Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[N:20][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2F)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].O>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=NNc2ccccc2)c2ccccc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
To a stirred solution, under nitrogen of 16.2 g of 4-[(phenylhydrazono)(2-fluorophenyl)methyl]-1-piperazine carboxylic acid ethyl ester in 150 ml of tetrahydrofuran was added, dropwise, a solution of 6.0 g of potassium t-butoxide in 60 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 16 hrs., poured into water, and extracted with dichloromethane. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. The oil was purified on a Water's Model 500 Preparative High Pressure Liquid Chromatograph utilizing two silica gel columns and hexane/ethyl acetate (3:1 by volume) as the eluent. Concentration of the appropriate fractions yielded 5.3 g (51%) of 4-(1-phenyl-1H-indazol-3-yl)-1-piperazine carboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.[OH:23][C:24]([CH3:37])([C:28]([NH:30][CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:29])[C:25](O)=[O:26].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:23][C:24]([CH3:37])([C:28]([NH:30][CH2:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[O:29])[C:25]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([F:14])([F:12])[F:13])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2)=[O:26]
Reactant: N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Reactant: CC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(C(=O)NCCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A solution of 200 mg (0.65 mmol) (S)-7-amino-5-(2,2,2-trifluoro-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 150 mg (0.65 mmol) (RS)-2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid in 7 ml tetrahydrofuran were cooled to 0° C. and 102 mg (0.65 mmol) 1-hydroxy-benzotriazole hydrate, 228 μl (1.31 mmol) diisopropylethylamine and 128 mg (0.65 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane (gradient 1/4 to 4/1) yielded 220 mg (65%) (R/S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(3,3,3-trifluoro-propyl)-malonamide as a white solid, MS (m/e): 518.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16].[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([C:27]2[N:35]3[C:30]([CH:31]=[N:32][C:33](OS(C(F)(F)F)(=O)=O)=[N:34]3)=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:33]2[N:32]=[CH:31][C:30]3=[CH:29][CH:28]=[C:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:22]=4)[N:35]3[N:34]=2)=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16]
Reactant: CN1CCCC1COc1cc(N)ccc1Cl
Reactant: CS(=O)(=O)c1cccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)c1
Product: CN1CCCC1COc1cc(Nc2ncc3ccc(-c4cccc(S(C)(=O)=O)c4)n3n2)ccc1Cl

Procedure:
Prepared by following a procedure analagous to Example 1220c by using 4-Chloro-3-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine and Trifluoro-methanesulfonic acid 7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester. 1H-NMR (DMSO) 69.8 (brs, 1H), 9.7 (s, 1H), 9 (s, 1H), 8.6 (s, 1H), 8.4 (d, J=7.9 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.8 (t, 1H), 7.5 (d, J=8.9 Hz, 1H), 7.4 (m, 2H), 7.3 (d, J=4.7 Hz, 1H), 7 (d, J=4.7 Hz, 1H), 4.2 (m, 2H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.3 (s, 3H), 3.1 (m, 1H), 3.0 (s, 3H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H), 1.6 (m, 1H); LC/MS (ESI+): 512 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][CH:12]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13]2)N)=[CH:4][CH:3]=1.CO[CH:21](OC)[CH2:22][CH2:23][CH2:24][NH:25][CH3:26]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13]1)[CH:21]=[C:22]2[CH2:23][CH2:24][NH:25][CH3:26]
Reactant: CC1(C)CCC(CCN(N)c2ccc(Cl)cc2)C1
Reactant: CNCCCC(OC)OC
