Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](=O)[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.Cl.[NH:30]1[CH2:33][CH:32]([C:34]([O:36][CH3:37])=[O:35])[CH2:31]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:26]([N:30]2[CH2:33][CH:32]([C:34]([O:36][CH3:37])=[O:35])[CH2:31]2)[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: CC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: COC(=O)C1CNC1
Agent: Cl
Product: COC(=O)C1CN(C(C)c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanone (1.76 g, 4.53 mmol) and methyl azetidine-3-carboxylate hydrochloride (1.03 g, 6.80 mmol) according to reference R and the general procedure for reductive amination gave racemic methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)azetidine-3-carboxylate. Separation of enantiomers was accomplished by SFC chromatography (Column: Chiralcel OJ-H (21×250 mm, 5 um)×2; A: Liquid CO2; B: Ethanol (0.2% IPA); Isocratic: 80:20 (A:B); Flow Rate: 70 mL/min; Outlet Pressure: 100 bar) to give (R)-methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)azetidine-3-carboxylate and (S)-methyl 1-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethyl)azetidine-3-carboxylate. MS (ESI) m/z: Calculated: 487.2; Observed: 488.1 (M++1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:11]1(OS(C)(=O)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CS(=O)(=O)OC1CCCCC1
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cc(I)ccc1OC1CCCCC1

Procedure:
In a manner similar to the methods described in Example 128a and 112b, 5-iodo-2-hydroxy-benzaldehyde was reacted with methanesulfonic acid cyclohexyl ester and potassium carbonate to give 5-Iodo-2-(cyclohexyloxy)-benzaldehyde, which was subsequently reacted with LHMDS, acetyl chloride, triethylamine and chloro-trimethyl-silane to give the title compound and directly used for the next step.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:28]([NH:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:29])[CH3:27])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].C(O)(=O)C.Br>CCOCC>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:28]([NH:30][C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][C:34](=[O:36])[NH2:35])=[O:29])[CH3:27])=[O:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.10 g of Z-Ile-Leu-Leu-Ala-Gln-OH was added 15 ml of acetic acid solution containing 25% of hydrogen bromide, then the mixture was stirred at a room temperature for 1 hour. After completion of the reaction, dried ether was added to the reaction mixture to obtain H-Ile-Leu-Leu-Ala-Gln-OH.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([C:13]1[CH:14]=[C:15]([P:25](=[O:52])([C:36]2[CH:41]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:39]([O:46][CH3:47])=[C:38]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:37]=2)[C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:16]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]=1[O:19][CH3:20])([CH3:12])([CH3:11])[CH3:10].CCCCCC>C(Cl)Cl>[Br:8][C:27]1[C:28]([O:34][CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:26]=1[P:25](=[O:52])([C:36]1[CH:37]=[C:38]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:39]([O:46][CH3:47])=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:41]=1)[C:15]1[CH:16]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([O:19][CH3:20])=[C:13]([C:9]([CH3:10])([CH3:11])[CH3:12])[CH:14]=1
Reactant: COc1cc(OC)cc(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cc(OC)c(Br)c(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
NBS (206 g, 115.7 mmol) was added to a solution of bis(3,5-di-tert-butyl-4-methoxyphenyl)(3,5-dimethoxyphenyl)phosphine oxide (70 g, 112.4 mmol) in CH2Cl2 (350 mL) at 0° C. The resulting suspension was stirred at 0° C. for 1 h then was warmed to RT and stirred for 4 h. The reaction was monitored by TLC until no starting material remained. The solution was washed with conc. Na2CO3 (300 mL×2) at RT. The organic layer was separated and dried over MgSO4. It was filtered and the solvent was removed to give the crude product. Hexane (400 mL) was added and the solution concentrated to 300 mL. It became cloudy and a white solid precipitated. Another 100 mL of hexane was added. The suspension was stirred at RT for 2 h. It was filtered and the solid dried under vacuum to give the product as a colourless solid (64.4 g). A second crop (7.2 g) was obtained from the mother liquor. Overall yield=90.9%. 1H NMR (400 MHz, CDCl3) δ: 7.55 (d, J=13.2 Hz, 4H), 7.04 (dd, J1=13.2 Hz, J2=2.8 Hz, 1H), 6.65 (d, J=2.8 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.68 (s, 6H), 1.36 (s, 36H). 31P NMR (162.0 MHz, CDCl3) δ: 32.4.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH3:24][O:25][NH2:26]>>[CH3:24][O:25][N:26]=[C:18]([CH2:17][C:16]([CH3:22])([CH3:21])[CH2:15][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]=[CH:13]1)[CH3:19]
Reactant: CON
Reactant: CC(=O)CC(C)(C)Cn1cnc2c(N)nc3ccccc3c21
Agent: Cl
Product: CON=C(C)CC(C)(C)Cn1cnc2c(N)nc3ccccc3c21

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one was reacted with O-methylhydroxylamine hydrochloride to provide 5-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one O-methyloxime as about a 2.9 to 1 mixture of E and Z isomers as a tan solid after recrystallization from aqueous methanol, mp 148-150° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])=[O:39])=[CH:36][C:35]=1[O:48][CH3:49]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:47]=[CH:46][C:37]([C:38]([NH:40][CH2:41][CH2:42][N:43]([CH3:44])[CH3:45])=[O:39])=[CH:36][C:35]=4[O:48][CH3:49])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NCCN(C)C)ccc1N
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Yield: 39.4 %

Procedure:
A mixture of 0.0663 g (0.219 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0625 g (0.33 mmole) of toluenesulfonic acid monohydrate, 0.052 g (0.219 mmole) of 4-amino-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-methanol-triethylamine (85:15:1) and then recrystallization from acetonitrile to give 0.0434 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-methoxy-benzamide (I-8) as a white solid.
Reaction SMILES: C(O)(=O)C(O)=[O:3].[CH2:7]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:31]=[CH:30][C:16]([CH2:17][CH2:18][NH:19]CC(C2C=CC=CC=2)CO)=[CH:15][CH:14]=1)[CH3:8]>CS(C)=O>[CH2:7]([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:31]=[CH:30][C:16]([CH2:17][C:18]([NH2:19])=[O:3])=[CH:15][CH:14]=1)[CH3:8]
Reactant: CCOCCOc1ccc(CCNCC(CO)c2ccccc2)cc1
Reactant: O=C(O)C(=O)O
Solvent: CS(C)=O
Product: CCOCCOc1ccc(CC(N)=O)cc1

Procedure:
from N-[(R or S)-3-hydroxy-2-phenylpropyl]-p-(2-ethoxyethoxy)phenylacetamide there was prepared (R or S)-β-[[[p-(2-ethoxyethoxy)phenethyl]amino]methyl]-phenethyl alcohol oxalate m.p. 152°-154° C., [α]D -9° (DMSO, c=1%)
Reaction SMILES: C(S)C.[H-].[Na+].[OH:6][CH:7]([C:9]1[CH:10]=[C:11]([S:23]([NH2:26])(=[O:25])=[O:24])[S:12][C:13]=1[S:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)[CH3:8].Cl>CN(C=O)C>[OH:6][CH:7]([C:9]1[CH:10]=[C:11]([S:23]([NH2:26])(=[O:25])=[O:24])[S:12][C:13]=1[S:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:8]
Reactant: COc1ccc(Sc2sc(S(N)(=O)=O)cc2C(C)O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CC(O)c1cc(S(N)(=O)=O)sc1Sc1ccc(O)cc1
Yield: 61 %

Procedure:
Ethanethiol (2.1 ml, 0.028 mol) was added dropwise over 10 minutes to a stirred suspension of 60% NaH in mineral oil (1.28 g, 0.032 mol) in DMF (30 ml) at ice bath temperature under nitrogen. After the sodium hydride had reacted, 4-(1-hydroxyethyl)-5-(4-methoxyphenylthio)thiophene-2-sulfonamide (1.0 g, 0.0029 mol) was added and the solution was stirred at steam bath temperature over night. The mixture was cooled in ice and acidified with 3N HCl (20 ml). The mixture was extracted with ethyl acetate and the extract was washed with saturated NaCl, saturated NaHCO3 and again with saturated NaCl. The extract was dried, filtered and concentrated in vacuo. The residual oil was washed with pet ether to remove the mineral oil and was purified by silica gel chromatography using 10% methanol in chloroform. The white solid product was obtained in 61% yield, mp. 133°-137° C. Purity and structure were confirmed by HPLC, C, H, N analysis and NMR.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH:8]2[C:13](=O)NC(=O)N[C:9]2=O)=[CH:2]1.ClC1C2[C:22](=[C:23]([F:28])[CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20]C=1.[OH-].[Na+].Cl>O>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:13]2[C:22]=1[N:21]=[CH:20][CH:9]=[C:8]2[CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: O=C1NC(=O)C(CCc2ccsc2)C(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc2c(CCc3ccsc3)ccnc12
Temperature: 150 °C
Yield: 100.1 %

