].[Na+].P([O-])([O-])([O-])=O>C1COCC1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]3[CH2:17][O:18][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2CO)c(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)OCC1CCCCN21
Yield: 76.1 %

Procedure:
A suspension of (+)-[I-(2-fluoro-4-nitrophenyl)-2-piperidinyl]-methanol (0.586 g, 2.30 mmol) and sodium hydride (60% mineral oil suspension, 0.101 g, 2.54 mmol) in 10 mL THF was heated at reflux for 16 h. The mixture was neutralized with phosphate buffer (pH 7), and the resultant solution was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (7:3 hexanes:EtOAc) afforded 0.410 g (76%) of (±)-3-nitro-6,6a,7,8,9, 10-hexahydropyrido[2,1-c][1,4]benzoxazine, a yellow-orange solid. Data for (±)-3-nitro-6,6a,7,8,9,10-hexahydropyrido[2,1-c][1,4]benzoxazine: Rf O. 71 (2:3, EtOAc:hexanes) 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, 1H, J=9.3, 2.9), 7.64 (d, 1H, J=2.9), 6.75 (d, 1H, J=9.3), 4.23 (dd, 1H, J=10.7, 2.9), 3.96 (dd, 1H, J=10.7, 7.8), 3.93 (m, 1H), 3,22-3.17 (m, 1H), 2.78 (td, 1H, J=12.8, 3.0), 1.95-1.92 (m, 1H), 1.88-1.84 (m, 1H), 1.75-1.71 (m, 1H), 1.66-1.60 (m, 1H), 1.58-1.48 (m, 1H), 1.35-1.27 (m, 1H).
Reaction SMILES: OCC([C@H]1NC(=O)[C@@H]1[C@H](OC(OCC1C=CC=CC=1)=O)C)=C.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][C:31]([C@H:33]1[N:36](C2CCCCO2)[C:35](=[O:43])[C@@H:34]1[C@H:44]([O:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[CH3:45])=[CH2:32]>>[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][C:31]([C@H:33]1[NH:36][C:35](=[O:43])[C@@H:34]1[C@H:44]([O:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[CH3:45])=[CH2:32]
Reactant: C=C(COC1CCCCO1)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C1CCCCO1
Agent: C=C(CO)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Product: C=C(COC1CCCCO1)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1

Procedure:
Following the procedure as described in Example 15-(1) but replacing the starting material by (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone, (3S,4S)-4-(1-tetrahydropyranyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-tetrahydropyranyl-2-azetidinone (Compound A) and (3S,4S)-4-(1-tetrahydropyranyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (Compound B) were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[F:14][C:15]1([F:20])[CH2:18][CH:17]([NH2:19])[CH2:16]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:11][C:6]1[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([NH:19][CH:17]2[CH2:18][C:15]([F:20])([F:14])[CH2:16]2)[N:3]=[C:4]([S:12][CH3:13])[N:5]=1
Reactant: NC1CC(F)(F)C1
Reactant: CSc1nc(Cl)c(CCO)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSc1nc(Cl)c(CCO)c(NC2CC(F)(F)C2)n1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 92.9 %

Procedure:
To a vial containing 2-[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]ethanol (600 mg, 2.51 mmol) and 3,3-difluorocyclobutylamine (540 mg, 3.76 mmol) in acetonitrile (12.5 mL) was added DIPEA (2.21 mL, 12.5 mmol) at room temperature, and the mixture was stirred at 100° C. in an oil bath for 6.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified via silica gel chromatography using a gradient of EtOAc/heptane (20-40%) to afford the title compound (722.5 mg, 93%) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J=5.5 Hz, 1 H), 4.82 (br s, 1 H), 4.38-4.26 (m, 1 H), 3.56-3.47 (m, 2 H), 3.03-2.87 (m, 2 H), 2.83-2.65 (m, 4 H), 2.42 (s, 3 H). m/z (APCI+) for C11H14ClF2N3OS 310.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[CH3:20][O:19][CH2:18][CH2:17][O:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)(=[O:28])=[O:27])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N)c2[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.1 %

