Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1I>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Fc1ccccc1I
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and a solution of 8.33 g of 4-bromotoluene in 30 ml of tetrahydrofuran were added in this order to 30 ml of tetrahydrofuran which had been cooled to −78° C. in a nitrogen atmosphere, and the mixture was then stirred at −78° C. for 1 hour. A solution containing 6.64 g of zinc chloride which had been dehydrated through heat-melting under reduced pressure in 30 ml of tetrahydrofuran was added thereto at −78° C., and the mixture was stirred at room temperature for 1 hour. This solution was added to a solution of 7.22 g of 2-fluoroiodobenzene and 0.52 g of tetrakis(trifluorophosphine)palladium (0) in 30 ml of tetrahydrofuran at room temperature, and the mixed solution was stirred for 24 hours. The reaction solution was diluted with 300 ml of ethyl acetate, and the dilute solution was extracted with the addition of 10% hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and then concentrated. The residue was purified through silica-gel column chromatography (eluent: hexane) to give 6.05 g of oily 2-fluoro-4′-methylbiphenyl.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:45])[C:11]2[CH:17]=[C:16]([CH2:18][N:19]([CH2:22][C:23]3[CH:44]=[CH:43][C:26]([C:27]([NH:29][C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])=[CH:25][CH:24]=3)[CH:20]=[O:21])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>C(O)(=O)C.[Pt]=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:45])[C:11]2[CH2:17][CH:16]([CH2:18][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:29][C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])=[CH:43][CH:44]=3)[CH:20]=[O:21])[CH2:15][NH:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN(C=O)Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CN(C=O)CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Yield: 750.9 %

Procedure:
To a solution of 1.09 g. (0.17 mmol) of diethyl N-[N-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylmethyl)-N-formyl-4-aminomethylbenzoyl]-glutamate in 50 mL of glacial acetic acid was added 164 mg of platinum oxide. The suspension was shaken in a Parr hydrogenation apparatus under an atmosphere (50 psi) of hydrogen at 25° C. for 3 hours. The reaction mixture was filtered through Celite and the filtrate evaporated under reduced pressure. The residue was dissolved in 100 mL of methylene chloride and extracted twice with a saturated solution of sodium bicarbonate. The aqueous layers were back extracted with 75 mL of methylene chloride and the organic layers combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure and the residue chromatographed, eluting with 5% methanol in methylene chloride to give 0.8 g of diethyl N-[N-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-ylmethyl)-N-formyl-4-aminomethylbenzoyl]-glutamate (73% yield). An analytical sample was recrystallized from acetonitrile; mp 149°-151° C.; 1H NMR (Me2SO d6) delta 1.11-1.16 (m, 6H), 1.18 (s, 9H), 1.83-2.15 (m, 4H), 2.30.varies.2.47 (m, 3H), 2.79-3.20 (m, 4H), 3.98-4.11 (m, 4H), 4.36-4.43 (m, 1H), 4.53-4.54 (m, 2H), 6.40-6.51 (m, 1H), 7.33-7.36 (m, 2H, AA'BB'), 7.80-7.85 (m, 2H, AA'BB'), 8.11 and 8.38 (s, 1H), 8.67-8.73 (m, 1 H). Anal. Calcd for C31H42N6O8 : C, 59.41; H, 6.75; N, 13.41. Found: C, 59.14; H, 6.73; N, 13.64.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[Si:7](Cl)([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9].CN1CCOCC1>C(Cl)Cl.O>[Cl:1][CH2:2][C:3]([O:5][Si:7]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:8][CH3:9])([CH3:6])[CH3:4]
Reactant: CC(C)(O)CCl
Reactant: CC[Si](Cl)(CC)CC
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CC[Si](CC)(CC)OC(C)(C)CCl
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A 250 mL round bottom flask was charged with 1-chloro-2-methylpropan-2-ol (2.0 g, 18 mmol). DCM (60 mL) was added, followed by Et3SiCl (3.4 mL, 20 mmol) and then NMM (3 mL, 27 mmol) and the reaction was stirred at rt for 36 hrs. Water (50 mL) and DCM (50 mL) were added and the aqueous layer extracted with DCM (two×30 mL). The combined organic extracts were washed with water and dried over MgSO4. After filtering, the solvents were removed in vacuo, keeping the bath temperature at 22° C. The intermediate was placed under a 10 mm Hg vacuum for 15 min to provide (ca. 18 mmol, 100% yield) of ((1-chloro-2-methylpropan-2-yl)oxy)triethylsilane as a pale yellow oil. This material was used as is in the next step.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([NH2:4])=[O:3].[CH3:7][N:8]([CH3:40])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:20]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:21](=[O:33])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1.[H][H]>C(O)C.[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([NH2:4])=[O:3].[CH3:40][N:8]([CH3:7])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:20]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:21](=[O:33])[CH:22]=[CH:23][C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: CCOC(=O)CN(Cc1ccccc1OCCCN(C)C)C(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: NC(=O)C(=O)O
Solvent: CCO
Product: CCOC(=O)CN(Cc1ccccc1OCCCN(C)C)C(=O)C=Cc1ccc(N)cc1