Procedure:
A mixture of 1.85 g of 5-[2-(3-thienyl)ethyl]-barbituric acid and 1.5 g of 4-chloro-8-fluoroquinoline was heated to 150° C. for 11/4hours, then cooled. To the cooled mixture were added 2 g of NaOH and 35 ml of water, and the mixture was heated to reflux overnight. The mixture was cooled, then acidified to pH 1.5 with concentrated HCl, and heated gently for about 11/4 hours. After cooling the mixture, the product was extracted into CH2Cl2. The CH2Cl2 solution was filtered through phase separating paper, then evaporated in vacuo, giving about 2 g of oil residue. The residue was absorbed onto silica gel and chromatographed, eluting with CH2Cl2. Fractions containing product were combined, and the title product was crystallized. Recrystallization from petroleum ether/ CH2Cl2 gave 0.68 g of the title product. M.P. 96°-97° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]([F:43])([C:33]([F:42])([F:41])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[CH2:44](O)[CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]/[CH2:50][CH2:51][CH2:52][CH3:53].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:44]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[N:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([F:13])([F:43])[C:33]([F:41])([F:42])[C:34]([F:39])([F:40])[C:35]([F:36])([F:37])[F:38])=[CH:25][N:24]=2)=[CH:31][CH:30]=1)[CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]/[CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: Oc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Reactant: CCCC/C=C/CCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC/C=C/CCCCOc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of DEAD (0.261 g, 1.50 mmol) in THF (20) was added dropwise to a stirred solution of 4-[5-(5,5,6,6,7,7,8,8,8-nonafluorooctyloxy)-pyrimidin-2-yl]-phenol (0.693 g, 1.50 mmol), trans-5-decen-1-ol (0.234 g, 1.50 mmol) and triphenylphosphine (0.399 g, 1.50 mmol) in THF (30) and the reaction mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residues purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1)] to yield a colorless solid, which was recrystallized from ethanol.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36](=[O:41])[CH2:35]3)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:34]6[C:38](=[CH:39][CH:40]=5)[NH:37][C:36](=[O:41])[CH2:35]6)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc5c(c4)CC(=O)N5)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (Combi-Blocks, San Diego, USA, 35 mg, 0.128 mmol) to give the title compound as an off-white solid. (HPLC: tR 2.40 min (Method A); M+H=425 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 10.52 (s, 1H), 8.92 (s, 1H), 8.17 (s, 1H), 8.05-8.03 (m, 1H), 7.86-7.83 (m, 1H), 7.46 (s, 1H), 7.33-7.29 (m, 2H), 6.90-6.88 (m, 1H), 3.94 (s, 3H), 3.57 (s, 3H), 3.54 (s, 2H), 1.93 (s, 3H))
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[N:3][C:2]=1[OH:8].C1C(=O)N([I:16])C(=O)C1>CC(O)=O>[I:16][C:5]1[C:4]([OH:7])=[N:3][C:2]([OH:8])=[N:1][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccnc(O)n1
Solvent: CC(=O)O
Product: Oc1ncc(I)c(O)n1
Reaction time: 7 h
Yield: 95.2 %

Procedure:
A mixture of pyrimidine-2,4-diol (100 g, 0.892 mol) and NIS (220 g, 1.981 mol, 1.1 eq) in AcOH (900 mL) was stirred for about 7 h. Solid 5-iodopyrimidine-2,4-diol (202 g, 95%) was obtained by filtration, washed with ethyl acetate. LC-MS (m/z)=238.9 [M+H]+.
Reaction SMILES: [ClH:1].[O:2]1[C:7]2=[CH:8][N:9]=[C:10]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[N:27][CH:28]=[C:29](F)[CH:30]=5)[CH:25]=[CH:24][C:23]4=[O:33])[CH2:16][CH2:15]3)[CH:11]=[C:6]2[CH2:5][CH2:4][CH2:3]1.C[O-].[Na+].CO.O.[C:40](OCC)(=[O:42])C>CO>[ClH:1].[O:2]1[C:7]2=[CH:8][N:9]=[C:10]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[N:27][CH:28]=[C:29]([O:42][CH3:40])[CH:30]=5)[CH:25]=[CH:24][C:23]4=[O:33])[CH2:16][CH2:15]3)[CH:11]=[C:6]2[CH2:5][CH2:4][CH2:3]1
Reactant: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCC3)CC1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCC5)CC3)c2c1
Reaction time: 4 h