Procedure:
To a mixture of ethyl 7-amino-5-(2-methoxyethoxy)-1H-indole-2-carboxylate (2.00 g) and pyridine (30 mL) was added thiophene-2-sulfonyl chloride (1.57 g) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1, volume ratio) to give the title compound (1.62 g, yield 53%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 106-107° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN(C=O)C.[CH3:11][CH:12]1[CH2:18][CH2:17][N:16]2[C:19](=[O:31])[C:20]3[C:25]4[CH2:26][CH2:27][CH2:28][C:29](=[O:30])[C:24]=4[S:23][C:21]=3[N:22]=[C:15]2[CH2:14][CH2:13]1.[CH:32](Cl)(Cl)[Cl:33]>>[Cl:33][C:32]1[C:24]2[S:23][C:21]3[N:22]=[C:15]4[CH2:14][CH2:13][CH:12]([CH3:11])[CH2:18][CH2:17][N:16]4[C:19](=[O:31])[C:20]=3[C:25]=2[CH2:26][CH2:27][C:28]=1[CH:29]=[O:30]
Reactant: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCC(C=O)=C4Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
POCl3 (2.91 mmol) was added dropwise into DMF (3.02 mmol) in CHCl3 (2 ml) at 0° C. After 30 minutes compound 17 (0.36 mmol) in CHCl3 (6 ml) was added slowly dropwise. The reaction mixture was allowed to reach room temperature and stirred overnight after which the reaction mixture was heated to 50° C. for 12 hours. The reaction mixture was cooled to room temperature and quenched with saturated NaOAc, extracted with CH2Cl2, washed with brine and water, and dried over Na2SO4. After filtration the solvent was evaporated. The product was purified by flash chromatography using CH2Cl2-EtOAc 9:1 as an eluent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:23]([OH:26])[C:24]#[CH:25]>O1CCCC1.C(OCC)C.[Cu]I.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:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][CH2:23][OH:26])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a degassed solution of 1-bromo-4-trifluoromethylbenzene (5.62 g, 25 mmol) in tetrahydrofuran (25 ml) was added in the following order: copper(I) iodide (143 mg, 0.75 mL), tetrakis(triphenylphosphine)palladium (0.85 g, 7.5 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.55 g, 30 mmol). The resulting mixture was degassed one more time, cooled in an ice bath and a solution of propargyl alcohol (1.68 g, 30 mmol) in tetrahydrofuran (5 mL) was added over period of 10 min. The reaction mixture was slowly heated up to 55° C. and then stirred at this temperature for 3 h and then at ambient temperature overnight. The mixture was diluted with diethyl ether (100 mL), washed with water (50 mL), 5% hydrochloric acid (35 mL) and saturated aqueous solution of sodium hydrogen carbonate (30 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, dichloromethane) affording 3-(4-trifluoromethylphenyl)prop-2-yn-1-ol.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[CH:14]=[N:15][C:16](Cl)=[N:17][CH:18]=2)=[C:8]([F:20])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(O)C>[CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[CH:14]=[N:15][C:16]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)=[N:17][CH:18]=2)=[C:8]([F:20])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cc(F)c(-c2cnc(Cl)nc2)c(F)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCc1cc(F)c(-c2cnc(-c3cc(F)cc(F)c3)nc2)c(F)c1

Procedure:
A mixture of 77 mmol of 1A, 92 mmol of 3,5-difluorophenylboronic acid (prepared from 3,5-difluorobromobenzene by reaction with magnesium and trimethyl borate), 200 ml of toluene, 92 ml of ethanol, 2.4 g of tetrakis[triphenylphosphine]palladium(0) and 125 ml of a 2 molar aqueous sodium carbonate solution is heated at the boil for 16 hours. Customary work-up gives the product, which can be processed further without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([F:23])[CH:13]=1.[C:24]([N:43]1[CH:47]=[C:46](B(O)O)[CH:45]=[N:44]1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[F-].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C)C=O>[F:23][C:14]1[CH:13]=[C:12]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:46]4[CH:45]=[N:44][N:43]([C:24]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH:47]=4)[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: OB(O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCOC(=O)c1ccc(-c2ncnc3ccc(Cl)cc23)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ncnc3ccc(-c4cnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c4)cc23)cc1F
Yield: 70.1 %

