Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[N:22]=[C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29](C([O-])=O)[N:28]=[CH:27]5)[C:20]4[C:15](=[CH:16][C:17]([O:47][CH3:48])=[C:18]([O:36][CH2:37][CH2:38][N:39]5[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[CH2:41][CH2:40]5)[CH:19]=4)[N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(Cl)Cl.O1CCOCC1>[C:1]1([C:7]2[CH:8]=[C:9]([C:13]3[N:22]=[C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][N:28]=[CH:27]5)[C:20]4[C:15](=[CH:16][C:17]([O:47][CH3:48])=[C:18]([O:36][CH2:37][CH2:38][N:39]5[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[CH2:41][CH2:40]5)[CH:19]=4)[N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCN1CCCN(C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCCN(C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
To a solution of 5-(2-[(3-phenyl)phenyl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate in CH2Cl2 (2 mL) was added HCl as a 4.0 M solution in 1,4 dioxane (8 mL) and the reaction was stirred at RT for 5 h. The volatiles were removed in vacuo and the crude product was washed with hexane and dried under vacuum to yield 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)quinazolin-4-amine (0.063 g, 0.105 mmole, 26% over 2 steps). MS 600.4 (M+1). HPLC retention time 5.01 mins.
Reaction SMILES: [CH:1]12[CH2:18][CH:4]([CH:5]([NH:7]C(=O)OCC3C=CC=CC=3)[CH2:6]1)[CH2:3][O:2]2.C[OH:20]>[Pd]>[NH2:7][CH:5]1[CH2:6][CH:1]2[CH2:18][CH:4]1[C:3](=[O:20])[O:2]2
Reactant: CO
Reactant: O=C(NC1CC2CC1CO2)OCc1ccccc1
Agent: [Pd]
Product: NC1CC2CC1C(=O)O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of benzyl 2-oxa-bicyclo[2.2.1]heptan-5-ylcarbamate (0.05 g, 2.0 mmol) and Pd/C (10%, 50 mg) in methanol (20 mL) was stirred under hydrogen atmosphere (1 atm) at room temperature for 16 hours. After completion of the reaction, the mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to afford 5-amino-2-oxa-bicyclo[2.2.1]heptan-3-one (360 mg, over 100%), which was used in the next step without further purification. LCMS (ESI) m/z: 128.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Cl[CH2:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1>>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([CH2:19][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:17])=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(c1)OCO2

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 5-(chloromethyl)benzo[d][1,3]dioxole. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.71 min.; [M+H]+: 369.68 g/mol.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([NH:10][C:11]2[NH:12][CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[C:15]=2[C:16]([NH2:18])=[O:17])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH2:7][C:8]([NH:10][C:11]2[NH:12][CH:13]=[C:14]([C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[C:15]=2[C:16]([NH2:18])=[O:17])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1NC(=O)CCC1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1c(-c2ccc(N)cc2)c[nH]c1NC(=O)CCC1CCCC1
Yield: 79.2 %

Procedure:
0.210 g (0.56 mmol) of 2-(3-cyclopentylpropionylamino)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide is added at a temperature in the region of 25° C. to a suspension of 0.055 g (0.0051 mmol) of 10% palladium on carbon in 25 cm3 of methanol. After hydrogenating for 5 hours in an autoclave under 2 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with twice 10 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.151 g of 2-(3-cyclopentylpropionylamino)-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide, in the form of a brown powder. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 1.09 (m, 2H); from 1.39 to 1.84 (m, 9H); 2.39 (t, J=8.0 Hz, 2H); 5.14 (broad s, 2H); from 6.20 to 7.50 (very broad m, 2H); 6.23 (d, J=2.5 Hz, 1H); 6.59 (d, J=8.5 Hz, 2H); 6.99 (d, J=8.5 Hz, 2H); 10.9 (broad s, 1H); 11.3 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:24]
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3c(Cl)cccc3Cl)c(=O)c12
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c(=O)n1-c1c(Cl)cccc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 17.4 %

