Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12]C2C=C(OC)C(OC)=C(OC)C=2)[C:9]([OH:11])=[O:10])[CH:2]=1.N[C@@H](C[C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH3:46])[C:38]=1[O:47][CH3:48])C(O)=O>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:41]2[CH:42]=[CH:37][C:38]([O:47][CH3:48])=[C:39]([O:45][CH3:46])[C:40]=2[O:43][CH3:44])[C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: COc1ccc(C[C@H](N)C(=O)O)c(OC)c1OC
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)c(OC)c1OC

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using (S)-2-Amino-3-(2,3,4-trimethoxy-phenyl)-propionic acid. Purification by MPLC (CH3CN/H2O/TFA) afforded the title compound; ES-MS: 408.2 [M+H]+; HPLC: single peak at tR=9.42 min (System 1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[N-:20]=[N+:21]=[N-].[Na+]>Cl.O.O1CCOCC1.CO>[N:4]([C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[N+:20]=[N-:21]
Reactant: Nc1ccccc1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: [N-]=[N+]=Nc1ccccc1C(=O)O
Yield: 57.9 %

Procedure:
Anthranilic acid (12.3 g, 90 mmol) was dissolved in a mixture of aqueous HCl (36%, 50 mL), H2O (100 mL), dioxane (50 mL) and methanol (50 mL) at 0° C. and treated dropwise with NaNO2 (7.6 g, 110 mmol) dissolved in H2O (50 ml) whereas the temperature of the reaction mixture was kept below 5° C. After 1 h at 0° C. the mixture was poured onto an icy solution of sodium acetate (26 g, 317 mmol) and sodium azide (15 g, 230 mmol) in ca. 300 ml of water. Repeated (ca. 3 times) extraction of the resulting suspension with ethylacetate, drying of the combined organic phases, and evaporation of the solvent gave (8.5 g, 58%) of 2-azido-benzoic acid. MS (ES+): 164 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=3)[C:10](=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:28][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]3[CH:25]=[CH:26][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][C:10]2=[O:24])=[CH:17][CH:18]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 300 mg (0.85 mmol) 4-(4-fluoro-benzyloxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 7.1a) in 5.0 mL of DCM is added 120 μL (1.27 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and is diluted with half saturated aqueous NaHCO3-solution. The layers are separated and the aqueous phase is extracted three times with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][C:10]2[N:11]([CH2:38][CH2:39][CH3:40])[N:12]=[C:13]3[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=[C:14]3[N:23](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[O:4][N:3]=1.[OH-].[K+]>Cl.C(O)C.O.[OH-].[K+]>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][C:10]2[N:11]([CH2:38][CH2:39][CH3:40])[N:12]=[C:13]3[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=[C:14]3[NH2:23])[O:4][N:3]=1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCc1cc(C)no1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCc1cc(C)no1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
A solution of di(tert-butyl) 1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (0.471 g, 0.856 mmol) in 6 M HCl in ethanol (5 mL) was heated at 60° C. for 1 hour. The solution was allowed to cool to room temperature, then was concentrated under reduced pressure to yield an oil that was dissolved in water (20 mL). The solution was adjusted to pH 12 with a few drops of 50% aqueous potassium hydroxide and then to pH 14 with 1 M aqueous potassium hydroxide. A precipitate formed that was isolated by filtration and crystallized from ethyl acetate/hexanes. The crystals were isolated by filtration and dried under vacuum at 70° C. to afford 0.123 g 1-[3-(3-methylisoxazol-5-yl)propyl]-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as white needles, mp 183.0-184.0° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:15]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[N:16]2)[CH:3]=1.COC1C(C)=C2C(C(O[CH:41]3[CH2:58][CH:57]4[CH:43]([C:44](=[O:64])[N:45]([CH3:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:51][CH:52]5[C:54]([C:60]([OH:62])=[O:61])([NH:55][C:56]4=[O:59])[CH2:53]5)[CH2:42]3)=CC(C3SC=CN=3)=N2)=CC=1>>[CH3:21][C:17]1[CH:18]=[C:19]([CH3:20])[N:15]([C:4]2[CH:3]=[C:2]([O:1][CH:41]3[CH2:58][CH:57]4[CH:43]([C:44](=[O:64])[N:45]([CH3:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:51][CH:52]5[C:54]([C:60]([OH:62])=[O:61])([NH:55][C:56]4=[O:59])[CH2:53]5)[CH2:42]3)[C:11]3[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[N:16]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nccs3)nc2c1C
Reactant: COc1ccc2c(O)cc(-n3nc(C)cc3C)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3nc(C)cc3C)nc2c1C

Procedure:
The title compound was prepared from 4-hydroxy-2-(3,5-dimethylpyrazol-1-yl)-7-methoxy-8-methylquinoline (129) and intermediate 26 following the procedure (Step D-F) reported for the preparation of 17-[7-methoxy-8-methyl-2-(thiazol-2-yl)quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (29): m/z=616 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(-c3ccno3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:12][C:25](=[O:26])[CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:28])([F:16])[F:29])[CH:19]=2)=[CH:9][CH:8]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: NCc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1cccc(C(F)(F)F)c1)NCc1ccc(C(F)(F)C(F)(F)F)cc1
Yield: 77.9 %

Procedure:
A solution of 4-pentafluoroethyl-benzylamine (485 mg, 2.16 mmol), 3-(trifluoromethyl)-phenylacetic acid (484 mg, 2.37 mmol), 4-methylmorpholine (654 mg, 6.46 mmol), and HBTU (1.23 g, 3.23 mmol) in DMF (30 mL) was stirred at RT for 16 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (692 mg, 78%). Light yellow solid, MS (ISP) 412.2 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].[CH2:18]([NH:20][CH2:21][CH2:22][OH:23])[CH3:19]>C(Cl)Cl>[Si:14]([O:23][CH2:22][CH2:21][NH:20][CH2:18][CH3:19])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CCNCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.5 %

Procedure:
DIPEA (5.48 ml, 31.38 mmol) and tert-butylchlorodimethylsilane (6.76 g, 22.42 mmol) were added to a solution of 2-(ethylamino)ethanol (1.998 g, 22.42 mmol) in DCM (39.3 ml) at room temperature. The mixture was stirred at room temperature for 20 hours, partitioned between H2O/Et2O (50 ml/50 ml). The aqeuous phase was extracted with ether (3×30 ml). The combined organic layers were concentrated under reduced pressure to give a residue which was re-dissolved in DCM (50 ml), dried (Na2SO4), filtered and concentrated under vacuum to give the title compound (3.9 g, yield: 85%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]2[C:30]([CH2:31]Cl)=[CH:29][N:28]=[CH:27]2)=[CH:23][CH:22]=1)#[N:20].C(N(C(C)C)CC)(C)C>C(#N)C>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]2[C:30]([CH2:31][N:10]3[CH2:11][CH2:12][C:7]([CH2:6][C:5]4[CH:15]=[CH:16][CH:17]=[C:3]([CH3:2])[CH:4]=4)([C:13]#[N:14])[CH2:8][CH2:9]3)=[CH:29][N:28]=[CH:27]2)=[CH:33][CH:34]=1)#[N:20]
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: Cc1cccc(CC2(C#N)CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(CC2(C#N)CCN(Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1

Procedure:
A solution of 4-(3-methylbenzyl)piperidine-4-carbonitrile hydrochloride salt (129 mg, 0.51 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (135 mg, 0.51 mmol; Example 52, Step D), and diisopropylethylamine (440 mL, 2.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 85:15 v/v mixture of chloroform saturated with ammonia gas and hexhne. After collection and concentration of appropriate fractions, the residue was triturated with a mixture of ethyl acetate and diethyl ether. The white solid precipitated was filtered to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:13](=[O:14])[CH:12](C(OCC)=O)[CH:11]2[CH:7]1[CH2:8][C:9](=[O:20])[CH2:10]2)=[O:5])[CH3:2]>C(O)C.P([O-])([O-])([O-])=O>[CH2:1]([O:3][C:4]([CH:6]1[C:13](=[O:14])[CH2:12][CH:11]2[CH:7]1[CH2:8][C:9](=[O:20])[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)C(C(=O)OCC)C2CC(=O)CC12
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C1C(=O)CC2CC(=O)CC21
Temperature: 30 °C
Reaction time: 44 h
Yield: 89.7 %

Procedure:
10 g of 2,4-bisethoxycarbonylbicyclo[3.3.0]-octane-3,7-dione is dissolved in 40 ml of ethanol and diluted with 0.1-molar phosphate buffer pH 7 to a volume of 1,000 ml. Thereafter, 5 g of α-chymotrypsin from bovine pancreas (activity 1150 U/mg, Chemie Pharmazie Commerz, Hamburg) is added and the mixture shaken on a rotary shaker for 44 hours at 30° C. Then the reaction mixture is extracted three times with methyl isobutyl ketone, the extracts are combined and concentrated to dryness under vacuum. The remaining oily residue (9.4 g) is chromatographed for purification over a silica gel column by means of a solvent gradient of hexane/ethyl acetate. After evaporation of the main fraction, 6.68 g (89.7% of theory) of pure 2-ethoxycarbonylbicyclo[3.3.0]octane-3,7-dione is obtained as a pale, colorless oil which does not crystallize.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][N:19]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:18][CH2:17]2.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][N:19]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[OH:11])[CH2:18][CH2:17]2
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: COc1cc2c(cc1OC)CN(CCCCN)CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(C)ccc1O)CC2
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of 5-methylsalicylic acid (0.691 g, 4.5 mmol), 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butan-1-amine (1.0 g, 3.8 mmol), N,N′-Dicyclohexylcarbodiimide (DCC) (0.94 g, 4.5 mmol) and 1-Hydroxybenzotriazole hydrate (HOBOt) (0.61 g, 4.5 mmol) in dichloromethane (20 mL) was stirred overnight under an atmosphere of nitrogen. The reaction mixture was washed with saturated sodium bicarbonate solution (3×10 mL). The organic solution was dried over Na2SO4 and volatiles were removed under reduced pressure. The residue was purified by silica gel column with methanol/ether (5/95, v/v) as the mobile phase to afford 4a as a viscous oil (1.39 g; 93%). 1H NMR (300 MHz, CDCl3): 1.70-1.78 (m, 4H), 2.09 (s, 3H), 2.50-2.60 (m, 2H), 2.68-2.76 (m, 2H), 2.78-2.88 (m, 2H), 3.44-3.60 (m, 4H), 3.82 (s, 3H), 3.83 (s, 3H), 6.48 (s, 1H), 6.58 (s, 1H), 6.83-6.87 (d, 1H), 7.00-7.04 (m, 1H), 7.10-7.16 (m, 1H), 7.70-7.90 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:13][OH:14].[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:14][CH2:13][C:12]2[CH:11]=[C:10]([F:9])[CH:17]=[C:16]([F:18])[CH:15]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Product: Fc1cc(F)cc(COc2cncc(Cl)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol), 3,5-difluorobenzyl alcohol (475 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). The solid product was collected, washed with water, and dried to give 0.77 g (100%) of the crude product that was used directly in the next step. An analytical sample was recrystallized from diethyl ether/hexane: mp 70-71° C. MS m/z 257 (M+H)+. Anal. (C11H7ClFN2O) C, H, N.
Reaction SMILES: O.NN.[CH3:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([O:13]C)=[O:12]>C(O)C>[CH3:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)Cc1cccn1C
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1cccc1CC(=O)O
Yield: 99.9 %

Procedure:
Hydrazine monohydrate (65 ml) was added dropwise to a solution of methyl 1-methyl-1H-pyrrole-2-acetate (0.326 mol) in ethanol (300 ml) and the mixture was refluxed for 4 hours. The mixture was evaporated till dryness. The residue was taken up in dichloromethane and an aqueous potassium carbonate solution (10%) and extracted with dichloromethane. The organic layer was dried (MgSO4) and evaporated. The residue (48.8 g) was taken up in 1,1'-oxybisethane and the precipitate was filtered off, yielding 45.3 g (90%) of 1-methyl-1H-pyrrole-2-acetic acid, hydrazine (interm. 7).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[C:8]([O:11][CH:12]=[C:13]([CH3:16])[CH:14]=[CH2:15])(=[O:10])[CH3:9]>C(OCC)C>[CH3:16][CH:13]([CH:14]1[NH:5][C:6](=[O:7])[CH2:15]1)[CH2:12][O:11][C:8](=[O:10])[CH3:9]
Reactant: C=CC(C)=COC(C)=O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOCC
Product: CC(=O)OCC(C)C1CC(=O)N1

