Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:44]([Cl:45])=[CH:43][C:5]2[NH:6][C:7]([O:9][CH:10]([C:19]3([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=5)=[CH:31][CH:30]=4)[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]3)COCC[Si](C)(C)C)=[N:8][C:4]=2[CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:44]([Cl:45])=[CH:43][C:5]2[NH:6][C:7]([O:9][CH2:10][C:19]3([C:29]4[CH:30]=[CH:31][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=5)=[CH:33][CH:34]=4)[CH2:20][CH2:21][N:22]([S:25]([CH3:28])(=[O:26])=[O:27])[CH2:23][CH2:24]3)=[N:8][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCC(Oc1nc2cc(Cl)c(Cl)cc2[nH]1)C1(c2ccc(-c3cccc(C#N)c3)cc2)CCN(S(C)(=O)=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(COc2nc3cc(Cl)c(Cl)cc3[nH]2)(c2ccc(-c3cccc(C#N)c3)cc2)CC1
Temperature: 60 °C
Yield: 44.9 %

Procedure:
To a solution of 0.044 g of crude 4′-{4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-1-methanesulfonyl-piperidin-4-yl}-biphenyl-3-carbonitrile from the previous step (˜0.05 mmol) in 2 mL of tetrahydrofuran was added tetrabutylammonium fluoride (1M in THF, 0.1 mL, 0.1 mmol, 2 eq) and the resulting mixture was heated to 60° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with 10 mL of ethyl acetate and washed with H2O and saturated brine. The organic extracts were combined and dried over Na2SO4, filtered and concentrated by rotary evaporation to give the crude product as a pale foam. Purification by flash silica gel chromatography eluting with a gradient of 20-70% ethyl acetate in hexane gave a pale foam which was re-purified by reverse phase preparative HPLC to yield 0.016 g of the desired product 4′-[4-(5,6-dichloro-1H-benzoimidazol-2-yloxymethyl)-1-methanesulfonyl-piperidin-4-yl]-biphenyl-3-carbonitrile 56 as a white foam. 1H NMR (300 MHz, CDCl3): δ 7.84-7.83 (t, 1H), 7.80-7.77 (dt, 1H), 7.66-7.44 (m, 8H), 4.54 (s, 2H), 3.64-3.40 (d, 2H), 3.02-2.95 (t, 2H), 2.74 (s, 3H), 2.60 (br. s, 1H), 2.47-2.43 (d, 2H), 2.22-2.12 (t, 2H). MS (ESI): Calcd m/z for C27H24Cl2N4O3S.H+=554.1. Found m/z=554.6/556.7 [(M+1)+/(M+3)+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:26]=[C:25]([OH:27])[C:24]([CH3:28])=[CH:23][CH:22]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:27][C:25]1[CH:26]=[C:21]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:22]=[CH:23][C:24]=1[CH3:28]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1cc2c(Cl)c(C#N)cnc2c(OC)c1OC
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2c(OC)c1OC
Yield: 76.3 %

Procedure:
A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile, 0.148 g of 5-amino-o-cresol, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.279 g of 4-(3-hydroxy-4-methyl-phenylamino)-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid, mp 200° C. (decomposed); mass spectrum (EI, m/e): M 365.1356.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][C:6](=O)[C:5]=2[CH:4]=[CH:3]1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:6]1[CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C:10]2[N:2]([CH3:1])[CH:3]=[CH:4][C:5]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NN
Reactant: Cn1ccc2c1CC(c1ccccc1)CC2=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1ccc2c1CC(c1ccccc1)CC2=NNC(=N)N
Yield: 52.5 %

Procedure:
A mixture of 1-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.50 g), aminoguanidine hydrochloride (0.26 g), concentrated hydrochloric acid (0.11 ml), water (0.11 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the mixture was added 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 4-guanidinoimino-1-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 7) (0.37 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c(N)c1
Yield: 93 %

Procedure:
3.0 g of 3,4-diaminobenzoic acid was suspended in methanol, and 1.86 ml of thionyl chloride was then added dropwise. Afterward, thionyl chloride was further added as much as 0.5 ml twice, and the suspension was then heated under reflux for 11 hours. Next, thionyl chloride and methanol were distilled off, and the residue was dissolved in methylene chloride, washed with a 0.5N aqueous sodium hydroxide solution and a saturated sodium chloride solution, and then dried over sodium sulfate. After the solvent was distilled off, the residue was sludged with n-hexane to obtain 3.04 g (93%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16](O)=[O:17])\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21].CN(C)C=O.S(Cl)([Cl:31])=O>ClCCl>[OH:19][C:5]1[C:6]([CH2:10][CH:11]=[C:12]([CH3:13])[CH2:14][CH2:15][C:16]([Cl:31])=[O:17])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[C:3]2[C:4]=1[C:20](=[O:21])[O:22][CH2:23]2
Reactant: O=S(Cl)Cl
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)Cl)C(=O)OC2

