Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[NH2:26][OH:27]>CCO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:26][OH:27])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: ON=C(c1ccccc1)c1ccc(Cl)nc1
Yield: 88.8 %

Procedure:
The ketone issued from the precedent step (XIX*), e.g., (6-chloropyridin-3-yl)(phenyl)methanone (435 mg, 2 mmol), was dissolved in EtOH (40 mL). DIEA (1.027 mL, 6 mmol) and hydroxylamine hydrochloride (417 mg; 6 mmol) were added. The mixture was heated under reflux overnight. The solvents were removed. The resulting crude mixture was dissolved in ethyl acetate (40 mL) and was washed with three portions of water. The organic layer was dried over magnesium sulfate, filtrated and evaporated to give the desired product (XXXXIII*), e.g., (6-chloropyridin-3-yl)(phenyl)methanone oxime (413 mg, 89% yield). It was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[C:12]([OH:14])=O.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:38]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C(Cl)Cl.O>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[C:12]([N:48]1[CH2:47][CH2:46][N:45]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:50][CH2:49]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1COc2c1ccc(O)c2C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(O)ccc3c2OCC3=O)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.1 %

Procedure:
A solution of 6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylic acid (0.060 g, 0.31 mmol) in methylene chloride (2.0 mL) was successively added with 1-hydroxybenzotriazole monohydrate (0.008 g, 0.052 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.086 g, 0.45 mmol), and N-Boc-piperazine (0.067 g, 0.36 mmol), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was added with water, the mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (99:1→90:10)) to obtain tert-butyl 4-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carbonyl)piperazine-1-carboxylate (0.072 g, 66%).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[N:8][N:7]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4].S1C=CC=C1.COCCO.[H][H]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6](=[O:21])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10](=[O:11])[CH:9]=[N:8]2)=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CCCCn1c(=O)cnn(-c2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Solvent: c1ccsc1
Solvent: COCCO
Solvent: CO
Product: CCCCn1c(=O)cnn(-c2ccc(N)cc2)c1=O
Yield: 92.8 %

Procedure:
A mixture of 33.9 parts of 4-butyl-2-(4-nitrophenyl)-1,2,4-triazine-3,5(2H,4H)-dione, 2 parts of a solution of thiophene in methanol 4% and 400 parts of 2-methoxyethanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 29 parts (92.8%) of 2-(4-aminophenyl)-4-butyl-1,2,4-triazine-3,5(2H,4H)-dione as a residue (int. 28).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[N:6]2[CH:13]=1.[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][C:16]1=[S:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][C:7]1[N:6]2[CH:13]=[C:3]([CH2:2][S:26][C:16]3[N:15]([CH3:14])[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=3)[N:4]=[C:5]2[N:10]=[C:9]([CH3:11])[CH:8]=1
Reactant: Cn1cc(-c2ccccc2)[nH]c1=S
Reactant: Cc1cc(C)n2cc(CCl)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)n2cc(CSc3nc(-c4ccccc4)cn3C)nc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 468.6 %

Procedure:
A mixture of 2-chloromethyl-5,7-dimethyl-imidazo[1,2-a]pyrimidine (1.55 g, 0.8 mmol), 1-methyl-4-phenyl-1,3-dihydro-imidazole-2-thione (1.5 g, 0.8 mmol) and K2CO3 (3.31 g, 2.4 mmol) in dry DMF (20 mL) was stirred under N2 at room temperature overnight. After removal of the solvent under vacuum, the residue was purified by preparative HPLC to afford the title compound (1.31 g, 47%) as a white solid. LC-MS: m/z=350.2 (MH+), tR=2.14 min, method D.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[N:28]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH:54]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:55]([C:59](O)=[O:60])[C@@H:56]([CH3:58])[OH:57].C(=O)([O-])O.[Na+]>C(#N)C.O.C(N(CC)CC)C>[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:62]([NH:54][C@H:55]([C:59]([NH2:28])=[O:60])[C@@H:56]([CH3:58])[OH:57])([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(N)=O

