Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:30]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C@H:31]1[C:40](O)=[O:41].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@H:2]([NH:1][C:40]([C@@H:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39][N:30]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:41])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1

Procedure:
tert-Butyl (3S)-3-{N-[(1S)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2S)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl)propan-1-one (Step 2) (380 mg, 0.87 mmol), according to the procedure for Preparation XIX using Boc-L-Tic-OH (250 mg, 0.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (540 mg, 1.8 mmol), HOAT (140 mg, 1.0 mmol), and DMF (25 mL). Crude material was obtained in a quantitative yield and used without further purification. MS (ESI, pos. ion) m/z: 696 (M+H), (ESI, neg. ion) m/z: 694 (M−H). Calc'd for C35H42ClN5O6S: 695.25.
Reaction SMILES: [C:1]1([C:7]2[N:17]3[C:18]4[N:10]([C:11](=S)[NH:12][C:13](=[O:19])[C:14]=4[CH:15]=[N:16]3)[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].OO.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[CH3:27][CH:26]([CH3:28])[CH2:25][NH:29][C:11]1[N:10]2[C:18]3[N:17]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8][CH2:9]2)[N:16]=[CH:15][C:14]=3[C:13](=[O:19])[N:12]=1
Reactant: CC(C)CN
Reactant: O=c1[nH]c(=S)n2c3c1cnn3C(c1ccccc1)=CC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)CNc1nc(=O)c2cnn3c2n1CC=C3c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg of 4,5-dihydro-8-phenyl-5-thioxo-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 7) in 10.0 ml of N,N-di-methylformamide was added 1.8 ml of 1N sodium hydroxide. The reaction mixture was cooled to 0° C. in an ice bath, then 0.6 ml of 30% hydrogen peroxide was added to the mixture dropwise. The reaction mixture was stirred at 0° C. for about 30 minutes, then 1.0 ml of isobutylamine was added in one portion and the mixture was allowed to warm to room temperature, then was stirred for 2 hours. The solid was collected and washed with water, then ether to give 253 mg of the desired product as a white solid, m.p. 265°-268° C. (dec). Following the procedure of Example 44 and reacting 4,5-dihydro-8-phenyl-5-thioxo-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one with the appropriate primary aliphatic amine or cyclic secondary amine, the products of Examples 45-51 were obtained as set forth in Table V.
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(O)nc1C(=O)OCC
Product: CCOC(=O)c1cnc(Cl)nc1C(=O)OCC
Yield: 30 %

Procedure:
The title compound was prepared as described in Example 7, but employing a solution of diethyl 2-hydroxypyrimidine-4,5-dicarboxylate (1.0 g, 4.2 mmol) and POCl3 (7.7 g, 50 mmol) resulting in a 30% yield (0.32 g); 1HNMR (CDCl3) δ 9.09 (d, 1H), 4.35 (m, 4H), 1.30 (m, 6H).
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1.Br[CH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]([C:22]([F:25])([F:24])[F:23])[O:19]2)=[CH:14][C:13]=1[Cl:31]>[Cl-].[Cl-].[Zn+2].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:31][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[CH2:11][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1)[O:19][CH:18]([C:22]([F:25])([F:24])[F:23])[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Reactant: Cc1ccc([Mg]Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(Cl)c(Cc3ccc(C)cn3)cc2OC1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
The bromo (5-methylpyridin-2-yl)magnesium (10.4 mL, 2.6 mmole) was diluted by 5 mL THF under nitrogen and the solution was cooled to −78° C. ZnCl2 (340 mg, 2.5 mmole) was added to above solution and the mixture was stirred for 0.5 hr. The ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (01597/1 PR) (1.0 g, 2.5 mmol) was added to above mixture and followed by PdCl2(PPh3)2 (18 mg, 0.025 mmole). The mixture was warmed to room temperature and heated to 50° C. for 3 hr. LCMS indicated that the product was formed around 15%. The solid was filtered off and the filtrate was concentrated to give a crude mixture, which was purified by RPHPLC eluted with 10 to 95% ACN in water with 0.05% TFA to afford 150 mg the desired product as a brown oil (yield 15%), which had suitable purity to use without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O)=[O:9])=[CH:4][CH:3]=1.[N:23]1([CH2:29][C:30]2[S:34][C:33]([NH2:35])=[N:32][N:31]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:13])[N:35]=[C:33]3[S:34][C:30]([CH2:29][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:31][N:32]3[C:16]=2[OH:18])=[O:9])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C(=O)NCc1ccc(Cl)cc1)C(=O)OCC
Reactant: Nc1nnc(CN2CCOCC2)s1
Solvent: Cc1ccccc1C
Product: O=C(NCc1ccc(Cl)cc1)c1c(O)n2nc(CN3CCOCC3)sc2nc1=O
Yield: 39.1 %