Procedure:
In words relative to the above diagram for the preparation of 3 (where R2 =H), the 4-(1-substituted-2-acetoxyvinyl)acetidinone-2-one (3') is prepared by reacting, for example (R1 =CH3): chlorosulphonyl isocyanate and acyloxybutadiene (1') such as 1-acetoxy-2-methylbutadiene in a solvent such as anhydrous diethyl ether at a temperature of from about 31 30° C. to 0° C. under a nitrogen atmosphere. The reaction intermediate 2' is converted to 3' by hydrolysis. The reduction of 3' to provide 4-(1-methyl-2-acetoxyethyl)-2-azetidinone (4') is conducted by any convenient means such as hydrogenation in the presence of a catalyst such as platinum, palladium or oxides thereof under a hydrogen pressure of from 1 to 20 atmospheres in a solvent such as ethanol, ethylacetate, or the like at a temperature of from 0° to 25° C. for from 5 minutes to 1 hour. The 4-(2-hydroxy-1-methyl-ethyl)-2-azetidinone species 5' is obtained from 4' by hydrolysis. The 8-oxo-2,2,5-trimethyl-3-oxa-1-azabicyclo[4.2.0]octane species 6' is obtained on treatment of 5' with 2,2-dimethoxypropane in the presence of a catalyst such as boron trifluoride etherate in a solvent such as methylene chloride at a temperature of from 0° to 40° C. for from 1 to 40 minutes. Alkylation of 6' provides 7'. Typically, 6' is treated with a strong base such as lithium diisopropylamide, sodium hydride, phenyl lithium or butyl lithium and the like in a solvent such as tetrahydrofuran (THF), ether, dimethoxyethane, and the like at a temperature of from -80° to 0° C., whereupon the alkylating agent of choice, R6X is added (R6 is as described above and X is chloro or bromo; alternatively, the alkylating agent may be R6 tosylate, R 6 -mesylate or an aldehyde or ketone such as acetaldehyde and the like) to provide mono-alkylated species 7'. When the desired dialkylated species 8' may be obtained from 7' by repeating the alkylating procedure, 6'→7'.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][CH3:13].CC(C)([O-])C.[K+].[CH3:20][C:21]1[N:26]=[C:25]([C:27](=[O:29])[CH3:28])[CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:13][O:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH2:28][C:27]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:20])[N:26]=3)=[O:29])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CC(=O)c1cccc(C)n1
Reactant: COc1ccnc2ccc(Cl)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccnc2ccc(CC(=O)c3cccc(C)n3)cc12
Temperature: 70 °C
Yield: 56 %

Procedure:
To a 20 mL threaded pressure tube was added 6-Chloro-4-methoxy-quinoline (298 mg, 1.54 mmol), palladium (II) acetate (7 mg, 0.03 mmol), 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (a.k.a. AMPHOS, 24 mg, 0.06 mmol), and potassium tert-butoxide (1 M in THF, 3.7 mmol). This mixture was stirred and 1-(6-Methyl-pyridin-2-yl)-ethanone was added. The pressure tube was then sealed and heated to 70° C. The reaction mixture was stirred at 70° C. for 18 hours. LC-MS showed product. The reaction mixture was then cooled and poured into a solution of 600 μL of glacial acetic acid in 30 mL of water. Title compound was extracted with 3×30 mL of chloroform. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated via rotary evaporator. The residue was purified by flash column chromatography (silica gel) using a 1% Methanol/Chloroform solvent system affording 255 mg of desired product (56% yield). HPLC=4.39 min, LC-MS=293 (M+H, mw=292.34).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.B1(C2C=CC([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=NC=2)OC(C)(C)C(C)(C)O1>>[O:36]1[CH2:37][CH2:38][N:33]([C:6]2[N:1]=[CH:2][C:3]([C:7]3[C:15]4[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=4)[NH:9][N:8]=3)=[CH:4][CH:5]=2)[CH2:34][CH2:35]1
Reactant: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Product: O=Cc1ccc2c(-c3ccc(N4CCOCC4)nc3)n[nH]c2c1

