Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Cl[C:13]1[N:18]=[N:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=4)[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[F:34][C:31]1[CH:32]=[C:33]2[C:28]([CH2:27][CH2:26][N:25]2[CH:22]2[CH2:23][CH2:24][N:19]([C:16]3[N:17]=[N:18][C:13]([C:6]4[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:14][CH:15]=3)[CH2:20][CH2:21]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: COc1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 2-methoxypyridine-5-boronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](O)(=[O:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=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>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:29]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[O:39])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1CN(C(=O)c2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), terephthalic acid (33.2 mg, 0.20 mmol), HATU (72.0 mg, 0.20 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was purified by RP-HPLC to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-benzoic acid (21.5 mg, 37.6%). HRMS (ES+) m/z Calcd for C30H26Cl2F2N2O3+H [(M+H): 571.1362; Found: 571.1363.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-:20]#[N:21].[K+].FC(F)(F)S(O[C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:39])[CH2:34][CH2:35][O:36]2)=[CH:31][CH:30]=1)(=O)=O.O>C(#N)C.[Zn].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Ni+2].[Br-].[Br-]>[C:20]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:39])[CH2:34][CH2:35][O:36]2)=[CH:31][CH:30]=1)#[N:21]
Reactant: [C-]#N
Reactant: O=C1CCOc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Ni+2]
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc2c(c1)OCCC2=O
Temperature: 60 °C
Yield: 74 %

Procedure:
A dry, 250 mL round bottom flask was charged with 0.27 g (1.01 mmol) of triphenylphosphine, 0.73 g (11.15 mmol) of potassium cyanide, 0.22 g (3.38 mmol) of zinc dust, and 0.38 g (0.51 mmol) of bis(triphenylphosphine)nickel (II) bromide. The flask was then purged with argon, and an air-free solution of 3 g (10.14 mmol) of 7-(((trifluoromethyl)sulfonyl)oxy)-4-chromanone [Koch et al., J. Org. Chem. 59, 1216 (1994)] in 40 ml of dry acetonitrile was introduced by syringe. The solution was then heated at 60° C. for 3 hours, under argon. After cooling the solution to room temp, the solution was added to an equal volume of water. The organic layer was extracted out, and the aqueous layer was extracted several times with ethyl acetate and ether. The combined organic phase was dried over magnesium sulfate, filtered and evaporated. The crude mixture was chromatographed using a 20% ethyl acetate/hexane solvent system which yielded 1.3 g (76%) of 7-cyano-4-chromanone as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[F:12][CH:13]([F:23])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=1.N>>[F:12][CH:13]([F:23])[O:14][C:15]1[CH:16]=[C:17]([C:21]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cccc(OC(F)F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cccc(OC(F)F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and 1-(difluoromethoxy)-3-ethynylbenzene (Fluorochemicals, 84 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 6.95 (s, 1H), 7.31 (dd, J=8.3, 2.0 Hz, 1H), 7.47 (s, 1H), 7.59 (t, J=8.1 Hz, 1H), 7.70 (t, J=2.1 Hz, 1H), 7.77-7.83 (m, 1H), 8.18 (ddd, J=9.3, 2.8, 1.8 Hz, 1H), 8.61 (d, J=2.8 Hz, 1H), 8.98 (t, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]([OH:25])[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCOC(C)=O.[ClH:32]>O1CCOCC1>[ClH:32].[ClH:32].[CH3:24][S:23][C:19]1[N:18]=[C:17]([CH:16]([OH:25])[CH2:15][NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:22]=[CH:21][N:20]=1
Reactant: CSc1nccc(C(O)CNC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1nccc(C(O)CNC2CCNCC2)n1
Reaction time: 8 h
Yield: 93.2 %

Procedure:
4-[2-Hydroxy-2-(2-methylsulfanyl-pyrimidin-4-yl)-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester (510.0 mg, 1.387 mmol) was dissolved into 3 mL of EtOAc and 3 mL of 4.0 M HCl in dioxane was added. The mixture was allowed to stir overnight with a white precipitate forming. The precipitate was triturated with 3×10 mL of EtOAc and dried under vacuum to give 441.4 mg, 93.2% of crude 1-(2-methylsulfanyl-pyrimidin-4-yl)-2-(piperidin-4-ylamino)-ethanol dihydrochloride salt. The material was carried on without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: COc1ccc(N)c(OC)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OC)c1
Yield: 83.2 %

