Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][CH2:23][S:24]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH2:33].OO>C(O)(=O)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][CH2:23][S:24]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)(=[O:33])=[O:25])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:8][CH:9]=1
Reactant: O
Reactant: NN=Cc1ccc(CCCCC(=O)NC(CCS(=O)Cc2ccccc2)CC(=O)O)cc1
Agent: OO
Solvent: CC(=O)O
Product: NN=Cc1ccc(CCCCC(=O)NC(CCS(=O)(=O)Cc2ccccc2)CC(=O)O)cc1
Reaction time: 24 h

Procedure:
(±)-3-[[5-[4-(Aminoiminomethyl)phenyl]-1oxopentyl]amino]-5-[(phenylmethyl)sulfinyl]pentanoic acid (2.5 g) was added to water (15 ml), acetic acid (5 ml) and 30% H2O2 (10 ml). The oxidation was allowed to proceed for 24 h. after which the reaction mixture was worked up. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to give 1.6 g of the title compound as a white solid: 1H NMR (d6 -DMSO) δ1.48 (m, 2H), 1.56 (m, 2H), 1.75 (m, 2H), 2.10 (m, 2H), 2.41 (m, 2H), 2.68 (m, 2H), 4.05 (m, 1H), 4.22 (s, 2H), 7.35 (m, 9H), 7.7 (bd, 1H, J=7.9 Hz), 9.10 (bs, 2H), 9.8 (bs, 2H); MS (FAB) m/e 474.2 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([OH:13])[CH2:4][CH2:3]1.[H-].[Na+].F[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=2)[CH:22]=1>CN(C=O)C>[F:12][C:9]1[CH:10]=[C:11]2[C:6]([C@H:5]([O:13][C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([CH:26]([CH3:28])[CH3:27])=[N:24][N:25]=4)[CH:22]=3)[CH2:4][CH2:3][C@@H:2]2[NH2:1])=[CH:7][CH:8]=1
Reactant: CC(C)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4cc(F)ccc43)cn12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
Intermediate 19a (837 mg, 4.62 mmol) was dissolved in dry DMF (15 mL) under Ar, then NaH (60% in mineral oil, 556 mg, 13.9 mmol) was added, and the mixture stirred for 15 min. Intermediate 1f (893 mg, 4.99 mmol) was added, and the reaction heated at 60° C. for 2 h. The reaction was cooled, quenched by addition of water and extracted with DCM (4×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by FCC, eluting with 0-20% [2M NH3 in MeOH] in DCM, to give the title compound (429 mg, 27%). LCMS (Method 3): Rt 1.96, m/z 363 [MNa+].
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=2)[N:3]=1.[NH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:19].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[S:13][C:12]([S:14]([NH:19][NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:16])=[O:15])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=S(=O)(Cl)c1ccc(-c2ncc(Cl)c(Br)n2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Br)n2)s1
Yield: 84.7 %

