Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][Si](C)(C)C)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Li+].C(C([Sn])=C(CCCC)CCCC)CCC>CN(C=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2cc(C#C[Si](C)(C)C)ccc21
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(ccn2C)c1
Temperature: 80 °C
Yield: 94.6 %

Procedure:
To a solution of 1-methyl-5-trimethylsilanylethynyl-1H-indole (0.50 g, 1.95 mmol) in DMF (10 mL) were added lithium chloride (0.32 mg, 7.59 mmol), bis(triphenylphosphine)palladium (II) (0.225 g, 0.195 mmol) and tributylvinyltin (0.80 g, 2.52 mmol). The resulting suspension was heated at 80° C. for 2 h and cooled to room temperature. The reaction mixture was filtered through Celite pad washing with ethyl acetate, organic solvents were evaporated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexane; 5:95) to give a product (290 mg, 94%). 1H NMR (DMSO-d6, 400 MHz) 3.77 (s, 1H), 5.10 (d, J=3.9 Hz, 1H), 5.70 (d, J=7.6 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 6.80 (dd, J=11.0, 17.3 Hz, 1H), 7.30-7.41 (m, 3H), 7.58 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) 32.9, 101.1, 110.2, 111.0, 119.2, 119.5, 128.5, 128.8, 130.6, 136.7, 138.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42]Br>C1COCC1.ClCCl>[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([O:18][C:16]2[C:17]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[C:10]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:20]1
Reactant: COC(=O)CCBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC4CCCNC4)c23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)CCN1CCCC(Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)C1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Dissolve 200 mg (0.5 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-4-(piperidin-3-yloxy)furo-[2,3-d]pyrimidine (Example 37A) in 1 ml of THF and add 69 μl (0.5 mmol) of triethylamine. After adding 54 μl (0.5 mmol) of 3-bromopropionic acid methyl ester, stir the mixture at 20-40° C. for approx. 8 h. In the meantime, add triethylamine (total of approx. 1.2 mmol) and 3-bromopropionic acid methyl ester (total of approx. 1.2 mmol) twice more. After diluting with dichloromethane, wash the mixture with saturated sodium hydrogencarbonate solution and concentrate under reduced pressure. Purify the crude product by means of preparative RP-HPLC (eluent: acetonitrile/water gradient). 118 mg (45.7% of theory) of the target product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][P:37]([CH3:42])([CH2:39][CH2:40][NH2:41])=[O:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:36][P:37]([CH3:42])([CH2:39][CH2:40][NH:41][CH2:31][C:29]1[O:30][C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][N:17]=[C:16]3[NH:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]2[CH:33]=[CH:34][CH:35]=[C:2]([F:1])[CH:3]=2)[N:7]=[CH:8]3)=[CH:27][CH:28]=1)=[O:38]
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2)o1
Reactant: CP(C)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CP(C)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2)o1
Temperature: 25 °C
Yield: 43 %

