Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[NH:25][NH2:26]>CN(C=O)C>[C:29]([O:28][C:24]([NH:25][NH:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NN
Reactant: BrCc1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
4-(Bromomethyl)biphenyl (2.0 g, 8.1 mmol, 1.0 eq.) and DIPEA (1.4 mL, 1.0 eq.) were dissolved in DMF (40.0 mL). t-Butyl carbazate (2.1 g, 16.2 mmol, 2.0 eq.) was added and the mixture was stirred at room temperature overnight. The mixture was partially concentrated, and the residue was partitioned between EtOAc and a saturated aqueous NaHCO3 solution. The EtOAc layer was then dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc/hexanes with 0.5% DIPEA) to yield compound 1, N′-biphenyl-4-ylmethyl-hydrazinecarboxylic acid t-butyl ester (1.7 g).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O>[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
To a mixture of N-Boc-L-proline (1.0 g, 4.65 mmol), aniline (0.433 g. 4.65 mmol), and HOBT (0.753 g, 5.58 mmol) in 10 mL of CH2Cl2 was added EDC (1.07 g, 5.58 mmol) and the solution was stirred overnight. To the solution was added 70 mL of EtOAc and washed with 50 mL 3N HCl, 50 mL water, 50 mL NaHCO3 (sat.), 50 mL 10% K2CO3, and 50 mL brine. The organic layer was then dried over MgSO4, filtered and concentrated under reduced pressure to give a white solid (1.2 g. 89%. ES (+) MS m/e=291 (M+H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].[C:30](Cl)(=[O:46])[O:31][CH2:32][CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2>O1CCOCC1.O>[CH:44]1[C:45]2[CH:33]([CH2:32][O:31][C:30]([N:12]3[CH2:13][C@H:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:10][C@H:11]3[C:14]([OH:16])=[O:15])=[O:46])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]=2[CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
To a solution of (2S,4R)-4-(benzyloxy)pyrrolidine-2-carboxylic acid, TFA (522 mg, 1.557 mmol) in 1,4-dioxane (4 mL) and water (16 mL) was added potassium carbonate (861 mg, 6.23 mmol) followed by (9H-fluoren-9-yl)methyl carbonochloridate (403 mg, 1.557 mmol) at 0° C. The mixture was stirred at RT for 18 hrs and treated with water (10 ml). The resulting mixture was extracted with diethyl ether (2×15 ml). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The crude product was purified via prep HPLC (10-100% CH3CN:Water 0.1% TFA buffer) to afford the pure product (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(benzyloxy)pyrrolidine-2-carboxylic acid (430 mg, 62.3% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) d 7.86-7.76 (m, 2H), 7.71-7.57 (m, 2H), 7.44-7.27 (m, 9H), 4.58-4.50 (m, 2H), 4.49-4.33 (m, 3H), 4.29-4.19 (m, 2H), 3.72-3.49 (m, 2H), 2.49 (br. s., 1H), 2.10 (ddd, J=13.4, 8.2, 4.8 Hz, 1H). ESI-MS (+) m/z=444 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:19](=[O:24])N(OC)C)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[I:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:13][CH:14]=1)[C:19]([C:30]1[CH:31]=[CH:32][C:27]([I:26])=[CH:28][CH:29]=1)=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1
Reactant: Ic1ccc(I)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from rac-[(methoxy-methyl-carbamoyl)-(4-trifluoromethyl-phenyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 10) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISN): 504.0 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[N:13][C:14](F)=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[Cl:24][C:25]1[N:26]=[C:27]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:28]2[CH:33]=[C:32]([C:34]3[CH:35]=[N:36][C:37](F)=[CH:38][CH:39]=3)[S:31][C:29]=2[N:30]=1.C([N:50](C(C)C)CC)(C)C>CN1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[N:13][C:14]([NH2:26])=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[Cl:24][C:25]1[N:26]=[C:27]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:28]2[CH:33]=[C:32]([C:34]3[CH:35]=[N:36][C:37]([NH2:50])=[CH:38][CH:39]=3)[S:31][C:29]=2[N:30]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Fc1ccc(-c2cc3c(N4CCOCC4)nc(Cl)nc3s2)cn1
Reactant: Fc1ccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cn1
Agent: CN1CCCC1
Product: Nc1ccc(-c2cc3c(N4CCOCC4)nc(Cl)nc3s2)cn1
Product: Nc1ccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cn1
Temperature: 135 °C

Procedure:
A mixture of 2-chloro-6-(6-fluoropyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidine or 2-chloro-6-(6-fluoropyridin-3-yl)-4-morpholinothieno[2,3-d]pyrimidine compound, about four equivalents of a primary or secondary amine (R═H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, or C1-C20 heteroaryl), and about two eq. diisopropylethylamine in N-methylpyrrolidine (˜0.1M) is heated to about 130-140° C. in a sealed microwave reactor for 10˜40 min, followed by removal of volatiles under high vacuum. The crude mixture is purified by flash chromatography to give intermediate 2-chloro-6-(6-aminopyridin-3-yl)-4-morpholinothieno[3,2-d]pyrimidine or 2-chloro-6-(6-aminopyridin-3-yl)-4-morpholinothieno[2,3-d]pyrimidine compound, which may be Suzuki coupled with a monocyclic heteroaryl, fused bicyclic heterocycle or heteroaryl boronate reagent following General Procedure A.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:20]([C:22]1[C:31]([CH3:32])=[C:30]([O:33][C:34](=[O:36])[CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:37])[CH:28]=2)[N:23]=1)=[O:21]>O.O1CCCC1>[OH:21][CH:20]([C:22]1[C:31]([CH3:32])=[C:30]([O:33][C:34](=[O:36])[CH3:35])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:37])[CH:28]=2)[N:23]=1)[C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)Oc1c(C)c(C=O)nc2ccc(F)cc12
Reactant: C#CCCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCCC#CC(O)c1nc2ccc(F)cc2c(OC(C)=O)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
1.32 ml of a hexane solution of 2.16 mmols of n-butyl lithium was added to a solution of 238 mg (2.16 mmols) of 1-octyne and 5 ml of tetrahydrofuran in an atmosphere of nitrogen at 0° C. and stirred at the same temperature for 15 minutes. The reaction solution was cooled to -78° C. to which a solution of 10 ml of tetrahydrofuran of 445 mg (1.80 mmols) of 2-formyl-3-methyl-4-acetoxy-6-fluoroquinoline was added, followed by heating gradually to room temperature and stirring at room temperature for 1 hour. The reaction solution was poured into 50 ml of water, extracted with ethyl acetate and dried with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (Wako gel C-200) (solvent: n-hexane ethyl acetate=5:1) to obtain 349 mg (yield 54 %) of 2-(1-hydroxy-2-nonynyl)-3-methyl-4-actoxy- 6-fluoroquinoline.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:47]([C:41]3[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=3[Cl:39])(=[O:49])=[O:48])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 2,5-Dichlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 133 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (126 mg, 68%) as a sticky off-white solid. MS cald. for C24H23Cl2FNO4S [(M+H)+]: 510, obsd. 510.2.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.II.[CH:11]([C:13]1[CH:14]=[C:15]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:18]=1)=[O:12]>O1CCCC1>[OH:12][CH:11]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[C:13]1[CH:14]=[C:15]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH:18]=1
Reactant: CCOC(=O)c1cc(C=O)cc(-c2ccc(C)cc2)c1
Reactant: Brc1ccccn1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2ccccn2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The Grignard reagent was generated by treatment of magnesium (100 mg, 4.3 mmol) with a solution of 2-bromopyridine (600 mg, 3.8 mmol) and iodine (30 mg) in tetrahydrofuran (5 mL) under nitrogen at 60° C. for 1 hour. The mixture was cooled at 0° C. and ethyl 5-formyl-4′-methylbiphenyl-3-carboxylate (332 mg, 1.24 mmol) was added. The reaction mixture was stirred at 0° C. for 2 h and then quenched by addition of 3 mL of 2 N aq. H2SO4. The mixture was extracted with EtOAc (20 mL×2). The combined organic layers were washed with 1 N aq. NaOH, brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was chromatographed to yield a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[OH:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33].C(N(CC)CC)C>C(O)CCC>[OH:20][CH2:21][CH2:22][N:23]([CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33])[C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13]
Reactant: COc1ccc(Cl)cc1CNCCO
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1ccc(Cl)cc1CN(CCO)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
5.7 g. 6-Chloro-9-(β-D-ribofuranosyl)-purine, 6 g. N-(2-hydroxyethyl)-2-methoxy-5-chlorobenzylamine and 2.5 g. triethylamine were heated under reflux for 2 hours in 100 ml. n-butanol. Subsequently, the solvent was removed in a vacuum and the residue taken up in 100 ml. chloroform. The chloroform phase was washed several times with water, initially with the addition of some dilute hydrochloric acid and thereafter with a dilute solution of sodium bicarbonate. From the so purified chloroform solution, there crystallized out 4.9 g. (53% of theory) N(6)-(2-hydroxyethyl)-N(6)-(2-methoxy-5-chlorobenzyl)-adenosine, which melted at 98°-100°C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:14]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:14])[CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)c1ccc2c(N)ncnn12