Procedure:
0.64 g ethyl 4-(6-chloroquinazolin-4-yl)-2-fluorobenzoate (compound in Production Example 385), 1.02 g 1-trityl-1H-4-pyrazolylboronic acid, 0.34 g potassium fluoride, 43 mg palladium (II) acetate, 0.11 g 2-(di-t-butylphosphino)biphenyl, 20 mL N,N-dimethylformamide and 2 mL water were heated at 70° C. for 24 hours under nitrogen atmosphere. Water was added thereto, the reaction solution was filtered, and crystals collected by filtration were washed with water. The crystals were dissolved in dichloromethane, washed with water and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), to give 0.82 g of the title compound (pale yellow crystals).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]1[CH:35]=[C:30]2[NH:31][CH2:32][CH2:33][CH2:34][C:29]2=[N:28]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:31]3[CH2:32][CH2:33][CH2:34][C:29]4=[N:28][N:27]([CH3:26])[CH:35]=[C:30]34)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cn1cc2c(n1)CCCN2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc2c(n1)CCCN2c1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Temperature: 150 °C
Yield: 98.8 %

Procedure:
A microwave vial was charged with a mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (77.9 mg, 182 μmol), 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine (25 mg, 182 μmol), xantphos (31.6 mg, 54.7 μmol), Pd2(dba)3 (16.7 mg, 18.2 μmol) and Cs2CO3 (119 mg, 364 μmol) in dioxane (2 mL). The mixture was purged with argon and then heated to 150° C. for 20 min under microwave irradiation. The mixture was diluted with CH2Cl2 and then filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue purified by chromatography (40 g column, 50 m silica-gel from Analogix, 0 to 5% 9:1 methanol:ammonium hydroxide in CH2Cl2, 20 min) to give N-tert-butyl-2-(2-methyl-6,7-dihydro-2H-pyrazolo[4,3-b]pyridin-4(5H)-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 99%) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 8.20 (s, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 5.64 (s, 2H), 3.91 (s, 3H), 3.50-3.63 (m, 2H), 2.93 (t, J=6.6 Hz, 2H), 2.15-2.30 (m, 2H), 1.53-1.62 (m, 11H), 0.86-1.05 (m, 2H), 0.00 (s, 9H). MS (EI/CI) m/z: 484.0 [M+H].
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:19]([CH3:21])[CH3:20])[N:16]=[CH:17][N:18]=1)[N:7]=3.C([O-])(=O)C.[K+].O1CCCCC1[O:35][CH2:36][CH2:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.Cl>CC#N.CCOC(C)=O.O.C(Cl)Cl.O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:19]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:41]5[CH:40]=[N:39][N:38]([CH2:37][CH2:36][OH:35])[CH:42]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][CH:17]=[N:16]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cnn(CCO)c3)cc1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a 10-mL microwave vial was added 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 (0.210 g, 0.56 mmol) and potassium acetate (0.17 g, 1.68 mmol), MeCN (1 mL) and water (2 mL). The mixture was thoroughly purged with N2. A solution of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.271 g, 0.84 mmol) in MeCN (1 mL) was added, followed by tetrakis(triphenylphosphine) palladium (65 mg, 0.056 mmol) and the vial was sealed immediately. The mixture was irradiated with microwave at 150° C. for 20 minutes. Complete conversion was observed by LC/MS (a small amount of des-THP product was observed). The reaction mixture was diluted with EtOAc and water and extracted three times with EtOAc. The organic phases were combined, dried with MgSO4 and concentrated. The residue was purified using ISCO chromatography using 10% MeOH/EtOAc, which gave 170 mg, 0.35 mmol (62%) a white foaming solid as product which was immediately dissolved in DCM (2 mL) and treated with 4 M hydrogen chloride in 1,4-dioxane (0.35 mL). A white precipitate developed during the addition. The reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness and dissolved in DMF/H2O. This mixture was purified by rp-HPLC to provide 105 mg (74% yield) of 182 as a white, partially crystalline solid. LS/MS (ESI+): m/z 406 (M+H). 1H NMR (400 MHz, DMSO) δ 8.37 (d, J=8.4, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.91 (s, 2H), 7.38 (dd, J=8.4, 1.8, 1H), 7.27 (d, J=1.7, 1H), 5.91 (dq, J=13.3, 6.7, 1H), 4.91 (t, J=5.3, 1H), 4.58-4.44 (m, 4H), 4.16 (t, J=5.6, 2H), 3.77 (q, J=5.4, 2H), 1.49 (d, J=6.6, 6H)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[C:23]=1[F:31]>>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[C:23]=2[F:31])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cccc([N+](=O)[O-])c1F)OCC