Procedure:
According to procedure for the synthesis of 3-(pyridin-3-yl)-1H-indazole-6-carbaldehyde, except substituting 2-(4-morpholino)pyridine-5-boronic acid pinacol ester (64 mg, 0.22 mmol), the title compound was prepared as a yellow powder (35 mg, 62%). 1H NMR (400 MHz, d6-DMSO) δ ppm 13.71 (br s, 1H), 10.14 (s, 1H), 8.77 (d, J=1.9 Hz, 1H), 8.02-8.18 (m, 2H), 8.15 (dd, J=8.9 Hz, 2.5, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 3.73 (t, J=4.5 Hz, 4H), 3.53 (t, J=5.1 Hz, 4H); MS ESI 309.1 (100) [M+H]+, calcd for [C17H16N4O2+H]+ 309.13.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:42])[N:15]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]1[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29]C2CCCCO2)[N:20]=1)[CH3:3].O.O.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:42])[N:15]([C:16]1[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[N:20]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)N(c1ccccc1)c1nnn(CCCCCCCCOC2CCCCO2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(c1ccccc1)c1nnn(CCCCCCCCO)n1
Reaction time: 46 h

Procedure:
To a stirred, room temperature solution of (±)N'-[2,6-bis(1-methylethyl)phenyl-N-phenyl-N-[2-[8-[(tetrahydro-2H-pyran-2-yl)oxy]octyl]-2H-tetrazol-5-yl]-urea (2.1600 g, 0.0037449 mol) in methanol (20 mL) was added dropwise water (1.0 mL) and 4-methylbenzenesulfonic acid monohydrate (0.0594 g, 0.000312 mol), and the mixture was stirred. After 46 hours the mixture was rotoevaporated, and the residue was chromatographed on silica gel (230 g, 230-400 mesh) using PET ether-diethyl ether (1:2, 15×200 mL) as eluent. Fractions containing product were rotoevaporated from dichloromethane to an oil. The oil was dried in vacuo (95° C., 15 min; 17h, 25° C.) to give the title compound, yield 1.482 g (80%). 1H NMR (CDCl3): δ 9.2 (br s, 1H), 7.5 (t, 2H), 7.4 (m, 3H), 7.3 (d, 1H), 7.2 (d, 2H), 4.5 (t, 2H), 3.6 (t, 2H), 3.2 (septet, 2H), 2.0 (m, 2H), 1.5 (m, 4H), 1.3 (m, 6H), 1.2 (d, 12H).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:14][CH2:15][O:16][C:17]([F:20])([F:19])[F:18])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:23][CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:9]([C:7]1[N:6]([CH2:14][CH2:15][O:16][C:17]([F:20])([F:19])[F:18])[C:5]2[CH:21]=[CH:22][C:2]([S:23][CH:24]3[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]3)=[CH:3][C:4]=2[N:8]=1)[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(S)C1
Reactant: CC(C)(C)Cc1nc2cc(Br)ccc2n1CCOC(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)Cc1nc2cc(SC3CN(C(=O)OC(C)(C)C)C3)ccc2n1CCOC(F)(F)F
Temperature: 160 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A mixture of 5-bromo-2-neopentyl-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazole (STEP A, 265 mg, 0.700 mmol), tert-butyl 3-mercaptoazetidine-1-carboxylate (STEP D of Example 1, 189 mg, 0.999 mmol), Xantphos (20.2 mg, 0.0350 mmol), tris(dibenzylideneacetone)dipalladium (16.0 mg, 0.0175 mmol) and N,N-diisopropylethylamine (245 microL, 1.40 mmol) in 1,4-dioxane (4 mL) was stirred at 160° C. for 1 h under microwave. The mixture was diluted with ethyl acetate and filtered through a celite. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, gradient) to give the title compound (278 mg, 81%).