Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:36][C:35]=1[C:46]1[N:51]=[CH:50][N:49]=[C:48]([NH:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[CH:55]=2)[CH:47]=1>ClCCl.CN(C)C1C=CN=CC=1>[N:40]1([C:37]2[CH:38]=[CH:39][C:34]([NH:33][C:14]([C:13]3[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])=[C:35]([C:46]3[CH:47]=[C:48]([NH:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[CH:55]=4)[N:49]=[CH:50][N:51]=3)[CH:36]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3N)ncn2)c1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (143 mg, 0.48 mmol, 1.00 equiv) in dichloromethane (10 mL), EDC HCl (139 mg, 0.72 mmol, 1.50 equiv), 4-dimethylaminopyridine (89 mg, 0.69 mmol, 1.50 equiv), and 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-methylbenzyl)pyrimidin-4-amine (180 mg, 0.48 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (5:1). This resulted in 200 mg (57%) of product as yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([S](F)(F)(F)[F:20])CC)C.C([O-])(O)=O.[Na+].C(Cl)[Cl:30]>>[ClH:30].[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([F:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)[S](F)(F)(F)F
Reactant: ClCCl
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cl
Product: FC1CCN(Cc2ccccc2)C1
Reaction time: 1.5 h
Yield: 53 %

Procedure:
To a solution of (RS)-N-benzyl-3-pyrrolidinol (354 mg, 2.0 mmol) in CH2Cl2 (6 ml) was added diethylaminosulfur tetrafluoride (DAST) (0, 52 ml, 4.0 mmol) over 5 min. at 0-5° C. The mixture was stirred for a further 1.5 hrs. at r.t., then satd. NaHCO3 was added and the oragnic phase was further washed with NaHCO3 (10 ml). After drying the organic phase with Na2SO4 the residue was chromatographed over SiO2 (Merck 230-400 mesh) with nhexane/EtOAc (4:1) gradient to (1:1). The product was treated with HCl/ether to afford (RS)N-benzy-3-fluoropyrrolidine hydrochloride salt (190 mg, 1.06 mmol, 53% yield) as off-white crystals. This product (250 mg, 1.16 mmol) was then hydrogenated (1 atm. H2) in acetic acid (4 ml) at 100° C. with Pd/C (10%, 25 mg) for 24 hrs. The mixture was then evaporated and dissolved in MeOH, filtered though a celite pad and finally recrystallised from EtOAc/ether to afford the title compound (117 mg, 81% yield) as off-white crystals after drying under high vacuum. MS: m/e=89 (M+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.Cl[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C[N-]C.CCOCC.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Reactant: COc1ccc(CCl)cc1
Agent: C[N-]C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c(CCCOc2cccc3ccccc23)c2cccc(Br)c2n1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 7-bromo-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (2.39 g, prepared in a similar manner as described herein) in N,N-dimethylamide (20 mL) was added 1-(chloromethyl)-4-methoxybenzene (1.0 g) and Cs2CO3 (5.16 g). The mixture was stirred overnight at room temperature. The mixture was diluted with ether (300 mL) and water (200 mL). The aqueous layer was extracted with ether. The combined extracts were washed with water (×3), brine and dried over Na2SO4. Concentration gave EXAMPLE 581A.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][N:16]([CH3:19])[C:17]#[N:18].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>C1C(O)=CC=CC=1C.CO>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[C:4]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][C:17]([N:16]([CH3:19])[CH3:15])=[NH:18]
Reactant: CN(C)C#N
Reactant: Nc1ccccc1-c1ccccc1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: Cc1cccc(O)c1
Product: CN(C)C(=N)Nc1ccccc1-c1ccccc1

Procedure:
A mixture of 2-aminobiphenyl hydrochloride (9.2 g) and N,N-dimethylcyanamide (4.8 g) in m-cresol (30 ml) was heated at 90°-95° C. for 10 hours to yield an oil which was dissolved in methanol (60 ml) and treated with fumaric acid (4.5 g) to give N-(2-biphenylyl)-N',N'-dimethylguanidine fumarate (m.p. 175°-176° C.) which was recrystallised from a 2:3 mixture of methanol and ether.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:16]=O)=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.COC1C2C(=CC=CC=2)C(OC)=CC=1/[CH:32]=[C:33](\C)/[C:34]([O:36][CH2:37][CH3:38])=[O:35].O(C(C)C)C(C)C>>[Br:1][C:2]1[C:3](/[CH:16]=[C:33](\[CH3:32])/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Reactant: COc1c(Br)c(C=O)c(OC)c2ccccc12
Solvent: CC(C)OC(C)C
Product: CCOC(=O)/C(C)=C/c1c(Br)c(OC)c2ccccc2c1OC

