Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([OH:28])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:60]([N:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1)([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>C1COCC1.CN(C=O)C>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([N:70]2[CH2:69][CH2:68][N:67]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:72][CH2:71]2)=[O:28])[CH:3]=1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(O)cc3c2[C@]2(C)CC[C@H]4C(C)(C)CCC[C@]4(C)[C@H]2CS3(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxyl ic acid (65) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methyl morpholine (0.1 mL, 1.5 mmol) and 1-Boc-piperazine (0.27 g, 1.5 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 10:1) to give tert-butyl 4-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]carbonyl}piperazine-1-carboxylate (99) (0.13 g, 46%) as a white solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH:15]([NH2:18])([CH3:17])[CH3:16].N1C=CC=CC=1>ClCCl>[CH:15]([NH:18][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3])([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.5 %

Procedure:
A suspension of 3 g of 5-chlorosulfonyl-2-oxindole, 1.15 g of isopropylamine and 1.2 mL of pyridine in 50 mL of dichloromethane was stirred at room temperature for 4 hours at which time a white solid was present. The precipitate was collected by vacuum filtration. The solids were slurry-washed with hot ethanol, cooled, collected by vacuum filtration and dried under vacuum at 40° C. overnight to give 1.5 g (45% yield) of 5-isopropylaminosulfonyl-2-oxindole.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[Cl:28][C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[S:32][C:33]=1[Cl:34].Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:5](=[C:6](/[CH:11]=[CH:12]/[C:13]([NH:38][S:35]([C:31]3[S:32][C:33]([Cl:34])=[C:29]([Cl:28])[CH:30]=3)(=[O:36])=[O:37])=[O:15])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(Cl)c(Cl)s1
Reactant: Cc1c[nH]c2c(/C=C/C(=O)O)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1c[nH]c2c(/C=C/C(=O)NS(=O)(=O)c3cc(Cl)c(Cl)s3)cccc12
Temperature: 25 °C
Reaction time: 32 h

