Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([SiH3:4])Cl.[C:5]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]2[C:20]([OH:33])=[C:21]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=2)[C:10]=1[OH:34])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:15]([C:13]1[CH:14]=[C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:10]2[O:34][SiH:4]([CH3:2])[O:33][C:20]3[C:21]([C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:22][C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:24][C:19]=3[C:11]=2[CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: [SiH3]C(Cl)Cl
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[SiH]1Oc2c(cc(C(C)(C)C)cc2C(C)(C)C)-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a flame-dried flask under a dry nitrogen atmosphere, a stirred solution of 23.0 grams (0.20 mole) of dichloromethylsilane in 200 ml toluene is treated slowly with a solution of 82.1 grams (0.20 mole) of 3,3',5,5'-tetra-tert-butyl-biphenyl-2,2'-diol and 40.5 grams (0.40 mole) of triethylamine in 250 ml toluene at 5°-10° C. The reaction mixture is stirred at room temperature for 12 hours following the addition, is then filtered to remove triethylamine hydrochloride, and the solvent removed in vacuo. The residue is recrystallized from acetonitrile-toluene giving 69.4 grams (77%) of white crystals, mp 191°-198° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[CH3:17][O:18][CH2:19][CH2:20]O>>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:16][CH2:20][CH2:19][O:18][CH3:17])[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Reactant: COCCO
Product: COCCOc1nc(NC(C)=O)nc2ccc(Cl)nc12
Yield: 13.5 %

Procedure:
5 mmol 2-acetamido-6-chloro-pyrido[3,2-d]pyrimidin-4(3H)-one (1.2 g) was reacted with 7.5 mmol 2-methoxyethanol (0.54 g) to give the pure title compound (0.2 g, yield: 14%) which was characterised as follows:
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][Si](C)(C)C)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].O>CO>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:10](=[C:4]2[CH2:3][C:2]([CH3:30])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:19][CH:20]=1)#[CH:25]
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#C[Si](C)(C)C)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
4-((3,3,5,5-Tetramethylcyclohexylidene){4-[(trimethylsilyl)ethynyl]phenyl}methyl)phenol (146) (0.175 g, 0.42 mmol) was dissolved in MeOH (10 mL). To this solution was added K2CO3 (0.18 g, 1.26 mmol). The reaction mixture was stirred at room temperature overnight, poured into water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown solid. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give 0.14 g (97%) of the title compound 147 as white solid. mp 138-139° C. 1H NMR (400 MHz, CDCl3): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.28 (s, 2H), 1.93 (s, 2H), 1.97 (s, 2H), 3.03 (s, 1H), 4.55 (br s, 1H), 6.73 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H). LCMS (ESI): m/z 343 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[NH:15]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>CN1C(=O)CCC1.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:15][C:11]3[N:12]=[CH:13][S:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ncsc1C#Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Fc1ccc(-c2cc3scnc3[nH]2)cc1
Temperature: 90 °C
Yield: 65.3 %

Procedure:
238 mg (0.75 mmol) of tert-butyl N-{5-[2-(4-fluorophenyl)ethynyl]-1,3-thiazol-4-yl}carbamate are dissolved in 4.5 ml of NMP in a microwave vessel, and 143 mg (1.27 mmol) of KOtBu are added. The reaction vessel is sealed under nitrogen and heated at 90° C. for 20 min in the microwave while cooling in a stream of nitrogen. The mixture is diluted with 50 ml of diethyl ether and washed with 50 ml of sat. NaCl solution. The aqueous phase is again extracted with diethyl ether. The combined organic phases are dried over sodium sulfate, evaporated in vacuo, and the residue is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1/1), giving 109 mg (0.49 mmol, 66%) of 5-(4-fluorophenyl)-4H-pyrrolo[2,3-d]-1,3-thiazole as white crystals; m.p. 244-245;
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[C:8](I)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.[C:24]([O:28][C:29](=[O:38])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([SH:37])[CH:32]=1)([CH3:27])([CH3:26])[CH3:25]>[Cu]I.CN(C=O)C>[C:24]([O:28][C:29](=[O:38])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37][C:8]2[C:9]3[C:14]([NH2:15])=[N:13][CH:12]=[N:11][C:10]=3[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH:32]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1cccc(S)c1
Reactant: Nc1ncnc2c1c(I)cn2C1CCCC1
Agent: [Cu]I
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Sc2cn(C3CCCC3)c3ncnc(N)c23)c1
Temperature: 110 °C
Yield: 85 %

Procedure:
To a round bottom flask with DMF (5 mL), was added 7-Cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, CuI, N-methylmorphline and (3-Mercapto-phenyl)-carbamic acid tert-butyl ester. The reaction was heated at 110° C. overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (80 mL) and saturated sodium bicarbonate solution (60 ml). The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. Purification through flash column afforded the product as a light yellow solid (108 mg, 85%). MS: 426.1 (MH+); HPLC Rf: 6.332 min.; HPLC purity: 96%.
Reaction SMILES: [F:1][C:2]([F:8])(F)S([O-])(=O)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13](C2SCCC[S+]=2)=[CH:12][CH:11]=1.[F:22][C:23]([F:36])([F:35])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(N(CC)CC)C.F.F.F.C(N(CC)CC)C.BrBr>ClCCl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]([F:8])([F:1])[O:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][CH2:24][C:23]([F:35])([F:36])[F:22])=[CH:29][CH:30]=2)=[CH:12][CH:11]=1
Reactant: Brc1ccc(C2=[S+]CCCS2)cc1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: Oc1ccc(OCCCC(F)(F)F)cc1
Agent: BrBr
Agent: F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)CCCOc1ccc(OC(F)(F)c2ccc(Br)cc2)cc1
Temperature: -55 °C
Reaction time: 0.75 h
Yield: 60.2 %

Procedure:
69.3 g (164 mmol) of 2-(4-bromophenyl)-5,6-dihydro-4H-1,3-dithiin-1-ium trifluoromethanesulfonate, are solubilised in 750 mL of dichloromethane. The solution is cooled down to −55° C. 53.94 g (245 mmol) of 4-(4,4,4-trifluorobutoxy)phenol and 36.5 ml (262 mmol) of triethylamine dissolved in 300 ml of dichloromethane is added to the previous solution. The solution was cooled down to −70° C. and stirred for 45 minutes. 120 ml (736 mmol) of triethylamine trihydrofluoride are added to the mixture. A solution of 8.43 ml (164 mmol) of bromine in 60 ml of dichloromethane is added at this temperature. The reaction is stirred for one hour. The reaction is quenched by addition of NaHCO3. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 400 g silica gel using toluene: ethyl acetate 95:5 as eluent yields 42 g of 1-bromo-4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}benzene.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH2:23])(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:22])=[O:21]
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1Cl
Yield: 93.4 %

Procedure:
According to the step of Example 6-1, by use of 2,3-dichloroquinoxaline (5.00 g, 25.1 mmol) dissolved in dimethyl sulfoxide (100 mL), 2-chlorobenzene-1-sulfonamide (4.81 g, 25.1 mmol) and potassium carbonate (3.47 g, 25.1 mmol), the mixture was stirred and reacted at 150° C. for 3 hours. Then, slurry purification was performed using diisopropyl ether, to give 2-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (Compound AD) (8.30 g, yield: 93%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCCl)CC2)nc1N
Reactant: C1CCNC1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCN3CCCC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(4-chloro-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 255) and pyrrolidine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H36N6O4SF [(M+H)+]535.2500, observed 535.2498.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=[C:4]([Cl:17])[N:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][OH:25])=[CH:21][CH:20]=1.C1COCC1>O1CCOCC1>[Cl:17][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])=[C:2]([O:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[N:3]=1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Reactant: OCCc1ccc(F)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1OCCc1ccc(F)cc1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
2,6-dichloro-N-cyclohexylnicotinamide (Intermediate 1, 273 mg, 1 mmol) was stirred in 1,4-dioxane (4 ml). To this solution was added 4-fluorophenethyl alcohol (154 mg, 1.1 mmol) followed by bis-sodium hexamethyldisilylamide 1.0M in THF (1.1 ml, 1.1 mmol). The tube was sealed and subjected to microwave heating 150° C. (Biotage Initiator 300 W) for 2 hours. The solvent was evaporated and the residue was diluted with water (15 ml) and extracted with dichloromethane (2×20 ml). The combined extract was washed with brine (20 ml) dried over MgSO4, filtered and evaporated. The crude product was purified on SiO2 (40 g) eluting with ethyl acetate/isohexane 0-40% and gave 6-chloro-N-cyclohexyl-2-[2-(4-fluorophenyl)ethoxy]nicotinamide (153 mg, 40%) as a white solid
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:47]([O:54][C:55](=[O:59])[CH2:56][CH2:57][NH2:58])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[CH2:47]([O:54][C:55](=[O:59])[CH2:56][CH2:57][NH:58][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:10]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1