Procedure:
A suspension of 10 parts of [[[2-[3-(dimethylamino)propoxy]phenyl]methyl][1-oxo-3-(4-nitrophenyl)-2-propenyl]amino]acetic acid, ethyl ester, oxamate salt (1:2) in 100 ml of ethanol is treated with 1 part of 5% palladium on carbon and placed under 3 atmospheres of gaseous hydrogen. The mixture is shaken until one equivalent of hydrogen is consumed, filtered and the solvent evaporated under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=O)[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:3]1[N:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ncc(Cl)c1Cl
Product: Clc1cnnc(Cl)c1Cl

Procedure:
A stirred solution of 20.0 grams of 4,5-dichloro-3-pyridazone in 150 ml of phosphorus oxychloride is heated under reflux for five hours. The excess phosphorus oxychloride is removed under reduced pressure, and the residue poured into ice water. The mixture is extracted with diethyl ether. The extract is dried with magnesium sulfate, filtered, and the filtrate concentrated to a residue. The residue is distilled under reduced pressure. A fraction, b.p. 117°-118° C./14-15 mm, 20 grams, solidifies on standing. The solid is recrystallized from acetone-water to yield 3,4,5-trichloropyridazine; m.p. 61° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:17][C:18]1[C:22]([CH3:23])=[C:21]([N:24]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])[S:25]([C:28]2[C:29]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[O:41][CH:42]=[CH:43][N:44]=4)=[CH:36][C:35]=3[CH2:45][CH2:46][NH:47][CH3:48])=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[O:20][N:19]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:17][C:18]1[C:22]([CH3:23])=[C:21]([N:24]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[CH:39]=[CH:38][C:37]([C:40]3[O:41][CH:42]=[CH:43][N:44]=3)=[CH:36][C:35]=2[CH2:45][CH2:46][N:47]([CH3:48])[C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:27])=[O:26])[O:20][N:19]=1
Reactant: CNCCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)N(COCCOC)c1onc(C)c1C
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CCN(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To phenylacetic acid (7.9 mg, 0.058 mmol) and 0.003 ml DMF in 1 ml CH2Cl2, oxalyl chloride (2M in CH2Cl2, 0.073 ml, 0.15 mmol) was added. The mixture was stirred at room temperature for 1.5 hr and concentrated. The residue was dissolved in 0.5 ml CH2Cl2 and cooled to 0° C. A solution of the title compound of Step (A) (29 mg, 0.053 mmol) in 0.5 ml CH2Cl2 was added and followed by Et3N (16 mg, 0.16 mmol). The reaction was stirred at room temperature for 2 hr and concentrated to give the title compound of this step.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:10](OCC)(OCC)[O:11][CH2:12][CH3:13].C(OC(=O)C)(=O)C>>[CH2:12]([O:11][CH:10]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(C)=O)C(=O)OCC
Temperature: 135 °C
Yield: 69.7 %

Procedure:
A mixture of ethyl acetoacetate (100 g, 0.77 mol), triethyl orthoformate (130 g, 0.92 mol), and acetic anhydride (150 g, 1.5 mol) was heated at 135° C. for 6-18 h in a round bottomed flask that was equipped with a distillation apparatus to collect the ethanol generated during the reaction. The reaction was cooled, concentrated and the residue was distilled under high vacuum to obtain the desired product (100 g, 70%) as a pale yellow oil: ESI MS m/z 187 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]CC)=[O:13])=[CH:7][CH:6]=1.N1CC[O:20][CH2:19][CH2:18]1.[S]>>[C:19]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)(=[O:20])[CH3:18]
Reactant: CCOC(=O)Cc1ccc(CCN)cc1
Reactant: C1COCCN1
Agent: Cl
Agent: [S]
Product: CC(=O)NCCc1ccc(CC(=O)O)cc1