Procedure:
(E)-3-(3-Methyl-1H-indol-7-yl)-acrylic acid (I-7) (1 mmol), 4-dimethyaminopyridine (DMAP, 2 mmol) and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 2 mmol) in CH2Cl2 (30 mL) was added 4,5-dichloro-thiophene-2-sulfonic acid amide (1.1 mmol). The reaction mixture was stirred at room temperature for 24-40 hr. Recation mixture was diluted with another 30 ml of dichloromethane and then acidified with 10% aqueous HCl solution until pH˜1-2 (pH stripes). Organic layers was washed with saturated brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, CH2Cl2; CH2Cl2/EtOAc/hexane=1:10:20-1:20:10) to afford desired product, I-9. 1H-NMR (500 MHz, CDCl3) ESI M.S. gave (M−1): 436.4 with 88%.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]C(C)(C)C.CN([CH:23]=[O:24])C>C1COCC1>[F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([CH:23]=[O:24])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(F)n1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(F)ccc1C=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
N-(6-fluoropyridin-2-yl)pivalamide (1.67 g, 8.5 mmol) was dissolved in THF (15 mL) at room temperature, and the colorless solution was cooled to −78° C., followed by dropwise addition of t-BuLi (10.3 mL, 1.7M in heptane, 17.4 mmol) under nitrogen gas over 10 min. The resulting yellow solution was continued stirring at −78° C. for 3 hr, followed by dropwise addition of DMF (2.0 mL, 25.5 mmol) over 5 min. The light yellow solution was stirred for additional 30 min at −78° C. Thus the mixture was quenched with saturated NH4Cl (30 mL), partitioned between H2O/EtOAc (100 mL/100 mL). After separation, the organic phase was washed with brine (30 mL), dried over MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 25˜50% EtOAc/hexanes (1400 mL) to afford an expected product, as a white solids (343 mg, 18% yield), plus the recovered starting material (622 mg); 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.30 (s, 9H), 8.12 (s, 1H), 8.18-8.27 (m, 2H), 10.13 (s, 1H); Mass spec. 225.13 (MH+), Calc. for C11H13FN2O2 224.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]([C:12]([C:14]1([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15]1)=[O:13])[NH2:11].[CH2:26]([O:33][N:34]1[C:40](=[O:41])[N:39]2[CH2:42][C@H:35]1[CH2:36][CH2:37][CH:38]2[C:43](O)=[O:44])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:21]([O:20][C:19](=[O:25])[NH:18][CH2:17][C:14]1([C:12]([NH:10][NH:11][C:43]([CH:38]2[CH2:37][CH2:36][C@@H:35]3[CH2:42][N:39]2[C:40](=[O:41])[N:34]3[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:44])=[O:13])[CH2:16][CH2:15]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: O=C(O)C1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)NN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(C(=O)NNC(=O)C2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
DIPEA (14 g, 0.11 mol) was added to a solution of tert-butyl (1-(hydrazinecarbonyl)cyclopropyl)methylcarbamate (10.0 g, 0.044 mol), (5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (10 g, 0.036 mol), and HATU (15 g, 0.04 mol) in CH2Cl2 (250 mL). The mixture was stirred at rt for 2 hrs. The mixture was diluted with CH2Cl2 (500 mL), washed with H2O (300 mL), dried over Na2SO4, and concentrated. The crude product was washed with EtOAc (200 mL), and filtrated to afford tert-butyl(1-(2-((5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)cyclopropyl)methylcarbamate (15 g, 85%) as a white solid. ESI-MS (EI+, m/z): 488.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([O:5][C@H:6]([C@@H:9]1[CH2:13][C@@H:12]([O:14]C(=O)C)[C@H:11]([N:18]2[C:22]3[N:23]=[C:24]([NH2:28])[NH:25][C:26](=[O:27])[C:21]=3[S:20][C:19]2=[O:29])[O:10]1)[CH2:7][CH3:8])=[O:4].C([O-])([O-])=O.[K+].[K+]>CO.O1CCCC1>[CH3:30][CH:2]([CH3:1])[C:3]([O:5][C@H:6]([C@@H:9]1[CH2:13][C@@H:12]([OH:14])[C@H:11]([N:18]2[C:22]3[N:23]=[C:24]([NH2:28])[NH:25][C:26](=[O:27])[C:21]=3[S:20][C:19]2=[O:29])[O:10]1)[CH2:7][CH3:8])=[O:4]
Reactant: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@@H](OC(C)=O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](OC(=O)C(C)C)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A mixture of [(1S)-1-[(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]propyl] 2-methylpropanoate (compound 42c, 70 mg, 0.16 mmol) and K2CO3 (13.2 mg, 0.096 mmol) in methanol (0.5 mL) and tetrahydrofuran (2 mL) was stirred at room temperature overnight. The reaction was quenched by addition of acetic acid (1 drop). The resulting mixture was concentrated in vacuo to remove the solvents and the residue was purified by preparative HPLC to afford 18.2 mg of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] 2-methylpropanoate (Example 42) as a pale solid.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.ClN1C(=O)CCC1=O.[Cl:30][C:31]1[C:32]([CH:38]=[CH2:39])=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])O.[K+]>C(OCC)(=O)C.O>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[C:32]=1[CH:38]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1c(O)cccc1Cl
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (400 mg) in ethyl acetate (10 ml) was added N-chlorosuccinimide (206 mg). The reaction mixture is stirred at reflux for 30 min. To the reaction mixture were added 3-chloro-2-vinylphenol (397 mg) and potassium hydrogencarbonate (257 mg) at room temperature, and then one drop of water. After stirring at room temperature overnight, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (345 mg).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[Cu][C:22]#[N:23].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CN(C)C=O>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([C:22]#[N:23])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3cc(OC)cc(C#N)c3o2)cc1
Yield: 97.5 %

Procedure:
A solution of 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole (200 mg, 0.60 mmol), in anhydrous N,N dimethylformamide (1.5 mL) was stirred and heated to reflux under dry nitrogen with copper(I) cyanide (80 mg, 0.90 mmol) for 4 h. The mixture was cooled and poured into an excess of aqueous ethylenediaminetetraacetic acid. Isolation of the crude product gave the nitrile (164 mg, 98% yield) as tan needles from (30% EtOAc/petroleum ether); m.p. 180-183° C.; MS m/e 281 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[NH2:14][C:15](N)=[S:16].O>N1C=CC=CC=1>[NH2:14][C:15]1[S:16][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC(N)=S
Solvent: O
Solvent: c1ccncc1
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1
Reaction time: 3 h
Yield: 118.8 %

