Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[C:26]([CH3:27])=[CH:25][C:16]([O:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[CH3:28])(=[O:12])=[O:11])=[C:5]([N+:29]([O-:31])=[O:30])[CH:4]=1.[C:32]1([CH3:44])[CH:37]=[CH:36][C:35]([S:38]([CH:41](O)[CH3:42])(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[C:14]([CH3:28])=[CH:15][C:16]([O:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20]([O:22][CH2:42][CH2:41][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:44])=[CH:33][CH:34]=3)(=[O:40])=[O:39])=[O:21])=[CH:25][C:26]=2[CH3:27])(=[O:12])=[O:11])=[C:5]([N+:29]([O-:31])=[O:30])[CH:4]=1
Reactant: COc1ccc(NS(=O)(=O)c2c(C)cc(OCC(C)(C)C(=O)O)cc2C)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)C(C)O)cc1
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2c(C)cc(OCC(C)(C)C(=O)OCCS(=O)(=O)c3ccc(C)cc3)cc2C)c([N+](=O)[O-])c1
Temperature: 36 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-{4-[4-methoxy-2-nitrophenylaminosulfonyl}-3,5-dimethylphenoxy]-2,2-dimethylpropionic acid (Intermediate A10, 24.2 g, 0.054 mol) and carbonyldiiuidazole (9.5 g, 0.059 mol) was diluted with 45 mL dichloromethane and warmed in a 36° C. bath for 15 min. Then, 4-tolylsulfonylethanol was added, the bath temperature was raised to 55° C., and the solvent was blown off in a nitrogen stream. After 1.5 hr, the stream was stopped, and after 2.5 hr, the cooled reaction mixture was partitioned between ethyl acetate and 1.2 M hydrochloric acid. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers were washed with water and saturated sodium chloride, concentrated at aspirator pressure and high vacuum. The product, title compound, (34 g, 99%) was carried on without further purification.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][C@@H:40]([CH2:43][CH3:44])[CH2:41][NH2:42]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([NH:42][CH2:41][C@@H:40]([CH3:39])[CH2:43][CH3:44])=[O:36])=[CH:37][CH:38]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: CC[C@H](C)CN
Product: CC[C@H](C)CNC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 100 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (S)-2-methylbutylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 60 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 600 [M+H]+.
Reaction SMILES: [Li]CCCC.[C:6]([Si:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:11][CH2:12][C:13]#[CH:14])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:31].[NH4+].[Cl-]>C1COCC1>[Si:10]([O:11][CH2:12][C:13]#[C:14][C:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:31])([C:6]([CH3:9])([CH3:7])[CH3:8])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 56.2 %

Procedure:
In an argon atmosphere, n-BuLi (10.3 mL, 2.64 N hexane solution) was added dropwise to a solution of t-butyldiphenyl(prop-2-yn-1-yloxy)silane (8.576 g) in THF (200 mL) at −78° C. over 10 minutes, and after stirring at room temperature for 50 minutes, the reaction mixture was added dropwise to a solution of (S)-t-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (5.01 g) in THF (200 mL) through a cannula and temperature was raised to room temperature over an hour. The reaction mixture was added to a saturated aqueous solution of NH4Cl (500 mL) and, after extraction with AcOEt, the organic layer was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt/hexane) to give the titled compound (5.36 g, colorless oil.)
Reaction SMILES: C(Cl)(Cl)Cl.[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1F)[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>CO>[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH:9]=[O:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=Cc1ccc(-n2ccnc2)c(Br)c1
Reaction time: 20 h
Yield: 64 %

Procedure:
According to the procedure described in the synthesis method of Intermediate Int. n-26 (Synthesis method NG) provided that the reaction was performed for 20 hours, and the column chromatography was performed with chloroform:methanol=100:1, 3-bromo-4-fluorobenzaldehyde (1.246 g, TCI), potassium carbonate (825.1 mg) and imidazole (444 mg, TCI) were reacted and treated to obtain the title compound (Intermediate Int. n-32, 986.1 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:3].C(OCC)(=O)C.Cl>[Pd].C(OCC)C>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:3]
Reactant: CN(C)CCC=Cc1ccccc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C)CCCCc1ccccc1-c1ccccc1