Procedure:
Compound 98e was prepared from 38 (0.515 g, 1.75 mmol) as described above for 28a to give 0.373 g (0.984 mmol, 56%) of the product as a white solid following flash chromatography (1:19 i-Pr2O:hexanes) and recrystallization from Et2O/hexanes. (0.314 g E; 0.059 g Z)
Reaction SMILES: N12CCCN=C1CCCCC2.[N+:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[C-:13].[N+]([C:23](=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24])([O-])=O>O1CCCC1.C(O)(C)C>[CH3:24][C:23]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:12][CH:13]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC(=Cc1ccccc1)[N+](=O)[O-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (3.70 g, 24.6 mmol) was added dropwise to a stirred solution of ethyl isocyanoacetate (1.50 g, 13.3 mmol) and 2-nitro-3-phenyl-2-propene (2.0 g, 12.3 mmol) in a mixture of tetrahydrofuran (15 mL) and iso-propanol (5 mL) at between 10 and 20° C. The reaction mixture was stirred at room temperature for 4 h. Excess tetrahydrofuran was removed in vacuo, water (15 mL) was added to the residue and the mixture was extracted with diethyl ether (3×25 mL). The combined organic phases were washed with brine (2×15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford ethyl 4-methyl-3-phenyl-1H-pyrrole-2-carboxylate (2.5 g, 90%) as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:54][C:55]1[CH:56]=[C:57](B(O)O)[CH:58]=[CH:59][C:60]=1[F:61]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)=[C:15]([C:58]4[CH:57]=[CH:56][C:55]([F:54])=[C:60]([F:61])[CH:59]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1C(Br)=C(c2ccc(Cl)cc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(F)c(F)c2)=C(c2ccc(Cl)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 43 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-chlorophenyl)-1H-inden-1-one obtained in Step 6 of Example 28 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3,4-difluorophenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (acetone/hexanes=1:4) to obtain the title compound (43%).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:34]>>[ClH:34].[ClH:34].[F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc3cccnc23)[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: F[C@@H]1CNCC[C@H]1Oc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (trans)-tert-butyl 3-fluoro-4-(quinolin-8-yloxy)piperidine-1-carboxylate (5.4 g, 15.6 mmol) in 100 mL DCM was added neat TFA (24.0 ml, 311.78 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, after which it was concentrated. The resulting residue was dissolved in 40 mL DCM, and this solution was added dropwise by addition funnel to a flask containing vigorously stirring 60 mL 2 M HCl in ether in 500 mL ether, causing precipitation. The solids were isolated by filtration through a medium pore glass fritted funnel by forcing solvent through the frit with nitrogen pressure, rinsed with ether, and dried in vacuo to give 8-(trans-3-fluoropiperidin-4-yloxy)quinoline dihydrochloride (6.6 g, 21 mmol) as a solid which was used without further purification in the next step. LC/MS ESI (+) m/z 247 (M+H)− detected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([F:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[F:15][C@H:10]1[C@@H:11]([OH:14])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1.[F:15][C@H:10]1[C@H:11]([OH:14])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1
Reaction time: 2.5 h
Yield: 65 %
Yield: 24 %

Procedure:
To a stirred solution of tert-butyl-3-fluoro-4-oxopiperidine-1-carboxylate (1.3 g, 6.0 mmol) in methanol (15 mL), NaBH4 (0.29 g, 7.7 mmol) was added at 0° C. and stirred for 2-3 h. Methanol was removed in vacuo and the residue was diluted with ethyl acetate and washed with water. The organic layer was separated, concentrated in vacuo and the residue was purified by flash column chromatography to give cis(±)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (0.850 g, 65%) and trans(±)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (0.315 g, 24%); MS: 242.1 (M+23).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH2:21].[OH2:22]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:12][CH2:13][CH2:14][N:15]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:16][CH2:17][N:18]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:19][CH2:20][NH:21][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:8])=[O:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCNCCNCCN
Reactant: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCN(CCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
To a stirred solution of p-toluenesulfonyl chloride (285 g, 1.50 mole) in pyridine (650 ml) at 5° C. was added a solution of 1,4,7,10-tetraazadecane (48.0 g, 0.328 mole) in pyridine (200 ml) under a dry argon atmosphere maintaining the temperature <20° C. The mixture was stirred for 3 days at room temperature. H2O (1 l) was slowly added to the cooled (ice bath) mixture. The solid was filtered, washed thoroughly with H2O and dried in vacuo to give 225 g (90% yield) of the product as a powder: mp 222-4° C.; 1H NMR (DMSO-d6) δ 2.38 (s,6 H), 2.41 (s, 6 H), 2.84 (quart, J=6.6 Hz, 4 H), 3.07 (t, J=7.0 Hz, 4 H), 3.12 (s, 4 H), 7.40 (m, 8 H), 7.66 (m, 8 H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[O:13]1[CH2:16][C:15](=[O:17])[CH2:14]1>C1COCC1.[Li]CCCC.[NH4+].[Cl-]>[Br:12][C:4]1[CH:3]=[C:2]([C:15]2([OH:17])[CH2:16][O:13][CH2:14]2)[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Reactant: O=C1COC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Br)cc(C2(O)COC2)c1
Reaction time: 1 h