Procedure:
A mixture of (4S,7R)-2-(2,6-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 15; 1.2 g, 3.6 mmol) and iodomethane (0.45 mL, 8.0 mmol) in N,N-dimethylformamide (20 mL) was heated to 80° C. and stirred for 4.5 h. The reaction mixture was allowed to cool and water (200 mL) was added. A solid precipitated. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered, concentrated and purified by chromatography, eluting with 5-80% ethyl acetate/dichloromethane. Fractions containing the product were combined, evaporated, and recrystallized from ethyl acetate/hexanes to give (4S,7R)-2-(2,6-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (220 mg 18%) as a light tan solid. ES(+)-MS (M+H) 351
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: Oc1cccc2ncccc12
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2cccc3ncccc23)n1
Yield: 61 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 5-hydroxyquinoline (270 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (264 mg). Yield: 61%. 1H NMR (250 MHz, DMSO-d6) δ 7.54-7.58 (m, 2H, Harom 3+8), 7.84 (t, 1H, Harom 7, J=8.1 Hz), 8.01 (d, 1H, Harom 6, J=8.5 Hz), 8.37 (d, 1H, Harom 4, J=8.0 Hz), 8.55 (s, 1H, HPz 5), 8.73 (s, 1H, HPz 3), 8.98 (dd, 1H, Harom 2, J=1.4 Hz, J=4.0 Hz). m/z: 258.0 [(M+H)+, calcd for C13H8ClN3O 257.0].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[CH:16]=[C:15](F)[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=1.C[C:20](C)([O-:22])C.[K+]>>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[CH:16]=[C:15]([O:22][CH3:20])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=1
Reactant: C[C@@H]1CN(c2cc(F)c(C#N)c(F)c2)[C@@H](C)CN1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: COc1cc(N2C[C@@H](C)NC[C@@H]2C)cc(F)c1C#N

Procedure:
The compound was synthesized in the similar manner as in Reference Example 4-1 using 4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2,6-difluorobenzonitrile and 1 equivalent of potassium tert-butoxide.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:5]2[C:16](=[O:26])[CH:17]([NH:18][C:19](=[O:25])[CH2:20][C:21](=[O:24])[CH2:22][Br:23])[C@H:4]2[S:3]1.O.[N:28]([O-])=[O:29].[Na+]>C(O)(=O)C.O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][C:12]([Cl:13])([Cl:15])[Cl:14])=[O:9])[N:5]2[C:16](=[O:26])[CH:17]([NH:18][C:19](=[O:25])[C:20](=[N:28][OH:29])[C:21](=[O:24])[CH2:22][Br:23])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CC(=O)CBr)[C@H]2S1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(=NO)C(=O)CBr)[C@H]2S1

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-7-(3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (2.54 g.) in glacial acetic acid (25 ml.) was added dropwise a solution of sodium nitrite hydrate (0.33 g.) in water (1 ml.) over 3 minutes with stirring at 10° to 15° C., and then the mixture was stirred for 1 hour at the same temperature. After the reaction mixture was poured into cold water (70 ml.), the precipitates were collected by filtration and then dried to give brown powder of 2,2,2-trichloroethyl 2-methyl-7-(2-hydroxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylate (a mixture of syn and anti isomers) (2.0 g.), mp 76° to 80° C. (dec.).
Reaction SMILES: [OH:1][C@H:2]([CH3:16])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[C:11]=2[N:13]=O)[CH:6]=[N:5]1.N1C=CC=CC=1.[CH3:23][O:24][CH2:25][C:26](Cl)=O>O1CCCC1.CN(C)C1C=CN=CC=1.[Pd]>[CH3:23][O:24][CH2:25][C:26]1[O:15][C:10]2[CH:9]=[CH:8][C:7]3[CH:6]=[N:5][N:4]([CH2:3][C@H:2]([OH:1])[CH3:16])[C:12]=3[C:11]=2[N:13]=1
Reactant: C[C@@H](O)Cn1ncc2ccc(O)c(N=O)c21
Reactant: COCC(=O)Cl
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCc1nc2c(ccc3cnn(C[C@@H](C)O)c32)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
A solution of the product from Step A (1.05 g, 4.75 mol) in tetrahydrofuran (50 mL) containing 10% palladium-on-carbon (0.1 g) was stirred under an atmosphere of hydrogen at room temperature for 18 hours. The reaction mixture was filtered, pyridine (1.0 mL, 12.3 mol) and methoxy acetyl chloride (0.43 mL, 4.75 mol) were added, and this mixture was stirred at room temperature. More pyridine (5.0 mL) was added and the reaction mixture was stirred at room temperature for 20 minutes followed by the addition of 4-dimethylaminopyridine (0.1 g); this mixture was heated at 60° C. for 3 hours followed by removal of solvents by heating at 220° C. for 30 minutes. The resulting dark liquid was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a yellow oil (200 mg, 16%): LC/MS m/z 262.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([NH:14][C:15]2[S:16][C:17]([S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=O)=O)=[N:18][N:19]=2)=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([NH:14][C:15]2[S:16][C:17]([S:20][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:18][N:19]=2)=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CCCCCCS(=O)(=O)c1nnc(NC(=O)Nc2ccc(Cl)c(Cl)c2)s1
Agent: OO
Solvent: CC(=O)O
Product: CCCCCCSc1nnc(NC(=O)Nc2ccc(Cl)c(Cl)c2)s1