Procedure:
A solution of 10.13 g of 2,4-dinitrochlorobenzene and 15.2 g of thiourea in 50 ml of pyridine is boiled, with stirring, under a reflux condenser for 3 hours. After cooling, the mixture is thoroughly stirred with 500 ml of water, and the solid is filtered off with suction, washed with water and dried. 11.6 g of 2-amino-5-nitrobenzothiazole having a purity of 66% by HPLC analysis, corresponding to a yield of 78.5% of theory, are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[NH:20][C:21]3[CH:22]=[N:23][N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=4)[CH:25]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([O:36]CC)=[O:35].[OH-].[Na+].Cl>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:33])[NH:20][C:21]3[CH:22]=[N:23][N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=4)[CH:25]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:34]([OH:36])=[O:35]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnn(-c5cccc(Cl)c5)c4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cnn(-c2cccc(Cl)c2)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 3 h
Yield: 103 %

Procedure:
Ethyl 6-chloro-7-(4-(1-(3-chlorophenyl)-1H-pyrazol-4-ylcarbamoyl)phenoxy)chroman-4-carboxylate (280 mg, 0.5 mmol) was dissolved in 2:1 tetrahydrofuran/ethanol (3 mL) and treated with sodium hydroxide (2 ml of a 1 N solution, 2.0 mmol) at ambient temperature. After 3 hours, the reaction was diluted with water (20 mL), acidified with 2N HCl (2 mL) and extracted with ethyl acetate. The combined organic phases were dried (sodium sulfate), filtered and the solvent removed under vacuum to provide the title compound (270 mg, 102%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:8].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>C(O)C>[CH3:1][NH:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH:8][CH2:24][CH2:23][C:22]([O:26][CH3:27])=[O:25]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C
Reactant: C=CC(=O)OC
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NCCC(=O)OC
Temperature: 70 °C

Procedure:
A solution of L-leucyl-L-phenylalanine N-methylamide (1.09 g) in ethanol (20 ml) was treated with methyl acrylate (0.33 ml). The resulting colourless solution was heated to 70° C. over 7.5 h. The crude product was purified by flash silica chromatography, eluting with ethyl acetate/methanol (9:1) to provide the title compound was isolated as a white solid (0.482 g).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[CH:12]1(CC(Cl)=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N>C(Cl)Cl.C(C(C)=O)C>[CH:12]1([CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(Cl)CC1CCCCC1
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: COC(=O)CC(=O)CC1CCCCC1
Yield: 98.9 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 176.7 g (1.1 mol) of cyclohexylacetyl chloride. The subsequent reaction time after the ammonia had been metered in was 6 hours at a pH of 9.5. This gave 196 g (GC purity 75.0%) of methyl 4-cyclohexylacetoacetate (yield 74.5%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13].N1C=CC=CC=1>ClCCl>[NH:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[NH:13][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)NN
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)NNC(=O)Oc1ccccc1
Yield: 90.4 %

Procedure:
Phenyl chloroformate (32.34 g, 0.207M) in dichloromethane (100 ml) was reacted with ethyl carbazate (20.8 g, 0.2M) in dichloromethane (150 ml) and pyridine (16.63 g, 0.21M) to give ethyl phenyl hydrazine-1,2-dicarboxylate (40.5 g). After chromatography on silica gel using dichloromethane and ethyl acetate, recrystallization from toluene gave colourless solid m.p. 89.5-90.5. (Found C 53.8%, H 5.5%, N 12.7%; C10H12N2O4 requires C 53.6%, H 5.4%, N 12.5%). The infra-red spectrum (0.5% in dichloromethane) showed bands at 3360 cm-1 (NH), 1775 and 1745 cm-1 (>C=O), and 1600 cm-1 (aromatic ring). Oxidation of the diester (5 g) in dichloromethane (25 ml) with t-butyl hypochlorite and evaporation of the solvent gave a red oil which was extracted with petroleum spirit (b.p. 30°-40° C.) to isolate ethyl phenyl azodicarboxylate (4 g). (Found C 53.9%, H 4.6%, N 12.4%, C10H10N2O4 requires C 54.1%, H 4.5%, N 12.6%). The infra-red spectrum (0.4% in dichloromethane) showed bands at 1792 with a shoulder at circa 1780 cm-1 (>C=O) and 1600 cm-1 (aromatic ring) and no >NH band at 3360 cm-1.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.CCO>[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:27][N:26]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Reactant: COc1ncc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccc2C)cn1