Procedure:
To a solution of 1,3-dibromo-5-(tert-butyl)benzene (316 mg, 1.05 mmol) in dry THF (15 mL), n-BuLi (1 mL, 2.5M) was added dropwise under N2 at −78° C. The mixture was stirred at this temperature for 1 h. Then oxetan-3-one (91 mg, 1.27 mmol) was added and the mixture was stirred at rt overnight, diluted with aq. NH4Cl (20 mL) and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the product P29a (120 mg, 40%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[F:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([F:28])[C:21]=1[N:29]=[C:30]=[S:31]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:30]([NH:29][C:21]1[C:22]([F:28])=[C:23]([F:27])[CH:24]=[C:25]([F:26])[C:20]=1[F:19])=[S:31]
Reactant: Fc1cc(F)c(F)c(N=C=S)c1F
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1c(F)c(F)cc(F)c1F
Yield: 88.6 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and 2,3,5,6-tetrafluorophenyl isothiocyanate (0.224 g, 1.1 mmol) to give the product (0.398 g); m.p. 170-174° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:23])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.[I-].[NH2:25][N+:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([F:23])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:15]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)[CH:5]=[CH:4][N:3]=1
Reactant: N[n+]1ccccc1
Reactant: O=C(Nc1cc(C#Cc2ccnc(Cl)n2)ccc1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of N-{5-[(2-chloro-4-pyrimidinyl)ethynyl]-2-fluorophenyl}-2,2,2-trifluoroacetamide (4.6 g, 13 mmol) in DMF (100 mL) was added aminopyridinium iodide (5.9 g, 27 mmol) and K2CO3 (5.5 g, 40 mmol). After stirring 2 h at rt, the reaction mixture was diluted with diethyl ether (250 mL) and EtOAc (250 mL), and washed with water. The organic layer was adsorbed to silica gel and purified by column chromatography to afford the desired product (3.2 g, 55%) as a tan solid. 1H NMR (400 MHz, CDCl3): δ 8.57 (m, 2H), 8.31 (d, J=5.5 Hz, 1H), 8.14 (s, 1H), 7.47 (m, 2H), 7.31 (t, J=9.4 Hz, 1H), 7.04 (t, J=6.8 Hz), 6.99 (d, J=5.3 Hz, 1H). ES-LC/MS m/z=436 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[Cl:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(NCc2cccc(Cl)c2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: O=C(O)c1cccc(NCc2cccc(Cl)c2)c1C(=O)O

