Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.[CH:33]1([O:38][C:39](=[O:46])[C@H:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH2:41])[CH2:37][CH2:36][CH2:35][CH2:34]1.[I-].[Na+].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:41][C@H:40]([C:39]([O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[O:46])[CH2:42][CH:43]([CH3:45])[CH3:44])=[CH:10][C:9]=2[F:22])[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1c(F)cc(OCCCCCCl)cc1F
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1)C(=O)OC1CCCC1
Temperature: 90 °C
Yield: 48 %

Procedure:
From Intermediate 4H. To a solution of 6-amino-1-{4-[(5-chloropentyl)oxy]-2,6-difluorophenyl}-5-(4-fluorobenzoyl)pyridin-2(1H)-one (99 mg, 0.21 mmol) in anhydrous DMF (3 ml) under an atmosphere of nitrogen was added cyclopentyl L-leucinate (Intermediate 8) (212 mg, 1.06 mmol, 5 eq), sodium iodide (64 mg, 0.43 mmol, 2 eq) and N,N-diisopropylethylamine (0.039 ml, 0.21 mmol, 1 eq). The mixture was heated at 90° C. for 20 hours, before being allowed to cool to room temperature and diluted with EtOAc (25 ml). The solution was washed with water (2×25 ml) and brine (25 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (2% MeOH in DCM) followed by preparative HPLC afforded the title compound as a yellow solid (64 mg, 48% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.ClCCl.CN(C1C=CC=CN=1)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCCc1ccccc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)CCCCc2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a cooled mixture of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.10 g, 0.40 mmol), pyridine (0.096 g, 1.21 mmol), and dimethylaminopyridine (0.010 mg) in anhydrous tetrahydrofuran (5 mL) was added 5-phenylpentanoyl chloride (0.16 g, 0.81 mmol) in anhydrous dichloromethane (1 mL) dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with dichloromethane (10 mL) and washed with saturated sodium bicarbonate solution (2×5 mL), 1 N hydrochloric acid (5 mL), and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrate in vacuo. The residue was purified by column chromatography over silica gel, eluting with ethyl acetate/hexanes (1/1) to afford the title compound as a clear oil (0.16 g, 97%) %); 1H NMR (CDCl3, 300 MHz) δ 11.19 (s, br, 1H), 7.33-7.09 (m, 10H), 6.40 (t, J=4.8 Hz, 1H), 4.58 (d, J=5.8 Hz, 2H), 2.60-2.39 (m, 7H), 1.74-1.56 (m, 4H); MS (ES+) m/z 408.6 (M+1).
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].ClC(Cl)(Cl)C(=N)O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)S(O)(=O)=O>C1CCCCC1>[CH2:23]([O:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OCc1ccccc1
Yield: 112.8 %

Procedure:
A suspension of 206.7 g of methyl (R)-3-hydroxytetradecanoate in 1000 ml of cyclohexane was treated under nitrogen and while stirring with 214.2 g of benzyl trichloroacetimidate and dissolved at 20°. 10 ml of trifluoromethanesulphonic acid were added dropwise while cooling in an ice/water bath in such a manner that the temperature remains between 20°-23°. The resulting suspension was stirred at 25°-30°. The precipitate was filtered off, the filter cake was washed with cyclohexane, the filtrates were extracted with sat. NaHCO3 solution, water and sat. NaCl solution. The organic phase was dried over magnesium sulphate, filtered, the filter cake was washed with cyclohexane and the filtrates were evaporated. 314.5 g of methyl (R)-3-(benzyloxy)-tetradecanoate were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([O:21]C)=[O:20].[Li+].[OH-]>CC(N(C)C)=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)O
Reaction time: 8 h
Yield: 73.4 %