Procedure:
5-(4-(1-(3-fluorobenzyl)-1H-indazol-5-ylamino)quinazolin-6-yl)furan-2-carbaldehyde and 2-(dimethylphosphinoyl)ethanamine (compound 2.2, 82 mg) were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodium triacetoxyborohydride (237 mg) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid (138 mg). LCMS ESI(+) m/z: 569 (M+1). Yield: 43%. 1H NMR (300 MHz, CD3OD) δ 8.75 (d, 1H), 8.40 (s, 1H), 8.18 (m, 1H), 8.12 (m, 2H), 7.76 (m, 1H), 7.68 (m, 1H), 7.61 (m, 1H), 7.30 (m, 2H), 7.03 (m, 2H), 6.92 (m, 3H), 6.46 (d, 1H), 5.69 (s, 2H), 3.91 (s, 2H), 2.99 (m, 2H), 2.10 (m, 2H), 1.52 (d, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:31][C@@H:32]([C@@H:34]4[CH2:38][C:37](=[O:39])[NH:36][CH2:35]4)[CH3:33])=[CH:10][C:11]([C:13]4[CH:22]=[C:21]5[C:16]([N:17]([CH3:30])[CH2:18][CH2:19][N:20]5C(OC(C)(C)C)=O)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([O:31][C@@H:32]([C@H:34]4[CH2:35][NH:36][C:37](=[O:39])[CH2:38]4)[CH3:33])=[CH:10][C:11]([C:13]4[CH:22]=[C:21]5[C:16](=[CH:15][CH:14]=4)[N:17]([CH3:30])[CH2:18][CH2:19][NH:20]5)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1cc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCN3C)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2ccc3c(c2)NCCN3C)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
tert-butyl 7-(1-cyclopropyl-7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)-4-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (40 mg, 0.075 mmol) was dissolved in DCM (2 mL), TFA (0.29 mL, 3.76 mmol) was added. The reaction was stirred at rt for 16 h. The mixture was quenched with saturated NaHCO3, extracted with EtOAc (3×30 ml). The combined organic layers were washed with water (2×5 mL), concentrated and purified by flash chromatography eluted with 5% to 20% MeOH/EtOAc to give 23.8 mg, (73.3%) of (R)-4-((R)-1-((1-cyclopropyl-5-(1-methyl-1,2,3,4-tetrahydroquinoxalin-6-yl)-1H-benzo[d]imidazol-7yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.57 (s, 1H), 7.19 (s, 1H), 6.88 (s, 1H), 6.74 (dd, J=2.4, 2.4 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.48 (d, J=8.1 Hz, 1H), 5.54 (s, 1H), 4.76-4.73 (m, 1H), 3.67-3.63 (m, 1H), 3.40-3.30 (m, 3H), 3.20-3.11 (m, 3H), 2.77 (s, 4H), 2.38-2.23 (m, 2H), 1.29 (d, J=6 Hz, 3H), 1.06-0.96 (m, 4H), LCMS-ESI+ (m/z): [M+H]+ calcd for C25H29N5O2:431.23; found 432.22.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([O:31]CC)=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[S:25][CH2:26][CH2:27][N:28]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23][C:24]3[S:25][CH2:26][CH2:27][N:28]=3)[CH2:19][CH2:20]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSC2=NCCS2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCSC4=NCCS4)CC3)c2c1
Temperature: 75 °C
Yield: 70.5 %

Procedure:
A mixture of 0.15 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(4,5-dihydrothiazol-2-ylthio)ethyl]piperidine-4-carboxylate in 5 cm3 of dioxane, 5 cm3 of methanol and 1 cm3 of aqueous 5N sodium hydroxide solution was maintained at a temperature in the region of 75° C. for 20 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (Bond Elut; particle size 70-200μ; mass 7 g), eluting with a mixture of dichloromethane/methanol/aqueous ammonia (40/5/0.5 by volume). The fractions containing the product were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and then oven-dried under reduced pressure (10 kPa) at about 50° C. 0.1 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(4,5-dihydrothiazol-2-ylthio)ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:11]=[C:12]4[O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][C:13]4=[CH:14][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.C[Si]([C:33]#[CH:34])(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[C:33]([C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:11]=[C:12]4[O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][C:13]4=[CH:14][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1)#[CH:34]
Reactant: Brc1cccc(Nc2ncnc3cc4c(cc23)OCCOCCOCCO4)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc4c(cc23)OCCOCCOCCO4)c1
Yield: 10.2 %

Procedure:
(3-Bromo-phenyl)-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalen-4-yl)-amine (Compound 10) (10 mg, 0.5 mmol) was dissolved in DMF (10 mL). Tetrakis(triphenylphosphine) palladium (20 mg), trimethylsilylacetylene (70 microliter, 0.65 mmol), potassium carbonate (10 mg) and copper (I) iodide (5 mg) was added under nitrogen atmosphere. The reaction mixture was refluxed for about 3 h and then the reaction cooled and concentrated in vacuo, to afford a residue, which was flash chromotographed to provide a white solid (20 mg). ES-MS m/z 392 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:3]1[CH2:7][O:6]C(C)(C)[N:4]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>CO>[OH:1][C@H:2]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C@H:3]([NH:4][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][OH:6]
Reactant: COc1ccc(C(O)C2COC(C)(C)N2C(=O)OCc2ccccc2)cc1
Solvent: CO
Product: COc1ccc([C@@H](O)[C@@H](CO)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.5 %