Procedure:
The ethyl 4-(2-aminoethyl)-phenylacetate hydrochloride used as starting material is prepared in the following manner: 4-(2-acetamidoethyl)-acetophenone is reacted with morpholine and sulfur to give the thiomorpholide of 4-(2-acetamidoethyl)-phenylacetic acid (m.p. 117°-118° C.). Subsequent alkaline saponification, followed by esterification with ethanolic hydrochloric acid, gives ethyl 4-(2-aminoethyl)-phenylacetate hydrochloride; m.p. 177°-178° C., after recrystallization from ethanol.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:19][O:20][C:21]([F:31])([F:30])[C:22]([F:29])([F:28])[CH2:23][C:24]([F:27])([F:26])[F:25])([CH2:6][O:7][C:8]([F:18])([F:17])[C:9]([F:16])([F:15])[CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:4][OH:5].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl.CS(Cl)(=O)=O>[S:33]([O:5][CH2:4][C:3]([CH2:6][O:7][C:8]([F:17])([F:18])[C:9]([F:15])([F:16])[CH2:10][C:11]([F:14])([F:13])[F:12])([CH2:19][O:20][C:21]([F:30])([F:31])[C:22]([F:28])([F:29])[CH2:23][C:24]([F:25])([F:26])[F:27])[CH2:2][Br:1])(=[O:35])(=[O:34])[CH3:32]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CBr)(COC(F)(F)C(F)(F)CC(F)(F)F)COC(F)(F)C(F)(F)CC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(CBr)(COC(F)(F)C(F)(F)CC(F)(F)F)COC(F)(F)C(F)(F)CC(F)(F)F
Yield: 95.1 %

Procedure:
In a manner similar to that described above, 3-bromo-2,2-bis-(heptafluorobutoxymethyl)-1-propanol (250.0 g, 0.44 mole) was reacted with methanesulfonyl chloride (58.45 g, 0.51 mole) and triethylamine (52.62 g, 0.52 mole) in methylene chloride (400+200 ml). Additional methanesulfonyl chloride (2.96 g, 0.03 mole) was added to bring the reaction to completion. Washing and removal of the solvent gave 268.4 g (95.2%) of 3-bromo-2,2-bis(heptafluorobutoxymethyl)-1-propanol mesylate (4), a yellow oil: IR 2940, 1350, 1223, 1176, and 1120 cm-1 ; 1H NMR (CDCl3) 3.02 (s, 3H), 3.49 (s, 2H), 3.68 (s, 4H), 3.97 (t, J=13.3 Hz, 4H), and 4.24 (s, 2H); 13C NMR (CDCl3) 31.66, 36.64, 44.60, 67.81 (t, J=26.44), 68.36, and 70.30. Anal. Calcd for C14H15BrF14O5S: C, 26.22; H, 2.36; Br, 12.46, F, 41.48. Found: C, 25.95; H, 2.33; Br, 12.88.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9](F)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)=[CH:10][C:9]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[N:8][CH:7]=2)#[N:14]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: NCc1cccnc1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Product: COC(=O)c1ccc(Nc2c(C#N)cnc3cnc(NCc4cccnc4)cc23)cc1
Yield: 2.5 %

Procedure:
Following the procedure described above in Example 29, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.200 g, 0.963 mmol) was reacted with methyl 4-aminobenzoate (0.16 g, 1.1 mmol), then with 3-(aminomethyl)pyridine. The crude product was purified by preparative HPLC and lyophilized to give a fluffy, bright yellow solid (9.7 mg, 2.5% yield): 1H NMR (400 MHz, DMSO-D6) δ 3.86 (none, 1 H) 4.55 (d, J=6.1 Hz, 2 H) 7.03 (s, 1 H) 7.20 (d, J=8.1 Hz, 2 H) 7.31 (dd, J=7.6, 5.1 Hz, 1 H) 7.48-7.61 (m, 1 H) 7.71 (d, J=8.1 Hz, 1 H) 7.91 (d, J=8.3 Hz, 2 H) 8.35-8.46 (m, 2 H) 8.56 (s, 1 H) 8.89 (s, 1 H).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>O>[CH:20]1([NH:23][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Reactant: NC1CC1
Solvent: O
Product: O=C(Nc1nc2cccc(NC3CC3)n2n1)c1cccnc1

