Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1Br)C(C)CNCC2
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.95 g, 2.59 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (25 mL), and stirred overnight at 20 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.687 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.92 (s, 1 H), 6.34 (s, 1 H), 3.87 (s, 3 H), 3.1-2.9 (m, 6 H), 2.75 (m, 1 H), 2.60 (bs, 1 H), 1.31 (d, J=7 Hz, 3 H). MS calculated for C12H16BrNO+H: 270, observed: 270.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:27]([CH3:29])[CH3:28]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([O:23][CH:27]([CH3:29])[CH3:28])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Product: Cc1nc2c(cc1OC(C)C)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 1 intermediate d), from (4R,9aR)-7-hydroxy-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 7, intermediate), sodium hydride and 2-bromopropane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[N:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Oc1ccc(-c2ccc(Cl)cc2)nc1
Yield: 73 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 4-chlorophenylboronic acid and 2-bromo-5-hydroxypyridine to afford the title compound as an off-white solid (1.3 g, 73%)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=[N:3]1.F[P-](F)(F)(F)(F)F.[PH4+].CCN(C(C)C)C(C)C.[NH2:36][C@@H:37]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([F:60])([F:59])[F:58])[CH2:38][N:39]1[C:47](=[O:48])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]1=[O:49]>C(Cl)Cl>[O:48]=[C:47]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:49])[N:39]1[CH2:38][C@@H:37]([NH:36][C:16]([C:9]1[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:18])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([F:59])([F:58])[F:60]
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1C(F)(F)F
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1C(F)(F)F
Reaction time: 2 h
Yield: 93.6 %

Procedure:
At room temperature, a mixture of 4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxylic acid (235 mg, 80% purity, 0.68 mmol), phosphoniumhexafluorophosphate (PyBrOP) (381 mg, 0.19 mmol), DIPEA (0.59 mL, 3.4 mmol) and 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (261 mg, 0.75 mmol) in DCM (5 mL) was stirred for 2 h. The reaction solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (386 mg, 86%) as a white solid: LC-MS (ES) 607 (M+H)+
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[NH3:12]>CN(C=O)C>[S:7]1[CH:8]=[CH:9][C:5]2[CH:4]=[C:3]([CH2:2][NH2:12])[CH:11]=[CH:10][C:6]1=2
Reactant: BrCc1ccc2sccc2c1
Reactant: N
Solvent: CN(C)C=O
Product: NCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.6 %