Procedure:
A mixture of 5-(4-bromo-5-chloropyrimidin-2-yl)thiophene-2-sulfonyl chloride (164 mg, 0.45 mmol, 1.0 equiv.), tert-butyl hydrazinecarboxylate (119 mg, 0.9 mmol, 2.0 equiv.) and DIPEA (5 mL) was stirred in DCM at r.t. for 2 h, The reaction was extracted with EA and the combined layers were dried (Na2SO4), filtered. The filtrate was concentrated to afford tert-butyl 2-(5-(4-bromo-5-chloropyrimidin-2-yl)thiophen-2-ylsulfonyl)hydrazinecarboxylate (179 mg, 85%). LC-MS (m/z)=469 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: COc1cccc(B(O)O)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c1
Yield: 66 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-methoxyphenylboronic acid (119 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 1.5 mL of toluene fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 144 mg (66%) of the title compound as a white solid. mp 140°. FDMS: m/e=335. α[D]589 =+77.45 (c=1.02, chloroform).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:23])[N:15]([CH2:19][C:20](=[O:22])[NH2:21])[CH:16]([CH3:18])[CH3:17])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:45]2[C@H:46]([CH3:69])[C@H:47]3[C@@H:64]([C@H:65]([OH:67])[CH3:66])[C:63](=[O:68])[N:48]3[C:49]=2[C:50]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=2)=[O:51])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C.CO.C(OCC)(=O)C>[C:20]([CH2:19][N:15]([CH:16]([CH3:18])[CH3:17])[C:14]([C:12]1[N:13]=[C:9]([N:7]2[CH2:6][CH:5]([S:4][C:45]3[C@H:46]([CH3:69])[C@@H:47]4[C@@H:64]([C@H:65]([OH:67])[CH3:66])[C:63](=[O:68])[N:48]4[C:49]=3[C:50]([O:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=3)=[O:51])[CH2:8]2)[S:10][CH:11]=1)=[O:23])(=[O:22])[NH2:21]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)N(CC(N)=O)C(C)C)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CC(N)=O)C(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of 3-acetylthio-1-[4-(N-carbamoylmethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]azetidine (347 mg, 0.97 mmol) (obtained as described in Reference Example 49) in dimethylformamide (10 ml) was added hydrazine acetate (108 mg, 1.17 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (696 mg,1.17 mmol) in acetonitrile (20 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.68 ml, 3.88 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate: methanol (10:1) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(N-carbamoylmethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (359 mg, yield 56%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:35][S:36]([O:24][CH2:23][CH2:22][CH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=1)=[O:9])=[C:19]2[OH:20])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCO)cc2c1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from Example No. 110 (0.13 g) in 10 mL DMF is added NEt3 (0.05 mL) and a spatula tip of DMAP. Methanesulfonyl chloride (0.030 mL) is added dropwise and the reaction is allowed to stir at room temperature overnight. The reaction is partitioned between EtOAc and H2O. The aqueous layer is extracted 3× with EtOAc. The organics are combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give a yellow liquid. The residue is dissolved in CH2Cl2, adsorbed onto silica and chromatographed on a Biotage Flash 40S column (eluent 1% MeOH:CH2Cl2 (1 L) followed by 3% MeOH:CH2Cl2 (2 L)) to afford the desired product as a white solid which is further purified by recrystallization with CH2Cl2 /hexanes. (0.045 g, 0.097 mmol, 29%).
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)=[CH:5][N:4]([CH:17]([CH3:19])[CH3:18])[N:3]=1.[NH2:20][CH2:21][C@@H:22]([OH:24])[CH3:23].CCCCCC.[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[I:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:20][CH2:21][C@@H:22]([OH:24])[CH3:23])[N:8]=2)=[CH:5][N:4]([CH:17]([CH3:19])[CH3:18])[N:3]=1
Reactant: CC(C)n1cc(-c2ccnc(S(C)(=O)=O)n2)c(I)n1
Reactant: C[C@H](O)CN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Yield: 96.8 %

