Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][NH2:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:19][CH2:20]O>>[ClH:1].[CH2:19]([NH:15][CH2:14][C@H:13]([NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([I:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[C:16]([OH:18])=[O:17])[CH3:20]
Reactant: CCO
Reactant: NC[C@H](NS(=O)(=O)c1ccc(I)cc1)C(=O)O
Agent: Cl
Product: CCNC[C@H](NS(=O)(=O)c1ccc(I)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
HCl gas was rapidly bubbled through a suspension of acid 29-3 (4.0 g, 10.81 mmol) in EtOH (50 ml) at 0° C. for 10 minutes. The cooling bath was removed and the reaction was heated to 60° C. After 18 h, the reaction was concentrated to provide ester 29-4 as a white solid.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH2:8][C@H:9]1[CH2:11][C@@H:10]1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>CC(C)=O.O.O.[Ru](=O)=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C@H:10]1[CH2:11][C@@H:9]1[C:8]([OH:2])=[O:7])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(C[C@H]1C[C@@H]1CO)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C[C@H]1C[C@@H]1C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 91.3 %

Procedure:
Sodium metaperiodate (1729 mg, 8.08 mmol) and ruthenium(IV) oxide hydrate (48.8 mg, 0.32 mmol) were added to a solution of benzyl 2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetate (712 mg, 3.23 mmol) in acetone (11.5 mL) and water (13 mL) at 0° C., and the mixture was stirred at 0° C. for 2.5 hr. The reaction mixture was poured into water (100 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give (1S,2R)-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (690 mg, 2.95 mmol, 91%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([C:9]3[S:10][C:11]([N:14]([CH3:16])[CH3:15])=[N:12][N:13]=3)[CH2:7][S:8][C@H:3]12.[C:35]1([CH2:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>ClCCl>[C:35]1([CH2:41][C:42]([NH:1][CH:2]2[C:33](=[O:34])[N:4]3[C:5]([C:17]([O:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])=[C:6]([C:9]4[S:10][C:11]([N:14]([CH3:16])[CH3:15])=[N:12][N:13]=4)[CH2:7][S:8][C@H:3]23)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CN(C)c1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)s1
Yield: 83.8 %

Procedure:
To a solution of 0.491 g of benzhydryl 7-amino-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate (obtained in Example 26) in 16 ml of dichloromethane is dropwise added 0.160 g of phenylacetylchloride and 0.10 g of triethylamine with stirring under ice-cooling, and stirring and cooling are maintained for 30 minutes. The reaction mixture is washed with water, dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residue is chromatographed on a column of silica gel [eluted with benzene-ethyl acetate(1:3)] to give 0.51 g of benzhydryl 7-phenylacetamido-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=C=O.[N:35]1[C:44]2[C:39](=[CH:40][C:41]([NH2:45])=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([NH:27][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:7])[C@H:9]([C:24]([NH:45][C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:35]=[CH:36][CH:37]=[CH:38]3)=[O:26])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: CCCCCN=C=O
Reactant: Nc1ccc2ncccc2c1
Product: CCCCCNC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)Nc1ccc2ncccc2c1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and 6-quinolinamine the title compound was obtained in 54% purity by LC/MS. MS(ESI+): m/z=542.6.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C@@H:24]([OH:35])[CH2:25][C@@H:26]2[OH:34])[CH:21]=[CH:20]3)[CH2:17][CH2:16]1)[CH3:14])[CH3:9].CO>CCOCC>[OH:34][C@@H:26]1[C@@:27]2([CH3:28])[C:22](=[CH:21][CH2:20][C@@H:19]3[C@@H:29]2[CH2:30][CH2:31][C@@:32]2([CH3:33])[C@H:18]3[CH2:17][CH2:16][C@@H:15]2[C@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:8]([CH3:9])[CH3:7])[CH2:23][C@@H:24]([OH:35])[CH2:25]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 72 %

Procedure:
A solution of 1α-hydroxycholesteryl tosylate (7, R' is 4-methylphenyl, 1.35 g) in anhydrous ether (80 ml) was heated under reflux with lithium aluminum hydride (0.098 g, 23.9 mmoles) under anhydrous conditions for 5 hours. Work-up of the reaction mixture as described in the above procedure for the preparation of 4,6-cholestadien-1α,3β-diol 4 followed by chromategraphy of the crude carbinol on silica gel (25 g) using low boiling petroleum ether-benzene as the eluent gave 705 mg (72% yield based on 1α-hydroxycholesterol 6) of 5.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])[CH2:10][C:11]([O:13][CH3:14])=[O:12])(C(C)(C)C)(C)C.F>>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1/[CH:18]=[CH:17]/[C:16](=[O:27])[CH2:15][C@@H:9]([OH:8])[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C[C@@H](CC(=O)/C=C/c1ccc(Cl)cc1Cl)O[Si](C)(C)C(C)(C)C
Agent: F
Product: COC(=O)C[C@H](O)CC(=O)/C=C/c1ccc(Cl)cc1Cl

