Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH3:22])[C:16]=1[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([C:16]3[C:17]([O:21][CH3:22])=[N:18][N:19]([CH3:20])[C:15]=3[NH:14][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)(=[O:12])=[O:11])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1nn(C)c(NS(=O)(=O)c2ccc(C(C)C)cc2)c1-c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 6.9 %

Procedure:
4-Isopropylbenzenesulfonyl chloride (176 mg) was added at room temperature under an atmosphere of nitrogen to a solution of 5-amino-4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazole (Preparation 43) (100 mg) and dimethylaminopyridine (50 mg) in anhydrous pyridine (4 ml). The reaction was stirred overnight. The mixture was concentrated under reduced pressure, then a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml), and brine (6 ml) were sequentially added. The aqueous phase was extracted with ethyl acetate (2*8 ml) and the combined organic fractions were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified to yield the title compound (11.9 mg).
Reaction SMILES: C1(C(=[N:14][C:15]([CH3:27])([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl>CO.C1COCC1>[NH2:14][C:15]([CH3:27])([CH2:20][C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(C)(N)Cc1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
To a suspension of methyl 2-[(diphenylmethylene)amino]-2-methyl-3-pyridin-4-ylpropanoate from Step B (5.28 g, 14.73 mmol) in 75 ml of 1:1 MeOH/THF was added 6N HCl (3.68 ml, 22.10 mmol). The reaction was concentrated in vacuo after stirring for 1.5 h at rt. Purification using ion exchange chromatography (SCX cartridge) afforded methyl 2-amino-2-methyl-3-pyridin-4-ylpropanoate as a yellow oil (2.76 g, 97%). LCMS [M+H]=195.3. 1H NMR (d4-MeOH) δ 8.43 (dd, J=4.6, 1.6 Hz, 2H), 7.24 (dd, J=4.6, 1.5 Hz, 2H), 3.70 (s, 3H), 3.09 (A of AB, d, J=12.9 Hz, 1H), 2.90 (B of AB, d, J=13.0 Hz, 1H), 1.39 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>>[Cl:37][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1
Reactant: OCc1ccc(COc2ccccn2)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A mixture of (4-(pyridin-2-yloxymethyl)-phenyl)methanol (540 mg, 2.51 mmol) described in Manufacturing Example 2-1-1, triphenylphosphine (856 mg, 3.27 mmol) and carbon tetrachloride (10.8 g, 10.2 mmol) was stirred under reflux for 2 hours and 10 minutes. The reaction solution was cooled to room temperature, and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:acetic acid=8:1) to obtain the title compound (300 mg, 51.1%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[C:8]([CH3:13])[C:6]=2[N:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(CO)sc2c(N3CCOCC3)nc(Cl)nc12
Reaction time: 2 h

Procedure:
To a suspension of 2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (400 mg, 1.34 mmol) in methanol at 0° C. was added sodium borohydride and. After stirring for 2 hours, the mixture was quenched with 50:50H2O:NaHCO3(sat. aq). The methanol was removed under reduced pressure to give a suspension which was filtered and washed with H2O followed by ether to give (2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]3[N:22]=[C:21]([C:23]([N:25]4[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]4)=[O:24])[CH:20]=[CH:19][N:18]=3)[CH2:10][CH2:9]2)[CH:7]=1.CS[C:36]1[NH:37][CH:38]=[CH:39][C:40](=[O:42])[N:41]=1>C1(C)C=CC=C(C)C=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:17]3[N:22]=[C:21]([C:23]([N:25]4[CH2:26][CH2:27][CH:28]([NH:31][C:36]5[NH:37][CH:38]=[CH:39][C:40](=[O:42])[N:41]=5)[CH2:29][CH2:30]4)=[O:24])[CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:13]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1N1CCN(CCNc2nccc(C(=O)N3CCC(N)CC3)n2)CC1
Reactant: CSc1nc(=O)cc[nH]1
Solvent: Cc1cccc(C)c1
Product: COc1ccc(Cl)cc1N1CCN(CCNc2nccc(C(=O)N3CCC(Nc4nc(=O)cc[nH]4)CC3)n2)CC1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
2.3 g (4.9 mmol) of 1-[2-[[2-[4-(5-chloro-2-methoxyphenyl)piperazin-1-yl]ethyl]amino]pyrimidin-4-ylcarbonyl]piperidin-4-amine, and 0.9 g (6.3 mmols) of 2-methylthiopyrimidin-4(1H)-one in solution in 40 ml of m-xylene are introduced into a 0.5 l, round bottomed flask and the mixture is heated at reflux of the m-xylene for 14 hours. The reaction mixture is cooled to room temperature and the solvent is then evaporated under reduced pressure. The crude product is purified by chromatography on a silica gel column (eluent: dichloromethane/methanol, 98/2 to 85/15) in order to obtain 1.56 g (2.74 mmols) of compound.
Reaction SMILES: [OH-].[Li+].[N+:3]([CH3:6])([O-:5])=[O:4].[F:7][C:8]([F:15])([F:14])[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].[O-]S([O-])(=O)=O.[Mg+2]>O.[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C(OCC)C>[F:7][C:8]([F:15])([F:14])[C:9]([CH2:6][N+:3]([O-:5])=[O:4])([OH:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(=O)C(F)(F)F
Reactant: C[N+](=O)[O-]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CC(C)C(O)(C[N+](=O)[O-])C(F)(F)F
Reaction time: 48 h

