Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=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+].[N:78]1([C:84]([NH2:86])=[O:85])[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>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].CN(C=O)C>[F:29][C:25]1[C:11]([C:12](=[O:13])[NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[C:10]([NH:9][CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:86][C:84]([N:78]3[CH2:83][CH2:82][O:81][CH2:80][CH2:79]3)=[O:85])[CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cn1cc2ccc(NC(=O)c3c(F)cccc3NCc3ccnc(Br)c3)cc2n1
Reactant: NC(=O)N1CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cn1cc2ccc(NC(=O)c3c(F)cccc3NCc3ccnc(NC(=O)N4CCOCC4)c3)cc2n1
Temperature: 110 °C
Yield: 52.4 %

Procedure:
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide (227 mg, 0.5 mmol) was suspended in dioxane (4 mL) and treated consecutively with DMF (1.6 mL), Pd2dba3 (13 mg, 0.013 mmol), Xantphos (18 mg, 0.031 mmol), cesium carbonate (193 mg, 0.59 mmol) and morpholine-4-carboxylic acid amide (244 mg, 0.75 mmol). The reaction mixture was placed under an argon atmosphere and heated for 3 hours at 110° C. (bath temperature). On cooling the reaction was partitioned between EtOAc and water. The organic phase was dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1) to give morpholine-4-carboxylic acid (4-{[3-fluoro-2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (132 mg, 52%) as a pale yellow resin. Further purification was accomplished by preparative reverse phase HPLC [Column: Kromasil C8 5μ, 125×20 mm. Eluant: 38% CH3CN in H2O (containing 0.2% NH3) to 95% CH3CN in H2O (containing 0.2% NH3)]; 1H-NMR (300 MHz, d6-DMSO) 10.43 (1H, s), 9.15 (1H, s), 8.26 (1H, s), 8.23 (1H, s), 8.15 (1H, d), 7.79 (1H, s), 7.64 (1H, d), 7.13-7.25 (2H, m),-6.95 (1H, d), 6.73 (1H, t), 6.48 (1H, t), 6.29 (1H, d), 4.40 (2H, d), 4.14 (3H, s), 3.56-3.59 (4H, m), 3.42-3.45 (4H, m); m/z (ES+) 504 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:7][C:8]=2[O:18][CH3:19])[O:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:25])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:7][C:8]=2[O:18][CH3:19])[O:3]1
Reactant: CCCCCc1cc(OC)c2c(c1)OC(C)(C)C=C2c1ccncc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1cc(OC)c2c(c1)OC(C)(C)CC2c1ccncc1

Procedure:
2,2-Dimethyl-5-methoxy-7-n-pentyl-4-(4-pyridyl)-2H-chromene (3.90g.) was hydrogenated for 4.5 hours at 20°C and 30 p.s.i. in ethanol (100 ml) in the presence of 5% palladium on charcoal (0.50g.). The solution was filtered and evaporated to dryness under reduced pressure to yield 2,2-dimethyl-5-methoxy-7-n-pentyl-4-(4-pyridyl) chroman as a yellow oil (3.90g.). (This compound was also prepared in low yield via treatment of 2,2-dimethyl-7-n-pentyl-4-(4-pyridyl) chroman-5-ol with (1) sodium hydride and (2) iodomethane in benzene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:26][C:25]([CH3:27])=[C:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:23]=1[CH3:33])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:26][C:25]([CH3:27])=[C:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:23]=4[CH3:33])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.5 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (6.3 mg, 0.0226 mmol), 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (4.9 mg, 0.0249 mmol) and piperidine (4 drops) in ethanol (1 mL) was stirred at room temperature for 24 hours. The reaction was concentrated and purified (reversed phase HPLC) to give 5.2 mg (51%) of the title compound. MS 456.4 [M++1].