Procedure:
For instance, methyl (3R,6E)-3-[(tert-butyldimethylsilyl)oxy]-7-(2,4-dichlorophenyl)-5-oxo-6-heptenoate (which is one of the compounds of the formula (1)) is subjected to the tert-butyldimethylsilyl removing step using hydrogen fluoride in the manner as described in Japanese Patent Provisional Publication H5(1993)-178841, to give methyl (3R, 6E)-7-(2,4-dichlorophenyl)-3-hydroxy-5-oxo-6-heptenoate. The obtained ester is then subjected to Syn reduction using diethylmethoxyborane and sodium borohydride (NaBH4), to give methyl (3R,5S,6E)-7-(2,4-dichlorophenyl)-3,5-dihydroxy-6-heptenoate. Subsequently, thus obtained ester is treated with sodium hydroxide and hydrochloric acid in the manner as described in Journal of Medicinal Chemistry, 1985, vol.28, No.3, pp.347-358, to give (+)-trans-(E)-6-[2-(2,4-dichlorophenyl)-ethenyl] 3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-on which has the 3-hydroxy-3-methylglutaryl Coenzyme A reductase preventive action.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH:10]([CH3:12])[C:9]([CH3:14])([CH3:13])[C:8]2[CH2:7][C:6]([CH3:16])(O)[CH:5](O)[CH2:4][C:3]1=2.CS(Cl)(=O)=O>N1C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:18])[CH2:11][CH:10]([CH3:12])[C:9]([CH3:14])([CH3:13])[C:8]2[CH2:7][CH:6]([CH3:16])[CH2:5][CH2:4][C:3]1=2
Reactant: CC1CC(C)(C)C2=C(CC(C)(O)C(O)C2)C1(C)C
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1CCC2=C(C1)C(C)(C)C(C)CC2(C)C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
85 g (0.337 mol) of the 2,2,4,5,5,8-hexamethyl-bicyclo[4.4.0]dec-1(6)-ene-8,9-diol are dissolved at room temperature in 218 ml of pyridine. The solution is now cooled to 0° C. and 30.2 ml of methanesulphonyl chloride are slowly added dropwise during 20 minutes. The mixture is stirred at room temperature for a further 24 hours. The mixture is thereupon diluted with ether and washed with 1.480 l of 2N hydrochloric acid and 400 ml of saturated sodium chloride solution. The aqueous phase is extracted with ether and the combined organic phases are washed neutral with dilute sodium bicarbonate solution, dried over sodium sulphate and evaporated.
Reaction SMILES: CN(CCN(C)C)C.C([Li])(C)(C)C.[CH3:14][C:15]1([CH3:63])[O:19][C:18]2[C:20]([C:29]([C:47]3[C:57]4[O:58][C:59]([CH3:62])([CH3:61])[O:60][C:56]=4[CH:55]=[C:49]4[O:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=34)([C:31]3[C:41]4[S:42][C:43]([CH3:46])([CH3:45])[S:44][C:40]=4[CH:39]=[C:33]4[S:34][C:35]([CH3:38])([CH3:37])[S:36][C:32]=34)[OH:30])=[C:21]3[O:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]3=[CH:28][C:17]=2[O:16]1.[C:64](=[O:66])=[O:65]>C1CCCCC1.CCOCC>[C:64]([C:28]1[C:22]2[O:23][C:24]([CH3:26])([CH3:27])[O:25][C:21]=2[C:20]([C:29]([C:47]2[C:48]3[O:52][C:51]([CH3:54])([CH3:53])[O:50][C:49]=3[C:55]([C:24]([OH:25])=[O:23])=[C:56]3[O:60][C:59]([CH3:62])([CH3:61])[O:58][C:57]=23)([C:31]2[C:32]3[S:36][C:35]([CH3:37])([CH3:38])[S:34][C:33]=3[C:39]([C:15]([OH:19])=[O:16])=[C:40]3[S:44][C:43]([CH3:45])([CH3:46])[S:42][C:41]=23)[OH:30])=[C:18]2[C:17]=1[O:16][C:15]([CH3:63])([CH3:14])[O:19]2)([OH:66])=[O:65]
Reactant: O=C=O
Reactant: CC1(C)Oc2cc3c(c(C(O)(c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(cc6c4SC(C)(C)S6)SC(C)(C)S5)c2O1)OC(C)(C)O3
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CC1(C)Oc2c(c(C(O)(c3c4c(c(C(=O)O)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(C(=O)O)c5c3SC(C)(C)S5)SC(C)(C)S4)c3c(c2C(=O)O)OC(C)(C)O3)O1
Reaction time: 0.33 h

