Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[Cl-].[CH2:14]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH2+:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:12][C:8]1[C:9]([CH3:11])=[CH:10][C:4]2[O:3][C:2]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]3[C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:23])=[N:6][C:5]=2[CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Reactant: Cc1cc2nc(Cl)oc2cc1C
Agent: [Cl-]
Product: Cc1cc2nc(N3CCCC[C@H]3C(=O)OCc3ccccc3)oc2cc1C

Procedure:
The title compound was prepared by a similar method to Preparation 2 from 2-chloro-5,6-dimethyl-1,3-benzoxazole [see J.Med. Chem. (1972), 15, 523-9] and (2S)-2-[(benzyloxy)carbonyl]piperidine [see EP 530167 A1 930303]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 80:20, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-[5,6-dimethyl-1,3-benzoxazol-2-yl]-2-piperidinecarboxylate as a yellow coloured solid.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[CH2:3][OH:4].ClCCl.[C:17]([N:21]=[C:22]=[S:23])([CH3:20])([CH3:19])[CH3:18]>C(O)C>[C:17]([NH:21][C:22]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[CH2:3][OH:4])=[S:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N=C=S
Reactant: NC(CO)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)NC(=S)NC(CO)c1cccc([N+](=O)[O-])c1
Reaction time: 7 h

Procedure:
The process is performed as in Example 2, starting with 5.1 g of 2-amino-2-(3-nitrophenyl)-1-ethanol in 170 cm3 of ethanol containing 85 cm3 of dichloromethane and 4.6 cm3 of tert-butyl isothiocyanate, at a temperature in the region of 20° C. for 3 days and then at a temperature in the region of 60° C. for 7 hours. After addition of a further 0.35 cm3 of tert-butyl isothiocyanate and 16 hours at a temperature in the region of 60° C., an identical work-up gives 5.7 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea in the form of an ocher-colored solid melting at 162° C.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[N:3]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1
Reactant: Clc1nc(Br)[nH]c1Cl
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(Br)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 2-bromo-4,5-dichloro-1H-imidazole (2.16 g, 10 mmol) in THF (25 mL) was added dropwise to a suspension of NaH (440 mg of a 60% suspension in mineral oil, 11 mmol) in THF (20 mL) at 0° C. The mixture was stirred at RT for 2 h, cooled to 0° C. and {2-[(chloromethyl)oxy]ethyl}(trimethyl)silane (1.9 mL, 11 mmol) was added dropwise. The mixture was stirred at RT overnight. Saturated NaHCO3 was added and the aqueous layer was extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (0-50% CH2Cl2/hexanes) to give the title compound (3.26 g, 95%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.26 (2H, s) 3.55-3.61 (2H, m) 0.88-0.94 (2H, m) −0.02 (9H, s). LCMS: m/z 346 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)([O-])=O.[C:20]([NH:27][C@:28]([CH3:34])([C:31](O)=[O:32])[CH2:29][OH:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].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>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:18]=[CH:19][C:4]([NH:1][C:29]([C@:28]([NH:27][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:34])[CH2:31][OH:32])=[O:30])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)C(=O)O
Reactant: O=[N+]([O-])c1ccc(OCCCCc2cccs2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@](C)(CO)C(=O)Nc1ccc(OCCCCc2cccs2)cc1
Yield: 66.8 %

Procedure:
This compound was synthesized from 2-(4-(4-nitrophenoxy)butyl)thiophene (280 mg), N-(Boc)-α-methylserine (205 mg), HATU (442 mg), and DIPEA (506 μl) following the procedure described in Example 5(A) to yield 280 mg product (62% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 7.44 (m, 2H), 7.29 (m, 1H), 6.9 (m, 1H), 6.84–6.81 (m, 3H), 5.00 (t, 1H), 3.93 (t, 2H), 3.61 (m, 2H), 2.84 (t, 2H), 1.73 (m, 4H), 1.48 (overlapping singlets, 9H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)(=[O:4])=[O:3].[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C.CC(N(C)C)=O>[Cl:18][C:19]1[N:24]=[C:23]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:22]=[CH:21][N:20]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CS(=O)(=O)CCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
4-(3-Methanesulfonyl-propoxy)-1H-indole (188.1 g), 2,4-dichloropyrimidine (221.25 g), HOBT (20.08 g), K2CO3 (143.68 g) and DMA (1.6 L) were heated to 85° C. for 20 h. IPA (5 was then added and the mixture was stirred for 20 min, then cooled to 0° C. for 3 h and filtered. The collected solid was rinsed with IPA and water, and the solid was dried in vacuo at 55° C. for 4 days to yield 1-(2-chloro-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (94%).
Reaction SMILES: [O:1]=[C:2]1[C:5](=[O:6])[C:4]([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH2:16][CH3:17])=[C:3]1[NH:18][C@H:19]([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]([C:4]2[C:5](=[O:6])[C:2](=[O:1])[C:3]=2[NH:18][C@H:19]([CH3:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[C:25](=[O:27])[CH3:26])=[C:9]([CH2:16][CH3:17])[CH:10]=1)#[N:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc(C#N)ccc1Nc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Solvent: c1ccncc1
Product: CCc1cc(C#N)ccc1N(C(C)=O)c1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Reaction time: 24 h