Procedure:
3-Iodo-4-methyl-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 13.1, 84 mg, 0.2 mmol), 2-methoxypyrimidin-5-ylboronic acid (61.6 mg, 0.4 mmol), Na2CO3 (63.6 mg, 0.600 mmol), Pd(PPh3)2Cl2 (7.02 mg, 10.00 μmol), water (200 μL), EtOH (133 μL) and DME (1 mL) were added to a vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min The RM was diluted with THF (1 mL) and stirred with Si-Thiol (69.4 mg, 0.100 mmol) for a 2 h. The filtrate was evaporated to dryness under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 4 g, DCM/MeOH+1% NH4OH, gradient from 1% to 15% MeOH+1% NH4OH) to afford the title compound as a beige solid. UPLC-MS (Condition 1) tR=2.89 min, m/z=404.1 [M+H]+, m/z=402.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.35 (s, 3H) 3.99 (s, 3H) 7.37 (d, J=8.6 Hz, 2H) 7.52 (d, J=8.1 Hz, 1H) 7.88 (d, J=9.3 Hz, 2H), 7.90 (br. s, br. s, 1H) 7.93 (dd, 1H) 8.74 (s, 2H) 10.36 (s, 1H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=O)[CH2:6][CH2:5]2.[Cl-].[Cl:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.O>O1CCCC1.CCOCC>[Cl:25][CH:26]=[C:7]1[CH2:6][CH2:5][C@@:4]2([CH2:3][S:2][CH3:1])[C:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:22])=[CH:8]1
Reactant: CSC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CSC[C@]12CCC(=CCl)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
500 mg of 19-methylthio-4-androstene-3,17-dione (European patent 100,566) is added to a suspension of 5.21 g of chloromethyl triphenylphosphonium chloride in 50 ml of tetrahydrofuran, which was stirred with 9.5 ml of (1.6 m of butyllithium in ether) 0.5 hours at 20° C., and stirred for 30 minutes at 0° C. Then it is mixed with water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated to dryness. 995 mg of raw product is obtained, which after chromatographic purification yields 273 mg of pure 3-chloromethylene-19-methylthio-4-androsten-17-one with a melting point of 114°-115° C., [α]D +241.5° C. (CHCl3), as pure E form.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@H:30]([OH:43])[CH2:29]1.[C:44]([O:48][C:49]([N:51]1[CH2:55][CH:54]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=2)[CH:53]([C:64](O)=[O:65])[CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45]>C(Cl)Cl>[Cl:63][C:58]1[CH:57]=[C:56]([CH:54]2[CH:53]([C:64]([N:40]3[CH2:39][CH2:38][N:37]([C:35]4[C:36]5[C@H:28]([CH3:27])[CH2:29][C@@H:30]([OH:43])[C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:42][CH2:41]3)=[O:65])[CH2:52][N:51]([C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])[CH2:55]2)[CH:61]=[CH:60][C:59]=1[Cl:62]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C(c2ccc(Cl)c(Cl)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C4CN(C(=O)OC(C)(C)C)CC4c4ccc(Cl)c(Cl)c4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HBTU (37 mg, 0.098 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 0.098 mmol) and 1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid (35 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (50 mL) and washed with brine (5×50 mL). The organic phase was dried and concentrated to afford tert-butyl 3-(3,4-dichlorophenyl)-4-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (LCMS (APCI+) [M+H]+ 576.1; Rt: 2.90 min). The product was treated with 4N HCl in dioxane to afford (4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone as the HCl salt (30 mg, 64%).