Procedure:
Diethyl 2-(((4-chlorobenzyl)amino)carbonyl)malonate (Preparation 5, 33 mg) and 5-(4-morpholinylmethyl)-1,3,4-thiadiazol-2-ylamine (Preparation 4, 20 mg) are dissolved in xylene and heated to reflux for 5 h. The solvent is evaporated and the residue is triturated with ether. The resulting percipitate is filtered and dried to afford 17 mg of the title compound as a brown solid. Physical characteristics: MS (ESI+) m/z 438 (M+H)+. 1H NMR (DMSO) δ 7.42, 7.38, 4.60, 3.92, 3.62, 2.62.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CN1CCOCC1.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[CH2:33]([O:32][C:30]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:31])[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)NCCO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCCCCCCCCCCC(=O)NCCOC(=O)OCC

Procedure:
3.0 g of N-(2-hydroxyethyl) hexadecanamide (10 mmoles) was dissolved in 75 ml of tetrahydrofuran (THF) at 45° C. with stirring. 1.11 g of N-methylmorpholine (11 moles) and 1.19 g of ethyl chloroformate (11 moles) were added and the resulting mixture was stirred for a further 3 hours at ambient temperature. The mixture was then evaporated to dryness under vacuum. The residue was taken up with 50 ml of water and extracted 3 times with 30 ml of ethyl acetate; the organic phases were washed twice with 20 ml of water, recombined and evaporated to dryness. The residue was crystallized from 30 ml of tert-butylmethyl ether. The crystallizate was separated by filtration, washed twice with 5 ml of cold tert-butylmethyl ether and finally dried under a high degree of vacuum. The yield of the reaction was 93%.
Reaction SMILES: [F:1][C:2]1[C:24]([S:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=[O:36].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[C:24]([S:25]([CH:26]2[CH2:27][CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]2)=[O:36])=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene 209 (194 mg, 0.40 mmol) in DCM (15 mL) was added TFA (93 μL, 1.20 mmol) followed by a solution of m-CPBA (76 mg, 0.440 mmol) in DCM (2 mL). The resulting mixture was stirred for 15 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 20-45% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 210 as a white solid (167 mg, 83%). LCMS: RT 2.61 min [M+H]+ 501.1. 1H NMR (DMSO, 400 MHz): δ 8.71 (1H, d, J=7.99 Hz), 7.93 (1H, s), 7.15 (1H, d, J=10.69 Hz), 5.69-5.57 (1H, m), 4.66-4.51 (4H, m), 2.89-2.76 (3H, m), 2.72-2.60 (1H, m), 2.26 (3H, s), 2.20-2.06 (2H, m), 1.94-1.85 (1H, bd, J=12.30 Hz), 1.59-1.40 (9H, m), 0.91 (6H, d, J=6.53 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[H-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)[C:31]([O:33][CH3:34])=[O:32])(=[O:10])=[O:11]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Yield: 83.5 %

Procedure:
A solution of methyl (1aRS,7bSR)-5-(2-bromo-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 41, 1.7 g) in THF (20 mL) was added to a suspension of sodium hydride (70% oil dispersion, 0.2 g) in THF (10 mL). The resultant solution was stirred for 30 minutes then methyl chloroformate (0.53 g) was added. The resultant mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether (30%) to give methyl (1aRS,7bSR)-5-[N-(2-bromo-4-fluorobenzenesulfonyl)-N-(methoxycarbonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (1.6 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[N:3]=1.C(C1N=C(C2C=C(O[CH:38]3[CH2:56][CH:55]4[N:40]([C:41](=[O:61])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:50]5[C:52]([C:58]([OH:60])=[O:59])([NH:53][C:54]4=[O:57])[CH2:51]5)[CH2:39]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:1][CH:38]1[CH2:56][CH:55]3[N:40]([C:41](=[O:61])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH:50]4[C:52]([C:58]([OH:60])=[O:59])([NH:53][C:54]3=[O:57])[CH2:51]4)[CH2:39]1)=[N:3][C:4]([N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1)=[CH:5]2
Reactant: COc1ccc2c(O)nc(-n3cccn3)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)nc(-n3cccn3)cc2c1