Product: CNCCc1cn(CCC2CCC(C)(C)C2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 1-(4-chlorophenyl)-1-(2-(3,3-dimethylcyclopentyl)ethyl)hydrazine (Example 5) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:37])[CH:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:25]=2)[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:7][CH:6]=1)=[O:4].Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[OH:37][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])[CH:25]=1)[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: COC(=O)c1ccc(C(=O)C(Cc2cccc(OC(F)(F)C(F)F)c2)C(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: COC(=O)c1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)C(=O)OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
While stirring zinc chloride (52.0 g, 382 mmol) in diethyl ether (250 ml), sodium borohydride (28.9 g, 764 mmol) was added at room temperature and the mixture was stirred as it was for 2 hrs. Insoluble material in the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. A solution of benzyl 3-[4-(methoxycarbonyl)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate (98.98 g, 190.9 mmol) in diethyl ether (100 ml) was added dropwise to the obtained solution under ice-cooling, and the mixture was stirred as it was for 1 hr. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride, and the mixture was extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−2/1) to give the objective substance.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][CH2:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 135.1) and (6-methylpyridin-3-yl)boronic acid. HPLC (Condition 4) tR=4.18 min, UPLC-MS (Condition 3) tR=0.93 min, m/z=459.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.48 (s, 3H) 2.58 (t, J=5.87 Hz, 1H) 3.39-3.47 (m, 4H) 3.69 (t, J=8.60 Hz, 2H) 4.66 (t, J=5.28 Hz, 1H) 7.33 (m, J=8.40, 2.50 Hz, 3H) 7.71 (dd, J=7.82, 2.35 Hz, 1H) 7.81-7.86 (m, 2H) 7.95 (d, J=2.35 Hz, 1H) 8.49 (d, J=2.35 Hz, 1H) 8.73 (d, J=1.95 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C(C)=CN=C(NCCC5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([CH3:56])=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][CH:61]5[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1>>[ClH:1].[ClH:1].[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([CH3:56])=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][CH:61]5[CH2:62][CH2:63][N:64]([CH3:3])[CH2:65][CH2:66]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:36][CH2:37]1
Reactant: Cc1cnc(NCCC2CCN(C)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: Cc1cnc(NCCCC2CCNCC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: Cl
Product: Cc1cnc(NCCCC2CCN(C)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-methyl-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-methyl-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 464 [M(free base)+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8]Br)[CH3:2].[Na+].[I-].[H-].[Na+].[CH2:17]([OH:20])[CH2:18][OH:19]>O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][O:19][CH2:18][CH2:17][OH:20])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)(C)CCCOCCO
Temperature: 70 °C
Reaction time: 20 h
Yield: 20 %

Procedure:
5-Bromo-2,2-dimethyl-pentanoic acid ethyl ester LVX (19 g, 74.5 mmol) was dissolved in ethylene glycol LXVI (150 mL) and stirred under argon. After NaI (1.13 g, 7.5 mmol) was added as a catalyst, NaH as a dispersion in mineral oil (3.0 g, 60%, in mineral oil; 75 mmol) was added slowly in five portions. After stirring for 20 min at rt, the mixture was subjected to gentle heating in an oil-bath to 70° C. After 20 h, the heating was discontinued and the mixture was cooled to rt. The reaction mixture was diluted with H2O (500 mL), then extracted with chloroform (5′ 100 mL). The chloroform extract was then washed with 10% aq Na2S2O3 (300 mL), then with H2O (400 mL). After drying over MgSO4, the solvent was evaporated to give crude product (13.1 g), which was further purified by vacuum distillation (80-83 C., 0.11 torr) to give the desired product (3.25 g, 20% yield) as a clear, colorless oil. 1H NMR (CDC13), d (ppm): 4.51 (t, 1 H, J=5.5); 4.05 (q, 2 H,J=7.1); 3.48 (m, 2H); 3.40-3.31 (m, 4H); 1.18 (t, 3 H,J=7.1); 1.11 (s, 6H). 