Procedure:
Using 2,4-dimethoxyaniline (2.53 g, 16.0 mmol) and 4-nitrobenzoic acid (2.50 g, 14.8 mmol), the procedure of Reference Example 16 was repeated to obtain 3.72 g (91.3%) of the title compound in the form of yellow needle crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH2:17][CH2:18][O:19][C:20]([F:23])([F:22])[F:21])=[C:6]([NH:8][C:9](=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:17][CH2:18][O:19][C:20]([F:23])([F:22])[F:21])[C:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCCOC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)Cc1nc2cc(Br)ccc2n1CCOC(F)(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of N-(5-bromo-2-[2-(trifluoromethoxy)ethyl]amino]phenyl)-3,3-dimethylbutanamide (step C, 728 mg, 1.83 mmol) and p-toluenesulfonic acid monohydrate (350 mg, 1.83 mmol) in toluene (20 mL) was stirred at 120° C. for 8 h. Then, the mixture was allowed to cool to room temperature overnight to afford crystalline precipitates. The precipitates were collected by filtration, and dissolved in ethyl acetate and saturated sodium hydrogencarbonate aqueous solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (555 mg, 80%) as an amber solid.
Reaction SMILES: I[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CC(OC)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Se:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=1
Reactant: Ic1ccc[se]1
Reactant: OB(O)c1ccccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: CCO
Product: Oc1ccc(-c2ccc[se]2)cc1

Procedure:
A mixture of 27.9 g (0.11 mol) of 2-iodoselenophene, 15.0 g (0.11 mol) of 2-hydroxyphenylboronic acid, 6.8 g (5.88 mmol) of tetrakis(triphenylphosphine)palladium(0) and 235 ml of 2 N sodium carbonate soln. in 600 ml of toluene/ethanol (1:1) is heated under reflux for 19 h. The mixture is diluted with MTBE and washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:MTBE=4:1→1:1). Further purification is carried out by digestion in cold n-heptane; 4-selenophen-2-ylphenol is obtained as a beige solid.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26](C(F)(F)F)=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].Br[CH2:38][C:39](=O)[C:40]([F:43])([F:42])[F:41]>>[F:34][C:33]([F:36])([F:35])[C:24]1[CH:25]=[C:26]([C:33]([F:36])([F:35])[F:34])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([C:2]1[S:3][CH:38]=[C:39]([C:40]([F:43])([F:42])[F:41])[N:1]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(N)=S)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc(C(F)(F)F)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 3-bromo-1,1,1-trifluoroacetone.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH:10]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.C(O)(=[O:23])C>>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[CH:10]1[CH2:9][C:8]2[C:13]3=[C:4]([NH:3][C:2](=[O:23])[N:12]3[CH2:11]1)[CH:5]=[CH:6][CH:7]=2)[CH2:16][CH3:17]
Reactant: CCCN(CCC)C1Cc2cccc3nc(Cl)n(c23)C1
Reactant: CC(=O)O
Product: CCCN(CCC)C1Cc2cccc3[nH]c(=O)n(c23)C1

Procedure:
2-Chloro-5,6-dihydro-N,N-dipropyl-4H-imidazo(4,5,1-ij)quinolin-5-amine was refluxed in acetic acid for 1 hour. The solvent was removed and the residue was partitioned between ethyl acetate and sodium hydroxide solution. Evaporation of the ethyl acetate afforded 5-(dipropylamino)-5,6-dihydro-4H-imidazo(4,5,1-ij)quinoline-2(1H)-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH2:13].[N:14]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[C:3]2[NH:13][N:14]=[N:12][C:4]=2[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Br)c2[nH]nnc2c1
Reaction time: 0.25 h