Procedure:
N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 50 mg; 0.16 mmol; 1.0 eq.) in cyclopropylamine (1 mL) was heated at 80° C. overnight. The reaction mixture was diluted with H2O and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The title compound was obtained by recrystallization in EtOAc/c-Hex as a white powder (16.60 mg; 35%). HPLC, Rt: 1.77 min. (purity 98.3%). LC/MS, M+(ESI): 295.4, M−(ESI): 293.4.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[C:19]([NH:22][C:23]1[C:35]([Cl:36])=[C:34]2[C:26]([C:27]3[C:32]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33]2)[CH2:31][CH2:30][C:29](=[O:41])[C:28]=3Br)=[CH:25][C:24]=1[F:43])(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.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>[C:19]([NH:22][C:23]1[C:35]([Cl:36])=[C:34]2[C:26]([C:27]3[C:32]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33]2)[CH2:31][CH2:30][C:29](=[O:41])[C:28]=3[C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[CH:25][C:24]=1[F:43])(=[O:21])[CH3:20]
Reactant: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(NC(C)=O)c(Cl)c1C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCC12CCC(=O)C(c3ccco3)=C1c1cc(F)c(NC(C)=O)c(Cl)c1C2
Temperature: 100 °C
Yield: 101.2 %

Procedure:
Tributyl(2-furyl)stannane (0.47 mL, 1.7 mmol) was added to a mixture of 7-(acetylamino)-4-bromo-9a-butyl-8-chloro-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.367 g, 0.86 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.121 g, 0.17 mmol) in anhydrous toluene (8.6 mL). The mixture was purged with N2, then stirred and heated in an oil bath at 100° C. for 2 hours. After cooling to room temperature, the mixture was added to a pad of silica gel and the product eluted with EtOAc (20 mL). The solvent was evaporated and the residue (0.93 g) was purified by Biotage flash chromatography on a 40S silica gel column (4×7 cm) using 2:1 hexane-EtOAc as eluting solvent. The product containing fractions were concentrated under vacuum to provide crude 7-(acetylamino)-9a-butyl-8-chloro-6-fluoro4-(2-furyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.362 g) as an orange foam.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](F)(F)F)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(N3CCNCC3)=CC=N2)=CC=1.C(N(C(C)C)CC)(C)C.[CH3:57][C:58]1[CH:75]=[CH:74][C:61]2[N:62]=C(C3C=CC(N=C=O)=CC=3)[S:64][C:60]=2[CH:59]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[S:64][C:60]6[CH:59]=[C:58]([CH3:57])[CH:75]=[CH:74][C:61]=6[N:62]=5)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2nc(-c3ccc(N=C=O)cc3)sc2c1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2nc(-c3ccc(NC(=O)N4CCN(c5ccnc6cc(Cl)ccc56)CC4)cc3)sc2c1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (120 mg, 0.49 mmol), diisopropyl(ethyl)amine (127 mg, 0.98 mmol), and 4-(6-methyl-2-benzothiazolyl)phenyl isocyanate (100 mg, 0.38 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [F:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C1C(=O)N([I:18])C(=O)C1>CN(C=O)C.O.CCOC(C)=O>[F:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([I:18])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1cncc2cc[nH]c12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cncc2c(I)c[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
To a solution of 7-fluoro-pyrrolo[3,2-c]pyridine (Preparation 62, 5 g, 36.76 mmol) in anhydrous DMF (35 mL) was added NIS (9 g, 40.44 mmol), and the reaction stirred at room temperature for 4 hours. The reaction was diluted with water and EtOAc. The organic layer was collected, washed with saturate aqueous NaHCO3 solution, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 50-100% EtOAc in heptanes followed by 5% MeOH in DCM to afford the title compound (5 g).
Reaction SMILES: [Na][Na].[OH:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>CS(C)=O.O.C1(C)C=CC=CC=1>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Reactant: Clc1ccc2ccccc2n1
Agent: [Na+]
Agent: [Na][Na]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ccc3ccccc3n2)cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
The disodium salt of 2-(4-hydroxyphenoxy)propionic acid was made by dissolving the acid (9.1 gm, 0.05 mole) in 50 ml of DMSO and adding a solution of sodium hydroxide (4.4 gm, 0.11 mole) in 13 ml of water. The mixture was stirred for 30 min. and warmed to 55° C. at which time a solution of 2-chloroquinoline (8.2 gm, 0.050 mole) in 20 ml of DMSO was added. The reaction mixture was heated at 97°-108° for 1.5 hr. and then at 122°-125° for one hour longer. At the end of this time the mixture was poured into 600 ml of cold water and acidified. It was allowed to stand until solids formed which were taken up in toluene. From this 6.5 gm of 2-(4-(2-quinolinyloxy)phenoxy)propanoic acid were obtained.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:10](O)[C:11]#C>C1(C)C=CC=CC=1.II>[O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH2:7][C:10]#[CH:11])=[O:5]
Reactant: C#CCO
Reactant: CCC(=O)CC(=O)OC
Agent: II
Solvent: Cc1ccccc1
Product: C#CCOC(=O)CC(=O)CC
Temperature: 115 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
To a solution of methyl 3-ketopentanoate (3) (822 mg, 6.00 mmol) and 2-propynol (686 mg, 12.0 mmol) in toluene (7 mL) is added I2 (46 mg, 0.18 mmol). The mixture is stirred at 115° C. for 6 h, then cooled to room temperature, and extracted with ethyl acetate (100 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is distilled (125-130° C., 2 mm) to give 401 mg (43%) of 4 as a colorless liquid. IR 3345, 2856, 1715, 1456 cm−1; 1H NMR (CDCl3) δ 1.10 (t, J=7.5 Hz, 3H, CH2CH3), 2.52 (t, J=2.4 Hz, 1H, CH≡CCH2), 2.58 (q, J=7.5 Hz, 2H, CH2CH3) 3.51 (s, 2H, CH2), 4.74 (d, J=2.4 Hz, 2H, CH≡CCH2).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[F:7][C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=1[CH3:15].N1C=CC=CC=1.[OH2:22]>>[F:7][C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=1[C:15]([OH:2])=[O:22]
Reactant: Cc1ccc(I)cc1F
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(I)cc1F
Temperature: 70 °C
Reaction time: 18 h