Procedure:
3-(3-Chloro-benzylamino)-phthalic acid dimethyl ester (1.61 g, 4.8 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid. The product, of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:6]([C:8](O)=[O:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[OH:57][C@@H:58]([CH3:62])[CH2:59][O:60][NH-:61]>C1COCC1>[OH:57][C@@H:58]([CH3:62])[CH2:59][O:60][NH:61][C:8]([C:6]1[CH:7]=[C:2]([F:1])[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:9]
Reactant: C[C@H](O)CO[NH-]
Reactant: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](O)CONC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
A suspension of 8-fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (100 mg, 0.23 mmol), HATU (130 mg, 0.34 mmol), DIPEA (0.06 mL, 0.34 mmol) and (S)-2-hydroxy-propoxy-amide hydrochloride (44 mg, 0.34 mmol) in THF (1 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (5 mL) and 1M HCl, the organic layer was isolated and washed with saturated aqueous NaHCO3 (2×5 mL) and brine (2×5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resultant residue was subjected to reverse-phase preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (13 mg, 8%). LCMS (method A): RT=8.13 min, [M+H]+=489. 1H NMR (DMSO-d6): 11.51 (1 H, broad), 8.95 (1 H, broad), 8.25 (1 H, s), 7.60 (1 H, s), 7.55 (1 H, d, J=10.7 Hz), 7.27 (1 H, d, J=8.4 Hz), 6.82 (1 H, d, J=11.1 Hz), 6.32 (1 H, t, J=8.8 Hz), 4.66 (1 H, broad), 3.64 (1 H, m), 3.43 (2 H, d, J=5.8 Hz), 0.94 (3 H, d, J=6.3 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: OC(CCl)CCc1ccc(Cl)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCl)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A solution of 1-chloro-4-(4-chlorophenyl)-2-butanol (125 g) in acetone (200 ml) at 0° C. was treated with 570 ml of Jones reagent (from sodium dichromate dihydrate (100 g), concentrated sulfuric acid (136 g) and water to 500 ml) and stirred overnight at room temperature. The resulting solution was diluted with water (200 ml), extracted with ether (3×300 ml) and the extracts washed with water, aqueous sodium bicarbonate, and dried (MgSO4). Evaporation of the ether gave 121 g of 1-chloro-4-(4-chlorophenyl)-2-butanone. The analytical sample from hexane had m.p. 65°-67° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]1=[O:13])C.O.[NH2:16][NH2:17]>C(O)C>[CH3:12][C:11]1[N:6]([CH2:5][C:4]([NH:16][NH2:17])=[O:3])[C:7](=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cn1c(C)cccc1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(=O)n1CC(=O)NN
Yield: 88 %

Procedure:
As described for example 112a, (6-methyl-2-oxo-2H-pyridin-1-yl)-acetic acid ethyl ester (Petride, Horia; Raileanu, Dan. Revue Roumaine de Chimie (1988), 33(7), 729-39.) in ethanol was reacted with hydrazine hydrate (1.8 equivalents) at rt for 96 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the compound was obtained as a white solid (yield: 88%). MS: m/e=204.2 [M+Na]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl>O1CCOCC1.O.O1CCOCC1>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:24]
Reactant: NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9 gm (42 millimols) of 4-[2-aminoethyl]-4'-hydroxy-biphenyl in a solution of 1.72 gm (43 millimols) of sodium hydroxide in 100 ml of a mixture of water/dioxane (1:1) was acylated at 0° C with a solution of 13 gm (76 millimols) of 2-methoxybenzoyl chloride in 50 ml of dioxane, while maintaining the pH at 10 by periodic addition of sodium hydroxide. After all of the acid chloride had been added, the mixture was stirred at room temperature for 2 hours, and then the pH of the resulting suspension was adjusted to between 4 and 5 by addition of 2 N hydrochloric acid. The suspension was now extracted with chloroform. After extraction with a dilute sodium bicarbonate solution, the chloroform phase was dried with sodium sulfate, evaporated, and the residue was recrystallized from ethyl acetate. Yield: 8.7 gm (59% of theory); m.p. 118° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1)(=[O:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1)=[O:41])(=[O:11])=[O:12]
Reactant: CC(=O)Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)Nc1cccc(CS(=O)c2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)methyl]phenyl}acetamide (105 mg, 0.216 mmol) in CH2Cl2 (3 ml) was added mCPBA (52 mg, ˜0.216 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was directly loaded onto Celite and purified by flash column chromatography on silica gel (50-100% EtOAc in hexane) to yield the title compound (55 mg, 51%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[C:2]=[O:3].[CH:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=2[CH:15]=[CH:14][N:13]=1.BrC1C=CC(CN=C=O)=CC=1>>[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:3])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CCCCCCCCN=C=O
Reactant: Nc1cccc2cnccc12
Agent: O=C=NCc1ccc(Br)cc1
Product: CCCCCCCCNC(=O)Nc1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 60F using 1-isocyanatooctane and 5-isoquinolinamine instead of the product from Example 60E and 1-bromo-4-(isocyanatomethyl)benzene. NMR (DMSO-d6) δ 9.53 (s, 1H), 9.23 (s, 1H), 8.65 (d, 1H), 8.99 (d, 1H), 8.05 (d, 1H), 7.86 (t, 1H), 7.01 (m, 1H), 3.15 (m, 2H), 1.51 (m, 2H), 1.28 (m, 5H), 0.83 (m, 3H); MS (ESI) (M+H)+300.