Procedure:
A solution of mycophenolic acid (320 g, 1 mol) and dimethylformamide (0.1 g) in dichloromethane (3.2L) at reflux was treated dropwise with thionyl chloride (82 mL, 1.12 mol). After one hour additional heating at reflux, the volatiles were distilled at reduced pressure leaving a gray solid residue of (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoyl chloride which was cooled and dissolved in anhydrous tetrahydrofuran (1L).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)=[CH:17][CH:16]=1)=[O:13]>>[F:29][C:28]([F:31])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:12](=[O:13])[N:4]([C:3]3[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=3[F:1])[CH3:5])=[CH:16][CH:17]=2)=[N:23][CH:24]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CNc1ccc(F)cc1F
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccc(F)cc1F

Procedure:
The title product was prepared from 2,4-difluoro-N-methylaniline and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (37%, white crystals). HPLC-MS m/z=425.1 (M+1), Rt: 4.90 min.
Reaction SMILES: [CH:1]([C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)=O.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:21][CH2:20]1.Cl.C([BH3-])#N.[Na+]>CO.[Cl-].[Na+].O>[CH:5]1[C:4]2[C:3]3([CH2:1][N:19]4[CH2:20][CH2:21][CH:22]([NH:25][C:26]5[N:27]=[CH:28][CH:29]=[CH:30][N:31]=5)[CH2:23][CH2:24]4)[CH2:17][CH:10]([C:11]4[C:16]3=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=CC12CC(c3ccccc31)c1ccccc12
Reactant: c1cnc(NC2CCNCC2)nc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: c1cnc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)nc1
Reaction time: 23 h
Yield: 19.4 %

Procedure:
9-Formyl-9,10-dihydro-9,10-methanoanthracene (0.683 g, 3.1 mmol) was stirred for 1 hour at room temperature in methanol (7.0 mL) with 2-(4-piperidylamino)pyrimidine hydrochloride (1.000 g, 4.7 mmol, prepared as described below) and activated, powdered, 3 angstrom molecular sieves (0.820 g). The pH was initially adjusted to 6.5 with methanolic hydrogen chloride. Sodium cyanoborohydride (0.137 g, 2.2 mmol) was added and the tan suspension stirred for 23 hours. The suspension was poured into strongly basic (NaOH) brine solution (pH>11) and extracted with methylene chloride. The combined extracts were dried (sodium sulfate) and concentrated to give the crude product. Flash chromatography on silica gel using 15% acetone/hexanes provided the title compound as a white solid (0.225 g, 0.6 mmol, 20%). Using a procedure similar to that described in Example 87, the hydrochloride salt was obtained, mp 290° C. (dec); MS(CI): 456 (M+H); NMR (250 MHz, DMSO-d6): 9.87(br m, 1H), 8.38-8.32(m, 2H), 7.64(br m, 1H), 7.37-7.31(m, 4H), 7.03-6.94(m, 4H), 6.70-6.63(m, 1H), 4.46(s, 1H), 4.34-4.32(m, 2H), 4.16(br m, 1H), 3.60-3.34(m, 4H), 2.73(s, 2 H), 2.11-1.88(m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C@H:11]3[O:26][C:25](=[O:27])[CH2:24][C@H:23]([OH:28])[C:22]([CH3:30])([CH3:29])[C:21](=[O:31])[C@H:20]([CH3:32])[C@@H:19]([OH:33])[C@@H:18]([CH3:34])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]3)=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:35].[OH:36]CC([C@H]([C@@H]([C@@H](CO)O)O)O)=O.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CC#N.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C@H:11]3[O:26][C:25](=[O:27])[CH2:24][C@H:23]([OH:28])[C:22]([CH3:29])([CH3:30])[C:21](=[O:31])[C@H:20]([CH3:32])[C@@H:19]([OH:33])[C@@H:18]([CH3:34])[CH2:17][CH2:16][CH2:15][C@H:14]4[C@@H:13]([O:36]4)[CH2:12]3)=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:35]
Reactant: Cc1nc2cc([C@@H]3CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O3)ccc2n1C
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cc1nc2cc([C@@H]3C/C=C/CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O3)ccc2n1C
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1nc2cc([C@@H]3C[C@@H]4O[C@H]4CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O3)ccc2n1C
Temperature: 0 °C