Procedure:
The title compound was prepared from 1-hydroxy-6-methoxy-3-(pyrazol-1-yl)-isoquinoline and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=574 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[F:28].[S:29]1[CH2:33][C@@H:32]([C:34]([OH:36])=[O:35])[NH:31][CH2:30]1>>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([N:31]3[C@H:32]([C:34]([OH:36])=[O:35])[CH2:33][S:29][CH2:30]3)=[O:21])=[CH:26][CH:27]=2)=[CH:4][C:3]=1[F:28]
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(O)c1cccc(COc2ccc(-c3cc(F)c(F)c4ccoc34)cc2)c1
Product: O=C(O)[C@@H]1CSCN1C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)c4ccoc34)cc2)c1
Yield: 2.8 %

Procedure:
An operation similar to that in Step 4 of Example 10 was performed using the compound (38.0 mg, 0.100 mmol) of Step 2 of Example 59 in place of 3-{[4-(5-fluoro-2,3-dihydro-1-benzofuran-7-yl)phenoxy]methyl}benzoic acid, and (4R)-1,3-thiazolidine-4-carboxylic acid (40.0 mg, 0.300 mmol) in place of L-proline to thus obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:11][CH:10]1[C:12](N(OC)C)=[O:13])#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:12]([CH:10]1[CH2:11][CH:9]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2])=[O:13]
Reactant: CON(C)C(=O)C1CC1c1ccccc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccccc1C1CC1C=O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
A solution of 2-(2-cyanophenyl)-N-methoxy-N-methylcyclopropanecarboxamide (250 mg, 1.086 mmol) in THF (5 mL) was stirred, maintaining the temperature below −40° C., as a suspension of LAH (82 mg, 2.171 mmol) in THF (20 mL) at −50° C. was added. After the addition was complete, the reaction was slowly allowed to warm to −30° C., and then cooled to below −40° C. The reaction was quenched with a EtOAc, followed by 1 N sodium hydroxide (1 mL). The reaction was stirred at rt for 30 min. The solution was diluted with EtOAc, filtered through celite, then concentrated. The material was purified on silica gel using 5-40% EtOAc/hexanes as the eluent to give 2-(2-formylcyclopropyl)benzonitrile (135 mg, 72.6%) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.42 (d, J=4.3 Hz, 1H), 7.67 (dd, J=7.8, 1.0 Hz, 1H), 7.56 (td, J=7.8, 1.3 Hz, 1H), 7.36 (td, J=7.6, 1.1 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 2.95 (ddd, J=9.2, 6.6, 4.3 Hz, 1H), 2.27 (ddt, J=8.5, 5.3, 4.3 Hz, 1H), 1.87 (dt, J=9.3, 5.3 Hz, 1H), 1.67-1.49 (m, 1H). LCMS: M+1=171.1.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:22][CH2:23][OH:24]>C(O)C>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([S:15][CH2:22][CH2:23][OH:24])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCSc1nc2ccc(Cc3ccccc3)cc2[nH]1