Procedure:
One-thousand milligrams (2.65 mmols) of (E)-3-(3-amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile hydrochloride, 1,300 mg of a BOP reagent and 880 mg of Boc-L-Thr (OtBu) were dissolved in 50 ml of acetonitrile, and 0.8 ml of triethylamine were added thereto. The mixture was reacted at 60° C. for 21 hours. One-hundred milliliters of water and a small amount of sodium hydrogencarbonate were added thereto, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified using a silica-gel column (eluent, mixture of ethyl acetate and hexane at a ratio by volume of 5:1), and then concentrated to produce 870 mg (1.46 mmols) of the final product in a yield of 55%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]#[N:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]([NH:28][NH2:29])=O)[CH2:21]1)[CH3:19]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:16]1[NH:17][C:26]([CH:22]2[CH2:23][CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21]2)=[N:28][N:29]=1
Reactant: CCN1CCCC(C(=O)NN)C1
Reactant: N#Cc1nc(-c2cccc(CO)c2)cnc1N
Product: CCN1CCCC(c2nnc(-c3nc(-c4cccc(CO)c4)cnc3N)[nH]2)C1

Procedure:
(3-{5-amino-6-[5-(1-ethylpiperidin-3-yl)-4H-1,2,4-triazol-3-yl]pyrazin-2-yl}phenyl) methanol was prepared from 3-amino-6-[3-(hydroxymethyl) phenyl]pyrazine-2-carbonitrile and 1-ethyl piperidine-3-carbohydrazide in a manner analogous to that described in the previous example: 1H NMR (400 MHz; DMSO-d6): 8.8 (s, 1H); 8.15 (s, 1H); 8.15 (s, 1H); 8.07 (d, 1H); 7.7 (br s, 1H); 7.47 (t, 1H); 7.4 (t, 1H); 5.25 (t, 1H); 4.6 (d, 2H); 3.1-2.9 (m, 3H); 2.4 (m, 2H); 2.2-1.9 (m, 3H); 1.8-1.6 1 (m, 3H); 1.04 (t, 3H); MS (EI) for C20H25N7O: 380 (MH+).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[C:29]([Si:33]([O:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30].CC(O)=O>O.C1COCC1>[C:44]([C:38]1[CH:39]=[CH:40][C:41]([B:16]([OH:21])[OH:17])=[C:42]([F:43])[C:37]=1[O:36][Si:33]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:35])[CH3:34])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)c1cccc(F)c1O[Si](C)(C)C(C)(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(B(O)O)c(F)c1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1.08 h
Yield: 71.7 %

Procedure:
To a 100 mL round-bottomed flask were added a stir bar, dry THF (15.0 mL) and 2,2,6,6-tetramethylpiperidine (2.3 mL, 13.6 mmol). The flask was cooled to −78° C. (bath temp) and then treated with 2.5 M n-BuLi in hexanes (5.46 mL, 13.6 mmol) over 2 min. The resultant mixture was stirred for 5 min and then warmed to 0° Celsius. After 65 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)3 (17.5 mL, 13.6 mmol) over 4 min. After 20 min, a solution consisting of tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (2.57 g, 9.1 mmol) and dry THF (5.0 mL) was added over the course of 2 min and stirring continued for 3 hours. The reaction was gradually warmed to room temperature while stirring for 18 hours, after which time, HOAc (5.2 mL, 91 mmol) was added. The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL), the extract dried over Na2SO4, filtered and concentrated to dryness. Purification by FCC yielded (4-(tert-butyl)-3-((tert-butyldimethylsilyl)oxy)-2-fluorophenyl)boronic acid (2.13 g, 72%).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH3:9][C:10]1[C:22]2[C:21]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([OH:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: Cc1cccc2c1C(=O)c1ccccc1-2
Product: Cc1cccc2c1C(O)(c1ccccc1)c1ccccc1-2