Procedure:
A solution of 5-bromomethylbenzo[b]thiophene (3.0 g, 13.20 mmol) in DMF (15 ml) was added to a solution of 25% aqueous ammonia (10 ml, 132 mmol) in DMF (10 ml). The reaction mixture was stirred for 4 hours at room temperature. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using first ethyl acetate/heptane (1:1;60 ml) and subsequently DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.40 g (19%) of ((benzo[b]thiophen-5-yl)methyl)amine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[Na+].[Cl-]>COC(C)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A mixture of pyridine-3-sulfonic acid (10.3 g, 64.8 mmol), phosphorus pentachloride (20.82 g, 100 mmol) and phosphorus oxychloride (10 mL, 109 mmol) was heated to reflux for 3 h (according to J. Org. Chem. 1989, 54(2), 389). Evaporated to dryness to give a yellow solid, dissolved in ice water and methyl-tert-butyl ether, added cautiously sat. NaHCO3-sol. until neutralized, saturated with solid NaCl, separated phases, dried organic layer over Na2SO4. Removal of the solvent in vacuum to give the title compound as an orange liquid (10.85 g, 94%). MS (ISP) 178.1 [(M+H)+] and 180.0 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]2[S:24][CH:25]=[CH:26][C:22]=2[CH:21]=1.C([O-])(O)=O.[Na+]>ClCCl>[S:24]1[CH:25]=[CH:26][C:22]2[CH:21]=[C:20]([NH:19][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[CH3:12])(=[O:10])=[O:9])[CH:28]=[CH:27][C:23]1=2
Reactant: Nc1ccc2sccc2c1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2sccc2c1
Reaction time: 0.08 h
Yield: 74 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (47 mg, 0.21 mmol) in dichloromethane (2 mL) was added pyridine (40 μL, 0.50 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-benzo[b]thiophene [20] (30 mg, 0.20 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a dark brown solid (50 mg, 74%), single spot at Rf 0.58 (3:1 hexane:ethyl acetate). mp 108.5-109.0° C., HPLC purity 99% (tR 2.20 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.87 (1H, d, J=7.9 Hz), 7.70 (1H, d, J=8.7 Hz), 7.54-7.51 (2H, m), 7.44 (1H, d, J=5.4 Hz), 7.21 (1H, d, J=5.4 Hz), 7.16 (1H, t, J=7.9 Hz), 6.98 (1H, dd, J=8.7, 2.2 Hz), 6.73 (1H, s, N—H), 2.74 (3H, s). LCMS: 336.07. FAB-MS (MH+, C15H12ClNO2S2): calcd 336.9998, found 337.0004.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].[O:12]=[C:13](C(OCC)=O)[C:14](OCC)=[O:15].[OH-].[K+]>C(O)(=O)C.O>[C:14]1(=[O:15])[C:1]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=[CH:3][C:2]=2[NH:11][C:13]1=[O:12]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2ccc3ccccc3c2C1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of 2-naphthylamine (8.0 g, 56 mmol) in glacial acetic acid (500 mL) was treated with diethyl ketomalonate (9.2 mL, 62 mmol), heated to 120° C. for 4 hours, and concentrated. The concentrate was suspended in a solution of KOH (36.8 g, 690 mmol) in water (736 mL) and stirred overnight with a stream of air blowing into the solution. The resulting mixture was filtered and the filtrate was adjusted to approximately pH 3 with concentrated HCl. The resulting suspension was cooled to 0° C. and filtered. The filter cake was dried under vacuum to provide the desired product (8.76 g, 79%). MS (DCI) m/e 198 (M+H)+, 215 (M+NH4)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[C:8]([C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[Br:7][C:5]1[CH:6]=[C:2]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:10]([CH:11]=2)[C:8]#[N:9])[S:3][CH:4]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1C#N
Reactant: Brc1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Oc1ccc(-c2cc(Br)cs2)cc1C#N

Procedure:
A 2 mL microwave vial was charged with 2,4-dibromothiophene (20 mg, 0.08 mmol), (3-cyano-4-isopropoxyphenyl)boronic acid (17 mg, 0.08 mmol), potassium carbonate (35 mg, 0.25 mmol) and 3:1 mixture of DME/H2O (4 mL). The reaction mixture was degassed by bubbling N2 through the stirred solution for 10 min. Pd(PPh3)4 (7 mg, 0.006 mmol) was added and the solution degassed for an additional 2 min. The vial was subjected to microwave irradiation at 70° C. for 30 min or until starting material consumed. 5-(4-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-3 was used in the next experiment without purification. LCMS-ESI (m/z) calculated for C14H12BrNOS: 320.9; no M+ observed, tR=4.15 min.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][N:22]2[CH2:25][CH2:26][O:27]C2CCCCO2)=[CH:18][CH:17]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[N:21][N:22]3[CH2:25][CH2:26][OH:27])=[CH:18][CH:17]=2)[CH2:4][CH2:3]1
Reactant: Fc1ccc2cnn(CCOC3CCCCO3)c2c1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@@H](Oc2ccc3cnn(CCO)c3c2)c2ccccc21
Reaction time: 0.33 h

Procedure:
Intermediate A (212 mg, 1.3 mmol) was added portionwise to a suspension of sodium hydride (60% in mineral oil, 120 mg, 3.0 mmol) in DMF (3 mL) at RT and stirred for 20 min. A solution of Intermediate 11a (264.3 mg, 1.0 mmol) in DMF (1 mL) was then added dropwise and the resulting mixture stirred at 60° C. for 2.5 h. After cooling, the mixture was diluted with EtOAc (50 mL) and poured onto ice water. The organic layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and concentrated in vacuo. The residue was loaded on to a SCX-2 cartridge, eluting with MeOH then 2M NH3 in MeOH. Further purification by FCC, using 0-10% [2M NH3 in MeOH] in DCM to give the title compound as a brown oil. LCMS (Method 1): Rt 1.80 min, m/z 323 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([CH3:17])[C:12](=[O:18])[N:11]([C@@H](C1C=CC=CC=1)C)[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@:13]1([CH3:17])[C:12](=[O:18])[NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(NC(=O)OC(C)(C)C)CCC[C@]2(C)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@]12CCC[C@]1(C)C(=O)NC2
Yield: 89.4 %

Procedure:
(1S,5S)-1-(tert-Butoxycarbonylamino)-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (77 mg, 0.22 mmol) was dissolved in ethanol (6.0 mL). 10% palladium-carbon (50% wet) (69 mg) was added, and the mixture was stirred in a hydrogen atmosphere at 45° C. for 19.5 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 50 mg of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:11]([OH:13])=O)=[O:7])([CH3:4])[CH3:3].C1C=CC2N(O)N=NC=2C=1.[NH2:35][C@H:36]([C:49]([NH:51][C@H:52]([C:55]([NH:57][C@H:58]([C:64]([NH:66][C@H:67]([C:71]([N:73]1[CH2:114][CH2:113][CH2:112][C@H:74]1[C:75]([NH:77][C@H:78]([C:83]([NH:85][C@H:86]([C:90]([NH:92][C@H:93]([C:97]([NH:99][C@H:100]([C:105]([O:107][C:108]([CH3:111])([CH3:110])[CH3:109])=[O:106])[CH2:101][CH:102]([CH3:104])[CH3:103])=[O:98])[C@@H:94]([CH3:96])[OH:95])=[O:91])[CH:87]([CH3:89])[CH3:88])=[O:84])[CH2:79][CH:80]([CH3:82])[CH3:81])=[O:76])=[O:72])[C@@H:68]([CH3:70])[OH:69])=[O:65])[CH2:59][CH2:60][C:61](=[O:63])[NH2:62])=[O:56])[CH2:53][OH:54])=[O:50])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:14]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:10]([C:11]([NH:35][C@H:36]([C:49]([NH:51][C@H:52]([C:55]([NH:57][C@H:58]([C:64]([NH:66][C@H:67]([C:71]([N:73]1[CH2:114][CH2:113][CH2:112][C@H:74]1[C:75]([NH:77][C@H:78]([C:83]([NH:85][C@H:86]([C:90]([NH:92][C@H:93]([C:97]([NH:99][C@H:100]([C:105]([O:107][C:108]([CH3:109])([CH3:110])[CH3:111])=[O:106])[CH2:101][CH:102]([CH3:103])[CH3:104])=[O:98])[C@@H:94]([CH3:96])[OH:95])=[O:91])[CH:87]([CH3:89])[CH3:88])=[O:84])[CH2:79][CH:80]([CH3:81])[CH3:82])=[O:76])=[O:72])[C@@H:68]([CH3:70])[OH:69])=[O:65])[CH2:59][CH2:60][C:61](=[O:63])[NH2:62])=[O:56])[CH2:53][OH:54])=[O:50])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])=[O:13])[CH2:9][CH2:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)[C@@H](C)O)C(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)[C@@H](C)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)[C@@H](C)O)C(C)C
Temperature: -22 °C

