Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[N:9]=[C:8]([C:10]([OH:12])=O)[CH2:7][C:5]=2[N:6]=1.CC[N:15](C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[S:3][C:4]2[N:9]=[C:8]([C:10]([NH2:15])=[O:12])[CH2:7][C:5]=2[N:6]=1
Reactant: O=C(O)C1=Nc2sc(Br)nc2C1
Reactant: CCN(C(C)C)C(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=O)C1=Nc2sc(Br)nc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Add to a solution of 2-bromo-6H-pyrrolo[3,2-d]thiazole-5-carboxylic acid (2.53 gm, 10 mmol) in DMF (45 ml), DIEA (diisopropylethylamine, 10 ml, 6 eq), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl, 5.0 gm, 3.5 eq); HOBT (1-hydroxybenzotriazole, 1.91 gm, 14 mmol, 1.4 eq) and NH4Cl (2.25 gm, 42.0 mmol). Stir the mixture at room temp for 6 hr and monitor by LC-MS. When complete, dilute the mixture with ethyl acetate, and wash with water and brine. Collect the solid by filtration (2.21 gm) and purify by chromatography on silica gel (ISCO silica cartridge, 4 gm, elute with methanol (10-40%) in methylene chloride) to afford the title compound (550 mg).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[C:10]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[N:17]=[C:16]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:18]1[CH:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:2]3[CH2:3][CH2:4][N:5]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:6][CH2:7]3)[CH:9]=2)[CH2:15][C:16]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:17]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(N3CCNCC3)c2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
5-[3-(piperazin-1-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (100.0 mg, 0.2 mmol) prepared in Step 1, triethylamine (143.0 uL, 1.02 mmol) and methanesulfonyl chloride (35.0 mg, 0.30 mmol) were added to dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 55.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH:7]=[N:8][C@H:9]([C:11]([O-:13])=[O:12])[CH3:10])=[CH:5][CH:4]=1.[Na+].[O:17]([CH2:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:7]2[N:8]([C:25](=[O:26])[CH2:24][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:9]([CH3:10])[C:11](=[O:13])[O:12]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C=N[C@@H](C)C(=O)[O-])cc1
Reactant: O=C(Cl)COc1ccccc1
Agent: [Na+]
Product: COc1ccc([C@@H]2OC(=O)[C@H](C)N2C(=O)COc2ccccc2)cc1

Procedure:
(2S,4S)-2-(4'-Methoxyphenyl)-4-methyl-N-phenoxyacetyl-1,3-oxazolidin-5-one (18) was prepared from sodium N-(para-methoxybenzylidene)-(L)-alaninate (2.29 g, 10.0 mM) and phenoxyacetyl chloride (1.37 mL, 10.0 mM) following general procedure D and obtained as a colourless oil after purification by flash column chromatography, using 20% ethyl acetate/petroleum ether as eluant (1.87 g, 55%, mixture of two diastereomers in a ratio of 4:1 by 1H-NMR). Upon trituration with diethyl ether 18 was obtained as very fine white needles and as a single diastereomer by 1H NMR: [α] D20 +224 (c 1.0, CHCl3); mp 95-97° C.; IR (KBr): 1795, 1715, 1670 cm-1 ; 1H NMR (500 MHz, d8 -toluene, 90° C.): δ 6.45-7.09 (m, 9H), 6.44 (s, 1H), 4.50 (q, J=7 Hz, 1H), 4.06 (d, J=14 Hz, 1H), 3.81 (d, J=14 Hz, 1H), 3.31 (s, 3H), 1.41 (d, J=7 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): δ 172.1, 167.3, 161.4, 156.7, 129.0, 128.5, 128.1, 122.1, 114.6, 114.0, 89.6, 67.8, 55.4, 52.7, 16.1; LRMS (NH3): 342 (MH+). Anal. Calcd for C19H19NO5 : C, 66.86; H, 5.57; N, 4.10; found: C, 66.69; H, 5.59; N, 4.01.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18](O)=[O:19])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:34])=O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18]([Cl:34])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)Cl)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3β-acetoxy-5-cholenic acid (50.0 g, 118 mmole) in dry dichloromethane (200 ml) was added dropwise oxalyl chloride (30 ml, 448 mmole). The solution was stirred at room temperature for one hour and then concentrated in vacuo to obtain 3β-acetoxy-5-cholenic acid chloride 331. 1H NMR (400 MHz, CDCl3) δ: 0.70 (3H, s, 18-CH3), 0.95 (3H, d, 21-CH3), 1.05 (3H, s, 19-CH3), 2.04 (3H, s, --OCOCH3), 4.60 (1H, m, 3α-H), 5.38 (1H, m, 6-H). Compound 331 was used in the following step without purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:6]=[CH:7][C:8]=1[S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])#[N:2]>C1COCC1.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:6]=[CH:7][C:8]=1[S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10]
Reactant: COC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(C#N)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc(S(=O)(=O)C(C)C)c(CN)c1
Reaction time: 6 h
Yield: 96.7 %