Procedure:
Dry TMEDA (1.21 mL, 8.04 mmol) and t-butyllithium (5.36 mL, 1.5M in pentane) were dissolved in dry cyclohexane (12 mL) at 0° C. Bis-(2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxol-4-yl)-mono-(2,2,6,6-tetramethyl benzo[1,2-d:4,5-d']-bis(1,3)dithiol-4-yl)methanol (0.608 g, 0.804 mmol) was then added at ambient temperature as a solid. After 20 min, solid carbon dioxide was added followed by dry ether (50 mL). After stirring for 17 h, the reaction mixture was filtered and the precipitate was dried. The acid was purified by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.O>CN(C)C=O.C(OCC)(=O)C>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([O:25][CH2:24][CH2:23][CH2:22][N:12]2[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:14][CH2:13]2)=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1ccc(OCCCBr)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(CCCOc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
1.44 g of 4-tert-butoxycarbonylaminopiperidine was dissolved in 14 ml of N,N-dimethylformamide. Thereafter, 1.99 g of potassium carbonate and 1.87 g of 4-(3-bromopropoxy)benzonitrile were successively added to the above solution, followed by stirring at room temperature for 24 hours. Water and ethyl acetate were added to the reaction mixture, so that the organic layer was separated. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed under a reduced pressure. The obtained solid was filtrated with a mixed solution consising of n-hexane and diisopropyl ether to obtain 2.12 g of tert-butyl 1-[3-(4-cyanophenoxy)propyl]-4-piperidinylcarbamate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B1OC(C)(C)C(C)(C)O1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[F:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: CC1(C)OB(c2ccccc2F)OC1(C)C
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-(2-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane.
Reaction SMILES: C(O[C:4]([N:6]([CH3:29])[N:7]=[C:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:5])C.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH2:49]([O:51][C:52](=[O:54])C)[CH3:50]>C1(C)C=CC=CC=1>[CH2:49]([O:51][C:52](=[O:54])[CH2:29][N:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[N:16]([CH2:17][C:18]([CH3:21])([CH3:19])[CH3:20])[C:4]1=[O:5])[CH3:50]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)N(C)N=C(c1ccccc1Cl)c1cc(Cl)ccc1NCC(C)(C)C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 2-neopentylamino-2',5-dichlorobenzophenone ethoxycarbonyl methyl hydrazone (0.16 g) and triethylamine (90 mg) in toluene (2 ml) was added triphosgene (54 mg). The mixture was stirred for one hour at 70° C., to which was added acetic acid ethyl ester (50 ml). The mixture was washed with water and, then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=3:1 v/v as an eluent) to give 0.16 g of an oily compound.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH:25]=O)=[C:15]1[CH2:27][CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH3:57])=[CH:52][CH:51]=1>>[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([N:56]([CH2:25][CH2:24][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[N:14]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:15]=2[CH2:27][CH2:28][O:29][Si:30]([C:43]([CH3:44])([CH3:46])[CH3:45])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:57])=[CH:52][CH:51]=1
Reactant: CC(C)(C)[Si](OCCc1c(CC=O)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNc1ccc(C(=O)OC)cc1
Product: COC(=O)c1ccc(N(C)CCc2c(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 73 %

Procedure:
Crude {1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-acetaldehyde from Intermediate No. 4 synthesis Step 7 was treated with 4-Methylamino-benzoic acid methyl ester according to the procedure in Intermediate No. 4 step 8 to yield the desired 4-[(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethyl)-methyl-amino]-benzoic acid methyl ester in 73% yield.
Reaction SMILES: [CH2:1]([N:8]([CH3:35])[C:9]1[CH:27]=[C:26]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:25]=[CH:24][C:10]=1[NH:11][CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14](OCC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:35])[C:9]1[CH:27]=[C:26]([CH2:28][N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[CH:25]=[C:24]2[C:10]=1[N:11]=[CH:12][C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=CNc1ccc(CN2CCOCC2)cc1N(C)Cc1ccccc1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(N(C)Cc3ccccc3)cc(CN3CCOCC3)cc2c1O
Yield: 50.7 %

