Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([S:5][C@@H:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:13]([O:15][CH3:16])=[O:14])[CH2:8]/[C:7]/1=[CH:24]\[C:25]1[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:26]=1)(=O)C>CO>[ClH:1].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:12]([N:9]1[CH2:10][CH2:11][C@@H:6]([SH:5])/[C:7](=[CH:24]/[C:25]2[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:26]=2)/[CH2:8]1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: CCOC(=O)CCn1ccc(/C=C2\CN(C(C(=O)OC)c3ccccc3F)CC[C@H]2SC(C)=O)n1
Agent: Cl
Solvent: CO
Product: CCOC(=O)CCn1ccc(/C=C2\CN(C(C(=O)OC)c3ccccc3F)CC[C@H]2S)n1
Temperature: 0 °C
Yield: 99 %

Procedure:
Hydrogen chloride was passed through a solution of (4R)-(E)-4-(acetylsulfanyl)-1-[(1RS)-1-(2-fluorophenyl)-2-methoxy-2-oxoethyl]-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)piperidine (223.8 mg) in methanol (6 ml) while stirring at 0° C. and the sealed mixture was stirred at room temperature for 7 hours. The solvent and excess hydrogen chloride were evaporated under reduced pressure and the residue was purified by silica gel chromatography using methanol and dichloromethane (3:97 to 15:85, v/v) as eluents to afford the title compound (213.9 mg, yield: 99%) as a colourless amorphous solid.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].CI.[Br:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2>CN(C=O)C>[CH3:1][O:21][C:20]([C:17]1[CH:18]=[CH:19][C:10]([Br:9])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)c2cccnc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)c2cccnc12
Temperature: 45 °C

Procedure:
K2CO3 (61.3 g, 444.0 mmol) and methyl iodide (63.1 g, 444.0 mmol) were added to a stirred suspension of 5-bromoquinoline-8-carboxylic acid (28.0 g, 111.0 mmol) in DMF (250 mL) at r.t. The reaction mixture was heated at 45° C. for 36 h, cooled to r.t, filtered the solids, washed with ethyl acetate (100 mL). The filtrate was diluted with water, extracted with ethyl acetate (3×300 mL) and washed with water (3×100 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate in hexanes (0-20%) to afford methyl-5-bromoquinoline-8-carboxylate as a cream color solid (20.5 g, 70% for 2 steps). 1H NMR (400 MHz, CDCl3) δ 9.07 (dd, J=4.3, 1.5 Hz, 1H), 8.60 (dd, J=8.7, 1.6 Hz, 1H), 7.88 (s, 2H), 7.58 (dd, J=8.6, 4.0 Hz, 1H), 4.05 (s, 3H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.N1CCCCC1.C(O)(=O)C>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1/[CH:21]=[C:9](\[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:17])/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C(=C/c1ccccc1Cl)C(=O)c1ccccc1O
Yield: 20.1 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (236 mg, 1.0 mmol), 2-chlorobenzaldehyde (113 μL, 1.0 mmol) 15 mL benzene, piperidine (10 μL, 0.1 mmol) and glacial acetic acid (5.6 μL, 0.1 mmol), refluxed for 90 min. Purified via recrystallization from hexanes/CH2Cl2, yielding 72 mg (20%) of a white solid. mp=75-78° C. IR (film) 2979.0; 1720.5; 1630.9; 1156.3 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.80 (bs, 1H); 8.19 (s, 1H); 7.50 (d, J=7.9 Hz, 1H); 7.44 (t, J=7.9 Hz, 1H); 7.36 (d, J=7.9 Hz, 1H); 7.26 (d, J=7.9 Hz, 1H); 7.21 (t, J=7.6 Hz, 1H); 7.08 (t, J=7.06, Hz, 1H); 6.97 (d, J=7.9 Hz, 1H); 6.82 (t, J=7.6 Hz, 1H); 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 200.6, 163.3, 162.8, 139.1, 137.2, 135.0, 134.0, 131.9 (double intensity), 131.3, 130.2, 130.1, 127.2, 120.0, 119.5, 118.5, 83.1, 28.1; LRMS (electrospray): Mass calculated for C20H19ClO4 [M]+, 358.09. Found [M+23]+, 381.5.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9](O[C:12](=[O:13])[CH:2]21)=[O:10].[NH3:14].O>O1CCCC1>[CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[C:9](=[O:10])[NH:14][C:12](=[O:13])[CH:2]21
Reactant: N
Reactant: O=C1OC(=O)C2C3CCC(CC3)C12
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(=O)C2C3CCC(CC3)C12

Procedure:
A solution of bicyclo[2.2.2]octane-2,3-dicarboxylic anhydride (3 g; 16.6 mmol) in tetrahydrofuran (9 ml) was dropwise added to a mixture of 29% aqueous ammonia (6 g; 83 mmol) and water (18 ml) while ice-cooling, and the resultant mixture was heated. After removal of the solvent by distillation under an ordinary pressure, acetic anhydride (10 ml) was added thereto, followed by refluxing for 30 minutes. The solvent was removed by distillation under reduced pressure, and the residue was combined with toluene (24 ml) and heated to dissolve. After cooling, the precipitated crystals were collected by filtration to give the objective compound. M.P., 199 -200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC>C1COCC1>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:21])[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:7]2[OH:9]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of methyl 5-bromo-2-(2-phenylacetamido)benzoate (7.71 g, 22.1 mmol, Intermediate 1: step a) in THF (50 mL) at −78° C. was added 1.0 M lithium bis(trimethylsilyl)amide in hexane (48.7 mL, 48.7 mmol) slowly, and the color changed from clear to clear red. The mixture was stirred at −78° C. to room temperature for 4 hours, during which time the color changed to cloudy yellow. The reaction was quenched with water, and acidified with 37% HCl until pH˜5. The precipitated solid was filtered, washed with water and Et2O, and air dried to provide the title compound. More solid was precipitated from the filtrate after standing overnight. The solid was collected by filtering, washing with water and Et2O, and air drying to afford additional title compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[N:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([F:33])[CH:32]=1>COCCOC.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>[Cl:26][C:27]1[CH:28]=[C:29]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: CCOC(=O)c1nc(-c2cccc(C#N)c2)c(Br)s1
Reactant: OB(O)c1cc(F)cc(Cl)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: [Na+]
Solvent: COCCOC
Product: N#Cc1cccc(-c2nc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At room temperature, 2.2 ml of an aqueous 2M sodium carbonate solution and 30.8 mg (0.027 mmol) of tetrakis(triphenylphosphine)palladium are added to 300 mg (0.890 mmol) of the compound from Example 35A and 233 mg (1.34 mmol) of (3-chloro-5-fluorophenyl)boronic acid in 12 ml of DME, and the mixture is subsequently stirred at 80° C. overnight. The crude product is filtered through a short kieselguhr column and the filtrate is concentrated under reduced pressure. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 116 mg (36% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:10].Cl[C:19](=[O:39])[CH2:20][NH:21][C:22](=[O:38])[O:23][CH2:24][CH:25]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2>C(Cl)(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:39])[CH2:20][NH:21][C:22](=[O:38])[O:23][CH2:24][CH:25]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]3[C:37]2=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[O:10])[CH:4]=1
Reactant: O=C(Cl)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1F
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Yield: 70.7 %

Procedure:
A round-bottomed flask was charged with (2-amino-5-bromophenyl)(2-fluorophenyl)methanone (1.45 g), 9H-fluoren-9-ylmethyl (2-chloro-2-oxoethyl)carbamate (1.6 g) and chloroform (150 mL). The mixture was heated to reflux for 2 h then concentrated to dryness. The residue was taken up in a mixture of a saturated solution of sodium bicarbonate and ethyl acetate. The resulting solids were collected on a filter and washed first with water then with diethyl ether. Thorough air-drying provided 9H-fluoren-9-ylmethyl [2-({4-bromo-2-[(2-fluorophenyl)carbonyl]phenyl}amino)-2-oxoethyl]carbamate (2 g) as a light yellow powder. H1 NMR (d6-dmso): 10.8 (br s, 1H), 7.95 (d, 1H), 7.75-7.90 (m, 4H), 7.45-7.70 (m, 5H), 7.20-7.42 (m, 6H), 4.30 (d, 2H), 4.20 (t, 1H), 3.65 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH3:18].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:31](OCCC(C)C)=O.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[NH:1]1[C:2]2[C:3](=[CH:4][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=3[C:9]#[N:10])=[CH:16][CH:17]=2)[CH:18]=[N:31]1
Reactant: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
In a 500 mL one-necked flask containing a large magnetic stir bar, 2-(4-amino-3-methylphenoxy)-5-fluorobenzonitrile (274.5 ml, 219.6 mmol) was taken up in chloroform (0.8 M) and treated with potassium acetate (25.86 g, 263.5 mmol) at room temperature. The reaction mixture was cooled to 0° C. and treated with acetic anhydride (62.28 mL, 658.8 mmol) via addition funnel over 5 minutes. The reaction was fitted with a reflux condenser, treated with additional 100 mL chloroform, and heated to 40° C. Isoamyl nitrite (58.74 mL, 439.2 mmol) was added dropwise via an addition funnel. The addition funnel was rinsed with 60 mL+40 mL of chloroform, removed, and replaced with a glass stopper. The reaction was heated to reflux for 20 hours, cooled to room temperature, and concentrated in vacuo to a brown solid. After being dried under high vacuum for 30 minutes, the brown solid was suspended in 1 L water, stirred vigorously for 15 minutes, and filtered. The resulting orange-brown solid (83 g) was taken up in 400 mL MeOH and treated with 1.0 M hydrochloric acid (241.6 mL, 241.6 mmol) at room temperature. The mixture was fitted with a reflux condenser and warmed to 70° C. for 20 hours. The reaction was cooled to 0° C. and 1.0 M sodium hydroxide (252.6 mL, 252.6 mmol) was added, followed by water (250 mL). The resulting yellow suspension was stirred in the ice bath for 10 minutes and then allowed to settle. The suspension was filtered, washed with water (1 L), air dried, dried with latex dam, and dried under high vacuum at 40° C. for 36 hours, to provide 50.7 g (91%) of the desired product as a free-flowing tan solid. MS (APCI+) m/z 254 (M+1) detected. 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br, 1H), 8.07 (s, 1H), 7.94 (dd, 1H, J=3.1 Hz, J=8.2 Hz), 7.64 (d, 1H, J=9. Hz), 7.54 (m, 2H), 7.21 (dd, 1H, J=9 Hz), 6.96 (dd, 1H, J=4.3 Hz, J=9.3 Hz).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1B(O)O)=[O:13]>>[CH:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:13]
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: COC(=O)c1ccccc1I
Product: COC(=O)c1ccccc1-c1ccc(OC)cc1C=O