Procedure:
To 15D (230 mg, 0.82 mmol) in THF (15 mL) was added Raney Ni (cat.) and the mixture was hydrogenated at 60 psi for 6 h. The reaction was filtered and concentrated to provide methyl 3-(aminomethyl)-4-(isopropylsulfonyl)phenylcarbamate (227 mg), which was suspended in ether. A solution of 4N HCl in dioxane (0.5 mL) was added and the reaction was concentrated to provide 15E (265 mg, 100%). LC-MS: 287.38 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][C:7]2[O:11][CH2:10][C:9](=[O:12])[C:8]=2[CH:13]=1.[Cl-].[NH4+]>CO.O>[Cl:3][C:4]1[C:5]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:6][C:7]2[O:11][CH2:10][CH:9]([OH:12])[C:8]=2[CH:13]=1
Reactant: O=C1COc2cc(N3CCCCC3)c(Cl)cc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: OC1COc2cc(N3CCCCC3)c(Cl)cc21
Reaction time: 4 h

Procedure:
528 mg (13.1 mmole) of sodium borohydride are added to a solution, cooled to 0°, of 3.3 g (13.1 mmole) of 5-chloro-6-(piperidin-1-yl)-benzofuran-3(2H)-one, according to Example 2, in 80 ml of methanol. The whole is subsequently stirred for a further 4 hours at 0°. The reaction mixture is diluted with water, adjusted to pH 6-7 with dilute ammonium chloride solution and extracted several times with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. Chromatography over silica gel using methylene chloride as eluant (Rf =0.12) yields 5-chloro-3-hydroxy-6-(piperidin-1-yl)-2,3-dihydrobenzofuran in the form of an oil.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[NH:4]1)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]1[CH2:8][C:7]([CH3:12])=[CH2:6])[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:22])[F:20])[CH3:2]
Reactant: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)CN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1CC
Temperature: 50 °C
Yield: 171.9 %

Procedure:
This compound was prepared by treatment of (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (20 mg, 0.059 mmol), 2-methallyl bromide (40 mg, 0.30 mmol) and K2CO3 (41 mg, 0.30 mmol) in 1 mL DMF heated at 50° C. for 16 h. The reaction was treated with an additional 2-methallyl bromide (60 mg) and was heated overnight at 50° C. The mixture was extracted with ethyl acetate (2×25 mL), and the combined organic layers were washed with water (25 mL), brine (25 mL), dried over MgSO4, filtered, and concentrated afford 20 mg (87%) of (3R)-3-ethyl-4-(2-methyl-2-propenyl)-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline after flash chromatography (9:1 hexanes:EtOAc). 1H NMR (400 MHz, CDCl3) δ7.39 (d, J=9.0, 1H), 7.18 (s, 1H), 7.12 (d, J=9.0, 1H), 5.47 (septet, J=6.2, 1H), 4.91 (broad s, 2H), 4.33 (dd, J=10.7, 2.1, 1H), 3.96 (dd, J=10.7, 2.6, 1H), 3.85 (d, AB, J=17.1, 1H), 3.80 (d, AB, J=17.1, 1H), 3.20–3.26 (m, 1H), 1.79 (s, 3H), 1.58–1.68 (m, 2H), 1.38 (d, J=6.2, 3H), 1.37 (d, J=6.2, 3H), 0.96 (t, J=7.4, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[OH-].[Na+]>>[O:7]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(Oc2ccncc2)cc1
Temperature: 150 °C
Yield: 64.3 %