Procedure:
5.75 g (24 mmoles) of 5-benzyl-benzimidazoline-2-thione, a solution of 1 g of sodium hydroxide and 8 ml of water, 2 ml (30 mmoles) of 2-chloroethanol and 30 ml of ethanol are refluxed for an hour. The reaction mixture is evaporated and extracted with water and dichloromethane, then the aqueous phase is extracted with dichloromethane. The residue of the combined organic phases is solidified under ether. After filtration and crystallization from ethyl acetate 4.63 g (68.1%) of title product are obtained. M.p.: 108°-109° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:28][C:29]1[C:33]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=2[O:31][C:30]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[NH:49][N:48]=[N:47][N:46]=1>C(Cl)Cl>[Br:28][C:29]1[C:33]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=2[O:31][C:30]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1[N:49]([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:48]=[N:47][N:46]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2oc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.89 g of triethylamine, 8.14 g of triphenylchloromethane and 0.10 g of 4-N,N-dimethylaminopyridine are added in succession to a suspension of 10.37 g of 3-bromo-2-[2'-(1H-tetrazol-5-yl)-phenyl]-5-methylbenzofuran in 300 ml of CH2Cl2 and the batch is stirred for 3 hours at room temperature. The reaction solution is washed with 150 ml of water and 150 ml of brine, concentrated in vacuo to a volume of 50 ml and chromatographed on silica gel 60 (40-63 μm) using CH2Cl2 as eluant. The product, of Rf =0.82 (CH2Cl2 /CH3OH (95:5) ), yields crystalline 3-bromo-2-[2'-(1-trityltetrazol-5-yl)-phenyl]-5-methylbenzofuran, m.p. 199°-200°, from ether.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1.[CH3:24][C:25](OC(C)=O)=[O:26]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:25]([O:1][CH2:2][C@@H:3]1[CH:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1)(=[O:26])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CCC(=O)CC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6α-hydroxymethylandrostane-3,17-dione (II-an, Prepn. 14, 42 mg) in pyridine (1.5 mL) at 0° C., DMAP (1 mg) and Ac2O were added. After stirring overnight at room temperature, the solution was evaporated. The residue was treated with 1N HCl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound II-ao (91%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.97 (m, 2H), 2.53-0.80 (m, 21H), 1.99 (m, 3H), 1.13 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][N:16]([C:19](=[O:25])[CH2:20][O:21]C(=O)C)[CH2:17][CH:18]=3)=[C:9]([F:26])[CH:8]=2)[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[OH:21][CH2:20][C:19]([N:16]1[CH2:17][CH:18]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:26])[CH2:14][CH2:15]1)=[O:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)COC(C)=O)CC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-3,6-dihydro-2H-pyridin-4-yl]phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 39, 475 mg) and anhydrous potassium carbonate (303 mg) in methanol (44 mL) is stirred under N2 at ambient temperature for 1.5 hours and then adjusted to pH 7 with aqueous hydrochloric acid (1 M) and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 40 g), eluting with a gradient of methanol/chloroform (5/95-10/90), and those fractions with an Rf =0.21 by TLC (methanol/chloroform, 10/90) are pooled and concentrated under reduced pressure. The resulting foam is then triturated with methylene chloride/diethyl ether and the precipitate filtered to give the title compound, Anal. calcd for C19H22N3O5F: C, 58.31; H, 5.67; N, 10.74. Found: C, 58.15; H, 5.64; N, 10.72.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17]/[CH:18]=[C:19](\[CH3:30])/[CH2:20][N:21]3[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[NH:23][C:22]3=[O:29])[CH2:13][CH2:12]2)[CH:8]=[C:7]([C:31]([F:34])([F:33])[F:32])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]([CH3:30])[CH2:20][N:21]3[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[NH:23][C:22]3=[O:29])[CH2:15][CH2:16]2)[CH:8]=[C:7]([C:31]([F:33])([F:34])[F:32])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C/C(=C\CN1CCN(c2cc(C(F)(F)F)nc(C(C)(C)C)n2)CC1)Cn1cc(C)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CO
Product: Cc1cn(CC(C)CCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)[nH]c1=O
Reaction time: 6 h

Procedure:
1-((2E)-4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbut-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (Example 36, 1.04 mmol, 0.50 g) in methanol (5 ml) was hydrogenated over Pd (10% on activated carbon) with hydrogen at room temperature for 12 h and then at 40° C. for a further 6 h. The mixture was filtered and the residue was washed with methanol. The filtrate was concentrated and purified on silica gel (mobile phase: dichloromethane/methanol: 97/3 v/v); yield 0.20 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33](OS(C)(=O)=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN1C(=O)CCC1.O>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (10.0 g, 45.4 mmol, 1.0 equiv) in NMP (100 ml) was added Cs2CO3 (44.4 g), 136.3 mmol, 3.0 equiv) and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.0 g, 68.2 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. and monitored until complete. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was washed successively with 2N KOH, water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The target molecule was purified by column chromatography (SiO2), eluted with 5→30% EtOAc-petrol to afford a colourless liquid (9.5 g) that crystallised on standing. 1H NMR (400 MHz, CDCl3): 7.42 (1H, d), 7.37 (1H, d), 7.31 (1H, t), 7.03 (1H, dd), 4.61-4.49 (1H, m), 3.76-3.62 (2H, m), 3.47-3.32 (2H, m), 1.99-1.86 (2H, m), 1.86-1.70 (2H, m), 1.49 (9H, s).