Procedure:
A solution of 3.0 g. of N,N-dimethyl-4-(1,1'-biphenyl-2-yl)-3-butenylamine in 200 ml. of ethyl acetate containing 2.0 g. of five percent palladium oncarbon was stirred for one hour at 25° C. under hydrogen at 40 psi. The reaction mixture then was filtered and the solvent was removed from the filtrate by evaporation to provide an oil. The oil was dissolved in 100 ml. of diethyl ether and stirred while excess hydrogen chloride was added to the solution. The precipitate which formed was collection by filtration and was recrystallized from ethanol and diethyl ether to provide 2.1 g. of N,N-dimethyl-4-(1,1'-biphenyl-2-yl)butylaminum chloride.M.P. 114°-116° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=2)[CH2:4]1)[CH3:2].CCN(CC)CC.[CH3:22][C:23](OC(C)=O)=[O:24]>CO.[Pd]>[CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:12][C:23](=[O:24])[CH3:22])[CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CCN1Cc2ccc([N+](=O)[O-])cc2C1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN1Cc2ccc(NC(C)=O)cc2C1
Temperature: 20 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
A solution of isoindole 245 (3.20 g, 16.7 mmol) in MeOH (100 mL) was stirred with Pd/C (5%, 300 mg) under H2 (60 psi) for 16 h. The solution was filtered through Celite, washed with MeOH (3×20 mL) and the solvent evaporated. The residue was dissolved in DCM (130 mL) and Et3N (13 mL, 93 mmol), Ac2O (13 mL, 138 mmol) was added dropwise and the solution stirred at 20° C. for 15 h. The mixture was partitioned between DCM and aqueous Na2CO3 solution. The organic solution was washed with water, dried and the solvent was evaporated to give acetamide 246 (3.00 g, 88%) as a dark oil: 1H NMR δ 7.45 (br s, 1H, H-4), 7.30 (br s, 1H, NH), 7.18 (br d, J=8.0 Hz, 1H, H-6), 7.12 (d, J=8.0 Hz, 1H, H-7), 3.90 (s, 2H, H-1), 3.87 (s, 2H, H-3), 2.76 (q, J=7.2 Hz, 2H, CH2), 2.15 (s, 3H, COCH3) 1.19 (t, J=7.2 Hz, 3H, CH3); HRMS (FAB+) calcd for C12H17N2O (MH+) m/z 203.1184, found 203.1188.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:13])[C@H:4]([NH:11][CH3:12])[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]=1[CH3:33]>C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:11]([C@@H:4]([C@H:3]([O:2][CH3:1])[CH3:13])[CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH3:12])=[O:29])=[CH:26][C:25]=1[CH3:33]
Reactant: CN[C@H](CN1CCCC1)[C@@H](C)OC
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H](C)[C@@H](CN1CCCC1)N(C)C(=O)c1ccc(F)c(C)c1
Yield: 73.6 %

Procedure:
To a solution of (2R,3R)-3-methoxy-N-methyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M6) (80 mg, 0.43 mmol) in DCM (1.5 mL) was DIPEA (0.090 mL, 0.52 mmol) and 4-fluoro-3-methylbenzoyl chloride (0.061 mL, 0.43 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was diluted with DCM (5 mL), washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (102 mg, 74%).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([CH:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][CH2:15][OH:16])=[CH:11][C:10]3[C:6](=[C:7]([C:28]([NH:30][CH3:31])=[O:29])[N:8]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:41][S:42]([O:16][CH2:15][CH2:14][CH:13]([C:12]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]2[C:10]([CH:11]=1)=[N:9][N:8]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:7]=2[C:28](=[O:29])[NH:30][CH3:31])[S:17]([CH3:20])(=[O:19])=[O:18])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c2cc(C3CC3)c(C(CCO)S(C)(=O)=O)cc2nn1-c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c2cc(C3CC3)c(C(CCOS(C)(=O)=O)S(C)(=O)=O)cc2nn1-c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of compound (viii) (9 mg, 0.02 mmol) in DCM (4 mL) at 0° C. were added DIPEA (30 μL, 0.17 mmol) and methanesulfonyl chloride (6 μL, 0.078 mmol). The reaction was stirred at 0° C. for 1 h, at which time it was diluted with DCM (12 mL) and saturated aqueous sodium bicarbonate (4 mL). The aqueous layer was separated and extracted with DCM (12 mL). The combined organic layers were washed with water (5 mL), dried (MgSO4) and evaporated to dryness. The residue was purified by flash column chromatography eluting with EtOAc/heptane (50-100%) to afford racemic 3-[5-cyclopropyl-3-(methylcarbamoyl)-2-(4-methylphenyl)-2H-indazol-6-yl]-3-(methylsulfonyl)propyl methanesulfonate (ix) as a white solid (8 mg, 69%).
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][NH:15][CH2:16][CH2:17][NH:18][C:19]([C:21]34[CH2:30][CH:25]5[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]5)[CH2:22]3)[CH2:28]4)=[O:20])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:31]OC1C2OC(CNCCNC(C34CC5CC(CC(C5)C3)C4)=O)=CC=2C=CC=1.Cl.C=O>C(O)C.[Pd]>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][NH:18][C:19]([C:21]34[CH2:22][CH:23]5[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]5)[CH2:30]3)[CH2:28]4)=[O:20])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2cc(CNCCNC(=O)C34CC5CC(CC(C5)C3)C4)oc12
Agent: [Pd]
Agent: C=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cccc2cc(CN(C)CCNC(=O)C34CC5CC(CC(C5)C3)C4)oc12
Reaction time: 24 h
Yield: 58.8 %