Procedure:
A cooled (0° C.) solution of lithium hydroxide (0.048 g, 2.015 mmol) in water (20 ml) was stirred and treated with nitromethane (1.23 g, 20.15 mmol), 1,1,1-trifluoro-3-methylbutan-2-one (3.11 g, 22.17 mmol), cetyltrimethylammonium Chloride (0.871 g, 2.72 mmol) and MgSO4 (0.485 g, 4.03 mmol). The white suspension was stirred at 0° C. for 1 hr, then at RT for 2 days. The resulting biphasic mixture was separated and the more dense lower layer was collected and dissolved in diethyl ether (30 ml). The mixture was dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The oil was taken up in diethyl ether (10 ml) and passed through a pre-packed SCX-2 cartridge eluting with 100% diethyl ether. The filtrate was concentrated in vacuo to afford the title compound as a colourless oil. 1H NMR (400 MHz, CDCl3): δ 4.74 (1H, d), 4.59 (1H, d), 4.29 (1H, s), 2.29 (1H, m), 1.1 (6H, two sets of unresolved doublets)
Reaction SMILES: [CH3:1][N:2]([CH3:51])[CH2:3][CH2:4][O:5][C:6](=[O:50])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3=[C:18]([CH:49]=2)[N:19]=[C:20]([NH:41]C(OC(C)(C)C)=O)[CH2:21][C:22]([C:24](=[O:40])[N:25]([CH2:29][CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH2:26][CH2:27][CH3:28])=[CH:23]3)=[CH:10][CH:9]=1>ClCCl.C(O)(C(F)(F)F)=O>[CH3:51][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6](=[O:50])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3=[C:18]([CH:49]=2)[N:19]=[C:20]([NH2:41])[CH2:21][C:22]([C:24](=[O:40])[N:25]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:26][CH2:27][CH3:28])=[CH:23]3)=[CH:12][CH:13]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCN(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCN(C)C)cc3)cc2N=C(N)C1
Reaction time: 1 h

Procedure:
2-(dimethylamino)ethyl-2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded 2-(dimethylamino)ethyl-2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, CDCl3) δ 7.59-7.64 (m, 2H), 7.48-7.51 (m, 1H), 7.28-7.38 (m, 4H), 6.87 (s, 1H), 4.19-4.24 (m, 2H), 3.58-3.74 (m, 6H), 3.44-3.52 (m, 2H), 2.84 (s, 2H), 2.54-2.61 (m, 2H), 2.27 (s, 6H), 1.79-1.86 (m, 2H), 1.65-1.76 (m, 2H), 0.89-0.97 (m, 3H); m/z (APCI-pos) M+1=507.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH3:30])[C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:31]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH3:30])[C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: OO
Reactant: COc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1OC
Product: COc1ccc(S(=O)CCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethoxy-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][OH:47])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][O:47][S:58]([CH3:57])(=[O:60])=[O:59])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCO)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 108d (105 mg, 0.16 mmol) in DCM (2 mL) was added DIPEA (43 μL, 0.25 mmol) followed by methanesulfonyl chloride (15 μL, 0.20 mmol). The reaction mixture was stirred for 2 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.09 min, m/z 717 [MH+].
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([O:7][CH3:8])=[O:6])[CH3:4].C(Cl)(Cl)Cl.Cl[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>>[CH3:8][O:7][C:5](=[O:6])[C@H:3]([CH3:4])[NH:2][C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: COC(=O)[C@H](C)N
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](C)Nc1nc2ccccc2o1
Temperature: 40 °C
Reaction time: 12 h
Yield: 16.6 %

