Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16](Br)[C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15].[C:22]([O-])(=[S:24])[CH3:23].[K+]>CO>[C:22]([CH:16]([C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=1)[C:17]([O:19][CH3:20])=[O:18])(=[S:24])[CH3:23]
Reactant: CC([O-])=S
Reactant: COC(=O)C(Br)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(C(C)=S)c1ccc(Cl)c(Cl)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
A toluene (403 mL) solution of methyl 2-(3,4-dichlorophenyl)-2-bromoacetate (134 g, 0.451 mol) was dropwise added to a methanol (403 mL) solution of potassium thioacetate (67.7 g, 0.586 mol, 1.3 equivalent amounts based on the starting material) at 5° C. over a period of 15 minutes, followed by stirring at 5° C. for 1 hour. The formed solid was subjected to filtration, and the filtrate was mixed with toluene (403 mL), sequentially washed with water, a saturated sodium hydrogencarbonate aqueous solution, a saturated ammonium chloride aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a yellow oil (136 g, yield: 103%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([O:34][C:35]4[CH:36]=[C:37]5[C:41](=[CH:42][CH:43]=4)[NH:40][C:39]([CH3:44])=[CH:38]5)=[N:29][CH:30]=[N:31]3)=[CH:26][C:25]=2[O:45][CH3:46])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:46][O:45][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:24]=1[O:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)[N:31]=[CH:30][N:29]=[C:28]2[O:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([CH3:44])=[CH:38]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCNCC1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
TFA (8 ml) was added to a solution of 7-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (2.75 g) in dichloromethane (30 ml) at 0° C. and the reaction mixture was stirred at this temperature for 1 hour before being concentrated in vacuum in a cold bath (˜20° C.). Cold water was added to the residue and the pH was adjusted to 10.5 with 1N sodium hydroxide. After several extractions with dichloromethane, the combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuum to give 6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(piperazin-1-yl)ethoxy]quinazoline (1.8 g) as a white solid.
Reaction SMILES: [NH2:1][C:2](=[O:27])[CH2:3][O:4][CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([C@@H:5]([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[O:4][CH2:3][C:2]([NH2:1])=[O:27])[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCC(N)=O)c2cccc(Cl)c2F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)CO[C@@H](c1cccc(Cl)c1F)C1CCCNC1
Yield: 96 %

Procedure:
A solution of (R)-tert-butyl 3-((2-amino-2-oxoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (100 mg, 0.25 mmol) in 20% TFA/CH2Cl2 (5 mL) was stirred at 0° C. for 30 min. The solvent was neutralized by adding saturated NaHCO3, extracted three times with CH2Cl2 and dried over Na2SO4. Evaporation of the solvent gave (R)-2-((3-chloro-2-fluorophenyl)(piperidin-3-yl)methoxy)acetamide (72 mg, 0.24 mmol, 98%). MS (E/Z): 301 (M+H+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[C:21]([F:25])[CH:22]=[C:23]([F:24])[C:16]=2[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:24][C:23]1[C:16]2[N:15]=[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:18]([CH3:19])[C:17]=2[CH:20]=[C:21]([F:25])[CH:22]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1nc2c(F)cc(F)cc2n1C
Product: Cn1c(CCC#Cc2cccc(CF)n2)nc2c(F)cc(F)cc21