Procedure:
843 mg Z-Glu(OtBU)-OH and 676 mg HOBt are dissolved in 10 ml DMF. After cooling to -22° C., 2.82 g H-Lys(Boc)-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-OtBu (Example VII.2) and 517 mg DCCI, dissolved in 2 ml DMF, are added to the solution. After stirring at -22° C. for some time, the DCHU is filtered out and the filtrate is evaporated to dryness.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:2]1
Reactant: OCCCC1CCCOC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCC1CCCOC1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To the solution of 3-(tetrahydro-2H-pyran-3-yl)propan-1-ol (10.35 g, 0.0719 mol) in CH2Cl2 (200 mL) was added Dess-Martin periodinane (61.24 g, 0.1438 mol). The mixture was stirred at rt. When the reaction was over, the solution was poured into Et2O (300 mL) and anhydrous K2CO3 (19.84 g, 0.1438 mol) was added. The mixture was filtered. The filtrate was dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified through column chromatography to give 3-(tetrahydro-2H-pyran-3-yl)propanal (8.25 g, 80%).
Reaction SMILES: ClC(OC(Cl)C)=O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:30][CH2:29][N:28](CC4C=CC=CC=4)[CH2:27][C:21]=3[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C>ClCCCl>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:30][CH2:29][NH:28][CH2:27][C:21]=3[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
1-Chloroethyl chloroformate (732 mg, 5.12 mmol) was added dropwise to the solution of N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (1.07 g, 2.56 mmol) and diisopropylethyl amine (660 mg, 5.12 mmol) in 1,2-dichloroethane (10 mL, anhydrous) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hr. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at room temperature overnight. Solvent was removed in vacuo, residue was dissolved in ethyl acetate and was washed by sodium bicarbonate's aqueous solution, brine and dried over sodium sulfate. Solvent was removed in vacuo and residue was triturated by diethyl ether to yield the product as a light brown solid (303 mg, 36%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([O:19][C:20]4[CH:25]=[C:24]([F:26])[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][C:21]=4[F:31])[C:15]3=[O:32])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:31][C:21]1[CH:22]=[C:23]([S:27]([CH3:30])(=[O:29])=[O:28])[C:24]([F:26])=[CH:25][C:20]=1[O:19][C@H:16]1[CH2:17][CH2:18][N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[CH:3][C:2]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[C:15]1=[O:32]
Reactant: CS(=O)(=O)c1cc(F)c(O[C@H]2CCN(C3CCN(c4ncc(Br)cn4)CC3)C2=O)cc1F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCN(C3CCN(c4ncc(-c5ccccc5)cn4)CC3)C2=O)cc1F
Temperature: 95 °C
Yield: 64 %

Procedure:
(S)-1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one (Example 90; 80 mg, 0.15 mmol) was dissolved in dioxane (2 mL) and phenylboronic acid (28 mg, 0.23 mmol), 2M Na2CO3 (301 μL, 0.60 mmol) and Pd(PPh3)4 (17 mg, 0.015 mmol) were added and the reaction heated to 95° C. under nitrogen for 2 hours. The reaction was cooled to ambient temperature and partitioned between water and CH2Cl2, and the organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (70% EtOAc in hexanes) to afford impure material. The material was then purified on C18 reverse phase chromatography (20 to 95% ACN in water) to afford (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1-(1-(5-phenylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (51 mg, 0.096 mmol, 64% yield) as a white solid. Mass spectrum (apci) m/z=529.3 (M+H).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)=[O:6]>C(O)(=O)C.C(OCC)(=O)C>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[C:11]=1[Br:1])=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
Bromine (1.69 g, 0.54 ml, 10.54 mmol) was added dropwise to a stirred solution of methyl-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (compound 49α, 1.85 g, 7.03 mmol) in acetic acid (20 ml) at 10° C. The resulting reaction mixture was stirred at room temperature for 15 hr. The progress of the reaction was monitored by TLC. Acetic acid was removed from the reaction mixture under reduced pressure and residue obtained was dissolved in ethyl acetate (150 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (50 ml) followed by washing with brine (50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was washed with a mixture of ethyl acetate in hexanes (10:90) to obtain the title compound (2.1 g, 87.5%)
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[C:4]([C:24]([CH:20]1[C:21]([CH3:23])([CH3:22])[C:19]1([CH3:27])[CH3:18])=[O:25])=[CH:5][NH:6]2
Reactant: Fc1c(F)c(F)c2[nH]ccc2c1F
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3c(F)c(F)c(F)c(F)c23)C1(C)C
Yield: 11.5 %

Procedure:
A mixture of 4,5,6,7-tetrafluoroindole (Matrix Scientific, 1.0 g. 5.3 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.4 mL, 6.4 mmol), zinc chloride (1.0 M solution in Et2O, 6.4 mL, 6.4 mmol) and the product of Example 1A (7.9 mmol) in 40 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.19 g, 0.61 mmol, 12% yield). MS (DCI/NH3) m/z 314 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][C:43]#[C:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42][C:43]#[C:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCC(O)(C#CCBr)CC
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(C#CCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 62.5 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (60.8 mg, 0.105 mmol), 6-bromo-3-ethyl-4-hexyn-3-ol (108 mg, 0.525 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=5:1, developed twice) to give the title compound as a colorless oil (38.4 mg, 63%).