Procedure:
13.39 g (84.74 mmol) potassium permanganate were added to a suspension of 5 g (21.18 mmol) of 2-fluoro-4-iodo-toluene and 25.13 g (317.77 mmol) of pyridin in water. The mixture was heated and stirred at 70° C. during 18 hours. As the reaction was not finished, 3.34 g (21.18 mmol) of potassium permanganate were added to the reaction mixture at room temperature and the mixture was stirred for another 6 hours at 70° C. The reaction mixture was then filtered through a celite pad, which was then washed with water and ethyl acetate. After decantation, the aqueous phase was acidified to pH=1 with an aqueous solution of HCl 6N. A white solid was first filtered and the aqueous phase extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvents were evaporated off under reduced pressure. The filtered white solid and the solid extracted with ethyl acetate were combined to give 4.1 g.
Reaction SMILES: Cl.Cl[CH:3]([C:17]1[CH:18]=[CH:19][C:20]([CH3:27])=[C:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][N:5]1[CH2:4][CH:3]1[C:17]1[CH:18]=[CH:19][C:20]([CH3:27])=[C:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=1
Reactant: COc1ccccc1OCCNCC(Cl)c1ccc(C)c(S(N)(=O)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccccc1OCCN1CC1c1ccc(C)c(S(N)(=O)=O)c1
Yield: 88.3 %

Procedure:
In 50 ml of ethyl acetate was suspended 4.35 g (0.01 mole) of 5-{1-chloro-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide hydrochloride and then 50 ml of an aqueous 10% sodium carbonate solution was added to the suspension with stirring. After further stirring overnight vigorously, the reaction mixture was recovered by decantation. After removing inorganic matter by passing the ethyl acetate layer thus recovered through a silica gel column (50 ml of silica gel), the reaction product was evaporated to dryness to provide 3.2 g (88%) of colorless resinous 5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamide.