Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:27][CH2:28][F:29].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOCC>[F:29][CH2:28][CH2:27][O:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: FCCBr
Reactant: O=c1cc(-c2ccccc2)c2ccc(OC3CCCCO3)c(O)c2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: O=c1cc(-c2ccccc2)c2ccc(OC3CCCCO3)c(OCCF)c2o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
To 8-hydroxy-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one (40 mg, 0.12 mmol) and 1-bromo-2-fluoroethane (22 mg, 0.17 mmol) in 0.4 mL NMP was added Cs2CO3 (46 mg, 0.14 mmol). The mixture was stirred at rt for 5 h under Ar atmosphere and diluted with ether (40 mL). It was washed with water (3×30 mL) and dried over MgSO4 and concentrated. The crude product was purified with chromatography (hexane/EtOAc) to afford 8-(2-fluoroethoxy)-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one as a white solid (34 mg, 73%). MS (ESI) m/z 385 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][O:18][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCCC(CO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-benzyloxycarbonyl-3-hydroxymethyl-piperidine (1.29 g, 5.24 mmol, 1 eq) in CH2Cl2 (50 mL) at 0° C. was added diisopropylethylamine (2.7 mL, 15.72 mmol, 3 eq) followed by methanesulfonylchloride (0.61 mL, 7.86 mmol, 1.5 eq) via syringe. Let stir 10 minutes and removed the cooling bath. After 30 minutes the reaction was complete by thin layer chromatography analysis. Removed the CH2Cl2 under reduced pressure and used material crude in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(S(F)(F)[F:21])CC>C(Cl)Cl>[F:1][C:2]1[C:3]([C:8]2([F:21])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2nccnc2F)CCOCC1
Solvent: ClCCl
Product: Fc1nccnc1C1(F)CCOCC1
Reaction time: 2 h

Procedure:
To a solution of 4-(3-fluoropyrazin-2-yl)tetrahydro-2H-pyran-4-ol (0.123 g, 0.621 mmol) in DCM (2 mL) cooled to 0° C. was added dropwise dast (0.164 mL, 1.241 mmol). The resulting mixture was stirred for 2 hr. Reaction was quenched with dropwise addition of saturated NaHCO3 solution and back extracted with DCM to produce product.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:30])[CH2:27][C:26]2[C:21](=[CH:22][C:23]([CH3:29])=[C:24]([CH3:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:30][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][C:23]([CH3:29])=[C:24]([CH3:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2cc(C)c(C)cc2C1
Reactant: O=C(O)c1cccc2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2cc(C)c(C)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (400 mg, 2.27 mmol), 2-amino-5,6-dimethyl-indan-2-carboxylic acid ethyl ester (636 mg, 2.72 mmol), HATU (1.30 g, 3.41 mmol) in anhydrous DMF (15 mL) is added DIPEA (563 μL, 3.41 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (78) as white solid (817 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]=1[C:13]#[N:14]>CS(C)=O>[C:2]1([NH:1][C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:12]=2[C:13]#[N:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1c(Nc2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
Aniline (0.168 g, 1.8 mmol) was dissolved in dimethyl sulfoxide (3 mL) and stirred under argon at room temperature. Sodium hydride (0.0043 g, 1.8 mmol) was added and a deep purple color developed while the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0° C. in an ice bath and the product of example 12a above, 2-fluoro-6-phenylbenzonitrile, (0.295 g, 1.5 mmol) dissolved in dimethyl sulfoxide (2 mL) was added and the mixture stirred at room temperature overnight. The solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water (5×), brine (1×) dried over anhydrous Na2SO4 filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0-30% CH2Cl2 in hexane to give the title compound as a white amorphous solid. ES (+) MS m/e=271 (MH+)
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH2:23][N:24]([CH3:26])[CH3:25])[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[NH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>CN(C=O)C.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>[CH3:25][N:24]([CH2:23][C:21]1[N:20]=[N:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:33]4[CH:34]=[CH:35][C:30]([C:28]([NH2:27])=[O:29])=[CH:31][CH:32]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH:22]=1)[CH3:26]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CN(C)Cc1cn(-c2ccc(Nc3ncc(Br)n4ccnc34)cc2)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN(C)Cc1cn(-c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4)n4ccnc34)cc2)nn1
Yield: 6.8 %

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(4-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-amine (63 mg, 0.152 mmol), 4-(aminocarbonyl)phenylboronic acid (50.3 mg, 0.305 mmol) 1.5 M Na2CO3 (0.813 mL, 1.22 mmol) and Pd(PPh3)4 (44.0 mg, 0.0381 mmol) in (2:1) DMF-dioxane (1.8 mL). Purification of the crude material by Isolute FlashSilicaII Cartridge chromatography eluting with 95:5 DCM:NH3 (7M in MeOH) followed by reverse phase preparative HPLC, affords the title compound as a white solid (4.7 mg, 7%). LCMS: Rt 1.92 min (96%) m/z (APCI) 455 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.24 (6H, s), 3.61 (2H, s), 7.51 (1H, br s), 7.64 (1H, s), 7.80 (1H, s), 7.85-7.91 (4H, m), 8.08-8.12 (3H, m), 8.16 (1H, br s), 8.36 (2H, d), 8.66 (1H, s), 10.09 (1H, s).
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C@H:18]3[CH2:22][C@H:21]([OH:23])[C@@H:20]([CH2:24][OH:25])[CH2:19]3)[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.Cl[S:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:44])=[O:43]>C(#N)C>[C@@H:1]1([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C@@H:18]3[CH2:19][C@H:20]([CH2:24][O:25][S:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])(=[O:43])=[O:44])[C@@H:21]([OH:23])[CH2:22]3)[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Reaction time: 2 h
Yield: 32.7 %

Procedure:
A neat mixture of (1S,2R,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-(hydroxymethyl)cyclopentanol (100. mg, 0.294 mmol) and 2,6-di-tert-butyl-4-methylpyridine (181 mg, 0.881 mmol) was dissolved in ACN (5.00 mL) before tert-butyl (chlorosulfonyl)carbamate (95.0 mg, 0.441 mmol, as prepared in Example 21c) was added. The reaction was stirred for 2 h before being quenched via addition of MeOH (2 mL). The resulting mixture was concentrated in vacuo and purified via silica gel chromatography eluting with a gradient of 10 to 20% MeOH in DCM to afford the title compound as an amorphous solid (50.0 mg, 33%). LC/MS: Rt=1.24 min, ES+ 520. (AA standard).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:20]3[C:21]([O:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:19]=3[F:18])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14]
Reactant: CCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cccc(F)c1B(O)O
Product: CCNC(=O)c1nnc2c(-c3c(F)cccc3OC)cccc2c1N

Procedure:
Using Method A, 4-amino-8-bromo-N-ethyl-cinnoline-3-carboxamide and 2-fluoro-6-methoxy-phenyl boronic acid were reacted to afford the title compound as a off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.50 (br, 1H), 7.90 (m, 1H), 7.74 (m, 2H), 7.36 (m, 1H), 6.84 (m, 2H), 3.70 (s, 3H), 3.52 (m, 2H), 1.25 (t, J=7.0 Hz, 3H). MS APCI, m/z=341 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:25]=[CH:24][C:23]2[CH:22]3[CH2:26][C:15]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]4)([C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=2[CH:13]=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[Cl:11][C:12]1[CH:25]=[CH:24][C:23]2[CH:22]3[CH2:26][C:15]([CH2:27][N:28]4[CH2:29][CH2:30][CH:31]([CH:34]=[O:35])[CH2:32][CH2:33]4)([C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=2[CH:13]=1
Reactant: OCC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
A solution of oxalyl chloride (4.51 g, 35.6 mmol) in dichloromethane (100 mL) was cooled to ←60° C. and was treated dropwise with dimethylsulfoxide (2.92 g, 37.4 mmol). The resulting solution was stirred at -65° C. for 15 min, then was treated dropwise with a solution of 1-((9RS,10RS)-2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinemethanol (8.40 g, 23.7 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at -65° C. for 1 h, then was treated with triethylamine (7.20 g, 71.2 mmol) and allowed to warm to room temperature. The mixture was then poured into 10% aqueous sodium hydroxide (100 mL) and was extracted with chloroform (3×150 mL). The organic extracts were washed sequentially with 1N aqueous sodium hydroxide (100 mL) and brine (100 mL), combined, dried (K2CO3), filtered and evaporated to leave the title compound as an amber foam (8.12 g, 23.1 mmol, 97%). 1H NMR (d6-DMSO): 9.57 (s, 1H, CHO), 7.25 (m, 4H), 6.94 (m, 3H), 4.33 (s, 1H, H--C(10)), 3.34 (m, 2H, CH2N), 2.87 (m, 2H, eq-H--C(2')), 2.50 (s, 2H, H--C(11)), 2.29 (m, 3H, ax-H--C(2'), H--C(4')), 1.75 (m, 2H, eq-H--C(3')), 1.46 (m, 2H, ax-H--C(3')).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8](C(C3C=CC=CC=3)=O)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1>O1CCOCC1.[OH-].[K+]>[Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1ccc2ccc(Br)nc21
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Brc1ccc2cc[nH]c2n1
Temperature: 25 °C

Procedure:
(6-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone, 586 was dissolved in 20 mL of dioxane and 20 mL of 2M KOH (aq). This was stirred at ambient temperature until analysis indicated all of the starting material had been consumed (2 to 4 hours). The reaction was diluted with 50 mL of ethyl acetate and washed with 2×25 mL of NaHCO3 (aq. satd.) and 25 mL of brine. The organic layer was dried with sodium sulfate, evaporated and purified by column chromatography. Combined steps 2 and 3 gave approximately 65% overall yield.
Reaction SMILES: ClCCl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1.[CH3:13][O:14]C(Cl)Cl>[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-].O>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]=[O:14])=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: COC(Cl)Cl
Reactant: c1ccc2c(c1)CCO2
Agent: [Ti+4]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCO2
Reaction time: 1 h
Yield: 61555.6 %

Procedure:
Titanium chloride (28 ml) was dropwise added to a dichloromethane (100 ml) solution containing 2,3-dihydrobenzofuran (10.0 g, 83.2 mmols) and dichloromethyl methyl ether (11.3 ml, 0.125 mmols), while cooling with ice. The mixture was stirred for 1 hour, while still cooling with ice, and then water was added thereto. Dichloromethane was removed under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified through silica-gel chromatography (hexane/ethyl acetate=1/1) to obtain 11.4 g (yield: 92%) of the target compound. This was oily.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]([NH:30][CH3:31])([CH3:29])[C:26]([NH2:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:30]([CH3:31])[C:25]([CH3:29])([CH3:24])[C:26](=[O:27])[N:28]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reactant: CNC(C)(C)C(N)=O
Product: CN1C(c2cc(-c3ccc(Cl)cc3)n(-c3ccc(Cl)cc3Cl)n2)=NC(=O)C1(C)C

Procedure:
Compound 14 was synthesized from 4b (249 mg, 0.68 mmol) and 5a (130 mg, 1.08 mmol) as a white solid (152 mg, 49%) in a manner similar to that described in Example 36. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.30-7.28 (m, 3H), 7.21 (d, 2H), 7.04 (d, 2H), 3.48 (s, 3H), 1.36 (s, 6H); ESMS m/z: 447.0 (M+1)
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5].C[O-].[Na+].[NH3:14]>C(O)CCC>[NH:5]=[C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[NH:14])[NH:10]1
Reactant: N
Reactant: N#Cc1ccccc1C#N
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCO
Product: N=C1NC(=N)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To 180 mi of n-butanol were fed 21 g (0.06325 mole) of a phthalonitrile represented by the formula (XXI) and 8.54 g (0.1581 mole) of sodium methoxide. The mixture was stirred at room temperature for 1 hour while blowing NH3 gas thereinto and, then, stirred with heating at 70°-80° C. for 3 hours (while blowing NH3 gas). After being cooled to room temperature, n-BuOH was removed by distillation. The concentrate was dissolved in 800 ml of chloroform and was washed well with water and with hot water. Water in the organic layer was removed with magnesium sulfate and chloroform was removed by distillation. The residue was recrystallized from hexane to obtain 21 g (yield: 95.1%) of a compound having the following formula (XXII). The compound is in the form of light yellow crystals and shows no melting point and a decomposition point of 205° C. The IR spectrum of this compound is shown in FIG. 8. ##STR53##
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.CN(C)C=O.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>N1C=CC=CC=1>[Si:32]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: -20 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
To 3α-hydroxy-5α-androstan-17-one (25.22 g, 290.5 g/mol, 86.8 mmol) dissolved in 65 mL of dry pyridine was added 65 mL of dry dimethylformamide, imidazole (14.77 g, 68.1 g/mol, 217 mmol), and t-butyldimethylsilylchloride (16.36 g, 151 g/mol, 109 mmol), and the reaction was allowed to stand at room temperature for 12 hours. The reaction mixture was then partitioned between 220 mL of water and 220 mL of ethyl acetate and the combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and absolute ethanol was added with cooling to -20° C. to give the titled compound (32 g, 91% yield).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[Cl:13].C([Li])CCC.[CH:19](N1CCCCC1)=[O:20].Cl>C(OCC)C>[Cl:13][C:3]1[CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:7]([Cl:8])[C:2]=1[CH:19]=[O:20]
Reactant: O=CN1CCCCC1
Reactant: FC(F)(F)c1cc(Cl)c(Br)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Yield: 66.6 %

Procedure:
1-Bromo-2,6-dichloro-4-trifluoromethylbenzene (80 g, 0.27 mol) was dissolved in anhydrous diethyl ether (480 ml) and the solution was cooled to -78° C. Butyllithium (2.5M solution in hexane, 100 ml) was added dropwise with stirring in an atmosphere of nitrogen while maintaining the temperature below -70° C. After stirring for a further 1 hour at -78° C. N-formylpiperidine (30.8 g, 0.27 mol) was added dropwise. The mixture was stirred at -78° C. overnight and allowed to warm slowly to 0° C. Hydrochloric acid (2M, 200 ml) was added dropwise to the solution with ice-cooling. The two layers were separated and the organic phase was washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The oily residue was dissolved in a mixture of ethyl acetate and petroleum spirit (b.p. 60°-80° C.) (1:10) and the solution was filtered through a column of silica. Evaporation of the filtrate and distillation of the resultant oil gave 2,6-dichloro-4-trifluoromethylbenzaldehyde (43.7 g) as a colourless liquid, b.p. 115° C. at 14 mmHg.
Reaction SMILES: [CH3:1][CH:2]([CH:9]=[CH2:10])[CH2:3][CH2:4][CH2:5][C@H:6]([OH:8])[CH3:7].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:8][C@@H:6]([CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:9]=[CH2:10])[CH3:7])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: C=CC(C)CCC[C@@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=CC(C)CCC[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
To a solution of (2R)-6-methyloct-7-en-2-ol (12 g, 84 mmol) in pyridine (16 mL) was added DMAP (0.51 g, 4.22 mmol) and the solution was stirred for 10 min. P-Toluenesulfonyl chloride (18.5 g, 97 mmol) was added to the reaction mass at 0° C. The reaction mass was allowed to come to room temperature and stirred overnight. Pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (200 mL). The organic solution was washed with aqueous 1.5 N HCl solution, saturated bicarbonate solution, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound (14.5 g, 32%). The crude compound was taken to the next step without further purification.
Reaction SMILES: Cl[C:2](/[CH:4]=[C:5](/[C:7]1[CH:8]=[CH:9][C:10]([O:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])\[CH3:6])=[O:3].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C1COCC1>[CH2:26]([N:28]([CH2:29][CH3:30])[C:2](/[CH:4]=[C:5](/[C:7]1[CH:8]=[CH:9][C:10]([O:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])\[CH3:6])=[O:3])[CH3:27]
Reactant: COC(=O)c1cc(/C(C)=C/C(=O)Cl)ccc1OC(C)c1ccccc1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OC(C)c2ccccc2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (E)-5-(2-chlorocarbonyl-1-methylvinyl)-2-(1-phenylethoxy)-benzoate (1.0 g, 2.79 mmol)in THF (50 mL) is added diethylamine (1.16 mL, 11.8 mmol), and the mixture is stirred at room temperature for 3 hours, after which time THF is removed in vacuo, and the residue is lssoved in CH2Cl2 (75 mL) and then washed with 1 N HCl (2×100 mL) and brine (1×50 mL), and dried over MgSO4. Chromatography (silica, 2:1 hexane/EtOAc) yields methyl (E)-5-(2-diethylcarbamoyl-1-methylvinyl)-2-(1-phenylethoxy)-benzoate.
Reaction SMILES: CS[C:3]([C:9]1[S:10][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)([CH3:8])[C:4]([O:6]C)=[O:5].[Na].CS.O>CO>[C:14]([C:11]1[S:10][C:9]([CH:3]([CH3:8])[C:4]([OH:6])=[O:5])=[CH:13][CH:12]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(SC)c1ccc(C(=O)c2ccccc2)s1
Agent: CS
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc(C(=O)c2ccccc2)s1
Yield: 67.7 %

Procedure:
Methyl α-methylthio-α-(5-benzoyl-2-thienyl)-propionate (320 mg) was dissolved in 1 ml of anhydrous methanol, and 1.0 ml (2.34 M) of a methanol solution of sodium salt of methyl mercaptan was added. The mixture was heated under reflux for 1 hour. In order to hydrolyze the ester, 1 ml of water was added and the mixture was heated under reflux for an additional 2 hours. After cooling, 20 ml of water was added, and the mixture was washed twice with 15 ml of methylene chloride. The aqueous layer was acidified to a pH of 1 with conc. hydrochloric acid, and extracted three times with 15 ml of methylene chloride. The organic layer was washed with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford 176 mg of α-(5-benzoyl-2-thienyl)propionic acid in a yield of 68%.