Procedure:
(+)-(R)-4-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethylbenzonitrile (0.36 g, 1.11 mmol), acetic anhydride (0.31 mL, 3.29 mmol) and pyridine (3.4 mL) were mixed and allowed to stand at room temperature for 24 hours. The reaction mixture was filtered to remove undissolved solid material and the filtercake was rinsed with ethyl acetate. The combined filtrate was concentrated and the resulting solid was purified by recrystallization (EtOAc/CH2Cl2) and trituration (EtOAc) to afford the title compound as 0.29 g (71%) of a white solid: mp 229°-231° C.; [α]D25 -224.43° (DMSO, c 0.0092); 1H NMR (CDCl3): δ 7.72 (s, 1H), 7.64 (m, 1H), 7.54-7.40 (m, 1H), 7.38 (m, 1H), 4.37 (m, 1H), 2.72-2.53 (m, 2H), 1.92 (s, 3H), 1.32-1.23 (m, 6H), 0.99 (d, 9H). IR (KBr): 3450, 3340, 2970, 2240, 1800, 1725, 1680, 1610 cm-1 ; MS (m/z) 367 (M+).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].[Br:24]N1C(=O)CCC1=O>C(#N)C>[Br:24][C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)([CH3:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(C)c1ccccn1
Reactant: O=C1CCC(=O)N1Br
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COC(=O)C(C)(Br)c1ccccn1
Reaction time: 8 h

Procedure:
Magnesium perchlorate (0.46 g, 2.08 mmol) was added to an acetonitrile (18 mL) solution containing the intermediate from Step A (1.04 g, 6.30 mmol). After stirring for 5 minutes N-bromosuccinimide (1.35 g, 7.55 mmol) was added and the reaction solution was stirred overnight. The solution was then partitioned between EtOAc and 1N NaHCO3 aq. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (400 MHz, CH3CN-d3): δ 8.48 (d, J=4.8 Hz, 1H); 7.85-736 (m, 2H); 7.32-7.26 (m, 1H); 3.72 (s, 3H); 2.24 (s, 3H). m/z=244.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+](CCCCCC)([O-])=O.F[C:20]1[CH:27]=[CH:26][CH:25]=C[C:21]=1[CH:22]=[O:23].[N+](CCC)([O-])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:22](=[O:23])[CH2:21][CH2:20][CH2:27][CH2:26][CH3:25]
Reactant: O=Cc1ccccc1F
Reactant: O=Cc1ccccc1Cl
Agent: CCCCCC[N+](=O)[O-]
Solvent: CCC[N+](=O)[O-]
Product: CCCCCC(=O)Cc1ccccc1Cl
Yield: 17 %

Procedure:
Following a procedure similar to that described in Preparation 9, except that equivalent amounts of 2-chlorobenzaldehyde and nitrohexane were used in place of the 2-fluorobenzaldehyde and nitropropane, the title compound was obtained as a pale yellow oil in a yield of 17%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH3:42][C:43]1([CH3:52])[CH2:48][CH:47]([NH2:49])[CH2:46][C:45]([CH3:51])([CH3:50])[NH:44]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:49][CH:47]5[CH2:48][C:43]([CH3:52])([CH3:42])[NH:44][C:45]([CH3:51])([CH3:50])[CH2:46]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CC(C)(C)NC(C)(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.12 mL (0.66 mmole) of ethyldiisopropyl amine and 0.039 g (0.25 mmole) of 2,2,6,6-tetramethyl-piperidin-4-ylamine in 2.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-60:40) gave 0.065 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2,2,6,6-tetramethyl-piperidin-4-yl)-benzamide (I-65) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(C)([O-])C.[Na+].Br[C:15]1[CH:22]=[C:21]([N:23]2[C:31]3[CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][C:27](=[O:34])[C:26]=3[C:25]([CH:35]([F:37])[F:36])=[N:24]2)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:32][C:29]1([CH3:33])[CH2:30][C:31]2[N:23]([C:21]3[CH:22]=[CH:15][C:16]([C:17]#[N:18])=[C:19]([NH:1][CH:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)[CH:20]=3)[N:24]=[C:25]([CH:35]([F:36])[F:37])[C:26]=2[C:27](=[O:34])[CH2:28]1
Reactant: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C#N)c(Br)c3)c2C1
Reactant: NC1CCOCC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C#N)c(NC4CCOCC4)c3)c2C1
Temperature: 120 °C
Yield: 284.8 %