Procedure:
N-[2-[[(7-Methoxy-2-benzofuranyl)methyl]amino]ethyl]tricyclo[3.3.1.13,7 ]decane-1-carboxamide hydrochloride hemihydrate (1.0 g, 2.4 mmole), prepared as in Example 2, was dissolved in 100 ml of ethanol and 5 ml of 38% aqueous formaldehyde and 500 mg of 10% palladium on carbon were added. The mixture was hydrogenated at 50 psi on a Parr apparatus for 24 hours. The mixture was then filtered through celite and 300 ml of ether added. It was washed with 100 ml portions of saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was purified by column chromatography on 100 g of silica gel with chloroform as eluant and recrystallized from acetone/diethyl ether with the addition of 3 ml of 4N HCl/isopropanol to give 560 mg of the title compound as a white solid, monohydrochloride, quarter hydrate, m.p. 156°-158° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[O:9][CH2:10][CH2:11][C:12]4[N:13]([N:14]=[C:15]([C:17]5[N:21]([CH:22]([CH3:24])[CH3:23])[N:20]=[CH:19][N:18]=5)[CH:16]=4)[C:7]=3[CH:6]=2)[CH2:2]1.Br[CH2:28][CH2:29][O:30]C1CCCCO1>>[CH:22]([N:21]1[C:17]([C:15]2[CH:16]=[C:12]3[N:13]([C:7]4[CH:6]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:28][CH2:29][OH:30])[CH2:4]5)[CH:26]=[CH:25][C:8]=4[O:9][CH2:10][CH2:11]3)[N:14]=2)=[N:18][CH:19]=[N:20]1)([CH3:24])[CH3:23]
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(CCO)C3)ccc1OCC2

Procedure:
Following the procedures of Example 142, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene 144 was reacted with 2-(2-bromoethoxy)-tetrahydropyran followed by acidic hydrolysis of the THP group to give 169 as a white solid, as illustrated in FIG. 13. 1H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1H); 7.88 (d, J=2.22 Hz, 1H); 7.42 (dd, J=8.35, 2.22 Hz, 1H); 7.26 (d, J=8.32 Hz, 1H); 6.89 (s, 1H); 5.62-5.54 (m, 1H); 4.83 (s, 1H); 4.50 (t, J=6.03 Hz, 2H); 4.06 (s, 2H); 3.94 (t, J=8.52 Hz, 1H); 3.70 (s, 2H); 3.51 (s, 3H); 3.18 (t, J=6.05 Hz, 2H); 2.94 (s, 2H); 1.49 (d, J=6.58 Hz, 6H). LCMS: RT=6.01 min, M+H+=395
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27]C(=O)C)[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+]>C(O)C>[N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH2:27])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Temperature: 85 °C
Yield: 69 %

Procedure:
To a solution of the compound of Example 28 (2.4 g, 5.59 mmol) in ethanol (40 ml) was added aqueous solution of NaOH (2.4 g, 60 mmol, 10.7 eq.) and the mixture was heated at 85° C. for 5 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 69% yield (1.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=2)[CH:3]=1.[K+].[C:18]([C:20]1[N:21]=[C:22]([C:33]([O-])=[O:34])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)#[N:19].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:33]([C:22]2[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[C:20]([C:18]#[N:19])[N:21]=2)=[O:34])=[C:4]([C:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=2)[CH:3]=1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 85.8 %

Procedure:
To a suspension of 4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine (0.640 g, 2.29 mmol) (prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (0.700 g, 2.30 mmol) (prepared in this example, step (d)) in DCM (12 mL) was added DIPEA (0.800 mL, 4.60 mmol) and PyBroP (1.29 g, 2.76 mmol) and the mixture allowed to stir at RT for 10 h. The mixture was diluted with DCM (50 mL) and washed with NaHCO3 (2×50 mL) and the organic layer dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE with 1:1 DCM/hexanes to give 1.04 g (86%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C25H33BrN4O2Si, 529.1 (M+H), found 529.1.
Reaction SMILES: [I:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:17]([Si:20]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]2[CH:3]=[C:2]([I:1])[S:6][C:5]=2[CH3:7])=[CH:10][CH:11]=1)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: Cc1sc(I)cc1Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1sc(I)cc1Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.2 %