Procedure:
To the suspension of 0.62 g (6 mmol) methyl alaninate hydrogen chloride salt and 4 ml chloroform 0.79 g (7.8 mmol) triethylamine and 0.46 g (3 mmol) 2-chloro-1,3-benzoxazole are added and the mixture is stirred at 40° C. for 4 hours and at room temperature for 12 hours. The chloroform solution is washed with water, citric acid solution and water, dried over sodium sulfate and evaporated in vacuum. The residue is treated with hexane, the crystals are filtered off and washed. 0.11 g title compound is obtained as white crystals. Mp: 112-113° C.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][O:43][Si](C(C)(C)C)(C)C)[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][OH:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO.Cl>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:51])([CH3:52])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][OH:43])[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][OH:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccccc1CO
Agent: Cl
Solvent: CO
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO)cc1-c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-{6-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-[2-(hydroxymethyl)phenyl]-3-pyridinyl}-N,2-dimethylpropanamide (D61, 24.6 mg, 0.0315 mmol) was suspended in dry MeOH (1 mL) before adding c.HCl solution (5 drops). The reaction mixture was then stirred at R.T. for 3 hours. Poured directly onto a 5 g SCX column, washing with MeOH (2×10 mL) before eluting the compound off with NH3 in MeOH (4×10 mL). Solvent evaporated. Residue purified on a 5 g sek pak column eluting with 0-100% EtOAc/Pent followed by 0-10% MeOH/EtOAc. Solvent evaporated to afford the title compound as a colourless gum.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C.[N+:15]([O-])([OH:17])=[O:16]>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7][CH:6]=1
Reactant: FCCCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(CCCF)cc1

Procedure:
1-Fluoro-3-phenylpropane was dissolved in acetic anhydride (10 mL) and to the solution was added acetic acid (1 mL) and fuming nitric acid (1 mL) at 0° C. The reaction mixture was reacted at rt and to 60° C. for 1 h, then diluted with ethyl acetate (100 mL). The organic solution was washed with water (3×100 mL) and brine (100 mL), and evaporated to give 1-fluoro-3-(4-nitrophenyl)propane.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[N:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[CH:12][C:4]=2[CH:3]=1.C([O:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)(=O)C.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>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.CCOC(C)=O>[F:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[N:10]1[C:5]2[N:6]([CH3:9])[C:7](=[O:8])[C:2]([C:35]3[CH:34]=[C:29]([CH:28]=[CH:27][C:26]=3[CH2:25][OH:24])[C:30]([OH:32])=[O:31])=[CH:3][C:4]=2[CH:12]=[N:11]1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Reactant: COC(=O)c1ccc(COC(C)=O)c(B2OC(C)(C)C(C)(C)O2)c1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1c(=O)c(-c2cc(C(=O)O)ccc2CO)cc2cnn(-c3c(F)cccc3F)c21
Temperature: 130 °C
Yield: 41.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (38 mg, 33 μmol), 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (373 mg, 1096 μmol), methyl 4-(acetoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (403 mg, 1206 μmol) were treated with 1,4-dioxane (5.4 mL) and 1 M aqueous Na2CO3 (2.74 mL, 2741 μmol) under argon and heated in a microwave at 130° C. for 30 min. The reaction mixture was treated with EtOAc (20 mL) and extracted with 1N NaOH (2×15 mL). The pH was adjusted to ca. pH 6 with 5N HCl and extracted with DCM (3×20 mL), dried over MgSO4, filtered and concentrated affording the title compound (186 mg) as a yellow tar. The crude residue was used in the next step without further purification. MS (ESI, pos.ion) m/z: 412.1 (M+1).
Reaction SMILES: [C:1]([CH:4]([C:10]([O:12]CC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][NH2:25])[CH:20]=[CH:21][C:22]=1[Cl:23].C([O-])(=O)C.[Na+].C(O)C>O>[Cl:16][C:17]1[CH:18]=[C:19]([N:24]2[C:10](=[O:12])[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:1]([CH3:2])=[N:25]2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1C(=O)N(c2ccc(Cl)c(Cl)c2)N=C1C