Procedure:
Methyl 1-methyl-4-(1-methyl-4-nitro-1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carboxylate (2.0 g, 6.53 mmol) in 50 ml of DMA was added 2 g of LiOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4to form precipitates. The precipitates were filtered, washed with water and dried over P2O5 with vaccum to afford 1.4 g (73%) of the title product. 1H NMR (DMF-d7) 10.34 (br, 1H), 8.17 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.00 (s, 1H), 4.09 (s, 1H), 3.91 (s, 1H); 13C NMR 158.47, 135.61, 129.11, 127.77, 123.65, 121.57, 121.50, 109.48, 108.52, 38.38, 37.05; MS m/z− 291.0 (M−H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][N:11]=[C:12]=[S:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[S:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)N1CCC(CN=C=S)CC1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(CNC(=S)Nc2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4 parts of 1-acetyl-4-(isothiocyanatomethyl)piperidine, 2.2 parts of 4-fluorobenzenamine and 90 parts of tetrahydrofuran was stirred overnight at reflux temperature. The reaction mixture was evaporated, yielding 6.2 parts (100%) of N-[(1-acetyl-4-piperidinyl)methyl]-N'-(4-fluorophenyl)thiourea as a residue (intermediate 12).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][CH:9]=1)[CH2:5][CH:6]=[CH2:7].O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[CH3:19][S:16]([NH:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH:4]([CH2:5][CH:6]=[CH2:7])[C:3]([OH:20])=[O:2])=[CH:9][CH:10]=1)(=[O:18])=[O:17]
Reactant: C=CCC(C(=O)OC)c1ccc(CNS(C)(=O)=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)c1ccc(CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-[4-(methanesulfonylamino-methyl)-phenyl]-pent-4-enoic acid methyl ester (1.85 g, 6.55 mmol) in a 1:1 mixture of tetrahydrofuran (25 cm3) and methanol (25 cm3) at ambient temperature under an atmosphere of dry nitrogen was added lithium hydroxide hydrate (1.16 g, 26.2 mmol) dissolved in water (25 cm3). The mixture was stirred at ambient temperature for 16 hours and volatile fractions removed in vacuo to leave an aqueous mixture. The mixture was diluted with water (25 cm3) and acidified with 1 N hydrochloric acid to pH 1.0. The aqueous mixture was extracted with dichloromethane (3×30 cm3), The combined dichloromethane extracts washed with brine (1×30 cm3), dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to a colorless oil (1.68 g, 90.7%) with a negative ion ESI (M−H)−282.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:19][CH:18]4[C:20]#[N:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.C(O)(C(F)(F)F)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:19][CH:18]4[CH2:20][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#CC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
To a stirred solution of 2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropanecarbonitrile (275 mg, 0.78 mmol) in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (2.0 mL, 2.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 12 hr, the mixture was quenched with MeOH, poured into a 1N sodium brine, extracted with ethyl acetate (2×100 mL), dried (MgSO4), concentrated and purified by HPLC to give 142 mg (39% yield) of (2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropyl)methanamine as the TFA salt. MS found: (M+H)+=358.
Reaction SMILES: [OH2:1].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:10]O.O=[C:13]([C:19]1[CH:20]=[CH:21][C:22]2[C:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=3[O:24][C:23]=2[CH:31]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]>>[OH:1][N:10]=[C:13]([C:19]1[CH:20]=[CH:21][C:22]2[C:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:25]=3[O:24][C:23]=2[CH:31]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: NO
Reactant: O
Reactant: O=C(O)CCC(=O)c1ccc2c3c(oc2c1)CCCC3
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)CCC(=NO)c1ccc2c3c(oc2c1)CCCC3
Temperature: 25 °C
Yield: 51 %