Procedure:
Phenol (2.82 kg, 30.0 mol) was heated to 50° C. and 4-chloropyridine hydrochloride (1.5 kg, 10.0 mol) was added. The resulting solution was heated at 150° C. for 15 hours. The dark amber solution was cooled to 25° C. then poured into 3 M aqueous sodium hydroxide (16 L). The aqueous was extracted with dichloromethane (3×4 L). The combined organic was washed with 1 M sodium hydroxide (2×4 L), water (4 L), and brine (4 L) then dried over sodium sulfate and filtered. The solvent was removed under vacuum and the residual oil was dissolved in hexanes (6 L). The mixture was cooled to -60° C. with stirring and the resulting solid was collected by filtration and dried to give 1.1 kg of 4-phenoxypyridine (64% yield). mp 46-49° C. 1H NMR (300 MHz, CDCl3) δ8.45 (dd, J=1.5, 8 Hz, 2H), 7.41 (dd, J=12, 12 Hz, 2H), 7.28 (dd, J=12, 1H), 7.06 (d, J=12 Hz, 2H), 6.84 (dd, J=1.5, 8 Hz, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:20][CH2:21][CH3:22])=[N:12][C:13]([CH3:19])=[CH:14][C:15]=1[S:16][CH2:17][CH3:18])=[O:8].[SH:23][C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[O:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[S:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:20][CH2:21][CH3:22])=[N:12][C:13]([CH3:19])=[CH:14][C:15]=1[S:16][CH2:17][CH3:18])=[O:8]
Reactant: CCSc1cc(C)nc(SCC)c1NC(=O)CCCCCBr
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1cc(C)nc(SCC)c1NC(=O)CCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 45.5 %

Procedure:
The reaction and the treatment were conducted in the same manner as in Example 26 except that 6-bromohexanoyl chloride was used instead of bromoacetyl bromide to obtain 6-bromo-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]hexanamide. To a DMF (2 ml) solution of this amide (122 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol) were added potassium carbonate (46 mg, 0.33 mmol) and 18-crown-6 (8 mg, 0.03 mmol), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through preparative thin-layer chromatography (eluent—hexane:acetone=5:2) to obtain 65 mg (yield 46%) of the desired compound as a light brown needle crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[N+:31]([O-])=O)[CH2:12][CH2:13][NH:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[C:21]([Br:23])[C:20]([O:24][CH3:25])=[C:19]([Br:26])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C.Cl>[NH2:31][C:30]1[CH:29]=[CH:28][C:11]([CH2:12][CH2:13][NH:14][C:15](=[O:27])[CH2:16][C:17]2[CH:22]=[C:21]([Br:23])[C:20]([O:24][CH3:25])=[C:19]([Br:26])[CH:18]=2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br