Procedure:
To a solution of 48 (24 mg, 0.0495 mmol) in 0.75 mL CH3CN/DMM—1/1 at rt were added successively 0.46 mL of a buffer solution (Na2B4O7.10 H2O [0.05M] in Na2EDTA [4.10−4M]), Bu4N(HSO4) (0.67 mg, 0.0019 mmol) and fructose-derived ketone (10.2 mg, 0.0396 mmol). The reaction mixture is cooled to 0° C. and were added separately, in a same time over 1 h30, Oxone® (42.6 mg, 0.089 mmol) in 0.6 mL Na2EDTA and K2CO3 (39.7 mg, 0.287 mmol) in 0.6 mL H2O. The solution is stirred 1 h30 at 0° C. and then is quenched with H2O, extracted 3 times with 10 mL AcOEt. The combined organic layers are dried (MgSO4) and concentrated in vacuum. Purification by flash column chromatography (Hexane/Acetone/MeOH—50/45/5) afforded 49 in a 8/1 ratio as white crystals.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[H+].[B-](F)(F)(F)F.N([O-])=O.[Na+].[CH2:22]([P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH:23]=[CH2:24]>O.CC([O-])=O.CC([O-])=O.[Pd+2].CO>[CH2:30]([O:29][P:25]([CH2:22]/[CH:23]=[CH:24]/[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1)(=[O:32])[O:26][CH2:27][CH3:28])[CH3:31]
Reactant: C=CCP(=O)(OCC)OCC
Reactant: Cc1cc(N)cc(C)c1C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CO
Product: CCOP(=O)(C/C=C/c1cc(C)c(C=O)c(C)c1)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Amino-2,6-dimethylbenzaldehyde (3.0 g, 20.1 mmol) was taken up in enough 42% HBF4 until the suspension stirred well and then was cooled to 0° C. To this was added a solution of NaNO2 (1.39 g, 20.1 mmol) in water (10 mL) slowly. After 30 min at 0° C., MeOH (50 mL) was added followed by Pd(OAc)2 (677 mg) and diethyl allylphosphonate (5.38 g, 30.2 mmol). The reaction mixture was heated to 80° C. for 30 min and the suspension was filtered through Celite, washed with CH2Cl2, and the filtrate was extracted with CH2Cl2. The combined organic layers were washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a gradient of heptane/EtOAc (10:1 to 5:1 then followed by 100% EtOAc) to give [(E)-3-(4-formyl-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester as a light yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:24]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][CH2:2][CH2:3][O:4][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@H:25]([NH:24][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: OCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OCCBr)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
2-Bromo-ethanol (0.61 mL, 8.03 mmol), followed by PPh3 (3.16 g, 12.05 mmol) was added to a solution of Boc-Tyr-OMe (2.85 g, 9.64 mmol) in anhydrous THF (50 mL). The mixture was cooled to 0° C. and DEAD (5.5 mL of 40% wt solution in toluene, 12.05 mmol) was added. The mixture was allowed to warm at room temperature and was stirred overnight. After the reaction was finished, the solvent was evaporated and the residue dissolved in EtOAc (100 mL) was washed with NaOH (0.1 M, 2×50 mL), followed by brine. The organic phase was dried over Na2SO4 and evaporated. The crude product was purified by flash column chromatography (SiO2, step-wise gradient from 2-40% EtOAc in Hexanes) to give 1A (1.61 g, 50%) as a white solid. 1H NMR (600 MHz, CDCl3): δ 7.04 (2H, d, J=8.4 Hz), 6.84 (2H, d, J=8.4 Hz), 4.96 (1H, d, J=7.8 Hz), 4.51-4.58 (1H, m), 4.27 (2H, t, J=6.6 Hz), 3.71 (3H, s), 3.62 (2H, t, J=6.6 Hz), 3.06 (1H, dd, J=13.8, 5.4 Hz), 3.00 (1H, dd, J=13.8, 5.4 Hz), 1.42 (9H, s); 13C NMR (150 MHz, CDCl3): δ 172.3, 157.2, 155.1, 130.4, 128.8, 114.8, 79.9, 67.9, 54.5, 52.2, 37.5, 29.1, 28.3; MS (ESI, m/z): 424 (M+Na)+.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([O:17]C)=[O:16])=[C:10]([OH:19])[CH:9]=[CH:8]2)#[N:4].Cl>O.CO>[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([OH:17])=[O:16])=[C:10]([OH:19])[CH:9]=[CH:8]2)#[N:4]
Reactant: COC(=O)c1c(O)ccc2cc(C#N)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc2c(C(=O)O)c(O)ccc2c1
Reaction time: 24 h
Yield: 65.7 %

Procedure:
A solution prepared by dissolving 71 g of potassium hydroxide in 1.5 liter of water was added to a solution prepared by dissolving 24.0 g of 6-cyano-1-methoxycarbonyl-2-naphthol in 4.7 liters of methanol, followed by stirring at 50°-60° C. for 24 hours. After cooling, the reaction mixture was made to an acidic solution with addition of 10% hydrochloric acid. The precipitate was collected by filtration and washed with a small amount of water to obtain 14.8 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[N:25]1[CH:26]=[CH:27][N:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=12.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O.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>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[CH:33][N:28]6[CH:27]=[CH:26][N:25]=[C:29]6[CH:30]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: OB(O)c1ccn2ccnc2c1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccn4ccnc4c3)cc2)C1
Temperature: 95 °C
Yield: 51.1 %