Procedure:
from phenylmagnesium chloride and 1-methyl-9-fluorenone;
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20](F)=[CH:19][CH:18]=[CH:17][C:16]=2F)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cn1c(-c2ccccc2)nc(C(=O)NCc2ccccc2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (62 mg, 0.2 mmol) and benzylamine (64 mg, 0.6 mmol). The title product was obtained as a white solid (45 mg, 61% yield). 1HNMR (500 MHz, CDCl3) δ:). 12.38 (1H, s), 7.82 (1H, br s), 7.53–7.47 (1H, m), 7.37–7.29 (5H, m), 7.25–7.26 (2H, m), 7.07–7.04 (2H, m), 4.60 (2H, d, J=5.8 Hz), 3.42 (3H, s). HRMS calcd for C19H16F2N3O3 (M+H): 372.1160; found: 372.1156. Anal. Cald for C19H15F2N3O3: C, 61.45, H, 4.07; N, 11.31; found: C, 61.12, H, 3.77; N, 11.06
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13](C2CCCCO2)[N:12]=[C:11]3[C:23]2[CH:28]=[C:27]([O:29]CC3C=CC(OCC)=CC=3)[N:26]=[C:25]([O:40][C@H:41]3[C@H:46]([F:47])[CH2:45][CH2:44][N:43](C(OCC4C=CC=CC=4)=O)[CH2:42]3)[N:24]=2)=[C:4]([F:58])[CH:3]=1.[C:59]([OH:65])([C:61]([F:64])([F:63])[F:62])=[O:60]>>[F:62][C:61]([F:64])([F:63])[C:59]([OH:65])=[O:60].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[C:11]3[C:23]2[N:24]=[C:25]([O:40][C@H:41]3[C@H:46]([F:47])[CH2:45][CH2:44][NH:43][CH2:42]3)[NH:26][C:27](=[O:29])[CH:28]=2)=[C:4]([F:58])[CH:3]=1
Reactant: CCOc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(-c5ccc(Cl)cc5F)cc34)nc(O[C@@H]3CN(C(=O)OCc4ccccc4)CC[C@H]3F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(-c2n[nH]c3ccc(-c4ccc(Cl)cc4F)cc23)nc(O[C@@H]2CNCC[C@H]2F)[nH]1
Temperature: 100 °C
Yield: 21 %

Procedure:
A glass microwave reaction vessel was charged with benzyl 3-((4-(5-(4-chloro-2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-6-((4-ethoxybenzyl)oxy)pyrimidin-2-yl)oxy)-(trans)-4-fluoropiperidine-1-carboxylate (200 mg, 0.25 mmol) and TFA (1 mL). The reaction was stirred and heated in a microwave reactor at 100° C. for 30 min. The solvent was removed in vacuo and the residue was purified with preparative HPLC (eluting with 20-100% MeCN in water with 0.1% TFA) to give 6-(5-(4-chloro-2-fluorophenyl)-1H-indazol-3-yl)-2-((trans-4-fluoropiperidin-3-yl)oxy)pyrimidin-4(3H)-one trifluoroacetate (racemic) (30 mg, 21%) as a off white solid. MS (ESI, pos. ion) m/z: 458.3 (M+1); 1H NMR (400 MHz, DMSO-d6): δ ppm 13.81 (s, 1H), 8.82 (bs, 1H), 8.55 (s, 1H), 7.76 (d, 1 H, J=8.8 Hz), 7.62-7.67 (m, 2H), 7.58 (dd, 1 H, J=8.8, 2 Hz), 7.43 (dd, 1 H, J=6.4, 1.6 Hz), 5.64 (s, 1H), 5.24 (s, 1H), 3.41-3.49 (m, 2H), 3.13-3.20 (m, 2H), 2.18-2.32 (m, 1H), 1.95-2.05 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1.O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][CH:35]=[N:36]2)=[CH:31][CH:30]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: COCCOCCOc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCOCCOc1cc2ncnc(Oc3ccc4cccnc4c3)c2cc1OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 54.9 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (200 mg, 0.64 mmol), potassium carbonate (102 mg, 0.74 mmol) and 7-hydroxyquinoline (107 mg, 0.74 mmol) in DMSO (5 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The mixture was poured into water, washed with dichloromethane and extracted twice with a 10/1 mixture of dichloromethane/methanol. The extracts were washed with water and brine, dried over magnesium sulphate, filtered and the filtrate evaporated under vacuum. The residue was purified by silica column chromatography, eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1) to give an oil which crystallised on trituration with ether to give 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-4-(quinolin-7-yloxy)quinazoline (148 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O-:11])=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Br:1][C:2]1[CH:18]=[CH:17][C:16]2[C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=C([O-])c1ccccc1COc1cccc(Br)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccccc2COc2cc(Br)ccc21
Temperature: 0 °C
Yield: 44 %