Procedure:
To a methanolic solution (50 mL) of 4-oxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid (Keumi T., Saga H., Shimakawa S., et al., Fufui Daigaku, Kogakubu Seni Kogyu Kenkyu Shisetsu Hokoku, 1976;14:71-7 (mp 143-146° C.; mp 148.5-149.50° C. (lit.)) (0.6 g, 0.0022 mol) and sodium acetate trihydrate (0.9 g, 0.0066 mol) at room temperature with stirring was added an aqueous solution (10 mL) of hydroxylamine hydrochloride (0.31 g, 0.0044 mol). The resulting solution was heated to reflux for 4 hours. The solution was then cooled to room temperature and concentrated in vacuo. The residue was recrystallized form ethyl acetate/hexane (1:1) to yield the title compound (0.32 g, 51%) as a white solid; mp 164° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[OH:1][CH2:2][C@@H:3]1[CH2:4][C@H:5]2[C@H:6]([O:17]2)[C@@H:7]1[OH:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC[C@@H]1CC=C[C@@H]1O
Solvent: ClCCl
Product: OC[C@@H]1C[C@@H]2O[C@@H]2[C@@H]1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
(1S,5S)-5-(Hydroxymethyl)cyclopent-2-en-1-ol (3.19 g, 27.9 mmol) was dissolved in DCM (143 mL) and the solution was cooled to 0° C. 3-Chloroperbenzoic acid (7.52 g, 33.5 mmol) was added and the mixture was stirred at 23° C. for 4 h. TLC indicated complete conversion. Silica gel (20 g) was added, the mixture was concentrated to dryness and was purified via silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in DCM to afford the title compound (2.75 g, 76%). 1H NMR (CDCl3, 300 MHz) δ: 4.58 (d, J=8.1 Hz, 1H), 3.69 (s, 1H), 3.68 (s, 1H), 3.60 (s, 1H), 3.52 (s, 1H), 2.47-2.40 (m, 1H), 2.14 (ddd, J=1.5, 10.2, 15.3 Hz, 1H), 2.01 (dd, J=1.5, 15.3 Hz, 1H), 1.62 (bs, 2H) ppm. LC/MS: Rt=0.37 nm, ES+ 131 (AA standard).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[Al](Br)(Br)Br>CCCCCC.C(Br)Br.[Al](Br)(Br)Br>[CH2:1]([C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: C=CCCCCCCCC
Agent: Br[Al](Br)Br
Solvent: CCCCCC
Solvent: BrCBr
Product: CCCCCCCCCCC12CC3CC(CC(C3)C1)C2
Yield: 80 %

Procedure:
Decyl adamantane was prepared by reacting 140 g 1-decene, 54.4 gram adamantane in 100 cc n-hexane solvent and using 3 mmoles 1.0 M AlBr3 in CH2Br2 or AlBr3 catalyst at 15°-50° C. reaction temperature. The product was isolated by quench the catalyst with dilute acid and aqueous work-up followed by distillation at 155° C. and 0.2 mm-Hg using a Kugelrohr to remove any C20 -material. The C30 + fraction was obtained in 80% yield. It was hydrogenated at 200° C. and 500 psi H2 using 1 wt.% Ni/SiO2 catalyst.
Reaction SMILES: [CH2:1]([S:11](Cl)(=[O:13])=[O:12])[CH2:2][S:3][S:4][CH2:5][CH2:6][S:7](Cl)(=[O:9])=[O:8].S(Cl)(Cl)(=O)=[O:16].[OH2:20]>C(#N)C>[CH2:1]([S:11]([OH:13])(=[O:16])=[O:12])[CH2:2][S:3][S:4][CH2:5][CH2:6][S:7]([OH:9])(=[O:8])=[O:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: O
Reactant: O=S(=O)(Cl)CCSSCCS(=O)(=O)Cl
Solvent: CC#N
Product: O=S(=O)(O)CCSSCCS(=O)(=O)O
Yield: 96 %

Procedure:
2,2′-Dithiobis ethane sulfonyl chloride (15.0 g, 47 mmol) was dissolved in a mixed solution of acetonitrile (100 mL) and water (30 mL). The reaction solution was stirred at room temperature for five days until no more sulfonyl chloride was detected. The reaction solution was then concentrated by rotary evaporation at elevated temperature to remove the volatile acetonitrile solvent and as much water as possible. The remaining aqueous solution was washed with dichloromethane (2×50 mL) and dried under high vacuum to give 12.7 g of disulfonic acid (96% yield). The product existed as a semi-solid form and was highly hygroscopic. It readily turned to a viscous liquid once exposed to air. No significant impurity was detected in the product by either NMR or HPLC.
Reaction SMILES: Cl.[C:2]([N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH3:6])(=O)C.N(CC(O)=O)C.C=O.[OH:19][PH:20]([OH:22])=[O:21].P(Cl)(Cl)Cl>C(O)(=O)C.O>[P:20]([CH2:2][N:5]([CH3:6])[CH2:7][C:8]([OH:10])=[O:9])([OH:22])([OH:21])=[O:19]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: O=[PH](O)O
Agent: C=O
Agent: CNCC(=O)O
Agent: Cl
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CC(=O)O
Product: CN(CC(=O)O)CP(=O)(O)O