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Br)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 190.7 %

Procedure:
To a cooled (0° C.) solution of 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanone (262.0 mg, 1.49 mmol) in DMF (21 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (212.6 mg, 0.74 mmol). The mixture was stirred for 80 min and then quenched by addition of saturated aqueous sodium sulphite (10 mL) and water (60 mL). The mixture was allowed to warm to rt and the precipitate was collected by filtration. The solid was air-dried to yield 360.0 mg (95%) of the title compound. 1H-NMR (DMSO-d6) δ 9.49 (bs, 1H), 8.49 (bs, 1H), 8.12 (s, 1H), 7.64 (s, 1H), 2.56 (s, 3H); MS [M+H]+=255.3; LCMS RT=1.96 min.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@:25]1([CH3:31])[CH2:29][O:28][C:27](=[O:30])[NH:26]1)[CH:19]=[CH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]1([C@H:7]2[CH2:8][CH2:9][C@H:10]([O:13][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[C:20]([C@:25]3([CH3:31])[CH2:29][O:28][C:27](=[O:30])[NH:26]3)[CH:19]=[CH:18]4)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: O[C@H]1CC[C@H](c2ccccc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1

Procedure:
The mixture of trans-4-phenyl-cyclohexanol (86.9 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (Example 4, 100.0 mg, 0.0004111 mol) and triphenylphosphine (129 mg, 0.000493 mol) in tetrahydrofuran (4 mL, 0.05 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred and refluxed for 3 hours. TLC monitoring showed the reaction to be complete. The mixture was taken up into DCM and subjected to chromatographic purification with EtOAc/hexane (10:90 to 80:20) to give (R)-4-(6-(trans-4-phenylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (160 mg, 97% yield). LCMS 402.28 ([M+1]+, 100%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.CO[CH:14](OC)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[OH:25][CH2:26][CH2:27][C@H:28]([OH:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(OCC)(=O)C>CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]2[O:40][C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:27][CH2:26][O:25]2)=[CH:16][CH:17]=1
Reactant: CCCCCCCCCCC[C@@H](O)CCO
Reactant: COc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC[C@@H]1CCOC(c2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
p-Toluenesulfonic acid (152 mg, 0.80 mmol) and 4-methoxybenzaldehyde dimethylacetal (2.9 g, 16.0 mmol) was added to a solution of (R)-1,3-dihydroxytetradecane (1.85 g, 8.0 mnuol) in dimethylformamide (20 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate. The ethyl acetate layer was successively washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using cyclohexane:ethyl acetate=9:1 as the eluant to give the desired product (2.78 g, yield 99%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CO>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](=[O:10])[CH:9]=[CH:16][N:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)C(C)Oc1ccc(F)cc1
Solvent: CO
Product: CC(Oc1ccc(F)cc1)C(=O)C=CN(C)C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(4-fluorophenoxy)-2-butanone (18.72 g) and N,N-dimethylformamide dimethylacetal (12.5 g) was heated under argon in an oil bath at 120° C. for 14 hours. The methanol produced in the reaction was removed under reduced pressure and the residual oil was precipitated with cold hexane and kept at 4° C. overnight to give 4-(4-fluorophenoxy)-1-(dimethylamino)-1-penten-3-one as an orange solid. Yield 19.97 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br-:13].[CH2:18]([O:17][C:15]([CH2:14][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:16])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)Cc1ccccn1
Product: CCOC(=O)Cc1cccc[n+]1CC(=O)OCC
Product: [Br-]
Reaction time: 72 h
Yield: 29.5 %

Procedure:
A mixture of ethyl 2-pyridylacetate (6.0 g, 0.036 mole) and ethyl bromoacetate (4.4 ml, 0.038 mole) was allowed to stand at room temperature for 72 h, during which time the product gradually crystallised out. The mixture was treated with acetone (80 ml) to dissolve unreacted starting materials and then filtered. The solid collected was dried under vacuum to afford 1,2-di-[(ethoxycarbonyl)methyl]pyridinium bromide as a beige solid (3.53 g, 30%).
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:13][C:14](=O)[O:15]CC)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])#[N:2].[N:19]1([CH2:25][C:26]([NH:28][NH2:29])=O)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(OCC)(=O)C.O>CN1C(=O)CCC1>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:4]1[N:13]=[C:14]([OH:15])[N:29]2[N:28]=[C:26]([CH2:25][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:2]=[C:1]2[CH:3]=1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Reactant: NNC(=O)CN1CCOCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1nc(-c2ccc(Cl)cc2Cl)cc2nc(CN3CCOCC3)nn12
Temperature: 160 °C
Reaction time: 3 h

Procedure:
1.33 g (4.7 mmol) of ethyl [2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate (Example 128A) and 740 mg (4.7 mmol) of 2-morpholin-4-ylacetohydrazide are dissolved in NMP (6 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 3 h. The reaction mixture is cooled to RT and ethyl acetate (100 ml) and water (50 ml) are added. The organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is chromatographed on silica gel (mobile phase dichloromethane/methanol 100:1 to 50:1). 1.25 g (70% of theory) of the product are obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:38])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:19]2([CH3:20])[C@H:14]([CH2:15][C@@H:16](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].O.Cl>N1C(C)=CC(C)=CC=1C>[C:1]([O:4][CH2:5][C:6](=[O:38])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:19]2([CH3:20])[C@H:14]([CH2:15][CH:16]=[CH:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 78.5 %

Procedure:
A solution of (3β,5α)-21-(acetyloxy)-3-{[(4-methylphenyl)sulfonyl]oxy}pregnane-11,20-dione (35 g) in collidine (350 ml) was heated under reflux for 2 h. The reaction mixture was poured into water (3.5 l) containing hydrochloric acid (614 ml; 5M) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. Crystallisation of the residue from methanol gave a mixture (3:1) (18.8 g) of (5α)-21-(acetyloxy)pregn-2-ene-11,20-dione and its 3-ene-isomer.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[C:3]([CH2:8][N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ncccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ncccc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a stirred suspension of 0.10 g (0.54 mmol) of 3-bromopyridine-2-carbaldehyde in 10 mL of dichloromethane was added activated powdered 4 Å molecular sieves, 0.20 mL (1.1 mmol) of N,N-diisopropylethylamine and 0.10 g (0.54 mmol) of tert-butyl piperazine-1-carboxylate. The resulting solution was stirred at ambient temperature for 1 h, then 0.34 g (1.6 mmol) of solid sodium triacetoxyborohydride was added in one portion. The heterogeneous reaction was allowed to stir at ambient temperature overnight and was then filtered through a pad of Celite®. The pad was washed with dichloromethane and the combined filtrates were washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-100% ethyl acetate in hexanes gradient to afford the title compound as a colorless gum (0.055 g, 29%). LC-MS: m/z (ES) 356.2, 358.2 (MH)+.