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2][C:3]([OH:5])=[O:4].O[C:24]1[C:33]([F:34])=[C:31]([F:32])[C:29]([F:30])=[C:27]([F:28])[C:25]=1[F:26].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])[CH2:2][C:3]([O:5][C:24]1[C:25]([F:26])=[C:27]([F:28])[C:29]([F:30])=[C:31]([F:32])[C:33]=1[F:34])=[O:4]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 15 h

Procedure:
To a solution of Fmoc-Gly-OH (891 mg, 3.0 mmol) and PfpOH(754 mg, 4.5 mmol) in DMF (12 mL) was added DCC (845 mg, 4.5 mmol) at 0° C. for 30 min and then room temperature for 15 h. The reaction mixture was filterd to remove DCUrea and the flitrate was evaporated in vacuo to give the crude Fmoc-Gly-OPfp. To a solution of Fmoc-Gly-OPfp and BocPNA-OH (436 mg, 2.0 mmol) in DMF (16 mL) was added diisoprppylethylamine (445 il, 2.6 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was evaporated in vacuo and the residue was flush-chromatographed (0-50% MeOH/CH2Cl2) to give Fmoc-Gly-BocPNA-OH (121 mg, 12%). 1H NMR (DMSO-d6) δ 7.88 (d, J=7.0 Hz, 2H), 7.72 (d, J=7.0 Hz, 2H), 7.62 (brt) and 7.56 (brt) (1H), 7.41 (t, J=7.0 Hz, 2H), 7.33 (t, J=7.0 Hz, 2H), 7.18 (m, 2H), 6.85 (brt) and 6.79 (brt) (1H), 4.35-4.15 (m, 3H), 4.05-3.85 (m, 3H), 3.77 (m, 1H), 3.40-3.25 (m, 2H), 3.10 (m) and 3.03 (s) (2H), 1.37 (brs, 9H); 13C NMR (DMSO-d6) δ 172.2 (d), 169.10 (d), 156.34 (d), 155.58 (d), 143.83, 140.66, 127.58, 127.04, 125.24, 120.04, 77.77 (d), 65.71, 47.34 (d), 46.72, 46.65 (d), 29.23 (d), 28.14 (d); FABMS m/z 498 [(M+H)+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[OH:39][CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Product: O=S(=O)(NCCO)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.29) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (370 mg, 66%). MS (ISP) 555.2 [(M+H)+]; mp 206-208° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)=[CH:17][CH:16]=3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1>ClCCl>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:13]([N:10]3[CH2:11][CH2:12][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]3)=[O:14])=[CH:16][CH:17]=2)[S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])=[CH:30][CH:29]=1)#[N:28]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#Cc1ccc(CNc2ccc(C(=O)N3CCN(c4ccccc4)CC3)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(CN(c2ccc(C(=O)N3CCN(c4ccccc4)CC3)cc2)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 23.5 %

Procedure:
A mixture of 4-{[4-(4-Phenyl-piperazine-1-carbonyl)-phenylamino]-methyl}-benzonitrile (50 mg, 0.13 mmol), phenylsulfonylchloride (80 mg, 0.42 mmol) and pyridine (0.04 mL, 0.44 mmol) in dichloromethane (5 ml) was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and the quenched by the addition of water (4 ml). The organics were collected, dried over magnesium sulfate and concentrated in vacuo The residue was purified by preparative thin layer chromatography (dichloromethane/ethyl acetate 1:1) to afford the title compound as a white solid (16.4 mg, 27% yield). HPLC retention time 6.71 min. Mass spectrum (ES+) m/z 475 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:12][CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(I)c2)CCOC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Ic1cccc(C2CCOC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