Procedure:
Methyl 2-iodobenzoate was coupled to 2-formyl-4-methoxyphenylboronic acid using the procedure described in Example 4, Part A to provide methyl 2-(2′-formyl-4′-methoxyphenyl)benzoate. 1HNMR (300 MHz, CDCl3) δ 9.74 (s, 1H); 8.02 (d, 1H, J=7.7 Hz); 7.57 (t, 1H J=7.7 Hz); 7.50 (m, 2H); 7.28, 1, m); 7.17 (s, 2H); 3.91 (s, 3H); 3.64 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87](O)=[O:88])=[O:72])([CH3:69])([CH3:68])[CH3:67]>C(Cl)Cl>[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9][CH2:8]1)=[O:88])=[O:72])([CH3:69])([CH3:67])[CH3:68]
Reactant: CN(CC1CCN(c2c(N)cnn2C)CC1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of Intermediate 1, tert-butyl methyl((1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methyl)carbamate (145 mg, 0.41 mmol) in MeOH (40 mL) was passed through the H-Cube® (full H2, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methyl(methyl)carbamate as a red-brown oil (117 mg). To a solution of this amine (115 mg, 0.36 mmol) in DCM (20 mL) was added DIPEA (1.0 mL), PyBOP (0.46 g, 0.89 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (127 mg, 0.36 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (80 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (75% EtOAc/isohexane) gave tert-butyl (1-(4-(5-tert-butoxycarbonylamino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methyl(methyl)carbamate as a lilac foam (200 mg). This foam (200 mg, 0.30 mmol) was stirred with HCl in 1,4-dioxane (4 M, 3.8 mL, 15.1 mmol) in MeOH (5 mL) at room temperature for 3 days. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH to yield 101 as a beige solid (99 mg, 53% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 8.75 (s, 1H), 7.59-7.49 (m, 3H), 7.44 (s, 1H), 7.32-7.22 (m, 2H), 6.90 (br s, 1H), 3.63 (s, 3H), 3.14-2.96 (m, 4H), 2.66 (d, J=6.8 Hz, 2H), 2.45 (s, 3H), 1.77 (d, J=12.6 Hz, 2H), 1.78-1.55 (m, 1H), 1.36-1.22 (m, 2H). LCMS (ES+) m/z 462 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=[N+]([O-])c1cccc(C2=CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCN1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Yield: 86 %