13C NMR (CDCl3), d (ppm): 176.7, 72.0, 70.5, 60.3, 59.8, 41.3, 36.7, 24.88, 24.78, 14.0. HRMS calcd. for C11H23O4 (MH+): 219.1613, found 219.1605.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:20][C:21]([NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[S:22])[C@H:13]([CH2:14]O)[C@@H:12]([C:16]([F:19])([F:18])[F:17])[O:11][CH2:10]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@H:12]([C:16]([F:18])([F:17])[F:19])[C@H:13]1[CH2:14][S:22][C:21]([NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:20]2
Reactant: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
N-(((3 S,4R,5 S)-3-(2,3-Difluorophenyl)-4-(hydroxymethyl)-5-(trifluoromethyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (2.99 g) was dissolved in pyridine (14 mL), and the mixture cooled to −20° C. Trifluoromethanesulfonic anhydride (1.55 mL) was added dropwise over 10 min and the reaction mixture was allowed to warm to −10° C. After stirring for 2 h, a further portion of trifluoromethanesulfonic anhydride (1.0 mL) was added dropwise over 10 min, the reaction was stirred for a further 2 h, and was then quenched by the addition of ammonium chloride (sat., aq., 50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography (5% to 20% EtOAc/hex) to obtain the title compound (1.20 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.86 (d, J=10.6 Hz, 1 H), 3.20 (br. s., 1 H), 3.55 (br. s., 1 H), 4.04 (br. s., 1 H), 4.65 (d, J=8.8 Hz, 1 H), 4.81 (br. s., 1 H), 7.06-7.24 (m, 3 H), 7.40-7.64 (m, 3 H), 7.82-8.21 (m, 2 H)
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([Br:16])[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]O)[N:6]2[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37].O>O1CCCC1>[Br:16][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][Br:37])[N:6]2[C:7]=1[C:2]([NH2:1])=[N:3][CH:4]=[N:5]2
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncnn2c(CCCCO)cc(Br)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCCCBr)cc(Br)c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
To a cooled (0° C.) solution of 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)butan-1-ol (600 mg, 2.10 mmol) and triphenylphosphine (828 mg, 3.16 mmol) in tetrahydrofuran (15 mL) was added carbon tetrabromide (837 mg, 2.53 mmol). The reaction was stirred (0° C.) for 90 min and then was warmed to rt and stirred an additional 1 h. Water (25 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organics were dried (Na2SO4) and evaporated. The crude material was purified via ISCO® chromatography using a gradient of 25 to 50% ethyl acetate in hexanes to afford 597 mg (82%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.82 (s, 1 H), 6.62 (s, 1 H), 3.54 (t, 2 H), 2.84 (t, 2 H), 1.86-1.70 (m, 4 H); ES-MS m/z 347.2 [M+H]+, HPLC RT (min) 2.58.
Reaction SMILES: [CH3:1][Si:2]([CH3:55])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([N:45]1[CH:49]=[C:48]([C:50](OCC)=[O:51])[N:47]=[N:46]1)=[N:34][C:35]=2[NH:39][CH:40]1CC[CH2:42][CH2:41]1)[C:3]([CH3:6])([CH3:5])[CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-].C1C[O:67][CH2:66]C1>>[CH3:1][Si:2]([CH3:55])([O:7][C@@H:8]1[C@H:21]([O:22][Si:23]([CH3:29])([CH3:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[C@@H:11]([CH2:12][O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([N:45]1[CH:49]=[C:48]([CH2:50][OH:51])[N:47]=[N:46]1)=[N:34][C:35]=2[NH:39][CH:40]1[CH2:41][CH2:42][O:67][CH2:66]1)[C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1cn(-c2nc(NC3CCCC3)c3ncn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c3n2)nn1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NC4CCOC4)nc(-n4cc(CO)nn4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C

