Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15](=[O:24])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15](=[O:24])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]1)=[O:5]
Reactant: COc1cccc2c(=O)[nH]nc(Cc3ccc(F)c(C(=O)O)c3)c12
Reactant: COC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c(=O)[nH]nc(Cc3ccc(F)c(C(=O)N4CCC(OC)CC4)c3)c12
Yield: 54 %

Procedure:
2-fluoro-5-((8-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (125) and 4-methoxypiperidine were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.163 mL, 0.91 mmol) and then HBTU (347 mg, 0.91 mmol). The solvent was removed and the residue was dissolved in acetonitrile. A white solid precipitated, which was filtered and dried to afford the desired material as a white crystalline solid (140 mg, 54.0% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.49-1.60 (1H, m), 1.62-1.83 (2H, m), 1.86-1.96 (1H, m), 3.07-3.19 (1H, m), 3.32-3.36 (3H, m), 3.41-3.62 (3H, m), 3.78-3.82 (3H, m), 3.94-4.04 (1H, m), 4.36-4.46 (2H, m), 6.93-7.00 (1H, m), 7.10-7.30 (3H, m), 7.64-7.72 (1H, m), 8.00-8.12 (1H, m), 9.98-10.07 (1H, m); m/z (ES+) (M+H)+=426.4; HPLC RT=1.71 min.
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)[C:4]([NH2:6])=[O:5])#[N:2].[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(O)C>[C:1]([C:3](=[C:7]([S:10][CH3:11])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CSC(Nc1ccc([N+](=O)[O-])cc1)=C(C#N)C(N)=O

Procedure:
Dissolved 10.00 g 2-cyano-3,3-bis(methylthio)acrylamide in 100 mL of ethanol. Then added 7.337 g (1.00 eq.) of 4-nitroaniline to the reaction vessel and stirred the reaction at 75° C. until starting amide was absent and confirmed by HPLC. Once complete (18 hrs), the reaction was brought to room temperature and filtered to obtain 2-cyano-3-(methylthio)-3-((4-nitrophenyl)amino)acrylamide as an off white to light yellow powder as product. The product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[OH-].[Na+]>C(O)C.O>[NH2:19][CH2:18][CH2:17][CH2:16][NH:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:27][O:28][CH2:29][CH3:30]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of tert-butyl {3-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}carbamate (1.30 g, 3.14 mmol) in 10 mL of ethanol was treated with a solution of 3 M hydrogen chloride in ethanol (5.0 mL, 15 mmol) and heated to 100° C. After 30 min, the solvent was concentrated under reduced pressure to yield a brown sludge. The material was triturated with diethyl ether and filtered to give a tan solid. The solid was dissolved in water and treated with 10% NaOH solution until pH 13 was reached. The aqueous solution was extracted with CH2Cl2 (4×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.77 g) as a gold colored foam.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:71])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:69])[C:57]4[CH:62]=[CH:61][C:60]([C:63]5[CH:64]=[N:65][CH:66]=[N:67][CH:68]=5)=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:70])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:71])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:69])[C:57]4[CH:62]=[CH:61][C:60]([C:63]5[CH:68]=[N:67][CH:66]=[N:65][CH:64]=5)=[CH:59][CH:58]=4)=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:70])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(-c5cncnc5)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(-c5cncnc5)cc4)cc3)cc2C1=O
Yield: 97 %

Procedure:
The compound of example 653 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 652.
Reaction SMILES: C(OC([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)(C)(C)C.Cl>>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:27])[N:11]1[CH2:28][CH2:29][NH:8][CH2:9][CH:10]12)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OCc4ccccc4)cccc3C2C1
Agent: Cl
Product: O=C1c2c(OCc3ccccc3)cccc2C2CNCCN12
Reaction time: 0.08 h

Procedure:
To N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-benzyloxy-pyrazino[2,1-a]isoindol-6(2H)-one (31 mg, 0.08 mmol) was added concentrated aqueous hydrogen chloride (1 mL). After 5 min, the solution was concentrated, treated with saturated aqueous ammonium chloride, and reconcentrated. The resulting mixture was purified via radial chromatography (8% methanol in dichloromethane containing 2% ammonium hydroxide) to give (±)-1,3,4,10b-tetrahydro-7-benzyloxy-pyrazino[2,1-a]isoindol-6(2H)-one. This material was treated with aqueous hydrogen chloride (1N), concentrated, diluted with water, and lypholized to give the desired product as an off-white solid (19 mg, 72%). MS (ESI) 295.3 (M−Cl).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[O:12][CH3:13])=[C:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:6]2=[O:21].[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1>>[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[O:12][CH3:13])=[C:9]([CH:14]3[CH2:16][CH2:15]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:6]4=[O:21])=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: COC(=O)c1cc(C2CC2)c2c(OC)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(OC)c(-c3ccc4[nH]ncc4c3)ccn2c1=O
Yield: 51.4 %

Procedure:
Methyl 8-(1H-indazol-5-yl)-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (50 mg, 0.16 mmol), and 1H-Indazole-5-boronic acid pinacol ester (47.6 mg, 0.20 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as an orange foam (32 mg, 46%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)=[O:9])([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)NCc2cccc([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)NCc2cccc(N)c2)cc(C(C)(C)C)c1O
Yield: 42.8 %