Procedure:
A mixture of 2.80 g (14.0 mmol) of 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine, 3.60 g (15.0 mmol) of tert-butyl N-(3-bromopropyl)carbamate, 11.6 g (84.0 mmol) of K2CO3, 14.6 mL (84.0 mmol) of diisopropylethylamine and 0.78 g (2.00 mmol) of tetrabutylammonium iodide in 250 mL of 1,4-dioxane was heated at reflux temperature for 14 hours. The reaction mixture was filtered and the filtrate was dried (MgSO4), concentrated in vacuo and the residue was purified by column chromatography (silica, 9:1, dichloromethane:methanol+1% isopropyl amine) to afford 4.35 g (85.7% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 8.24 (t, 1H, J=1.9 Hz), 8.09 (dd, 1H, J=1.9, 8.0 Hz), 7.70 (apparent d, 1H, J=8.0 Hz), 7.49 (t, 1H, J=8.0 Hz), 6.23 (m, 1H), 3.29-3.18 (m, 4H) 2.75 (t, 2H, J=5.6 Hz), 2.64-2.54 (m, 4H), 1.82-1.70 (m, 2H), 1.44 (s, 9H); ESMS m/e: 362.2 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[CH:43]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)([CH3:45])[CH3:44].C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[OH:31][C:27]1[C:26]([CH3:39])=[CH:25][C:24]([C:14]2([C:10]3[CH:9]=[C:8]([CH3:40])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:50]3[CH:49]=[CH:48][CH:47]=[C:46]([CH:43]([CH3:45])[CH3:44])[CH:51]=3)[C:15]2=[O:23])=[CH:29][C:28]=1[CH3:30]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(c3cccc(C(C)C)c3)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.350 g, 0.581 mmol), 3isopropylphenylboronic acid (0.190 g, 1.16 mmol), copper (II) acetate (0.106 g, 0.581 mmol), triethylamine (0.16 mL, 1.16 mmol), 4 angstrom molecular sieves, and dichloromethane (10 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound (0.189 g, 0.268 mmol), in THF (4 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (0.67 mL). Stir for 1 h. Add saturated aqueous ammonium chloride(10 mL), water and ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with 25% to 50% ethyl acetate in hexanes to give 0.089 g (31%) of the title compound: mass Spectrum (ion spray): m/z=492(M+1); 1H NMR(DMSO-d6); δ8.36 (s, 2H), 7.54 (t, 1H), 7.41-7.37 (m, 2H), 7.32-7.27 (m, 3H), 7.16 (t, 1H), 6.83-6.80 (m, 5H), 3.05-3.01 (m, 1H), 2.13 (s, 12H), 1.28 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[OH:5].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[O:5][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](O)c1cccc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Yield: 99 %

Procedure:
A solution of (R)-(3-chloro-phenyl)-hydroxy-acetic acid methyl ester (21.0 g), imidazole (14.25 g), and tert-butyidimethylsilyl chloride (25.0 g) in N,N-dimethylformamide (250 ml) was stirred at room temperature for 18 h. The mixture was poured into water (2.5 l) and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine, dried, and concentrated. The residue was purified by flash chromatography, eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a colourless oil (32.63 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[CH:31]=[CH2:32].Cl>CN(C=O)C.O>[CH2:32]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH3:23])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C)CO3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C
Temperature: 50 °C
Reaction time: 12 h
Yield: 68.5 %

Procedure:
To a suspension of (R)-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (13 mg, 0.04 mimol) and K2CO3 (28 mg, 0.2 mmol, 5 eq) in 1 ml DMF (0.04 M) was added allylbromide (0.03 mL, 0.4 mmol, 10 eq). The reaction was heated to 50° C. and allowed to stir for 12 h, whereupon the reaction was poured into 10 mL water and neutralized with 1N HCl. The aqueous layer was extracted with EtOAc (2 ×40 mL/mmol) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated to afford 10 mg (75%) of (R)-4-allyl-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (10 mg, 0.03 mmol) was carried on directly according to General Method 4 (EXAMPLE 1) by treatment with 2 mL concentrated HCl (001.M) and heated at 50° C. for 6 h to afford 6 mg (67%) of Compound 106 after silica gel column chromatography (gradient 3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution) 1H NMR (500 MHz, CDCl3) δ 11.89 (bs, 1H), 7.11 (s, 1H), 7.00 (d, J=8.8, 1H), 6.93 (d, J=8.8, 1H), 5.86 (m, 1H), 5.24 (m, 2H), 4.10 (m, 2H), 3.90 (m, 2H), 3.55 (m, 1H), 1.22 (d, J=6.8, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO.CCOCC>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CSc1nc(Cl)c(C#N)c(Nc2ccccc2)n1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445–453] (0.222 grams (hereinafter “g”), 1.0 millimoles (hereinafter “mmol”)) in EtOH (2 mnililiters (hereinafter “mL”)) and Et2O (mL) was treated with aniline (184 microliter (hereinafter “uL”), 2.0 mmol) in EtOH (1 mL). A clear solution formed initially but rapidly formed a heavy precipitate. The mixture was stirred 30 minutes (hereinafter “min”) and was filtered, and the solid was washed with 1:1 Et2O, EtOH and then Et2O, dried to afford 162 miligrams (hereinafter “mg”) (59%) of the title compound as a white solid. LC MS m/e=277 (NM+), Rt=2.32 min.