Procedure:
A mixture of 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine B-1-2 (16 g, 40 mmol) and (s)-1-amino-propan-2-ol (9 g, 122 mmol) in THF (160 mL) was heated to reflux overnight. TLC (hexane: EtOAc=2:1) showed the reaction was complete, EtOAc (80 mL) and saturated aqueous NaCl (80 mL) were added to the mixture, and the layers were separated. The organic layer was separated, washed with saturated aqueous NaCl (30 mL), dried over Na2SO4 and concentrated to give (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (15 g, 96.9%) as a brown oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[ClH:7].Cl.[NH2:9][C@@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:11]([NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:12].[CH:26](=O)[CH2:27][CH:28]([CH3:30])[CH3:29].C([BH3-])#N.[Na+]>C(O)C.O>[ClH:7].[ClH:7].[CH2:26]([NH:9][C@@H:10]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:12])[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CC=O
Reactant: CN(C)CCNC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCO
Product: CC(C)CCN[C@@H](Cc1ccccc1)C(=O)NCCN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
Anhydrous potassium carbonate (3.32 g) and molecular sieves 3A (5 g) are added successively to a solution of (2S)-2-amino-N1-[2-(dimethylamino)ethyl]-3-phenylpropionamide dihydrochloride (Reference compound No. 8-8, 2.47 g) and isovaleraldehyde (0.69 g) in ethanol (40 ml), and the mixture is stirred at room temperature for two hours. Sodium cyanoborohydride (0.55 g) is further added thereto, and the mixture is stirred at room temperature for two hours. Water is added to the reaction mixture, and the mixture is filtered with Celite. The filtrate is concentrated under reduced pressure, saturated brine is added to the residue, and the whole is extracted with ethyl acetate. The organic layer is washed with a 10% aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, and the resulting oily matter is dissolved in ether (5 ml). A 4.6 N solution of hydrogen chloride in ethyl acetate (4 ml) is added thereto, and the resulting precipitate is filtered off to give 0.40 g (13%) of the titled compound (Reference compound No. 9-1) as crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=3)[CH2:10][C:11](O)([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:32]=[C:33]([Si:36]([CH3:39])([CH3:38])[CH3:37])[S:34][CH:35]=1)CCC>>[F:25][C:17]1[CH:16]=[C:15]([N:9]2[CH:10]=[C:11]([CH3:13])[N:12]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([C:31]3[N:32]=[C:33]([Si:36]([CH3:39])([CH3:38])[CH3:37])[S:34][CH:35]=3)=[CH:3][CH:4]=2)[CH:20]=[CH:19][C:18]=1[S:21]([NH2:24])(=[O:23])=[O:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc([Si](C)(C)C)n1
Reactant: CC1(O)CN(c2ccc(S(N)(=O)=O)c(F)c2)C(c2ccc(Br)cc2)=N1
Product: Cc1cn(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(-c3csc([Si](C)(C)C)n3)cc2)n1

Procedure:
The title compound was prepared according to the procedure of Example 153 (step 4) using 4-[2-(4-bromophenyl)-4-hydroxy-4-methyl-1H-imidazol-1-yl]-2-fluorobenzenesulfonamide instead of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole and using 4-(tributylstannyl)-2-trimethylsilylthiazole instead of 4-(tributylstannyl)thiazole.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([SH:22])[CH:17]=2)=[O:14])[CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:42][CH3:43])=[C:31]([O:34][CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:32]=2)[N:27]=[CH:26][N:25]=1>O1CCCC1.C(OCC)(=O)C.O>[C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:42][CH3:43])=[C:31]([O:34][CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[CH:17]=2)=[O:14])[CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
To a suspension of sodium hydride (11 mg, 0.44 mmol) in anhydrous tetrahydrofuran (2 mL) cooled to 0° C., was added 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea from the previous step (117 mg, 0.40 mmol) as a solution in tetrahydrofuran (1 mL) and the mixture stirred at 0° C. for 30 minutes. To this suspension 4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline from Example 41B Step 1 (133 mg, 0.40 mmol) was added and the resulting mixture was stirred at 0° C. and slowly allowed to reach room temperature. After stirring for additional 1 h, the mixture was taken up in ethyl acetate/water and extracted. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)urea (10.30 mg, 4%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.73 (bs, 1H), 9.19 (bs, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.53-7.27 (m, 5H), 6.49 (s, 1H), 4.32 (bs, 2H), 4.01 (s, 3H), 3.35 (2H), 3.07 (s, 3H), 2.28 (bs, 2H), 1.28 (s, 9H); LC-MS (ESI) m/z 586 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9](Cl)=[CH:8][C:7]([C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])=[N:6][CH:5]=1.B(CC)(CC)[CH2:23][CH3:24].C([O-])([O-])=O.[Na+].[Na+].CCCCCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([CH2:23][CH3:24])=[CH:8][C:7]([C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])=[N:6][CH:5]=1
Reactant: CCB(CC)CC
Reactant: CCc1cccc(CC)c1-c1cc(Cl)c(C(=O)OC)cn1
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: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1cc(-c2c(CC)cccc2CC)ncc1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-nicotinic acid methyl ester (2.5 g, 8.2 mmol), Et3B (1M in Hexane, 49 mL, 49 mmol), Na2CO3 (2M in H2O, 12.3 mL) and Pd(PPh3)4 (500 mg) in toluene (36 mL) is heated at 80° C. under argon for 2 days. On cooling, hexane (50 mL) is added and the organic layer separated. The organic layer is washed with saturated Na2CO3 and water, dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (hexane/EtOAc 4:1) to give 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester. 1H NMR (CDCl3) 9.15 (s, 1H), 7.30 (m, 1H), 7.21 (s, 1H), 7.15 (d, 2H), 3.97 (s, 3H), 3.06 (q, 2H), 2.31 (m, 4H), 1.26 (t, 3H), 1.03 (t, 6H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[O:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.C(OCC)(=O)C>[O:12]([C:4]1[CH:3]=[C:2]([N:26]2[CH2:27][CH2:28][C:23]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:24][CH2:25]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(F)cc1Oc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1Oc1ccccc1
Temperature: 130 °C