Procedure:
A mixture of benzyl 4-(hydroxy-(4-methoxyphenyl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (1.679 g, 4.5 mmol) and amberlyst 15 (1.85 g) in MeOH (20 mL) was stirred at room temperature for 2 days. The mixture was centrifuged and the solid was washed with MeOH (2×40 mL). The solvent was removed to dryness and after purification by column chromatography (SiO2 using a mixture of CH2Cl2/EtOAc) the product was obtained as a white solid (1.26 g, 84% yield).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:6]([N+:15]([O-])=O)=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>C1(C)C=CC=CC=1.[Pd]>[NH:15]1[C:6]2[C:5](=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]1
Reactant: COC(=O)c1cccc(/C=C/N(C)C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2cc[nH]c12

Procedure:
A solution of methyl 3-[2-(E)-(dimethylamino)ethenyl]-2-nitrobenzoate (12.0 g, 48 mmol) in toluene (200 ml) was hydrogenated at 60 psi over 10% palladium on charcoal (1.5 g) until hydrogen uptake ceased. The catalyst was filtered off, the filtrate was evaporated and the residue was chromatographed on silica to give the product.
Reaction SMILES: C(B(CC)CC)C.[CH3:8][O:9][C:10](=[O:28])[CH:11](I)[CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.CCCCCC.[Cl-].[Na+].O>[CH3:8][O:9][C:10]([CH:11]1[CH2:12][CH2:13][N:14]2[C:15]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=[C:18]12)=[O:28]
Reactant: COC(=O)C(I)CCn1cccc1C(=O)c1ccccc1
Agent: CCB(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(=O)C1CCn2c(C(=O)c3ccccc3)ccc21
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A 1.0N solution of triethylborane in hexane (1.6 mL, 1.6 mmoles) was added to a stirred solution of 4-(2-benzoylpyrrol-1-yl)-2-iodobutyric acid methyl ester (IV, 530 mg, 1.3 mmoles) in dimethylsulfoxide (5 mL) under normal air atmosphere. After 1 hour, additional triethylborane (1.0 mL, 1.0 mmole) in hexane was added and the reaction was stirred. After 30 minutes, the reaction was diluted with brine (50 mL) and extracted with diethyl ether (2×50 mL). The organic layer was dried over NaSO4 and evaporated. The crude product was purified by flash chromatography on silica eluting with 1:4 ethyl acetate/hexane to give pure 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid methyl ester (V, 220 mg, 61%) as an amber oil. 1H NMR (CDCl3): delta 2.75-3.0 (m, 2H); 3.76 (s, 3H); 4.07 (dd, 1H); 4.38-4.61 (m, 2H); 6.09 (d, 1H); 6.81 (d, 1H); 7.4-7.55 (m, 3H); 7.80 (dd, 2H). 13C NMR (CDCl3): delta 30.9, 42.3, 7.4, 52.5, 103.0, 124.8, 127.0,128.0, 128.8, 131.3, 139.1, 142.2, 171.6, 184.8.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][C@@H:11]([NH:17]C(OC(C)(C)C)=O)[C:12]([N:14]([CH3:16])[CH3:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>>[ClH:26].[ClH:26].[CH2:1]([O:8][C:9](=[O:25])[CH2:10][C@@H:11]([NH2:17])[CH2:12][N:14]([CH3:15])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Borane-dimethyl sulfide complex (1.57 mL, 3.14 mmol) was added dropwise at 0° C. to a solution of (R)-3-tert-butoxycarbonylamino-N,N-dimethyl-succinamic acid benzyl ester (500 mg, 1.43 mmol). The reaction mixture was warmed to room temperature and heated at reflux for 3 hours, then cooled to 0° C. and treated dropwise with 6 M aq. hydrochloric acid solution (0.68 mL, 4.1 mmol). The reaction mixture was allowed to warm to room temperature and concentrated in vacuo. Residual water was azeotroped with toluene and concentrated under high vacuum to afford (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride (384 mg, 87%). White solid, m/e=237.4 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:24])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:24][C@H:22]([C:15]1[N:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]1)[CH3:23]
Reactant: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](O)c1ccc2c(n1)N1[C@@H](CNC[C@H]1C)C2