Procedure:
1.5 g of ethyl 1-(9-{(2R,3R,4R,5R)-3,4-bis(1,1,2,2-tetramethyl-1-silapropoxy)-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]oxolan-2-yl}-6-(cyclopentylamino)purin-2-yl)-1,2,3-triazole-4-carboxylate prepared as described in Example 9A is dissolved in 10 mL of THF and chilled in a 0° C. bath. 2 ml of LiAlH4 is added to this solution. The mixture is then allowed to warm to room temperature over a course of several hours. A saturated solution of NH4Cl is added dropwise to the room temperature solution until no bubbles are observed. The resulting precipitate may be filtered off and the filtrate concentrated down to remove all of the remaining solvent. The remaining aqueous solution is extracted with dichloromethane and the organic layer dried of MgSO4, filtered, and concentrated down to provide the product, [1-(9-{(2R,3R,4R,5R)-3,4-bis(1,1,2,2-tetramethyl-1-silapropoxy)-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]oxolan-2-yl}-6-(oxolan-3-ylamino)purin-2-yl)-1,2,3-triazole-4-yl]methan-1-ol, was purified by chromatography in a 5% methanol/dichloromethane solution.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.Br[C:14]1[N:15]([CH3:38])[C:16]2[C:21]([C:22]=1[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:28]([NH:30][C:31]1([C:35]([OH:37])=[O:36])[CH2:34][CH2:33][CH2:32]1)=[O:29])[CH:17]=2.[Cl-].[NH4+].Cl.[OH-].[Na+].C(O)(=O)C>[Zn+2].[Br-].[Br-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)CC.C1COCC1.CN1CCCC1=O>[CH:23]1([C:22]2[C:21]3[C:16](=[CH:17][C:18]([C:28]([NH:30][C:31]4([C:35]([OH:37])=[O:36])[CH2:32][CH2:33][CH2:34]4)=[O:29])=[CH:19][CH:20]=3)[N:15]([CH3:38])[C:14]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cn1c(Br)c(C2CCCC2)c2ccc(C(=O)NC3(C(=O)O)CCC3)cc21
Reactant: Brc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cn1c(-c2ccccn2)c(C2CCCC2)c2ccc(C(=O)NC3(C(=O)O)CCC3)cc21
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of i-PrMgCl in THF (10 mL, 20 mmol) was added 2-bromopyridine (1.93 g, 20.2 mmol) at room temperature in one portion. The mixture was stirred at 35° C. for 0.5 h. To the deep-red solution was added ZnBr2 (2.477 g, 11 mmol) under argon and the resulting mixture was stirred at 70° C. for 0.5 h to brown-red solution. 1-Methyl-2-pyrrolidinone (20 mL) was added and the mixture was stirred at 70° C. for 10 minutes. Palladium acetate (11.2 mg, 0.05 mmol), triphenylphosphine (52.5 mg, 0.20 mmol) and 1-[(2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carbonyl)-amino]-cyclobutanecarboxylic acid (2.097 g, 5 mmol) were added. The mixture was stirred at 90° C. for 6 h. Saturated ammonium chloride (20 mL) and THF (20 mL) were added. The pH of the mixture was adjusted to 4-5 using 4 HCl (˜3 mL) and the mixture was stirred at 60° C. for 5 minutes. The aqueous layer was separated and extracted with isopropyl acetate (20 mL) at 60° C. The combined organic phases were combined and washed with a mixture of saturated ammonium chloride (10 mL) and water (10 mL) at 60° C. The organic layer was extracted with 4 N HCl (10 and 5 mL). To the combined extracts cooled in an ice-water bath was slowly added 50% NaOH (5.60 g, 70 mmol). The mixture was heated to reflux until the internal temperature reached 89-90° C. The mixture was cooled to 60° C. and n-propanol (10 mL) was added. While stirring, acetic acid (1.14 mL, 20 mmol) was added to adjust the pH to 5-6. The resulting white suspension was stirred at 60° C. for 1 h and allowed to cool to room temperature (@200° C.). The white precipitate was collected by filtration and the wet cake was rinsed with 2:1 water/n-propanol (15 mL) and water (50 mL). The solid was dried under vacuum to provide the title compound (1.65 g, 79%).