A solution of the product of step A (2.0 g, 3.79 mmol) in dichloromethane (15 mL) was cooled to 0° C. under a nitrogen atmosphere before addition of triethylsilane (5.0 mL, 31.38 mmol), TFA (4.4 mL, 55.74 mmol) and borontrifluoride-diethyletherate complex (7.0 mL, 55.74 mmol). The reaction mixture was stirred for 48 h at ambient temperature, then poured into K2CO3 (aq.) solution and extracted with dichloromethane. The combined organic layer was dried over Na2SO4, concentrated and the residue purified by flash column chromatography (SiO2, 98:2 hexanes/ethyl acetate) to give 3-(3-iodophenyl)tetrahydrofuran (0.89 g, 86%) as a colorless liquid: 1H NMR (CDCl3, 300 MHz) δ 7.60 (t, J=1.8 Hz, 1H), 7.56 (td, J=7.8 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.04 (t, J=7.8 Hz, 1H), 4.15-4.00 (m, 2H), 3.96-3.84 (m, 1H), 3.76-3.66 (m, 1H), 3.33 (p, J=7.8 Hz, 1H), 2.43-2.29 (m, 1H), 2.04-1.89 (m, 1H). Step C: The product of step B was coupled with lithium 2-(tert-butoxycarbonyl)-6-chloro-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine-8-sulfinate following the procedure of Example 50, step A. The crude product was purified by flash column chromatography (SiO2, 4:1 hexanes/ethyl acetate) to give tert-butyl 6-chloro-8-(3-(tetrahydrofuran-3-yl)phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (55 mg, 8%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.02-7.91 (m, 1H), 7.87-7.76 (m, 3H), 7.51-7.44 (m, 2H), 4.57 (s, 2H), 4.18-4.02 (m, 2H), 3.97-3.78 (m, 3H), 3.77-3.67 (m, 1H), 3.46 (p, J=7.5 Hz, 1H), 2.98-2.84 (m, 2H), 2.49-2.34 (m, 1H), 2.06-1.89 (m, 1H), 1.50 (s, 9H); APCI MS m/z 418 [(M+H)—C5H9O2]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].[N:15]#[C:16]Br>>[C:9]1([CH:7]([O:6][CH2:5][C@H:2]2[CH2:3][O:4][C:16]([NH2:15])=[N:1]2)[CH3:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CBr
Reactant: CC(OC[C@H](N)CO)c1ccccc1
Product: CC(OC[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1d (R)-2-amino-3-(1-phenyl-ethoxy)-propan-1-ol was reacted with cyanogen bromide to give (4S)-4-(1-phenyl-ethoxymethyl)-4,5-dihydro-oxazol-2-ylamine. Light yellow oil. MS (ISP): 221.3 ([M+H]+)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH2:30][OH:31])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[CH3:35]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:21]=[C:22]([CH2:30][O:31][CH3:35])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CO)c(OC)c(OC)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
After dissolving 322 mg of [2-(3-hydroxymethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 5 ml of dichloromethane, 364 mg of 1,8-bis(dimethylamino)naphthalene and 240 mg of Me3O+BF4 were added and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (169 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]2[C:4](=[C:5]([C:28]([NH:30][CH3:31])=[O:29])[N:6]([C:14]3[CH:15]=[N:16][C:17]([O:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:18][CH:19]=3)[N:7]=2)[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:40]1([B-](F)(F)F)[CH2:42][CH2:41]1.[K+].C(Cl)Cl>C1(C)C=CC=CC=1.O.CCOC(C)=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]>[CH:40]1([C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]3[C:4](=[C:5]([C:28]([NH:30][CH3:31])=[O:29])[N:6]([C:14]4[CH:15]=[N:16][C:17]([O:20][C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)=[CH:18][CH:19]=4)[N:7]=3)[CH:3]=2)[CH2:42][CH2:41]1
Reactant: F[B-](F)(F)C1CC1
Reactant: CNC(=O)c1c2cc(Br)c([N+](=O)[O-])cc2nn1-c1ccc(Oc2ccc(F)cc2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=O)c1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Oc2ccc(F)cc2)nc1
Yield: 74.5 %

Procedure:
A degassed suspension of 5-bromo-2-[6-(4-fluorophenoxy)pyridin-3-yl]-N-methyl-6-nitro-2H-indazole-3-carboxamide (10 mg, 0.021 mmol), potassium phosphate (35 mg, 0.16 mmol), potassium cyclopropyltrifluoroborate (19 mg, 0.13 mmol) and Pd(dppf)Cl2.CH2Cl2 (3 mg, 0.004 mmol) in toluene (1 mL) and water (0.1 mL) was heated under microwave irradiation at 110° C. for 1 h. The reaction mixture was diluted with EtOAc (3 mL), washed with water (1 mL) and brine (1 mL), then dried (MgSO4) and concentrated to dryness. The residue was purified by flash column chromatography eluting with MeOH/DCM (0-10%) to give 5-cyclopropyl-2-[6-(4-fluorophenoxy)pyridin-3-yl]-N-methyl-6-nitro-2H-indazole-3-carboxamide as a tan solid (7 mg, 73%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH3:23][NH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=1)[C:28](O)=[O:29]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:28]([C:27]4[CH:31]=[CH:32][N:33]=[C:25]([NH:24][CH3:23])[CH:26]=4)=[O:29])[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: CNc1cc(C(=O)O)ccn1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Agent: Cl
Product: CNc1cc(C(=O)N2CCC[C@H](COc3cccc4c3C(N)=NS(=O)(=O)N4)C2)ccn1
Yield: 44 %

Procedure:
Prepared as in Example 2 from (S)-4-amino-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 2a) and 2-(methylamino)isonicotinic acid. (Yield: 44%). 1H NMR (400 MHz, DMSO-d6, 60° C.) δ1.45 (br m, 2H), 1.68 (br m, 1H), 1.91 (br m, 1H), 2.15 (br m, 1H), 2.77 (d, J=7.6 Hz, 3H), 3.02 (br m, 1H), 1.97 (br m, 1H), 2.13 (br m, 2H), 2.80 (br m, 2H), 3.19 (br m, 1H), 3.30-4.09 (br m, 4H), 6.34 (br m, 1H), 6.38 (br m, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.74 (m, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.73 (br s, 2H), 8.01 (m, 1H), 10.70 (br s, 1H). MS 445 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:22]([NH:23][C:24](=[O:57])/[C:25](=[N:51]\[O:52][CH2:53][CH:54]3[CH2:56][CH2:55]3)/[C:26]3[N:27]=[C:28]([NH:31]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:29][CH:30]=3)[C:21](=[O:58])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([O:17][C:18](=[O:20])[CH3:19])[CH3:16])=[O:13])(=[O:3])[NH2:2].O>C(O)=O>[NH2:31][C:28]1[S:29][CH:30]=[C:26](/[C:25](=[N:51]/[O:52][CH2:53][CH:54]2[CH2:56][CH2:55]2)/[C:24]([NH:23][C@@H:22]2[C:21](=[O:58])[N:10]3[C:11]([C:12]([O:14][CH:15]([O:17][C:18](=[O:20])[CH3:19])[CH3:16])=[O:13])=[C:6]([CH2:5][O:4][C:1](=[O:3])[NH2:2])[CH2:7][S:8][C@H:9]23)=[O:57])[N:27]=1
Reactant: CC(=O)OC(C)OC(=O)C1=C(COC(N)=O)CS[C@@H]2[C@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Solvent: O=CO
Solvent: O
Product: CC(=O)OC(C)OC(=O)C1=C(COC(N)=O)CS[C@@H]2[C@H](NC(=O)/C(=N\OCC3CC3)c3csc(N)n3)C(=O)N12
Reaction time: 1.5 h
Yield: 51 %

Procedure:
1-Acetoxy-1-ethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-cyclopropylmethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylate (1.5 g) was dissolved in formic acid (15 ml) and water (7.5 ml) was added. After 1.5 hour at 21°, the mixture was filtered and the filter-cake was leached with formic acid-water (2:1). The combined filtrates were concentrated and the residue was mixed with isopropanol when a solution formed. This was evaporated to dryness and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous layer was extracted with more ethyl acetate and the combined organic layers were washed with brine and dried with magnesium sulphate. After evaporation, the residue was triturated with isopropanol (5 ml) to give the title compound (540 mg); [α]D21 +17.9° (c 1.2, CHCl3); λmax (ethanol) 238.5 nm (E1 cm1% 287), λinfl 256 nm (E1 cm1% 249) and λinfl 280 nm (E1 cm1% 179).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:21][CH2:22][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)(=[O:19])[CH3:18]