Procedure:
A solution of 3.09 g (9.27 mmol) (4R,9aR)-6-(1-(RS)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 38, intermediate) in 33 ml dichloromethane was cooled to 0 deg C. and treated with 8.8 ml (12.7 g, 0.11 mol) trifluoroacetic acid. The cooling bath was removed and the volatile components were removed on a rotary evaporator. The residue was chromatographed on silica gel (0.032–0.063 mm) with dichloromethane:methanol:ammonia (19:1:0.1). The remaining oil was dissolved in dichloromethane and saturated aqueous sodium bicarbonate solution and extracted until all product was extracted from the aqueous phase. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining light brown oil was chromatographed on a Chiralpak-AD column with 7% ethanol/n-heptane yielding the two diastereomers, the R-diastereomer being eluted first.
Reaction SMILES: CC(C)([O-])C.[K+].C(S)CCCCCCCCC.[Cl-].C[O:20][C:21]1[CH:22]=[N:23][C:24]([CH3:28])=[NH+:25][C:26]=1[CH3:27].Cl>CCCCCCC.C(O)CCC>[CH3:28][C:24]1[N:25]=[C:26]([CH3:27])[C:21]([OH:20])=[CH:22][N:23]=1
Reactant: COc1cnc(C)[nH+]c1C
Agent: CC(C)(C)[O-]
Agent: CCCCCCCCCCS
Agent: Cl
Solvent: CCCCO
Solvent: CCCCCCC
Product: Cc1ncc(O)c(C)n1
Temperature: 107.5 °C
Reaction time: 0.67 h
Yield: 74.2 %

Procedure:
To a 22-Liter round bottomed flask was charged potassium tert-butoxide (1200 g, 11 mol, 3.5 equiv.) and 1-butanol (2700 mL). The mixture was stirred for 40 mins and then 1-decanethiol (1300 mL, 6.1 mol, 2.0 equiv.) was added. To the resulting slurry was added portionwise, 5-methoxy-2,6-dimethylpyrimidin-1-ium chloride (17, 532 g, 3.05 mol, 1.0 equiv.), using a minimal amount of 1-butanol for rinses as needed. The mixture was heated to 105-110° C. and stirred for 24 hours at this temperature. The mixture was cooled to room temperature and aqueous hydrochloric acid solution (6 N, 2000 mL) was added slowly, maintaining the internal temperature below 35° C. Heptane (2700 mL) was added and the mixture stirred for 10 mins. Stirring was halted and the phases were separated. The upper organic phase was backwashed with additional 6 N HCl solution (1000 mL). The aqueous phases were combined and neutralized by addition of aqueous sodium hydroxide solution (50% w/w, 789 mL) to pH=7-8, then extracted with 2-methyltetrahydrofuran (2×3000 mL) The 2-methyltetrahydrofuran was removed by vacuum distillation and replaced with heptane (3000 mL). The mixture was concentrated to near dryness and heptane (1300 mL was added). The resulting slurry was filtered and the wet cake was washed with heptane (3×400 mL). The cake was dried under vacuum with a nitrogen sweep to afford 2,4-dimethylpyrimidin-5-ol (18, 281 g, 74% yield) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=O.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)C.C(O)(=O)C>[CH2:20]([O:19][C:15](=[O:18])[NH:16][N:17]=[CH:13][C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:6][C:2]=1[CH3:1])[CH3:21]
Reactant: CCOC(=O)NN
Reactant: Cc1[nH]c(-c2ccccc2)nc1C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)NN=Cc1nc(-c2ccccc2)[nH]c1C
Temperature: 0 °C