Procedure:
To a suspension of 60 mg of 1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride in 2 mL of methanol, 60 mg of a 28% sodium methoxide/methanol solution, and the mixture was heated under reflux while stirring for 4 hours. Thereto were added water and ethyl acetate, the organic layer was separated, and the aqueous layer was saturated with sodium chloride, and then extracted with ethyl acetate twice. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, 1 mL of ethyl acetate was added, and 1 mL of a 4.0 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature. The solvent was distilled off under reduced pressure, ethyl acetate was added to the resultant residue, and the solid was filtered off to obtain 31 mg of 1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH:15]([CH2:22]O)[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])[CH3:2].P(Br)(Br)[Br:25]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH2:12][CH2:13][CH2:14][CH:15]([CH2:22][Br:25])[C:16]=3[C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3c(c2c1COC)C(CO)CCC3
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1ncc2[nH]c3c(c2c1COC)C(CBr)CCC3

Procedure:
From 5,6,7,8-tetrahydro-5-hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester (example 2) by reaction with phosphorus tribromide in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:11]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(-c2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C(=O)OC(C)(C)C)cc1
Reaction time: 3 h

Procedure:
To a solution of the product from step D (6.8 g, 21.7 mmol) in 50 mL of N,N-dimethylformamide was added cesium carbonate (10.6 g, 32.6 mmol) and the resultant mixture stirred at ambient temperature for 15 min. Methyl 4-(bromo-methyl)benzoate (5.46 g, 23.9 mmol) was added and stirring continued for 3 h. The reaction mixture was diluted with ethyl acetate and the organic layer washed successively with six portions of water and one portion of brine then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 5% ethyl acetate/hexanes) to give the title compound as a light tan solid. 1H NMR (500 MHz, CDCl3) δ; 8.03 (d, J=8.4 Hz, 2H); 7.75 (d, J=1.8 Hz, 2H); 7.35 (m, 3H); 7.12 (s, 1H); 5.88 (s, 2H); 3.94 (s, 3H); 1.57 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:21][N:22]=1)=[CH:14]2>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][N:22]=1)=[CH:14]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4nccn4C)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
Ethyl (2-{7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (1 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), 1M aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. The mixture was washed with ethyl acetate, and the aqueous layer was concentrated under reduced pressure. Ethanol was added to the residue, and the insoluble substance was filtered off. The filtrate was concentrated, and the obtained yellow solid was recrystallized from ethanol to give the title compound (170 mg) as yellow crystals. MS 541 (MH+).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH2:31]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1.CCCCCC>[CH2:31]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:42][CH:41]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCc1ccc(C=O)cc1
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC=Cc1ccc(CCCCCCCCC)cc1
Reaction time: 0.5 h

Procedure:
A suspension of 13.9 g of pentyltriphenylphosphonium bromide in 150 ml of tetrahydrofuran is cooled to -20° under argon, 21.2 ml of 1.6M butyllithium solution in hexane are added within a period of 5 minutes and the whole is stirred for a further 30 minutes at 0°-10°. 6 g of 4-nonylbenzaldehyde in 40 ml of tetrahydrofuran are added dropwise over a period of 30 minutes to the mixture, which has been cooled to from -60° to -70°. The reaction mixture is allowed to warm spontaneously to 0°-10°, stirred at this temperature for a further 45 minutes and concentrated by evaporation. The residue is taken up in hexane/ethyl acetate (1:) and filtered over silica gel. The filtrate is concentrated by evaporation and chromatographed on silica gel with hexane. The title compound (mixture of cis- and trans-isomers) is obtained in the form of a colourless oil, which is used directly in the next stage.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](=[N:7][OH:8])Cl)[CH3:2].[N:10]1([C:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:23])[CH3:22])[CH2:19][CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[CH:20]2[CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16][C:15]2([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[O:8][N:7]=1)=[O:9])[CH3:2]
Reactant: CC(=O)N1CC=C(N2CCCC2)CC1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(C)=O)CC12

Procedure:
A solution of 17.9 g (0.118 mol) of 2-chlorohydroxyiminoacetic acid ethyl ester in 20 mL of DCM was added to a solution of 16.3 g (84 mmol) of 1-(4-pyrrolidin-1-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (A) in 150 mL of DCM. On so doing, the solution warmed up and turned red. After cooling to 0° C. (ice bath), 16.4 g (0.118 mol) of triethylamine were slowly added dropwise with stirring. The mixture was stirred for 12 h at RT and then washed, firstly with 10% (weight percent) citric acid solution in water, and then with sat. aq. common salt solution. After removal of the solvent under a vacuum, the residue was purified by column chromatography (SiO2, EtOAc/EtOH 9:1). 18.5 g (71% of theoretical) of the desired product 5-acetyl-7a-pyrrolidin-1-yl-3a,4,5,6,7,7a-hexahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (B) were obtained in the form of a brown oil.