Procedure:
For the preparation of the ester starting material, m-(1-t-butoxyformamido)benzoic acid in THF is activated (2 hours, 0° C.) with 2-chloro-4,6-dimethoxy-1,3,5-triazine and N-methylmorpholine and reacted with β-alanine benzyl ester p-toluenesulphonate and N-methylmorpholine to give N-[m-(1-t-butoxyformamido)benzoyl]-β-alanine benzyl ester, m.p. 130°-131° C. Cleavage with trifluoroacetic acid gives N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate. Nα -Z-Nω -Nitro-L-arginine is activated (4 minutes, -10° C.) with isobutyl chloroformate and triethylamine in THF and coupled with N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate and triethylamine to give the desired benzyl ester, m.p. 157°-160° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]([F:61])[F:60])=[CH:53][CH:52]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:62][OH:63])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:52]=[CH:53][C:54]([O:57][CH2:58][CH:59]([F:60])[F:61])=[CH:55][CH:56]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:62]=[O:63])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
Oxalyl chloride (0.18 mL, 2.16 mmol) was dissolved in 5 mL methylene chloride and cooled to −78° C., followed by dropwise addition of a solution (3 mL) of dimethyl sulfoxide (0.23 mL, 3.31 mmol) in methylene chloride, and the reaction mixture was stirred for 15 minutes. 10 mL solution of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 12h (1.23 g, 1.66 mmol) in methylene chloride were dropwise added before the mixture was stirred for 40 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours after triethylamine (1.2 mL, 8.31 mmol) was dropwise added. Thereafter, the reaction mixture was partitioned after 5 mL 1 M hydrochloric acid were added. The aqueous phase was extracted with ethyl acetate (20 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoro-ethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 12i (1.10 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: CC1(C)O[C:6](=O)[CH2:5][C:4](=O)[O:3]1.C(OC)(OC)OC.[Cl:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH2:23])=[CH:21][CH:20]=1.O>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:22](=[C:24]([CH3:26])[CH:25]=1)[N:23]=[CH:6][CH:5]=[C:4]2[OH:3]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Cc1cc(Cl)ccc1N
Solvent: O
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: Cc1cc(Cl)cc2c(O)ccnc12
Temperature: 25 °C

Procedure:
A solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.58 g, 11.0 mmol) in trimethyl orthoformate (10 mL, 90 mmol) was refluxed for one hour. The mixture was cooled slightly, then a solution of 4-chloro-6-methylaniline (1.4 g, 10 mmol) in DMF (10 mL) was added. The mixture was refluxed for 2 hours then cooled to room temperature. The mixture was poured into cold water (150 mL) then extracted with EtOAc. The organic phase was washed with water then saturated NaCl (aq), dried over Na2SO4, filtered, then concentrated. The resulting light yellow, crystalline solid was used directly for the following step. LC4: 2.14 min. (M+H) 296.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: O=C(CCc1ccc(O)c(F)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1F