Procedure:
A mixture of 10.25 gm. of 5-methyl-2-phenyl-4-imidazolecarboxaldehyde and 5.72 gm. of ethyl carbazate in 30 ml. of ethanol containing one drop of acetic acid is boiled for 30 minutes. The mixture is cooled to 0° C. and concentrated under an air stream on a steam bath. A 50 ml. portion of carbon tetrachloride is added and the mixture is cooled to 0° C. overnight. The solid is collected giving the desired product, m.p. 209°-211° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:18](OC)=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([CH:18]=[O:19])[CH2:15][CH2:14][NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC=O
Reactant: COc1ccc(C2NCCNC2=O)cc1OC
Product: COc1ccc(C2C(=O)NCCN2C=O)cc1OC

Procedure:
23.6 g (0.1 mol) of 3-(3,4-dimethoxyphenyl)-piperazin-2-one, prepared in accordance with Example 1, are heated at 110° C. with 150 ml of methyl formate for 3 hours in an autoclave. The residue remaining after the mixture has been concentrated in vacuo is triturated with ether, filtered off with suction and dried.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]1[CH2:17][C:18](O)=[O:19].[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH2:27])[S:25][CH:26]=1>>[Br:21][C:22]1[C:23]([C:28]2[NH:32][N:31]=[CH:30][N:29]=2)=[C:24]([NH:27][C:18](=[O:19])[CH2:17][N:3]2[C:4]3[C:9](=[CH:8][C:7]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:26]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21
Product: O=C(Cn1c(=O)ccc2cc(OC(F)(F)F)ccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethoxy)quinolin-1(2H)-yl)acetic acid (40 mg, 0.14 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (28 mg, 0.11 mmol) according to protocol A. Retention time (min)=6.06, method [7], MS(ESI) 514.0 (M+H); 1H NMR (300 MHz, CD3Cl) δ 7.85 (d, J=9.35 Hz, 1H), 7.73 (s, 1H), 7.50 (s, 1H), 7.44-7.41 (m, 1H), 7.35-7.33 (m, 1H), 6.97 (d, J=9.9 Hz, 1H), 6.95 (s, 1H), 5.31 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[Cl:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)cc(Cl)c2N1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (74-3; 20 g, 0.088 mol) in N,N-dimethylformamide (200 mL) was added N-chlorosuccinimide portion wise (17.7 g, 0.132 mol) at 80° C. Reaction mass was allowed to stir at 80° C. for 2 h. The reaction mixture was cooled and diluted with ice cold water. The precipitated solid filtered and dried to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.61 (bs, 1H), 7.52-7.51 (d, J=1.6 Hz, 1H), 7.41 (s, 1H), 2.93-2.90 (t, J=8 Hz, 2H). MS (M+1); 261.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]([O:37][C:38]([N:40]1[CH2:46][CH2:45][CH:44]([OH:47])[CH:43]([NH2:48])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH2:42][CH:43]([NH:48][C:12]([C:10]2[S:11][C:7]3[C:6]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:14])[CH:44]([OH:47])[CH2:45][CH2:46]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CCC3O)nc12
Reaction time: 16 h
Yield: 79 %

Procedure:
0.50 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.31 g 1,1′-carbonyl-diimidazole in 25 ml dimethylformamide were stirred at room temperature for 16 hours. 0.43 g 4-amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester were added and stirring was continued for 16 hours at room temperature. Water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with dichloromethane/methanol 98:2 yielded 0.68 g (79%) 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester as a yellow solid; M.p.: 71–73° C.; MS (ISP): m/e=507 (M+H+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([Cl:21])[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[C:5]1=[O:22])(=O)C.N1CCCCC1>CO>[Cl:21][C:13](=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:22])[C:14]1[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(Br)cc2)c2ccccc21
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccccc2C1=C(Cl)c1ccc(Br)cc1

Procedure:
Prepared from the compound obtained in (b) by reacting with 1 equivalent of piperidine in MeOH (5 hours, 40° C.)