Procedure:
As depicted, one equivalent of N-methylacetamide IX is reacted with one equivalent each of carbon monoxide and formaldehyde in the presence of a carboxymethylation catalyst precursor and solvent to yield N-acetylsarcosine XX. In the presence of water and an acid such as hydrochloric acid, N-acetylsarcosine XX is hydrolyzed to sarcosine XXIII and acetic acid. Sarcosine XXIII is reacted with formaldehyde and H3PO3, PCl3 or other H3PO3 source to produce N-(phosphonomethyl)-N-methyl-glycine XXI which is oxidized in the presence of a platinum catalyst and oxygen to glyphosate I.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O.Cl.C(=O)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)ccc1Cl
Reaction time: 8 h
Yield: 100 %

Procedure:
8.00 kg 2-chloro-5-bromobenzoic acid was suspended in 80.00 L methylene chloride (KF of methylene chloride <0.1% H2O) and 0.02 L of DMF added at 20° C. 5.18 Kg oxalyl chloride were slowly added and the internal temperature maintained below 25° C. The addition was slightly exothermic; gas evolution of HCl and CO2 occurred. The reaction was run at 20–25° C. overnight; a clear solution was obtained. The mixture was concentrated in vacuum to an oily residue and degased at 40° C. in vacuum. Yield of 2-chloro-5-bromobenzoic acid chloride: 8.63 kg (33.98 mol, yield 100.0%)
Reaction SMILES: [Cl:1][C:2]1[N:12]2[C:13]3[C:8]([C:9](=[O:14])[CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[F-].[K+].[N:17]1[C:22](C)=[CH:21][CH:20]=[CH:19][C:18]=1C>CN(C)C=O>[Cl-:1].[CH3:2][N+:12]1([CH:20]2[CH2:19][CH2:18][N:17]([C:2]3[N:12]4[C:13]5[C:8]([C:9](=[O:14])[CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[CH2:22][CH2:21]2)[CH2:13][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Cc1cccc(C)n1
Reactant: O=C1CCn2c(Cl)nc3cccc1c32
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[N+]1(C2CCN(c3nc4cccc5c4n3CCC5=O)CC2)CCCCC1
Product: [Cl-]
Temperature: 140 °C
Reaction time: 5 h

Procedure:
400 mg of 2-chloro-4,5-dihydro-6H-imidazo[4,5,1-ij]quinolin-6-one in 5 mL of dimethylformamide, 70 mg of potassium fluoride, 0.2 mL of 2,6-lutidine and 1.6 g of 4-(N-methylpiperidinium)piperidine chloride are added to a three-necked flask under argon and left stirring for 5 hours at 140° C. The mixture is evaporated on a vacuum pump and the residue obtained is chromatographed with 70 g of Silica H (Merck) (eluent: dichloromethane with 10% methanol and 0.5% triethylamine). 50 mg of pure product are obtained, the NMR spectrum of which corresponds to the desired structure.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[Na+].[OH:16][CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:18][CH2:19][C:20]([O-:22])=[O:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.CCOCC>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3](=[O:4])[CH2:2][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH:17]([OH:16])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC(O)CCC(=O)[O-]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCC(O)CCC(=O)OCC(=O)c1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 26.6 %