Procedure:
A vial was charged with a slurry of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.256 mmol), imidazo[1,2-a]pyridin-7-ylboronic acid (83 mg, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.026 mmol) and tripotassium phosphate (217 mg, 1.022 mmol) in absolute ethanol (5.0 mL) and water (5.00 mL) then purged with nitrogen and sealed with a standard teflon septa (crimped aluminum seal). The reaction was then heated in an aluminum block at 95° C. for 6 h. The resulting yellow solution was evaporated in vacuo to a residue that was triturated in DMSO, filtered through a nylon syringe adapter, then purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA). The desired product fractions were combined, treated with saturated aqueous sodium bicarbonate and evaporated to a residue that was slurried in 5% MeOH in dichloromethane and filtered through a short pad of silica (˜2 g). The filtrate was evaporated in vacuo to afford the title compound as a tan solid (56 mg, 48.6%). MS(ES)+ m/e 429.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]1=[O:1])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1ccc(C)cc1=O
Yield: 77 %

Procedure:
As described for example 320a, 2-hydroxy-4-methyl-pyridine was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 40:60) afforded the title compound as a colorless liquid (yield: 77%). MS: m/e=196.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[C:22]([CH3:26])[NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[C:22]([CH3:26])[C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Reactant: Cc1[nH]nc(N)c1C#N
Product: Cc1nn2c(C(F)(F)F)cc(-c3ccc(F)c(Cl)c3)nc2c1C#N
Yield: 68.5 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (243 mg, 69%). MS (ISP) 355.0 [(M+H)+]; mp 196° C.
Reaction SMILES: Cl[C@@H:2]1[C@H:19]2[O:20][C@:18]32[C@:13]([CH3:28])([CH2:14][CH2:15][C@H:16]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17]3)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C:7](=[O:29])[C@H:6]2[CH2:30][C@@H:5]12>C(O)(=O)C.O1CCCC1.[Zn]>[OH:20][C@@:18]12[CH2:17][C@@H:16]([O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:15][CH2:14][C@:13]1([CH3:28])[C@@H:12]1[C@H:3]([C@H:4]3[C@@:8]([CH2:10][CH2:11]1)([CH3:9])[C:7](=[O:29])[C@H:6]1[CH2:30][C@@H:5]31)[CH:2]=[CH:19]2
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3C=C[C@]2(O)C1
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A solution of 196 g of 7α-chloro-5,6β-epoxy-15β,16β-methylene-3β-pivaloyloxy-5β-androstan-17-one in 500 ml of acetic acid and 800 ml of tetrahydrofuran is combined at 70° C. with 392 g of zinc dust in two portions at an interval of 30 minutes and stirred for one hour at this temperature. After cooling, the zinc is filtered off over "Celite" and washed with 5 l of methylene chloride. The combined filtrates are combined with 1.5 l of water and neutralized under agitation by adding solid sodium bicarbonate. The organic phase is then washed with water, dried over sodium sulfate, and concentrated under vacuum. By trituration of the resultant solid product with ethyl acetate, 134.7 g of 5-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androst-6-en-17-one is obtained, mp 242°≥243° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH:30][C:39](=[O:41])[CH3:40])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(OCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCOc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 0 °C

Procedure:
The product of Example 131 (61 mg, 0.14 mmol)was dissolved in CH2Cl2 (2 mL) and stirred at 0° C. under Ar. Triethylamine (0.1 mL) was added followed by the addition of acetic anhydride (0.2 g, 2 mmol). The reaction was allowed to slowly warm to 23° and stir for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed eluted with 10-30% EtOAc/CH2Cl2 to give the title compound as a white-amorphous solid. mp 75-79°, LC MS m/z=469 (MH+) Retention time=1.95 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1(C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1N2CCN(CC2)C1>CC1C=CC=CC=1C>[CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([Cl:7])[Cl:8])[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Yield: 20.1 %

Procedure:
13 g of diethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1,1-dicarboxylate were dissolved in 50 g of o-xylene and 20 g of triethylenediamine were added. The mixture was then heated to the boil for 6 hours. After cooling, ice-cold dilute hydrochloric acid was added so that a neutral or weakly acid pH value resulted. The organic phase was separated off and dried with Na2SO4 and the xylene was distilled off in vacuo. The residue weighed 10 g. Fractional distillation gave 2 g of ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1-carboxylate as well as 6.7 g of recovered starting material. The yield was thus 40%.