Procedure:
In a 250 ml Parr flask, 2.40 g (6.2 mmoles) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide is dissolved in 45 ml of an absolute ethanol/TXF mixture (1/2) in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for three hours. After filtration on celite, the filtrate is concentrated to dryness and the residue is purified on a silica column (eluant: heptane/ethyl acetate: 60/40). The pure fractions are collected and concentrated under reduced pressure to produce 0.94g (45%) of a white powder. Melting point: 171-172° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH:9]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[C:10]#[N:11])=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2oncc2-c2ccncc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(C(=O)c1ccc(F)cc1)c1ccncc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A suspension of 5-(4-fluorophenyl)-4-(pyridin-4-yl)isoxazole (5.35 g) in 1N sodium hydroxide aqueous solution (50 ml) was stirred for one hour at 60° C. The solution was cooled and adjusted to pH 6 with concentrated hydrochloric acid. The separated solid was collected, washed with water, and dried to give 3-(4-fluorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile (5.27 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:12]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
3-Fluoro-4-nitro-phenol (10 g, 0.064 mol) was reacted with benzyl bromide (8.3 ml, 0.070 mol), cesium carbonate (22.7 g, 0.07 mol), and tetrabutyl ammonium iodide (0.05 g) in N,N-dimethylformamide (100 mL) at 25° C. for 18 hr. The reaction mixture was poured into distilled water (500 mL) and stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and solvent removed under reduced pressure to give the title compound as a light yellow solid (15 g). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.27 (s, 2 H) 7.06 (dd, J=9.56, 2.57 Hz, 1 H) 7.29 (dd, J=13.60, 2.57 Hz, 1 H) 7.44 (m, 5 H) 8.17 (t, J=9.19 Hz, 1 H). ESI m/z (M+H)+: 248
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([C:34](=[O:42])[C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].C(#N)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:53][CH2:54][CH2:55][O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CCOC(C)=O>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([C:34](=[O:42])[C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:53][CH2:54][CH2:55][O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: BrCCCOCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(O)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(OCCCOCc4ccccc4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 90.8 %

Procedure:
To a 0.5 L stirred round bottom, purged with nitrogen, charge in order: [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-(4-hydroxybenzoyl)-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (13.58 mmol), acetonitrile (250 mL), and potassium carbonate (67.92 mmol). To this stirred solution, at room temperature, add 3-bromopropoxymethylbenzene (27.2 mmol) and heat at 60° C. for 16 hours under nitrogen. Dilute with EtOAc (200 mL) and filter. Concentrate the filtrate and purify by flash chromatography (330 g silica gel) eluting with 2-40% EtOAc/chloroform. Concentrate the product containing fractions to give the title compound (9.0 g. 90.79%): mass spectrum (m/z): 730.4 (M+H).
Reaction SMILES: Cl.O1CCOCC1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19])([O-])=O>O.[Fe]>[F:19][C:18]([F:20])([F:21])[C:12]1[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=1[NH2:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Fe]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(N)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 86.3 %

Procedure:
100 g of iron fillings are heated to 95° C. in 300 ml of water, 5 ml of hydrochloric acid and 5 ml of dioxane in a stirred vessel, and 57 g of 2-nitro-5-methylbenzotrifluoride are added dropwise in the course of about 1 hour. The mixture is stirred for a further 2 hours, and a distillation is then carried out using steam. The organic material extracted with dichloromethane and re-distilled. 42 g (boiling point: 92°-95° C./20 mbar) of 2-trifluoromethyl-4-methylaniline are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:39])[C:15]2[C:16]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200.0 mg, 0.42 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (50.0 mg, 2.08 mmol) at 0° C. and stirred for 30 minutes at room temperature. Subsequently, iodomethane (350.0 mg, 2.47 mmol) was added and stirred overnight at room temperature. The reaction mixture was then quenched by the addition of NH4Cl solution (100 mL), extracted with dichloromethane (3×15 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (210 mg, crude).
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]([C:10](=[O:26])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][N:21]=1)[CH3:9])(C)(C)C.Cl.ClC1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2[CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1.CCN(C(C)C)C(C)C>O1CCOCC1.CC(O)C.CCOC(C)=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10](=[O:26])[C@@H:8]([NH:7][C:6]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][N:34]3[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH3:9])=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)[CH:14]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccncn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1Nc1ccncn1
Yield: 42.9 %