Procedure:
A suspension of 20.00 g of 2-bromo-2′-acetonaphtone, 18.01 g of 4-hydroxy-undecanoic acid sodium salt, and 0.5 g of tetrabutylammonium bromide in 180 ml of dimethylformamide was stirred for 6 hours at 50° C. Then, the reaction mixture was diluted with ether and washed with water, 2N HCl, saturated sodium bicarbonate, and brine. Then, the mixture was dried, filtered, and evaporated to dryness. The resulting solid was purified by recrystallization to yield 7.92 g of colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][C:15](O)=[O:16])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[Cl:27][C:15](=[O:16])[CH2:14][CH:13]([C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12][CH:11]=1)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(CC(=O)O)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CC(CC(=O)Cl)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-[2-(4-chlorophenyl)-1,3-thiazol-5-yl]-5-ethoxy-5-oxopentanoic acid (9.68 mmol) was dissolved in CH2Cl2 (10 mL) and cooled to 0° C. Oxalyl Chloride (2.0M in CH2Cl2; 25 mL) was added slowly. One drop of DMF was added to the reaction mixture. The reaction was warmed to room temperature and stirred for 18 hours. The reaction was concentrated in vacuo to give the crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(NCC)C.[CH3:37][CH:38]([OH:42])[CH2:39][C:40]#[CH:41]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:41]#[C:40][CH2:39][CH:38]([OH:42])[CH3:37])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCC(C)O
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(O)CC#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reaction time: 96 h

Procedure:
A flame-dried flask under an atmosphere of nitrogen gas containing N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Preparation # 15) (0.55 g) is treated with copper (I) iodide (0.02 g) and dichlorobis(triphenylphosphine)palladium (II) (0.07 g). The solids are treated with dimethylformamide (DMF) (6 mL) and diethylamine (6 mL). The resulting suspension is treated with 4-pentyn-2-ol (0.2 mL) and stirred for 4 days. The reaction is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and phosphate buffer (pH=7). The aqueous phase is extracted with dichloromethane:ethyl acetate. The combined organic layers are washed with phosphate buffer (pH=7), brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is flash column chromatographed on silica eluting with 5% to 11% methanol in ethyl acetate. The product-containing fractions are combined and concentrated under reduced pressure. The resulting material is crystallized from acetonitrile:methanol and then re-crystallized from toluene to afford the title compound (0.33 g) as off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[N:11]([CH3:14])[CH:12]=[N:13][C:8]2=[C:7]([F:15])[C:6]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=[O:4].C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[N:11]([CH3:14])[CH:12]=[N:13][C:8]2=[C:7]([F:15])[C:6]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:31])=[CH:19][C:18]=1[F:23])=[O:4]
Reactant: COC(=O)c1nc2c(ncn2C)c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-fluoro-6-(2-fluorophenylamino)-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1.00 equivalent) in DMF is added NBS (1.20 equivalents) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C1COCC1.C(Cl)Cl>[Br:2][CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:6][CH:5]=1
Reactant: BrCc1ccc2cn[nH]c2c1
Reactant: C1=COCCC1
Agent: Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: BrCc1ccc2cnn(C3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
A yellow suspension of 6-(bromomethyl)-1H-indazole hydrogen bromide (9.0 g, 43 mmol) (4-5) and 3,4-dihydro-2H-pyran (7.2 g, 86 mmol) in THF (200 mL) was heated at its reflux temperature for 2 hours. After cooling down to room temperature, the reaction mixture was stirred at room temperature for 12 hours under nitrogen. The reaction solution was diluted with methylene chloride (500 mL), washed with saturated NaHCO3, water and brine. After drying (MgSO4), the solvent was removed under vacuum to give a yellow oil. Flash chromatography yielded the title compound (6.6 g, 72%). TLC Rf 0.52 (80:20 of hexane-ethyl acetate); MS (electrospray) 295, 297 (M+1); 1H N MR (CDCl3) δ1.57-1.84 (m, 3H), 2.16 (m, 2H), 2.55 (m, 1H), 3.75 (m, 1H), 4.01 (m, 1H), 4.65 (s, 2H), 5.71 (d, 1H, J=9.2 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.59 (d, 1H, J=8.8 Hz), 7.73 (s, 1H), 8.00 (s, 1H).