Procedure:
A solution of N-(3-Benzyloxy-4-nitrophenethyl)-3,5-dibromo-4-methoxy-phenylacetamide (3.49 g, 0.006 mol) and tin (II) chloride dihydrate (16.10 g, 0.071 mol) in a mixture of ethanol (300 mL) and 1.2 N HCl (150 mL) was refluxed for 3h, cooled and concentrated. Tin salts were dissolved in 1N NaOH solution. The reaction mixture was extracted with methylene chloride 3 times. The extracts were dried over Na2SO4 and concentrated. A residue was crystallized from ethyl acetate-hexanes mixture. Yield 1.57 g (47.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:15]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:16](=[O:19])[O:17][CH3:18])[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:7]=1[F:8].[O:29]1[CH2:32][C:31](=O)[CH2:30]1.C(OC)(OC)OC.C([O-])(=O)C.[K+].C([BH3-])#N.[Na+]>CO.O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([N:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:16](=[O:19])[O:17][CH3:18])[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH:31]3[CH2:32][O:29][CH2:30]3)[CH2:13][CH2:14]2)[C:7]=1[F:8]
Reactant: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCNCC2)c1
Reactant: O=C1COC1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: C1CCOC1
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N)c(F)c(N2CCN(C3COC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
methyl (3-amino-4-fluoro-5-(piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (470 mg, 0.605 mmol) (crude product from above, contains DCE and TFA) was dissolved in methanol (5 ml)+Tetrahydrofuran (5 ml). oxetan-3-one (0.15 ml, 2.56 mmol), Trimethyl orthoformate (1 ml, 9.05 mmol) and potassium acetate (119 mg, 1.210 mmol) were added and the mixture stirred at room temperature for 15 minutes. pH was checked to be ˜4.5. Sodium cyanoborohydride (160 mg, 2.55 mmol) was added and stirring at room temperature continued for 20 hours. The reaction mixture was partitioned between EtOAc and dilute aq. NaHCO3 solution. The organic layer was washed with brine, then dried over MgSO4 and evaporated to dryness to give crude methyl (3-amino-4-fluoro-5-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (248.4 mg) which was used without further purification.
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[C:11]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=[O:22])[N:15]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:12]2=[N:13][CH:14]=1)=C\C1C=CC=CC=1.[O:35]1CCOCC1>O.O=[Os](=O)(=O)=O>[CH:1]([C:9]1[N:10]=[C:11]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=[O:22])[N:15]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:12]2=[N:13][CH:14]=1)=[O:35]
Reactant: C1COCCO1
Reactant: C[Si](C)(C)CCOCn1c(-c2cccc(C(=O)O)c2)cc2nc(/C=C/c3ccccc3)cnc21
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2cccc(C(=O)O)c2)cc2nc(C=O)cnc21
Yield: 100 %

Procedure:
(E)-3-(2-Styryl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)benzoic acid (0.940 g, 1.99 mmol; prepared using D from Preparation #V.1 with (E)-styrylboronic acid), OsO4 (2.5 wt % in t-BuOH, 1.00 mL, 0.080 mmol) and NaIO4 (1.71 g, 7.97 mmol) were added to a stirred mixture of 1,4-dioxane (10 mL) and water (2 mL) at rt. After about 4.5 h the mixture was diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to provide 3-(2-formyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)benzoic acid (0.792 g, 100%): LC/MS (Table 2, Method c) Rt=1.45 min; MS m/z 398 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: Cc1cc(N)c(N)cc1C
Solvent: Cc1ccccc1C
Product: Cc1cc2c(cc1C)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from commercially available 4,5-dimethyl-1,2-phenylendiamine (136 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) in xylene (20 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light brown solid (294 mg, 86%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[BrH:12].N([O-])=O.[Na+].C(OCC)(=O)C>O>[Br:12][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: Br
Reactant: Nc1ccc(C(=O)O)c(O)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Br)cc1O
Reaction time: 0.5 h
Yield: 73 %

Procedure:
4-Aminosalicylic acid (15.0 g, 98 mmol) and hydrobromic acid (47%, 100 ml) were mixed with water (100 ml). A solution of sodium nitrite (6.8 g, 98 mmol) in water (50 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at the same temperature for 30 minutes. A mixture of cuprous bromide (16.9 g, 117 mmol) and hydrobromic acid (47%, 45 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was combined with ethyl acetate and extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (15.5 g, 73%) as a gray solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][C:3]=1[O:11][CH3:12].C[O:14][C:15]1C=C([CH:21]=[CH:22][C:23]=1[N+]([O-])=O)C(N)=N>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:22]([CH2:23][CH2:15][OH:14])=[CH:21][N:8]=2)=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=N)N)ccc1[N+](=O)[O-]
Reactant: COc1cc(C(N)=S)ccc1N
Product: COc1cc(-c2ncc(CCO)s2)ccc1N