Procedure:
Methyl 4-fluoro-2-phenoxybenzoate (2 g) and 1,4-dioxa-8-azaspiro[4.5]decane (1.279 g) were combined in dimethylsulfoxide O (12 mL) in a 250 mL round-bottom flask. Sodium carbonate (1.291 g) was added. The reaction flask was sealed and heated to 130° C. overnight. The reaction mixture was diluted with ethyl acetate, washed thoroughly with water and with brine, and dried over MgSO4, filtered and concentrated to obtain the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[N:27]=[C:26]([CH2:28][OH:29])[NH:25][C:24]=2[CH:30]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[N:27]=[C:26]([CH2:28][OH:29])[NH:25][C:24]=4[CH:30]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc2cnc(O)nn12
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4nc(CO)[nH]c4c3)nn12

Procedure:
{6-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1H-benzoimidazol-2-yl}-methanol was prepared from 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1052a. Product isolated as a yellow solid (55 mg, 46%). m.p.=239-243° C.; LCMS (m/e) 387 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 12.05 (bs, 1H), 9.23 (s, 1H), 8.93 (s, 1H), 8.15-7.42 (m, 2H), 7.87 (d, 1H, J=7.2 Hz), 7.50-7.40 (m, 1H), 7.40-7.22 (m, 1H), 7.22 (d, 1H, J=8.3 Hz), 7.19-7.07 (m, 1H), 6.99-6.85 (m, 2H), 5.60 (bs, 1H), 4.64 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:14](=[O:52])[CH2:15][N:16]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:19](=[O:33])[CH:18]([CH2:34][C:35]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37](C(OC(C)(C)C)=O)[N:36]=4)[C:17]3=[O:51])[C:7]=2[CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([CH2:34][CH:18]2[C:17](=[O:51])[N:16]([CH2:15][C:14]([N:13]3[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:52])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19]2=[O:33])=[N:36]1
Reactant: COc1cccc2c1CCCCN2C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1CCCCN2C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 19.7 %

Procedure:
A solution of tert-butyl 3-({1-[2-(6-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-2-oxoethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl}methyl)-1H-indazole-1-carboxylate (83 mg) in methylene chloride (10 mL) was treated with trifluoroacetic acid (1 mL). The reaction was stirred overnight then concentrated to dryness. The residue was chromatographed on silica gel (Hexane:Ethyl Acetate. The residue was triturated with Ethyl Ether and filtered to yield the title compound as a white powder (14 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[C:12](Cl)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[O:22])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OC(=O)CCCCCCCCC(=O)Oc2ccc(C(=O)OC)cc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 15.2 g of methyl p-hydroxybenzoate and 12 g of sebacic acid dichloride to yield di(p-methyloxycarbonylphenyl)sebacate, m.p. 109.5°-110.5° C., as white crystals.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1CCCC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(OC)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(Cl)c(CC(CC=O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c(Cl)c1
Yield: 49 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[(S)-2-(4-methoxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (6.65 g, 14.87 mmol), tetrahydrofuran (140 mL) and water (45 mL) with 2.5% osmium tetroxide in t-butanol (378 mL, 1.487 mmol). Add sodium periodate (9.55 g, 44.63 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 3.35 g (49%) of desired product. MS (m/z): 451 (M+).