Procedure:
Tert-butyl 2-(2-fluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(3-fluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:31]3[CH2:35][CH2:34][C:33]([F:37])([F:36])[CH2:32]3)[C:26]([C:28]([OH:30])=O)=[CH:27][C:20]=2[N:19]=1.ClC(N(C)C)=C(C)C.[F:46][C:47]([F:57])([F:56])[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1.N1C=CC=CC=1>CC#N.C(Cl)Cl>[F:46][C:47]([F:56])([F:57])[O:48][C:49]1[CH:50]=[CH:51][C:52]([NH:53][C:28]([C:26]2[C:25]([N:31]3[CH2:35][CH2:34][C:33]([F:36])([F:37])[CH2:32]3)=[CH:24][C:21]3[N:22]([CH3:23])[C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:12])[CH3:13])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:27]=2)=[O:30])=[CH:54][CH:55]=1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(F)(F)C3)cc21
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CC#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c(N3CCC(F)(F)C3)cc21
Reaction time: 0.5 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-[3,3-difluoro-pyrrolidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid (50 mg, 0.090 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.026 mL, 0.20 mmol) and DCM (2 mL) is stirred for 30 min. This mixture is added to 4-trifluoromethoxyaniline (0.100 mmol) and pyridine (25 μL, 0.32 mmol) in MeCN (1 mL) and it is stirred for 2 h at 40° C. and overnight at 60° C. The mixture is concentrated and the residue diluted with DMF/water 19/1 (2 mL) and purified via reverse phase HPLC.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](O)[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:6])[CH:2]=[CH2:3].[C:20]([OH:28])(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:27][C:20](=[O:28])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: OC(=S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1Cc1ccccn1
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-pyridylmethyl) pyrrolidine (1.0 g), thiobenzoic acid (973 μl) and triphenylphosphine (1.30 g) in tetrahydrofuran (20 ml) was added dropwise diethyl azodicarboxylate (1.2 ml) at 0° C. The reaction mixture was stirred for 30 minutes, and then diluted with water and ethyl acetate. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed with water (twice) and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-(2-pyridylmethyl)pyrrolidine (1.34 g).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH:28]=[CH2:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@@H](CO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:31]1>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH2:28][CH2:29][OH:31])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C=C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCCCC1[C@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 96 %

Procedure:
17,17-Bis(ethylendioxy)-6α-(2-hydroxyethyl)androstane was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)-6α-vinylandrostane (Prepn. 11) by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6β-hydroxymethylandrostane (Prepn. 9). The crude was purified by flash chromatography (SiO2, n-hexane/acetone 80/20). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.25 (t, 1H), 3.86-3.70 (m, 8H), 3.35 (m, 2H), 1.91-0.42 (m, 23H), 0.75 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][C:28]([C:30]1[C:35]([NH2:36])=[CH:34][C:33]2[O:37][CH2:38][O:39][C:32]=2[CH:31]=1)=[O:29]>O1CCCC1>[C:28]([C:30]1[C:35]([NH:36][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:34][C:33]2[O:37][CH2:38][O:39][C:32]=2[CH:31]=1)(=[O:29])[CH3:27]
Reactant: COc1cc(OCc2ccccc2)cc(C(=O)Cl)c1
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OCc2ccccc2)cc(C(=O)Nc2cc3c(cc2C(C)=O)OCO3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into solutions of 163 (2.77 g, 0.01 mmol) in 200 mL of dry tetrahydrofuran were added triethylamine (10 mL) and 2-amino-4,5-methylenedioxy acetophenone (148) (1.79 g, 0.01 mmol). The mixtures were stirred at room temperature for 24 h and then evaporated. The residue was purified by column chromatography (SiO2, CH2Cl2/EtOAc=3/1) to give 164.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].[C:10]1(C#C)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(#N)C1C=CC=CC=1>>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: Cc1ccc(C#Cc2ccccc2)cc1
Reaction time: 42 h
Yield: 81 %

Procedure:
The procedure was identical to Example 1, with the exception that 4-ethynyltoluene (0.507 ml; 0.465 g; 4.00 mmol) was used as a substrate instead of phenylacetylene. GC analysis of the organic phase of the hydrolyzed reaction sample after 42 h at 65° C. showed the presence of 1.62 mmol (81% yield) of 1-methyl-4-(phenylethynyl)benzene, and 0.25 mmol of benzonitrile remaining in the reaction mixture.