Procedure:
The starting material is prepared as follows: The mixture of 1.3 g of diethyl α-acetyl-malonate, 1.3 g of 3,4-dichlorophenylhydrazine hydrochloride, 0.5 g of sodium acetate, 30 ml of ethanol and 10 ml of water is warmed on the steam cone for 10 minutes. It is diluted with water, extracted with diethyl ether, the extract washed with water, dried and evaporated. The residue is taken up in 50 ml of xylene, the solution distilled for 10 minutes and refluxed for 85 minutes. It is evaporated and the residue triturated with diethyl ether to yield the 1-(3,4-dichlorophenyl)-3-methyl-4-carbethoxy-2-pyrazolin-5-one, melting at 147°-148°.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]1[CH2:11][NH:10][C:9]1=[O:12])=[O:6])[CH3:3].C([Li])(CC)C.[CH3:19][S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>O1CCCC1.C1CCCCC1>[CH3:3][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]1[CH2:11][N:10]([C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:25])[C:9]1=[O:12])=[O:6])[CH3:1]
Reactant: CS(=O)(=O)N=C=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC1=O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)NS(C)(=O)=O)C1=O
Temperature: -75 °C

Procedure:
(S)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-azetidinone (1.12 g) was dissolved in dry tetrahydrofuran (120 ml) and stirred at -75° C. under dry nitrogen. sec-Butyl lithium (4.44 ml of a 1.35 M solution in cyclohexane) was added and followed in two minutes by methylsulfonyl isocyanate (0.72 ml). After stirring for 25 minutes at -75° C., the reaction was quenched by the addition of 0.5 M pH 5.5 monobasic potassium phosphate buffer (60 ml), diluted with ethyl acetate-water, acidified to pH 2.5 with 3N hydrochloric acid, and (60 ml), diluted with ethyl acetate-water, acidified to pH 2.5 with 3N hydrochloric acid, and extracted with ethyl acetate (three times). The extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo to yield the desired product as a foam (1.73 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:34][CH:33]=1)=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:42]=[CH:41][C:35]([O:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:34][CH:33]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)COc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and (4-formyl-phenoxy)-acetic acid according to the procedure of Example 66. MS (ESI) m/z 557.
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][C:6]1([CH2:13][N+]([O-])=O)[CH2:10][C@@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)C.[CH3:18]O>[Ni]>[CH3:11][C@H:9]1[C@H:8]([CH3:12])[CH2:7][C:6]2([CH2:5][C:4](=[O:17])[CH2:18][CH2:13]2)[CH2:10]1
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Reactant: CO
Agent: [Ni]
Product: C[C@@H]1CC2(CCC(=O)C2)C[C@H]1C
Reaction time: 4 h
Yield: 99 %

Procedure:
The nitroester (3) (0.83 g, 3.4 mmol) was dissolved in methanol (30 mL) and shaken over Raney nickel catalyst under an atmosphere of hydrogen (40 psi) at 30° C. After 4 hours, the catalyst was removed by filtration through celite. The solvent was removed in vacuo to give 567 mg (99%) of a pale yellow oil which solidified on standing.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24](I)[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[S:31][C:32]([Cl:35])=[CH:33][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O-:39])(=[O:38])C.[K+]>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]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([C:36]([OH:39])=[O:38])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[S:31][C:32]([Cl:35])=[CH:33][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2ccc(Cl)s2)c(=O)[nH]c2cc(Cl)c(I)cc12
Reactant: CC(=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2ccc(Cl)s2)c(=O)[nH]c2cc(Cl)c(C(=O)O)cc12
Temperature: 60 °C
Reaction time: 5.5 h
Yield: 63 %

Procedure:
To a solution of 2-{2-[7-chloro-3-(5-chlorothiophen-2-yl)-6-iodo-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (612 mg in 15 ml methylsulfoxide) was added 34 mg [1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (II) followed by 410 mg potassium acetate and the mixture heated to 60° C. under an atmosphere of carbon monoxide. After 5.5 hours, the mixture was cooled to room temperature and partitioned between ethyl acetate and 0.5N hydrochloric acid and extracted. The organic portion was dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane, 20:80; then 30:70; then 40:60; then 50:50) to give the title compound (337 mg).