Procedure:
To a cooled (15° C.) solution of 3-bromo-5-(trifluoromethyl)benzene-1,2-diamine (1.82 g, 7.14 mmol) in acetic acid (20 mL) was added a solution of sodium nitrite (0.517 g, 7.49 mmol) in water (10 mL). After 15 min, the product was collected by filtration and washed with 65% HOAc in water and air dried to give 1.5 g (79%) as a faint pink powder. 1H-NMR (4:1 CDCl3/CD3OD, 500 MHz) δ 8.08 (s, 1H), 7.71 (s, 1H), 4.23 (bs, 1H); 13C-NMR (4:1 CDCl3/CD3OD, 126 MHz) δ 139.9, 129.0 (q, J=33 Hz), 125.3, 123.3 (q, J=273 Hz), 113.4, 108.2. Mass spec.: 265.82 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[N:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:34]([N:31]1[C:26]2=[N:27][C:28]([CH2:29][CH3:30])=[C:23]([CH2:22][NH:21][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:3]=[C:2]([C:49]5[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=5)[C:7]([F:8])=[CH:6][CH:5]=4)=[O:12])[N:14]=3)=[O:20])[C:24]([NH:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:25]2[CH:33]=[N:32]1)[CH3:35]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(Br)c2)n1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)n1
Temperature: 100 °C

Procedure:
A mixture of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (187 mg, 0.293 mmol), (3-formylphenyl)boronic acid (43.9 mg, 0.293 mmol), Na2CO3 (93 mg, 0.879 mmol) and PdCl2(dppf) (21.43 mg, 0.029 mmol) was diluted in a mixture of 1,4-dioxane (9 mL) and water (3 mL) in a 20 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 minutes and it was then heated in a Biotage microwave at normal absorption for 10 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and then washed with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was concentrated under vacuum to give a crude residue. It was then purified with flash chromatography eluting with 0 to 100% ethyl acetate in dichloromethane (product came out at 70% ethyl acetate in DCM). The product fractions were combined and concentrated under vacuum to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide as an yellowish oil. LC-MS m/z 664.5 (M+H)+, 0.89 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=1[F:23].Cl([O-])=[O:25].[Na+].CC(=CC)C.P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:25])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=1[F:23]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCCO)cc3F)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCO)cc3F)cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 33.4 %

Procedure:
To a solution of 6-chloro-5-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde (40 mg, 0.12 mmol) in water (1 mL) and t-butanol (1 mL) was added sodium chlorite (210 mg, 2.30 mmol), 2-methyl-2-butene (0.5 mL) and sodium dihydrogen phosphate (350 mg, 2.30 mmol). The reaction solution was stirred at room temperature for 10 hrs. The reaction was diluted with water (5 mL) and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with water (20 mL), brine (20 mL) dried over sodium sulfate and concentrated to give a crude product. The crude was purified by reverse phase HPLC to give the title compound (14 mg, 59% yield) as an off-white solid. MS (ES−) 348.1 (M−H)−. 1H NMR (400 MHz, CD3OD) δ 8.04 (s, 2H), 7.63 (s, 1H), 7.28 (s, 1H), 6.91 (dd, 2H), 6.86 (dd, 2H), 4.16 (t, 2H), 3.96 (t, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([CH3:22])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[Cl:23][C:24]1[C:25]([C:30](O)=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:22][C:5]1[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)=[CH:7][N:8]=[CH:9][C:4]=1[CH2:3][NH:2][C:30]([C:25]1[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:31]
Reactant: Cc1c(CN)cncc1-c1ccc2c(c1)CCC(=O)N2C
Reactant: O=C(O)c1ncccc1Cl
Agent: Cl
Product: Cc1c(CNC(=O)c2ncccc2Cl)cncc1-c1ccc2c(c1)CCC(=O)N2C

Procedure:
In analogy to the procedure described for the preparation of example 75, 6-(5-aminomethyl-4-methyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 222) has been coupled with 3-chloro-pyridine-2-carboxylic acid to give the title compound as a colorless solid. MS: 421.5 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24].[C:29]([C:33]1[CH:41]=[CH:40][C:36]([CH:37]=[N:38][OH:39])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[CH:41]=[CH:40][C:36](/[CH:37]=[N:38]/[O:39][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:28])=[C:5]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:24])([F:26])[F:25])[CH:6]=2)=[CH:35][CH:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Product: CC(C)(C)c1ccc(/C=N/OCCCOc2ccc(C(=O)O)c(NC(=O)c3ccccc3C(F)(F)F)c2)cc1
Yield: 64 %