Procedure:
Diethyl 2-{[2-[benzyl(methyl)amino]-4-(4-morpholinylmethyl)anilino]-methylene}malonate (3.7 g, 7.7 mmol) is stirred in a mixture of phenyl ether (9 g) and biphenyl (3 g) at 260 ° C. A slow stream of nitrogen is passed through the solution to remove volatile materials produced in the reaction. The reaction is stopped as soon as HPLC shows that conversion of the starting material to product is complete (60 min). After cooling, the reaction mixture is applied in ethyl acetate to a silica gel column which is eluted with ethyl acetate (400 mL) to remove phenyl ether and biphenyl. The column is then eluted with 5-10% methanol/chloroform and the product obtained is recrystallized from ethyl acetate/hexane (3:1, 15 mL) to give 1.70 g of the title compound.
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:38]([F:39])=[CH:37][C:10]3[N:11](CC4C=CC(C5C=CC=CC=5)=CC=4)[C:12]([O:14][CH2:15][CH:16]4[CH2:18][CH:17]4[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:13][C:9]=3[C:8]=2[F:40])=[CH:3][CH:2]=1.C1CC=CCC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:1]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:38]([F:39])=[CH:37][C:10]3[NH:11][C:12]([O:14][CH2:15][CH:16]4[CH2:18][CH:17]4[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:13][C:9]=3[C:8]=2[F:40])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CC1COc1nc2c(F)c(-c3ccc(-c4ccccc4)cc3)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCC=CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC1COc1nc2c(F)c(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1

Procedure:
To a solution of ethyl 2-({[5-(biphenyl-4-yl)-1-(biphenyl-4-ylmethyl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}methyl)cyclopropanecarboxylate (0.270 g, 0.439 mmol) and Pd(OH)2 (0.080 g, 0.114 mmol) in 3.6 mL of EtOAc and 1.8 mL of EtOH was added 1,4-cyclohexadiene (1.06 mL, 11.3 mmol). The resulting black suspension was microwaved at 130° C. for 2 h, and then filtered through a Celite™ pad, and washed with 100% EtOAc. The resulting filtrate was concentrated. Purification of the resulting crude product by reverse phase Gilson™ HPLC (50-100% AcCN/H2O) afforded the desired product. LCMS: calculated for C26H22F2N2O3 448.46, observed m/e 448.9 (M+H)+ (Rt 2.37/4 min).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CC3CCCCO3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N2-butyl-8-methoxy-9-(tetrahydro-2H-pyran-2-ylmethyl)-9H-purine-2,6-diamine in dry methanol (5 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (1.5 ml) in one go. The reaction was left to stir at room temperature overnight. The reaction was concentrated in vacuo and the product purified by MDAP. This afforded the title compound 6 mg (slower-running on MDAP).
Reaction SMILES: O[C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.COCCN(S(F)(F)[F:32])CCOC.C1(C)C=CC=CC=1.[Cl-].[NH4+]>C(#N)C>[F:32][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)cc2)[C@H](F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of (3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (15.5 g, 61.4 mmol, intermediate D) in 270 mL of acteonitrile was chilled to 0° C. To the stirred solution was added bis(2-methoxyethyl)aminosulfur trifluoride 50% solution in toluene (Deoxo-fluor, 58.4 mL, 159 mmol) dropwise via addition funnel over 65 min. After the addition, the reaction mixture was stirred for 30 min at 0° C. and then allowed to come to rt and stirred for an additional 2 h. A saturated ammonium chloride solution (150 mL) was then added, and the mixture was extracted with two 150 mL portions of DCM. The organic layers were combined, dried over sodium sulfate, and concentrated to afford the crude product. The product was purified by silica gel chromatography (1.5 kg of silica) eluting with a gradient of 0-15% acetone in hexanes to afford 11.9 g (75%) of the desired (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate. LC/MS RT (conditions B)=3.295 min, (M+H with loss of t-butyl and elimination of fluorine)+=220.0. 1H NMR (400 MHz, chloroform-d) δ 7.15 (d, J=8.6 Hz, 2H), 6.83 (dt, J=8.6, 2.0 Hz, 2H), 4.59-4.48 (m, 1H), 4.47-4.37 (m, 1H), 4.23-4.12 (m, 1H), 2.88-2.68 (m, 3H), 1.96-1.84 (m, 1H), 1.80-1.66 (m, 1H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:23][C:21]1[CH:22]=[C:17]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[C:10]2=[O:13])[CH:18]=[N:19][CH:20]=1
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Reactant: Fc1cncc(Br)c1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cncc(F)c1
Yield: 26.9 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-16c: 90 mg, 0.419 mmol) was reacted with 3-bromo-5-fluoro-pyridine (73.67 mg, 0.419 mmol), 1,4-dioxane (10 mL), copper iodide (7.98 mg, 0.0419 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (17.85 mg, 0.126 mmol) and potassium phosphate (222 mg, 1.048 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in DCM) afforded 35 mg of the product (27.19% yield).