Procedure:
Analogously to the process described in Example 64A/Step 1, 1.0 g (3.62 mmol) of the compound of Example 4A and 876 mg (3.98 mmol) of 1-bromo-2-fluoro-3-nitrobenzene gave 1.11 g (73% of theory) of the title compound.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1>ClCCl.N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:21]1[CH:22]=[CH:23][C:18]([C:17]([F:26])([F:25])[F:16])=[CH:19][CH:20]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(C(F)(F)F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
A solution of trifluoromethanesulphonic anhydride (1.0 g) in dichloromethane (2 ml) was added dropwise to a solution of 4-(trifluoromethyl)phenol (0.5 g) in dichloromethane (10 ml) and pyridine (0.5 ml) at 0° under nitrogen. The resulting suspension was stirred for 1 h at room temperature, diluted with dichloromethane (20 ml) and washed with aqueous sodium carbonate (2N; 20 ml). The dried organic phase was evaporated and the residue was purified by FCC eluting with ether to give the title compound as a colourless oil (710 mg).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[CH2:13][CH2:14][CH3:15].[F:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1>O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:13][CH2:14][CH3:15])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
A N,N-dimethylformamide (DMF) solution (3 ml) of potassium carbonate (3.48 g, 25.2 mmol) and 1-iodopropane (3.95 g, 23.2 mmol) was added to a DMF solution (7 ml) of 4-fluoro-2-nitrophenol (3.3 g, 21.0 mmol). The mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution twice, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (n-hexane:ethyl acetate=9:1). The purified product was concentrated under reduced pressure to thereby obtain 4.03 g of oily yellow 4-fluoro-2-nitro-1-propoxybenzene (yield: 96%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:22]([C:26]#[N:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1>CO.O.Cl>[CH2:28]([C:21]1[C:22]([C:26]#[N:27])=[CH:23][CH:24]=[C:25]2[C:20]=1[CH2:19][CH2:18][C@H:17]2[O:16][C:14]1[CH:13]=[CH:12][C:11]2[C@H:7]([CH2:6][C:5]([OH:35])=[O:4])[CH2:8][O:9][C:10]=2[CH:15]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccccc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc2c(c1Cc1ccccc1)CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1 M aqueous NaOH solution (0.60 mL) is added to a solution of {(S)-6-[(R)-4-benzyl-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.10 g) in methanol (3 mL) at room temperature. The mixture is stirred at 40° C. for 1 h. The mixture is diluted with water and neutralized with 1 M aqueous HCl solution. The resulting mixture is extracted with ethyl acetate, and the combined extract is washed with brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100) to give the title compound. In case the product is insufficiently pure after this procedure the product is submitted to HPLC on reversed phase (MeCN/water). LC (method 4): tR=1.14 min; Mass spectrum (ESI+): m/z=424 [M+H]+.