Procedure:
The title compound (0.117 g, 64%) was prepared as a white solid from 4-(3-bromo-propoxy)-2-(2-trifluoromethyl-benzoylamino)-benzoic acid methyl ester and 4-tert-butyl-benzaldehyde oxime using a procedure similar to step 1 of example 6. mp=121.1-122.0° C.; mass spectrum API-ES, (M−H) m/z 541. 1H NMR (400 MHz, DMSO-d6); δ 13.40 (bs, 1H), 11.90 (bs, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 7.96 (d, 1H), 7.88 (d, 1H), 7.80 (m, 3H), 7.50 (d, 2H), 7.39 (d, 2H), 6.82 (dd, 1H), 4.28 (t, 2H), 4.18 (t, 2H), 2.15 (m, 2H), 1.25 (s, 9H). Elemental analysis: Calcd. for C29H29F3N2O5: C, 62.2; H, 5.39; N, 5.16, Found: C, 63.8; H, 5.26; N, 5.04.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:7]=1
Reactant: OCc1ccc(F)cc1O
Reactant: BrCCc1ccccc1
Product: CC(Oc1cc(F)ccc1CO)c1ccccc1

Procedure:
The title compound was prepared from 5-fluoro-2-(hydroxymethyl)phenol and (bromoethyl)benzene according to the procedure for the preparation of Example 136, part A.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:12].[Cl:13]N1C(=O)CCC1=O.[Cl-].[Li+]>CN(C)C=O>[NH2:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[F:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1c(F)ccc2c1OCCC2
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Nc1c(F)cc(Cl)c2c1OCCC2
Reaction time: 1.5 h
Yield: 49.6 %

Procedure:
To a stirred solution of 3.7 grams (0.022 mole) of 8-amino-3,4-dihydro-7-fluoro-2H-1-benzopyran in 50 mL of N,N-dimethylformamide was added dropwise a solution of 3.0 grams (0.022 mole) of N-chlorosuccinimide in about 20 mL of N,N-dimethylformamide. Upon completion of the addition, the reaction mixture was stirred for about 90 minutes and poured into an aqueous 10% lithium chloride solution. The mixture was extracted with diethyl ether. An insoluble material was collected by filtration and dissolved in methylene chloride. The methylene chloride solution was washed with water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was set aside. The diethyl ether extract was washed with an aqueous 10% lithium chloride solution and dried with magnesium sulfate. The mixture was filtered, and the filtrate was combined with the methylene chloride filtrate. The combination was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel with 1:4 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.2 grams of 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5]>[Pd].C(O)C>[NH2:17][C:15]1[CH:14]=[CH:13][C:12]2[N:6]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:7][CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: COCC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: COCC(=O)N1CCCOc2cc(N)ccc21
Yield: 84.6 %

Procedure:
2-Methoxy-1-(3-nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (269 mg, 1.01 mmol) and 10% Palladium on Carbon (50% Wet) (65 mg) in Ethanol (10 mL) was shaken under an atmosphere of Hydrogen (40 psi) for 6 h. Following filtration and conc., 1-(3-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-2-methoxy-ethanone (202 mg, 85%) was isolated as white solids. 1H-NMR (CDCl3): 7.05 (d, 1H, J=8.2 Hz), 6.80 (m, 2H), 4.79 (m, 1H), 4.40 (m, 1H), 4.02 (m, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 3.34 (s, 3H), 2.72 (m, 1H), 2.24 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:35][CH:34]([N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:35][CH:34]([N:36]2[CH:40]=[C:39]([C:2]3[CH:24]=[CH:23][C:5]4[C:6]5[N:7]=[C:8]([C:14]6[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=6)[S:9][C:10]=5[CH2:11][CH2:12][O:13][C:4]=4[CH:3]=3)[CH:38]=[N:37]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CN(C(=O)OC(C)(C)C)C5)c4)ccc2-3)n(C(C)C)n1

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-azetidine-1-carboxylic acid tert-butyl ester to give 3-{4-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester which was treated with acid via General Procedure F to give 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([CH3:34])OS1(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[N:15]([C@H:32]([CH3:34])[CH2:33][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:9]2=[N:10][C:11]([Br:14])=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(Br)nc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2ccc(Br)nc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to Example 1, intermediate a) from 6-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium tert-butoxide and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.