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (109 mg, 0.57 mol) and 2-(but-3-ynyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (126 mg, 0.57 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: from 100/0 to 99/1 as eluent) to afford 43 mg of a light brown solid. The resulting solid was dissolved in Dioxane and 0.5N HCl in dioxan was added (0.14 mL, 0.07 mmol). A green solid was formed and it was collected by filtration and washed with AcOEt. The chlorhydrate salt was dissolved in MeOH, neutralized by saturated NaHCO3. The aqueous layer was extracted twice with AcOEt. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure to afford 9 mg of 4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole (Yield: 5%) as purple oily solid (Mp=103° C.-104° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([C:19](=[O:21])[CH3:20])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2cc3ccccn3n2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (2.00 g, 9.42 mmol) in acetic anhydride (20 mL) and conc. H2SO4 (2 drops) was stirred and heated at reflux for 30 min. The mixture was cooled to room temperature, poured into ice water (300 mL), and basified (pH=10) using 1N NaOH(aq). The resulting orange precipitate was collected by filtration, washed with water, air-dried, then dried under high-vacuum to afford the title compound as an orange solid, 2.60 g (quant.). 1H NMR (CDCl3) δ 8.56 (d, 1H, J=6.9 Hz), 8.45 (d, 1H, J=9.3 Hz), 7.62 (m, 2H), 7.54 (m, 1H), 7.24 (m, 2H), 7.08 (m, 1H), 2.20 (s, 3H): MS (+ve ion electrospray) 255 (100), (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14]>C(N(CC)CC)C.[Cu]I>[OH:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: OCCCc1cccc(Br)c1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cccc(CCCO)c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a degassed solution of 3-(3-bromophenyl)propan-1-ol (8) (0.95 g, 4.5 mmol) and 2-methyl-3-butyn-2-ol (9) (1.6 mL, 16 mmol) in triethylamine (25 mL) was added PdCl2(PPh3)3 (0.095 g, 0.14 mmol) and CuI (0.027 g, 0.14 mmol). The resulting mixture was degassed and stirred under argon at 70° C. for 15 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL). The solution was filtered through filter paper, washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (10 to 100% EtOAc-hexanes gradient) gave 4-(3-(3-hydroxypropyl)phenyl)-2-methylbut-3-yn-2-ol (10) as a light brown oil: Yield (0.78 g, 80%): 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.18 (m, 4H), 5.46 (s, 1H), 4.48 (t, J=5.2 Hz, 1H), 3.38 (q, J=6.0 Hz, 2H), 2.59 (t, J=7.2 Hz, 2H), 1.66-1.73 (m, 2H), 1.46 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[N:37]1([C:43]2[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[S:45][N:44]=2)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>[I-].[K+].CN(C=O)C>[S:45]1[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:43]([N:37]2[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][CH2:4][CH:5]3[C:20](=[O:21])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[F:19])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:41][CH2:42]2)=[N:44]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (1.36 g) and DMF (40 ml) was added anhydrous potassium carbonate (0.3 g), diisopropylethyl amine (0.8 ml), 3-piperazinyl-1,2-benzisothiazol (1.26 g) and potassium iodide (27 mg) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 12 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 20% triethylamine/ether) afforded 1.0 g of 5-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propyl]-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one as a foam. The product was flushed through alumina with dichloromethane. The hydrochloride was prepared by dissolving the free amine with menthanol and adding ethereal HCl. The salt was filtered and washed with pentane, m.p. 215° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].O([C:14]1[C:15]2[C:20]([N:21]=[C:22]3[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]3)=[CH:19][CH:18]=[CH:17][CH:16]=2)C1C=CC=CC=1.CCOCC>C1(O)C=CC=CC=1>[C:4]([CH2:3][CH2:2][NH:1][C:14]1[C:15]2[C:20]([N:21]=[C:22]3[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]3)=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:6])=[O:5]
Reactant: NCCC(=O)O
Reactant: c1ccc(Oc2c3ccccc3nc3ccccc23)cc1
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: O=C(O)CCNc1c2ccccc2nc2ccccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
β-Alanine (1 g, 11.2 mmol) was added to a solution of 9-phenoxyacridine (2.7 g, 10 mmol) in phenol (15 g). The suspension was stirred at 120° C. for 2 h. The solution was cooled to room temperature and poured into ether whereby the product precipitated as a yellow-green solid. It was triturated with hot ethanol, filtered and then washed with ethanol, giving crude 9-(2-carboxyethyl)aminoacridine. Yield 1.9 g (71%).
Reaction SMILES: C([O:3][P:4]1(=[O:14])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]([CH3:13])[O:5]1)C>O>[OH:14][P:4]1(=[O:3])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]([CH3:13])[O:5]1
Reactant: CCOP1(=O)OC(C)c2ccccc21
Solvent: O
Product: CC1OP(=O)(O)c2ccccc21

Procedure:
The 1-ethoxy-3-methyl-1,3-dihydro-2,1-benzoxaphosphole-1-oxide was added to 25 ml. of water and then heated on a steam bath for 1 hour. The reaction mixture was cooled, washed with chloroform and taken to dryness under vacuum to yield a clear oil which crystallized upon scratching. Recrystallization from acetone-ether yielded 1-hydroxy-3-methyl-1,3-dihydro-2,1-benzoxaphosphole-1-oxide as a white powder. A second crop was obtained from the filtrate to give a total yield of 2.4 g (67% yield) of 1-hydroxy-3-methyl-1,3-dihydro-2,1-benzoxaphosphole-1-oxide having a melting point of 148°-149° C. and the following analysis:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23][CH2:24][CH2:25]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([Cl:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:25][CH2:24][CH2:23][Cl:22])[C:6]=2[CH:12]=1
Reactant: ClCCCI
Reactant: CCc1c(Cl)cc2c(c1Cl)OCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCc1c(Cl)cc2c(c1Cl)OCC(=O)N2CCCCl
Yield: 67.1 %