Procedure:
A suspension of 2-(3-bromophenoxymethyl)benzoate (35 g, 0.11 mole) in 100 mL of trifluoroacetic anhydride containing 20 drops of boron trifluoride-ether complex was refluxed for 4 hours. The mixture was poured into ice-water and then extracted with diethyl ether. Concentration of ether solution under reduced pressure and chromatography of the residue on a silica gel column (Waters Associates, Prep 500) with hexane/methylene chloride (70:30) gave the pure product (14 g). m.p. 110°-112° C. pmr (CDCL3) δ: 8.10 (d, J=9.1 Hz, 1H, H1), 7.90 (dd, J=1.4, 7.6 Hz, 1H, H10) 7.57 (dt, J=1.4, 7.4, 7.4 Hz, 1H H8), 7.48 (dt, J=1.4, 7.6, 7.6 Hz, 1H, H9), 7.36 (dd, J=1.3, 7.3 Hz, 1H, H7), 7.27 (d, J=1.8 Hz, 1H, H4), 7.24 (dd, J=1.8, 9.1 Hz, 1H, H2), 5.18 (s, 2H, ArCH2O).
Reaction SMILES: C([O:8][C:9](=[O:43])[CH2:10][CH2:11][NH:12][C:13](=[O:42])[C@@H:14]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:15][C@@H:16]([C:24]([O:26][CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1>C(O)C.[Pd]>[C:29]([O:28][CH2:27][O:26][C:24]([C@@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:15][C@H:14]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:43])=[O:8])=[O:42])=[O:25])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O

Procedure:
0.92 g of N-[4-pivaloyloxymethoxycarbonyl-2,4-(R*,R*)-dibenzylbutyryl]-3-aminopropionic acid benzyl ester in 20 ml of ethanol is hydrogenated at atmospheric pressure in the presence of 0.1 g of 5% palladium on carbon. The reaction is filtered and evaporated to give N-(4-pivaloyloxymethoxycarbonyl-2,4-(R*,R*)-dibenzylbutyryl)-3-aminopropionic acid.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:25])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:22])[CH:14]=[C:15]1[CH3:21])[C@@H:10]([CH3:23])[C:9]3=[CH2:24].[OH-:26].[Na+]>CO>[O:26]1[C:11]23[C@:16]([CH3:17])([C@H:15]([CH3:21])[CH2:14][C:13](=[O:22])[CH:12]12)[C@@H:18]1[C@H:8]([C@H:6]2[C@@:4]([CH2:20][CH2:19]1)([CH3:5])[C:3](=[O:25])[C@H:2]([F:1])[CH2:7]2)[C:9](=[CH2:24])[C@H:10]3[CH3:23]
Reactant: [OH-]
Reactant: C=C1[C@H](C)C2=CC(=O)C=C(C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Agent: [Na+]
Solvent: CO
Product: C=C1[C@@H]2[C@H](CC[C@]3(C)C(=O)[C@H](F)C[C@@H]23)[C@@]2(C)[C@H](C)CC(=O)C3OC32[C@@H]1C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
345 mg of 16α-fluoro-1β,6β-dimethyl-7-dimethylenandrost-4-ene-3,17-dione (its preparation is described in Example 2) is dissolved in methanol (20 ml) and the resulting solution cooled to 0° C. Thereupon ice cold 36% hydrogen peroxide (2 ml) and 2% sodium hydroxide (1 ml) are added. The mixture is stirred for about 24 hrs at 0°-5° C. and then poured into ice water. The product is filtered off, washed with water and then dried to give 4,5-epoxy-16α-fluoro-1β,6β-dimethyl-7-methylenandrostane-3,17-dione.
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH:5]=[CH:4][C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:29]([O:3][C@@H:2]1[CH:4]=[CH:5][C@H:6]2[CH2:8][O:9][C@@H:1]1[O:7]2)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccccc1
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1C=C[C@H]2CO[C@@H]1O2)c1ccccc1
Yield: 74.9 %