Procedure:
To a solution of phenol 23 (0.54 g, 1.64 mmol) in DMF (15 mL) were added TBDMSCl (1M in CH2Cl2, 3.5 mL, 3.28 mmol), imidazole (0.35 g, 4.92 mmol) and DMAP (50 mg, 0.33 mmol) at room temperature. The mixture was stirred at ambient temperature for 15 hours. The mixture was extracted with EtOAc/H2O (50 mL/150 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 24 (0.65 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[O:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:30]3[CH2:29][CH2:28][N:27]([CH:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH2:32][CH2:31]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CCN2CCN(C3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.3 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (72 mg, 0.24 mmol) in DCE (15 mL) was added 1-(tetrahydropyran-4-yl)piperazine (60 mg, 0.35 mmol), powdered 4 Å molecular sieves and sodium triacetoxyborohydride (103 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a yellow solid (37 mg, 34%). LCMS (Method H): RT=2.46 min, [M+H]+ 450.5
Reaction SMILES: [Br:1][C:2]1[N:16]([Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[C:34]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:35][C:36](=[O:42])[N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH2:7][N:6]1[CH3:43]>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:16]([Si:17]([C:30]([CH3:33])([CH3:31])[CH3:32])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[C:34]3[C:3]=1[CH2:4][C@@H:5]1[C:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)=[CH:9][C@H:8]([NH:35][C:36](=[O:42])[N:37]([CH2:38][CH3:39])[CH2:40][CH3:41])[CH2:7][N:6]1[CH3:43]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(c(Br)n4[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C[C@H]2N(C)C1
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3c(c(Br)n4[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C[C@H]2N(C)C1
Yield: 19 %

Procedure:
3-[2-bromo-1-(tert-butyldiphenylsilyl)-6-methyl-8α-ergolinyl]-1,1-diethylurea, yield: 19%, [α]D =-0.6° (0.5% in chloroform);
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C@@H:7](N3CCN(CCN4CCOC4=O)CC3)[C:6]=2[CH:31]=1.C(Cl)(Cl)Cl.CS(O)(=O)=[O:38]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([OH:38])[C:6]=2[CH:31]=1
Reactant: CS(=O)(=O)O
Reactant: Cc1ccc2c(c1)C[C@@H](N1CCN(CCN3CCOC3=O)CC1)c1cc(F)ccc1S2
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)CC(O)c1cc(F)ccc1S2
Yield: 97 %

Procedure:
5.0 G. of enriched (-)-(R)-3-{2-[4-(8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]ethyl}-2-oxazolidinone αD20 = -9.5°; α365 = +125.0° (chloroform; c = 2.50%)] are heated under reflux for 18 hours with stirring in 81 ml. of 0.5-M methanesulfonic acid and the mixture is subsequently treated with benzene. The organic phase is washed with water, dried over sodium sulfate and evaporated. The residue is crystallized from n-hexane, and there is obtained racemic 8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-ol having a melting point of 89.5°-90° C. The yield is 97%. This compound can be converted in accordance with the procedure described in Example 1 into the 10-chloro compound which can subsequently be used in Example 1 or 11.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[C:26]12([NH2:36])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:36][C:26]34[CH2:27][CH:28]5[CH2:34][CH:32]([CH2:31][CH:30]([CH2:29]5)[CH2:35]3)[CH2:33]4)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2cc(NC34CC5CC(CC(C5)C3)C4)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.078 mmol) in 1.5 mL of ethanol is added 10 μL of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]2[N:13]=[C:14]([NH2:16])[S:15][CH:2]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)Cc1ccc(Cl)cc1
Solvent: CCO
Product: Nc1nc(Cc2ccc(Cl)cc2)cs1
Temperature: 85 °C
Yield: 86 %

Procedure:
A mixture of 1-bromo-3-(4-chlorophenyl)propan-2-one (25.4 grams, 103 mmol) and thiourea (8.59 g, 113 mmol) in ethanol (1.51 L) was heated at 85° C. for 2 hours. The reaction was cooled and concentrated in vacuo and the residue was taken up in ethyl acetate (300 mL) and saturated sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was recrystallized from ethyl acetate/hexanes to give 19.9 grams of the title compound as a tan powder (86% yield). LC/MS (FA) ES+ 225. 1H NMR (300 MHz, CDCl3) δ: 7.29-7.24 (m, 2H), 7.20-7.15 (m, 2H), 6.04 (m, 1H), 5.00 (bs, m, 2H), 3.83 (s, 2H).