Procedure:
The following reaction was conducted at the 300 mg scale and in duplicate at the 500 mg scale: 4-Aminotetrahydropyran (154 mg, 1.52 mmol, 2.0 eq.) and sodium tert-butoxide (146 mg, 1.52 mmol, 2.0 eq.) were added to a stirred solution/suspension of 2-bromo-4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (300 mg, 0.76 mmol, 1.0 eq.), palladium (II) acetate (8.5 mg, 0.04 mmol, 0.05 eq.), and 1,1′-bis(diphenylphosphino)ferrocene (42 mg, 0.08 mmol, 0.1 eq.) in toluene (2.25 mL). The reaction vial was capped, and the reaction mixture was heated for 20 min at 120° C. under microwave irradiation. The reaction mixture was diluted with water and ethyl acetate and combined. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on a Biotage system (SiO2, hexanes-ethyl acetate) to afford 4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydropyran-4-ylamino)-benzonitrile (897 mg, 65% yield) as a tan solid: LC/MS (m/z): [M+H]+ 415.2. Further elution with ethyl acetate afforded the title compound, 4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide, (131 mg, 9%) as a yellow solid: LC/MS (m/z): [M+H]+ 433.3.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10])=[O:4]
Reactant: Nc1ccccc1CO
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To chloroacetyl chloride (3.0 mL, 37.7 mmol) in dry DCM (100 mL) was added 2-aminobenzyl alcohol (4.3 g, 34.9 mmol) followed by addition of diisopropylethylamine (13.0 mL, 78.6 mmol). The mixture was stirred at ambient temperature for 2 hrs. The mixture was quenched with saturated sodium bicarbonate. The organic layer was separated and washed with sat NaHCO3 (50 mL) and water (50 mL×2). The resulting solution was dried over MgSO4 and evaporated to afford 2-chloro-N-(2-hydroxymethyl-phenyl)acetamide as a brown oil in quantitative yield (7.0 g). MS: 182.0 (M−H2O)+; tR=1.46 min (method 1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (253 mg, 1.02 mmol) [prepared according to the procedure of Example 164], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (335 mg, 1.00 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (574 mg, 1.23 mmol) in chloroform (10 mL). DIEA (930 μL, 5.32 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (132 mg, 0.25 mmol, 24%): LC-MS (ES) m/z=517 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH2:22][OH:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH:22]=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CCCCC(CO)Cc1ccc(C(=O)OCC)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCC(C=O)Cc1ccc(C(=O)OCC)cc1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
10 g (30 mmol) of 7-(4-ethoxycarbonylphenyl)-6-hydroxymethylheptanoic acid ethyl ester are dissolved in 100 ml of methylene chloride of analytical purity and methylene chloride containing 6.45 g (30 mmol) of pyridinium chlorochromate is added under cooling with tapwater. After stirring for 2 hours at room temperature 3.25 g (15 mmol) of pyridinium chlorochromate are once again added and the mixture is stirred for 1 hour. The reaction mixture (including the oily residue) is applied to a chromatographic column filled with 500 g of silica gel (Merck Si 60, 0.04-0.063 mm) and elution is carried out under a slightly elevated pressure using methylene chloride as the mobile solvent. A fraction is thus obtained which, after being evaporated in vacuo, yields 7.7 g of an oily product.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19]Cl)[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C(#N)C>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3CCCC3)cc12
Yield: 68.6 %