Procedure:
{(S)-1-[4-Fluoro-2-(pyrimidin-4-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (0.27 g, 0.72 mmol) was treated with 4M HCl in dioxane (10 mL) for 45 min at 20° C. The solvent was removed by evaporation under reduced pressure to give a solid, (0.29 g). 0.145 g of this solid was treated in a sealed tube with 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (103 mg, 0.43 mmol) and DIPEA (0.25 mL), 1.44 mmol) in IPA (1.5 mL) at 80° C. under argon for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (5 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and purified by column chromatography (Si—PCC, gradient 0-10% (9:1 MeOH/0.880 NH3) in DCM) to give the title compound as an orange gum, (88 mg, 51%). LCMS (Method B): RT 1.99 min [M+H]+ 478.13
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]5[C:35]=4[N:34]=[CH:33][CH:32]=[CH:31]5)(=[O:25])=[O:24])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]5[C:35]=4[N:34]=[CH:33][CH:32]=[CH:31]5)(=[O:25])=[O:24])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)(=[NH:41])[NH2:2]
Reactant: [NH4+]
Reactant: N#Cc1ccc(CC(=O)N2CCc3ccc(NS(=O)(=O)c4cccc5cccnc45)cc3C2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: N=C(N)c1ccc(CC(=O)N2CCc3ccc(NS(=O)(=O)c4cccc5cccnc45)cc3C2)cc1

Procedure:
Prepared analogously to Example 1e from 2-[(4-cyanophenyl)-acetyl]-7-(quinoline-8-sulphonylamino)-1,2,3,4-tetrahydro-isoquinoline and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15])([CH3:25])[CH3:24]
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: CC(C)N
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(C(=O)NC(C)C)c(C)n(C)c2c1

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c, oxalyl chloride and isopropylamine in a manner as previously described for example 16d. 1H NMR (300 MHz, CDCl3) δ7.53 (1H, d, J=8.7 Hz), 6.85 (1H, dd, J=2.3, 8.7 Hz), 6.77 (1H, d, J=2.3 Hz), 4.35 (1H, m), 3.87 (3H, s), 3.63 (3H, s), 2.69 (3H, s), 1.30 (3H, s), 1.27 (3H, s). LCMS (ESI+) [M+]H/z Calc'd 261, found 261.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH2:14][CH:15]=[CH2:16])C=C.C(Cl)Cl>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[N+:10]([C:6]1[C:5]2[O:13][CH2:14][CH:15]=[CH:16][CH2:1][C:4]=2[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: C=CCOc1c(CC=C)cccc1[N+](=O)[O-]
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2c1OCC=CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-allyl-2-allyloxy-3-nitrobenzene (100 mg, 0.0004 mol) in methylene chloride (6 mL, 0.09 mol) at room temperature was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (20 mg, 0.00002 mol). The reaction mixture was stirred at room temperature overnight. The reaction solvent was removed in vacuo leaving a dark solid which was purified by ISCO column chromatography on silica gel using hexane-methyl-t-butyl ether (3:1). The fractions corresponding to product were combined and concentrated in vacuo to give 9-nitro-2,5-dihydrobenzo[b]oxepine as a dark solid which was further purified to give product as an off-white solid (80 mg, 90%). 1H NMR (CDCl3, 400 MHz) δ 7.66 (d, 1H, J=8.09 Hz), 7.33 (d, 1H, J=7.32 Hz), 7.11 (dd, 1H, J=7.58, 8.09 Hz), 5.86 (m, 1H), 5.54 (d, 1H, J=11Hz), 4.79 (s, 2H), 3.54 (s, 2H);
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=[O:8].[Na+].CC(=CC)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:34]=[C:35]([CH:39]([CH2:46][CH:47]=[O:48])[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:36]=[CH:37][CH:38]=2)=[CH:27][C:26]=1[CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51].Cl>O.CC(O)(C)C>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][CH:39]([C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][O:31][C:28]2[CH:29]=[CH:30][C:25]([C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[F:16])=[C:26]([CH2:49][C:50]([CH3:52])([CH3:51])[CH3:53])[CH:27]=2)[CH:34]=1)[CH2:46][C:47]([OH:8])=[O:48])[CH3:45]
Reactant: [O-][Cl+][O-]
Reactant: CCOC(=O)CC(CC=O)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)CC(CC(=O)O)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium dihydrogenphosphate (230 mg), sodium chlorite (174 mg) and 2-methyl-2-butene (339 μL) were successively added to a mixture of ethyl 3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)-5-oxopentanoate, 2-methyl-2-propanol (4 mL) and water (1 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (269 mg) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([NH2:11])[C:7]=2[CH:12]=1.O.[C:16]([OH:20])(=[O:19])[CH:17]=O.CC(O)=O>CO>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([NH:11][CH2:17][C:16]([OH:20])=[O:19])[C:7]=2[CH:12]=1
Reactant: Nc1noc2ccc(C(F)(F)F)cc12
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CNc1noc2ccc(C(F)(F)F)cc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-Trifluoromethyl-benzo[d]isoxazol-3-ylamine (2.5 g, 12.4 mmol) and glyoxylic acid monohydrate (Aldrich, 1.14 g, 12.4 mmol) in MeOH (10 mL) were treated with a few drop of AcOH and heated at 80° C. for 30 min. The reaction was then cooled to room temperature and NaBCNH3 (Aldrich, 1.17 g, 18.6 mmol) was added in one portion and the resulting solution was stirred at room temperature for another 2 hours. The solvent was removed and the residue was partitioned between ether and 1 N NaOH. The aqueous layer was then acidified with 1 N HCl to pH=3 and then extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as white solid.