Procedure:
2-[2-(4-amino-3-methoxy-phenyl)-thiazole-5-yl]-ethanol is prepared analogously to the processes described above. For the cyclisation, 4-amino-3-methoxy-thiobenzamide is used (analogously to J. Am. Soc. 82, 2656, 1960) instead of 3-methoxy-4-nitro-benzamidine.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]3[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=3)[CH:9]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (47.4 mg, 0.173 mmol) in CH2Cl2 (2 mL) was added 3-chlorophenyl isocyanate (0.24 μL, 0.197 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 134 as a colorless solid (31.0 mg, 42%). LCMS m/z (%)=428 (M+H35Cl, 100), 430 (M+H37Cl, 39), 1H NMR (400 MHz, DMSO-d6) δ: 8.64 (bs, 1H), 8.59 (bs, 1H), 7.47-7.41 (m, 3H), 7.45 (d, J=1.79 Hz, 1H), 7.37 (d, J=2.71 Hz, 1H), 7.30-7.23 (m, 2H), 7.09 (d, J=8.97 Hz, 1H), 6.98-6.92 (m, 1H), 6.24 (d, J=1.85 Hz, 1H), 3.97 (t, J=6.36 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.04 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].[BH4-].[Na+]>CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][OH:13]
Reactant: O=Cc1ccc2ccccc2c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc2ccccc2c1Br
Reaction time: 0.25 h
Yield: 92.3 %

Procedure:
A solution of 1-bromo-2-naphthaldehyde (2.12 g, 8.91 mmol) in MeOH under N2 at 0° C. was treated with NaBH4 (0.51 g, 13.4 mmol), stirred for 15 minutes, quenched with acetone, and concentrated. Purification on silica gel with 5% ethyl acetate/CH2Cl2 provided 1.95 g (92%) of the desired compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[C:20]([CH3:35])[CH:19]=2)[CH2:15][CH3:16])=[CH:12][CH:13]=1)=[O:8].[OH-].[Na+].Cl>CO>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([C:21]2[C:20]([CH3:35])=[CH:19][C:18]([O:17][CH:14]([C:11]3[S:10][C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[O:8])=[CH:13][CH:12]=3)[CH2:15][CH3:16])=[CH:23][C:22]=2[CH3:24])=[CH:26][CH:27]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCC(Oc1cc(C)c(-c2ccc(C(C)(C)C)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(Oc1cc(C)c(-c2ccc(C(C)(C)C)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A solution of 3-({5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (Isomer 2) (90.2 mg, 0.178 mmol) in methanol (1.8 mL) is treated with 5N NaOH (0.178 mL) and shaken at rt overnight. The reaction is neutralized with 1N HCl (0.182 mL), and extracted into ethyl acetate (2×). The combined organic layers are dried and concentrated, giving the title compound (70.5 mg). MS (ES): 494.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[NH:7][C:6]2=[O:22].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[NH:7][C:6]2=[O:22]
Reactant: COc1ccc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c(-c2cccc([N+](=O)[O-])c2)nc2ccc(O)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a suspension of 6-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (3.90 g, 13.1 mmol), in CH2Cl2 (30 mL) cooled to −78° C. under an atmosphere of N2 was added BBr3 as a 1.0M solution in CH2Cl2 (20 mL, 20.0 mmol). The resulting mixture was stirred at −78° C. for 1 h, then allowed to warm to RT upon which it was stirred for a further 3 h. The mixture was re-cooled to −78° C. and stirred overnight. The reaction was quenched by the addition of EtOH (60 mL) and allowed to warm to RT. Stirring was continued for 1 h at RT, upon which a precipitate formed. Sat. NaHCO3 solution was added and the yellow solid was collected via filtration and washed with Et2O and EtOH and dried under vacuum to give 6-hydroxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (2.96 g, 10.5 mmol, 80%). HPLC retention time 5.588 min.