Procedure:
A solution of 6.0 g. (0.015 mole) of 1-(3,4-dichlorophenyl)-3-[5-(hexylthio)-1,3,4-thiadiazol-2-yl]urea (Example 18) was prepared in 30 ml. of glacial acetic acid. The mixture was heated to about 85°-90° C. and 4.08 g. (0.036 mole) of 30 percent hydrogen peroxide was added dropwise. After addition was complete, the temperature of the reaction mixture was maintained at about 85°-90° C. for an additional 1.5 hours. The reaction mixture was then cooled and poured onto ice. A precipitate formed which was filtered off and washed with water. The solid thus obtained was recrystallized from a mixture of ethyl acetate and normal hexane to yield product having a melting point of about 204°-206° C., and identified by elemental analyses and NMR spectrum as 1-(3,4-dichlorophenyl)-3-[5-(hexylsulfonyl)-1,3,4-thiadiazol-2-yl]urea.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:20]#[N:21])=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:20]#[N:21])=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Agent: [Na+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1cc(C#N)c(=O)c2cc([N+](=O)[O-])c(N=[N+]=[N-])cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 6.0 g (15.8 mmol) of 7-chloro-6-nitro-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile in 120 mL of dimethyl sulfoxide is added 5.13 g (79.0 mmol) of sodium azide and the resulting mixture is stirred at room temperature for 3 hours. The mixture is then heated at 60° C. for 10 minutes, room temperature for 1 hour and then poured on to ice. The solid is collected by filtration, washed thoroughly with water and dried in vacuo to yield 6.1 g of 7-azido-6-nitro-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-3-quinolinecarbonitrile as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[S:5][CH:6]=1.Br[CH2:14][CH:15]([C:17]1[CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[OH:16].C(N(CC)CC)C>CCOCC>[OH:16][CH:15]([C:17]1[CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH2:8][CH2:9]1
Reactant: Cc1csc(N2CCNCC2)n1
Reactant: NC(=O)c1cc(C(O)CBr)ccc1O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1csc(N2CCN(CC(O)c3ccc(O)c(C(N)=O)c3)CC2)n1
Reaction time: 2 h

Procedure:
18.9 g of 1-(4-methyl-2-thiazolyl)-piperazine and 26 g of 5-(2-bromo-1-hydroxyethyl)-salicylamide (obtainable by acylation of salicyamide with bromoacetyl bromide/AlCl3 to give 5-bromoacetyl-salicylamide and subsequent reaction with NaBH4) are dissolved in 400 ml of ether, 15 ml of triethylamine are added, the mixture is boiled for 2 h and subjected to the usual working-up, and 5-[1-hydroxy-2-(4-(4-methyl-2-thiazolyl)-piperazino)-ethyl]salicylamide ("A"), m.p. 182°, is obtained. Dihydrochloride m.p. 244°-245°.
Reaction SMILES: [CH:1]1([CH2:4][O:5]/[N:6]=[C:7](/[C:13]2[N:14]=[C:15]([NH:18]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:16][CH:17]=2)\[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.O>C(O)=O>[CH2:11]([O:10][C:8](=[O:9])/[C:7](/[C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1)=[N:6]\[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH3:12]
Reactant: CCOC(=O)/C(=N\OCC1CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: CCOC(=O)/C(=N\OCC1CC1)c1csc(N)n1
Yield: 93 %

Procedure:
Ethyl (Z)-2-cyclopropylmethoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (2.39 g) was dissolved in 98% formic acid (18.7 ml), water (5.6 ml) was added, and the mixture vigorously stirred. After 6 h the solvents were evaporated, toluene added to the residue and the process repeated. This was done twice more. The residual solid was chromatographed on silica to give the title compound as a white solid (1.17 g), νmax (Nujol) 3440, 3250, 3120, 1720, and 1620 cm-1 ; δH (CDCl3) inter alia 1.35 (3H, t, J 7 Hz), 4.0 (2H, d, J 7 Hz), 4.37 (2H, q, J 7 Hz), 5.4 (2H, broad s, exch. D2O), and 6.67 (1H, s).
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[S:21][CH3:22])[O:11][CH3:12])=[O:9])[C:4](=[O:23])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:23])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[S:21][CH3:22])[O:11][CH3:12]
Reactant: CON(Cc1ccc(F)cc1SC)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1SC)OC
Yield: 88 %