Reaction SMILES: [CH:1]1[C:14]2[C:5]3=[C:6]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH2:15][C:4]3=[CH:3][CH:2]=1>[Pd].CCO>[CH:10]1[C:11]2[CH2:12][CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[C:4]4[CH2:15][C:7]([C:6]=2[C:5]=34)=[CH:8][CH:9]=1
Reactant: c1cc2c3c(c1)ccc1cccc(c13)C2
Agent: [Pd]
Solvent: CCO
Product: c1cc2c3c(c1)Cc1cccc(c1-3)CC2
Yield: 92 %

Procedure:
4H-cyclopenta[def]phenanthrene (4.75 g, 25 mmol) was placed in a Par reactor bottle, and EtOH (200 ml) was added thereto. 5% Pd/C (3.99 g) was added to the reaction solution, and the resultant solution was incubated under a hydrogen pressure of 40 psi for 24 hours. After the reaction was terminated, the reaction solution was filtered, and the filtrate was concentrated under a reduced pressure to give a white product (4.42 g, 90%).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[N:14]([CH2:23][C:24]([O:26]CC)=[O:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:3]1.C1COCC1.[OH-].[Li+].Cl>CO>[O:30]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:29])[N:14]([CH2:23][C:24]([OH:26])=[O:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:3]1
Reactant: CCOC(=O)Cn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a suspension of the product of Example 52B in 1:1 THF:methanol (6 mL) was added 0.5 N aqueous lithium hydroxide (6 mL). The mixture was stirred at room temperature for 2 hours, adjusted to pH 3 with 1.0 N HCl, and filtered. The filter cake was washed with water and dried to give the title compound (0.133 g, 86%). MS (ESI−) m/z 399 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 5.16 (s, 2H), 7.54 (m, 2H), 7.67 (d, J=7.72 Hz, 1H), 7.77 (t, J=7.72 Hz, 1H), 7.92 (d, J=7.72 Hz, 1H), 8.60 (dd, J=8.09, 1.84 Hz, 1H), 8.84 (dd, J=4.60, 1.65 Hz, 1H), 13.11 (br s, 1H), 13.79 (br s, 1H).
Reaction SMILES: [Li].[CH3:2][C@@:3]12[C@H:12]3[CH2:13][C:14]([O:16][C@:11]3([CH3:17])[CH2:10][CH2:9][C@H:8]1[C:7]([CH3:19])([CH3:18])[CH2:6][CH2:5][CH2:4]2)=[O:15]>>[OH:16][C:11]1([CH3:17])[CH2:10][CH2:9][CH:8]2[C:3]([CH3:2])([CH2:4][CH2:5][CH2:6][C:7]2([CH3:18])[CH3:19])[CH:12]1[CH2:13][CH2:14][OH:15]
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CC(=O)O[C@]3(C)CC[C@@H]12
Agent: [Li]
Product: CC1(C)CCCC2(C)C1CCC(C)(O)C2CCO
Yield: 92 %

Procedure:
Isomerization and subsequent lithium alanate reduction of sclareolide by the method of G. Ohloff, Helv. Chim Acta, 68 (1985), 2022-29, was used to obtain a diastereoisomeric decahydro-2-hydroxy-2,5,5,8a-tetramethyl1-naphthaleneethanol (mp. 191° C.). 142 g of this diol were dissolved in 2,110 g of toluene, and the solution was admixed with 120 g (3 mol) of sodium hydroxide in 120 ml of water and then with 48 g (0.15 mol) of tetrabutylammonium bromide. 101 g (0.5 mol) of p-toluenesulfonyl chloride were then added twice in the course of 1 hour, and the reaction mixture was subsequently stirred for 2 hours, and admixed with 500 ml of water and thereafter thoroughly stirred for a further 10-20 minutes. The bottom, aqueous phase was separated off and washed once with 200 ml of water, and thereafter the solvent was distilled off at 300 mbar. Recrystallization of the residue left 121.6 g of isomeric dodecahydro-3a,6,6,9a-tetramethylnaphtho[2,1-b]furan (formula Ib; R1, R2 =CH3), of mp. 60° C. and [a]20D =+7.5°, which corresponds to a yield of 92%.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.ClCCl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Anisole (27.5 grams), 4-fluorobenzoyl chloride (35 grams) and dichloromethane (250 mL) were combined in a reaction flask. Aluminum chloride (30.8 grams) was added to the reaction mixture slowly over 20 minutes. Stirred the reaction mixture at room temperature for two hours and then poured it into a mixture of 70 mL concentrated HCl and 500 mL of water. The layers were phase separated and the aqueous layer was extracted with 2 portions of dichloromethane (300 mL each). The organic portions were combined and washed with saturated aqueous sodium bicarbonate (400 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to yielding 48.0 grams of 4-fluoro-4′-methoxy-benzophenone as a white solid. This material was not purified further but was used directly in the next step.