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCn1cnc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (75 mg) was reacted with 2-bromoethyl acetate via General Procedure C to give 2-(2-chloro-6-morpholino-9H-purin-9-yl)ethyl acetate which was reacted with 150 mg tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate via General Procedure A and purified via reverse phase HPLC to give 59.4 mg of 144 as a white solid. MS (Q1) 342.2 (M)+
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]O.O>ClCCl.O1CCCC1>[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2]
Reactant: OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCCCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: OCCCCCC=CCCCCCCCCCCBr
Yield: 45.8 %

Procedure:
A solution of (6-hydroxyhexyl)triphenylphosphonium bromide (5.0 g) in dichloromethane (20 ml) was added dropwise to a mixture of potassium tertiary-butoxide (2.8 g) in tetrahydrofuran (100 ml) at 5°. After ten minutes, 11-bromoundecanol (2.8 g) in tetrahydrofuran (20 ml) was added and the reaction stirred at 5° until TLC indicated completion of the reaction. Water (20 ml) was added and the mixture then concentrated in vacuo. Water (20 ml) was added to the residue and the aqueous phase extracted with ether (2×50 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a brown oil. This was subjected to column chromatography to yield 17-bromoheptadec-6-en-1-ol (1.7 g, 45%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([C:28]4[S:29][C:30]([CH3:34])=[C:31]([CH3:33])[N:32]=4)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:35][CH3:36])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:33][C:31]1[N:32]=[C:28]([C:21]2[C:20]([O:19][C:13]3[C:12]4[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:35][CH3:36])[CH:11]=4)[N:16]=[CH:15][CH:14]=3)=[CH:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=2)[S:29][C:30]=1[CH3:34]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
7-Benzyloxy-4-[2-(4,5-dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-yloxy]-6-methoxy-quinoline (compound 454) (254 mg) was dissolved in trifluoroacetic acid (3 ml) to prepare a solution. Methanesulfonic acid (0.3 ml) was added to the solution, and the mixture was stirred at 70° C. for one hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. An aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (189 mg, yield 91%).
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].CS(C)=O.[CH3:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]2=[CH:26][S:27][CH:28]=[C:17]2[C:16]1=[O:29]>Cl.CCOCC>[CH3:4][N:5]([CH3:6])[CH2:7][CH2:8][N:19]1[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:15]([CH3:14])[C:16](=[O:29])[C:17]2=[CH:28][S:27][CH:26]=[C:18]12
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CN(C)CCN1c2cscc2C(=O)N(C)c2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 0.72 g. of 55% sodium hydride-mineral oil dispersion and 0.60 g. of dimethylaminoethylchloride hydrochloride in 25 ml. of dimethylsulfoxide is stirred at room temperature for 0.5 hours. To the mixture is added 0.46 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 3 hours. The reaction mixture is quenched by dropwise addition of water, diluted with about 200 ml. of water, acidified, filtered, made alkaline with 5N sodium hydroxide and extracted several times with chloroform. The chloroform extracts are dried over magnesium sulfate and concentrated under reduced pressure to give an amber oil. The oil is dissolved in a minimal volume of ethanolic hydrogen chloride solution and diluted with ether to give an oily semi-solid which slowly crystallizes. Recrystallization from ethanol-ether gives tan crystals, m.p. 245°-248°C. (dec.).