Procedure:
2(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methoxy-acetamide was reacted with methanol to give 3-[(4-fluoro-2-methylsulfanyl-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester as a white sticky solid (0.0807 g, 88% yield). This was then reacted with paraformaldehyde and 4-amino butyric acid following the procedure described for Compound 810 to give the title compound as an orange solid (0.0360 g, 64% yield). 1HNMR (300 MHz, DMSO) δ: 12.10 (1H, bs), 11.35 (1H, bs), 7.30 (1H, m), 7.14 (1H, dd, J=12.44, 2.20 Hz), 6.97 (1H, td, J=8.41, 2.65 Hz), 4.86 (2H, s), 4.18 (2H, s), 3.69 (3H, s), 3.42 (2H, t, J=6.73 Hz), 2.50 (3H, t, J=1.83 Hz), 2.22 (2H, t, J=6.73 Hz), 1.78 (2H, m).
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.I[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH:14]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: Oc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2cccnc2)cc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of potassium tert-butoxide in THF (1.0 M, 8.73 mmol) was slowly added to a solution of 3-hydroxypyridine (830 mg, 8.73 mmol) in anhydrous DMF (5.0 mL) and was stirred for 2 hours. A solution of 4-iodobenzonitrile in DMF (5.0 mL) was then added to the reaction mixture and was then heated at 160° C. for 18 hours. The mixture was cooled and partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were dried with MgSO4, filtered and concentrated in vacuo. The crude oil was placed on a silica gel column and purified (EtOAc/Hex 1:8) to give the product as a yellow oil (640 mg, 75%). 1H NMR (500 MHz, CDCL3) δ(ppm): 7.05 (2H, d, J=9.0 Hz), 7.10 (1H, dd, J=8.4, 4.6 Hz), 7.24 (1H, ddd, J=8.4, 2.6, 1.6 Hz), 7.65 (2H, d, J=9.0 Hz), 8.46 (1H, d, J=2.6 Hz), 8.22 (1H, dd, J=4.6, 1.6 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 107.1, 118.3 (CH), 118.6, 124.7 (CH), 127.5 (CH), 134.5 (CH), 142.8 (CH), 146.4 (CH), 151.8, 160.9. MS (FAB+): 197 (MH+). HRMS for C12H8N2O (MH+): calculated: 197.0713; found 197.0696.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([CH2:13][S:14]([CH2:17][S:18]([CH2:21][C:22](O)=O)(=[O:20])=[O:19])(=[O:16])=[O:15])(O)=O>C(O)(=O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[S:14]([CH2:17][S:18](/[CH:21]=[CH:22]/[C:5]2[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=2)(=[O:20])=[O:19])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(I)cc1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccc(I)cc1)CS(=O)(=O)/C=C/c1ccc(I)cc1
Yield: 78 %

Procedure:
A solution of 4-iodobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 78% yield. m.p. 253-255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]>Cl.O1CCOCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)nccc34)no2)cc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)O)nccc34)no2)cc1Cl
Reaction time: 2 h
Yield: 4.5 %

Procedure:
1,1-Dimethylethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate (D53; 54 mg, 0.111 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (10 ml) and the mixture allowed to stand at room temperature for 2 h. The solvent was evaporated in vacuo to give a colourless gum which was triturated under dry ether (5 ml) to give a white solid which was dissolved in NMP (0.5 ml) and purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)). The solvent was evaporated in vacuo to give the title compound (2.2 mg)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].[CH3:38][C@@H:39]1[CH2:41][O:40]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:40][C@H:39]([CH3:41])[CH2:38][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: C[C@@H]1CO1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1OC[C@@H](C)O
Yield: 24.4 %

Procedure:
The title compound was prepared according to the procedure described in Example 15 by using N-(4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (5.5 g, 11.1 mmol), (R)-2-methyloxirane (8 ml, 111 mmol) and K2CO3 (3.1 g, 222.2 mmol) in DMF/H2O (25 mL/5 mL). The crude product was purified by a silica gel column chromatography (DCM/MeOH(V/V=40/1)) to afford the title compound as a gray-white solid (1.5 g, 25%).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:23]2[C:31]3[C:26](=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)([CH2:21][CH3:22])[C:17](OC)=[O:18])=[CH:12][CH:11]=1>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:23]2[C:31]3[C:26](=[C:27]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)([CH2:21][CH3:22])[C:17](=[O:18])[CH2:2][C:1]#[N:3])=[CH:12][CH:11]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(C(=O)CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of acetonitrile (180 mg, 4.4 mmol) in tetrahydrofuran (3 mL) was added BuLi (1.9 mL, 4.8 mmol, 2.5 M in hexane) at −78° C. After stirring for 30 min, a solution of methyl 2-(4-chlorophenyl)-2-(4-(methylsulfonamido)-1H-indol-1-yl)butanoate (840 mg, 2.0 mmol, Enantiomer A), as described in Example 3 step D, in tetrahydrofuran (3 mL) was added to the mixture at −78° C. The resulting mixture was stirred at −78° C. for another 1 h, and then quenched with water (15 mL), extracted with ethyl acetate. The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with PE/EA (5/1 to 3/1, v/v) to get the title compound as a colorless amorphous solid (Enantiomer A). LC/MS m/z=429.8[M+H]+.