Procedure:
A mixture of 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) (64 mg, 0.16 mmol), potassium carbonate (64 mg, 0.46 mmol) and pyrrolidine (19 μl, 0.24 mmol), in acetonitrile (1.5 ml) was heated in a sealed tube at 100° C. for 18 hours. The yellow suspension was filtered, the solid washed with ethyl acetate and the combined filtrates concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient ethyl acetate/methanol 0-2%) to yield the title compound (49 mg, 71%) as a yellow solid.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=1[CH3:22].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][S:6][C:2]=2[C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[C:15]([CH3:22])[CH:16]=1)#[N:21]
Reactant: CCOC(=O)CCc1csc(Br)c1-c1ccc(C#N)cc1C
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2scc(CCC(=O)O)c2-c2ccc(C#N)cc2C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of ethyl 3-(5-bromo-4-(4-cyano-2-methylphenyl)thiophen-3-yl)propanoate (35 mg, 0.09 mmol), 4-methoxyphenylboronic acid (16 mg, 0.10 mmol), Na2CO3 (19 mg, 0.18 mmol), Pd(PPh3)2Cl2 (6 mg, 0.009 mmol) in a mixture of dioxane and H2O (5 mL, 4:1) was stirred at 100° C. overnight under nitrogen. The mixture was neutralized to pH=5, and extracted with EtOAc. The organic layer was concentrated, and purified by preparative TLC to give 3-(4-(4-cyano-2-methylphenyl)-5-(4-methoxyphenyl)thiophen-3-yl)propanoic acid (30 mg, yield 86%) as yellow oil.
Reaction SMILES: NC1N=C2C=CC(C3C=C(NS(C)(=O)=O)C(Cl)=NC=3)=NN2C=1C1C=CC=C(F)C=1.[Cl:30][C:31]1[N:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]3[N:41]([C:43]([C:50]4[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=4)=[C:44]([NH:46]C(=O)C)[N:45]=3)[N:42]=2)=[CH:33][C:32]=1[NH:56][S:57]([CH3:60])(=[O:59])=[O:58].[OH-].[Na+]>>[NH2:46][C:44]1[N:45]=[C:40]2[CH:39]=[CH:38][C:37]([C:34]3[CH:33]=[C:32]([NH:56][S:57]([CH3:60])(=[O:58])=[O:59])[C:31]([Cl:30])=[N:36][CH:35]=3)=[N:42][N:41]2[C:43]=1[C:50]1[CH:51]=[CH:52][N:53]=[CH:54][CH:55]=1
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)nn2c1-c1ccncc1
Agent: CS(=O)(=O)Nc1cc(-c2ccc3nc(N)c(-c4cccc(F)c4)n3n2)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1cc(-c2ccc3nc(N)c(-c4ccncc4)n3n2)cnc1Cl
Yield: 72.1 %

Procedure:
Following the procedure described for N-(5-(2-amino-3-(3-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl)-2-chloropyridin-3-yl)methanesulfonamide (Example 23), N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (TFA salt) (Example 26) (0.040 g, 0.070 mmol) was reacted with sodium hydroxide (0.200 mL, 2.0 mmol, 10 M) at 50° C. for 28 h to afford the title compound as a yellow solid (0.0210 g, 72%). MS (ESI, positive ion) m/z: 416 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.20 (s, 3H), 6.26 (s, 2H), 7.88 (d, J=9.2 Hz, 1H), 7.95 (d, J=9.2 Hz, 1H), 8.08 (d, J=6.1 Hz, 2H), 8.57 (d, J=2.2 Hz, 1H), 8.63 (d, J=6.1 Hz, 2H), 8.89 (br s, 1H), 9.94 (br s, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].[OH-].[K+].[C:15](O)(=O)[CH3:16]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:6]1[CH:16]=[CH:15][CH:3]=[C:4]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][NH:6][C:5]3=[O:12])[CH:5]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]cnc2ccc(I)cc12
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: O=c1[nH]cnc2ccc(-c3cccnc3)cc12
Yield: 39 %

Procedure:
6-Iodo-3H-quinazolin-4-one (4.0 gm, 14.7 mmol), 3-diethylborate pyridine (1.72 gm, 11.75), potassium hydroxide (2.63 gm, 46.95 mmol), tetrabutyl ammonium iodide (2.16 gm, 5.87 mmol) and tetrakis[triphenyl-phosphine] palladium (680 mg, 0.586 mmol) were combined in 70 mL of anhydrous THF and refluxed for 24 hours. The reaction was neutralized with 1.83 mL of acetic acid and filtered product off as a black precipitate. The precipitate was washed with water and THF and then chromatographed on silica gel using 1% pyridine/5% MeCH/CH2Cl2. 1.29 gm (39%) of a pale yellow solid product was obtained.