Procedure:
2.56 g (20.0 mmol) of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose, 10.49 g (40.0 mmol) of triphenyl phosphine, and 4.88 g (40 mmol) of benzoic acid were added to 32 ml of dry THF, and a solution obtained by dissolving 6.97 g (40.0 mmol) of diethylazodicarboxylate in 32 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 23 hours. The solvent was distilled from the reaction solution at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:ethyl acetate=5:1 to 4:1). The purified residue was recrystallized from a solvent mixture of hexane and diethyl ether (a mixing ratio of 1:1) to obtain 3.48 g (yield: 74.9%) of 1,6-anhydro-3,4-dideoxy-2-O-(benzoyl)-β-D-erythro-hex-3-enopyranose.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[C:4]([F:12])[CH:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[C:2]([F:1])=[CH:3][C:4]=2[F:12])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cc(F)c2ccoc2c1Br
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Product: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)cc(F)c2ccoc12
Yield: 77.5 %

Procedure:
Beginning with 1.27 gm (5.45 mMol) 4,6-difluoro-7-bromobenzofuran and 1.16 gm (5.72 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 1.51 gm (78%) of the desired compound were prepared essentially as described in EXAMPLE 19.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[N:20]([CH2:30][CH3:31])[N:19]=2)=[C:9]1[CH3:32])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:30]([N:20]1[N:19]=[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:33])=[O:5])[C:9]=2[CH3:32])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21]1(=[O:29])=[O:28])[CH3:31]
Reactant: CCN1N=C(c2c(C)n(CC(=O)OC(C)(C)C)c3ccc(F)cc23)c2ccccc2S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1N=C(c2c(C)n(CC(=O)O)c3ccc(F)cc23)c2ccccc2S1(=O)=O

Procedure:
[3-(2-Ethyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ 8.09 (d, 1H), 7.91 (t, 1H), 7.84 (t, 1H), 7.48 (d, 1H), 7.42 (dd, 1H), 6.97 (m, 2H), 4.52 (s, 2H), 3.96 (q, 2H), 2.21 (s, 3H), 1.39 (t, 3H) ppm. MS calculated for C20H18FN3O4S—H: 414, observed: 414.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:19][C:20]2[CH:40]=[CH:39][C:23]3[NH:24][C:25]([C@@H:27]4[CH2:31][CH2:30][CH2:29][N:28]4[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:26][C:22]=3[CH:21]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Bi](Cl)(Cl)Cl.[BH4-].[Na+]>C(O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]([CH2:19][C:20]2[CH:40]=[CH:39][C:23]3[NH:24][C:25]([C@@H:27]4[CH2:31][CH2:30][CH2:29][N:28]4[C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])=[N:26][C:22]=3[CH:21]=2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc([N+](=O)[O-])cc3)c3ccc(F)cc3)ccc2[nH]1
Agent: Cl[Bi](Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc(N)cc3)c3ccc(F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product from Example 99C (0.67 g, 1.23 mmol) was dissolved in ethanol (15 mL) and cooled in an ice bath. Bismuth trichloride (0.245 mL, 3.68 mmol) was added and a slurry formed to which was added sodium borohydride (0.743 g, 19.7 mmol) portionwise causing a black precipitate to form. This mixture was stirred at ambient temperature for 20 minutes, then re-cooled and quenched with methanol (2 mL), stirring for 10 min before filtering through celite. The filtrated was concentrated to give the title compound.