Procedure:
6,8-Dichloro-7-ethyl-4H-benzo[1,4]oxazin-3-one (95MF46) (0.342 g, 1.39 mmol), Cs2CO3 (0.678 g, 2.08 mmol) and 3-chloro-1-iodopropane (0.313 g, 1.52 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF52(2226)) (0.301 g, 67%). 1H NMR (CDCl3) δ 7.01 (s, 1H), 4.68 (s, 2H), 4.06 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H), 2.91 (q, J=7.6 Hz, 2H), 2.10-2.18 (m, 2H), 1.16 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3) δ 163.8, 140.6, 135.8, 127.9, 127.7, 123.6, 113.8, 67.9, 42.2, 39.3, 30.0, 24.7, 12.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:8][C:6]2[CH:5]=[CH:4][C:3]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]([CH3:20])[C:10]3=[O:21])=[C:2]([F:1])[CH:7]=2)=[CH:25][CH:24]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(O)cc2F)c1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(OCc3ccc(Cl)cc3)cc2F)c1=O
Yield: 81.6 %

Procedure:
A stirred solution of 0.6 gram (0.002 mole) of 3-(2-fluoro-4-hydroxyphenyl)-1-methyl-6-trifluoromethyluracil, 0.3 gram (0.002 mole) of 4-chlorophenylmethyl chloride, and 0.5 gram (0.004 mole) of potassium carbonate in 50 mL of N,N-dimethylformamide was heated at 80° C. for about 18 hours. After this time the reaction mixture was poured into aqueous 0.25N hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined extracts were washed with water. The organic layer was dried with magnesium sulfate, and the mixture was filtered. The filtrate was then subjected to column chromatography on silica gel. Elution was accomplished using 1:4 heptane in ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.7 gram of 3-[4-(4-chlorophenylmethoxy)-2-fluorophenyl]-1-methyl-6-trifluoromethyluracil, mp 134°-135° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([C@H:44]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]2)[CH3:45])=[CH:14][N:13]=1.[F:56][C:57]1[CH:58]=[C:59]([NH2:65])[CH:60]=[N:61][C:62]=1[O:63][CH3:64]>C1COCC1>[F:56][C:57]1[CH:58]=[C:59]([NH:65][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[N:19]=3)=[CH:16][C:15]([C@H:44]([N:46]3[CH2:47][CH2:48][N:49]([S:52]([CH3:55])(=[O:53])=[O:54])[CH2:50][CH2:51]3)[CH3:45])=[CH:14][N:13]=2)[CH:60]=[N:61][C:62]=1[O:63][CH3:64]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M in hexane; 31.9 mL, 31.9 mmol) was added (dropwise over 10 min) to a mixture of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 146, Step 6; 6.75 g, 10.62 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 2.264 g, 15.93 mmol) in THF (100 mL) at 0° C., and the resulting solution was stirred at 0° C. for 1 h. Excess LiHMDS was then quenched with saturated aqueous NH4Cl (140 mL) and the reaction mixture was partitioned between EtOAc (500 mL) and half-saturated aqueous NH4Cl (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×200 mL). The combined organic extracts were sequentially washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/hexanes) furnished (R)-4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (7.25 g, 90% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.88 (1H, s), 8.72 (1H, d, J=2.0 Hz), 8.25 (1H, d, J=2.2 Hz), 8.06 (1H, dd, J=12.3, 1.6 Hz), 7.96 (1H, d, J=2.0 Hz), 7.21 (4H, t, J=8.2 Hz), 6.86 (4H, dd, J=14.1, 8.4 Hz), 4.70-4.96 (4H, m), 4.01 (3H, s), 3.81 (3H, s), 3.78 (3H, s), 3.55 (1H, q, J=6.7 Hz), 3.15 (4H, br s), 2.68 (3H, s), 2.59 (3H, s), 2.48-2.57 (4H, m), 1.38 (3H, d, J=6.7 Hz). 19F NMR (376 MHz, CDCl3) δ −139.13 (1 F, d, J=13.0 Hz). m/z (ESI, +ve) 758.3 (M+H)+.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CCCCCC>[CH:15]1([NH:21][SiH:2]2[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]2[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1NC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
In an argon atmosphere, 5.70 g (24.5 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 100 mL of hexane and after adding 4.86 g (49.0 mmol) of cyclohexylamine, the mixture was stirred at room temperature for 4 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was sublimated (heating temperature: 160° C./7.0×102 Pa) to obtain 2-cyclohexylamino-1,3-di-tert-butyl-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NHCy) as a white solid (yielded amount: 6.95 g, yield: 96%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][S:7][C:6](=[N:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[CH3:20])[NH:5]1)([CH3:3])[CH3:2].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>>[CH2:21]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8][S:7][C:6]1=[N:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[CH3:20])[CH:22]([CH3:24])[CH3:23]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](C(C)C)CCS1
Reactant: CC(C)CBr
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC[C@H](C(C)C)N1CC(C)C
Yield: 32 %

Procedure:
(R)-4-Isopropyl-2-(2-methyl-4-nitrophenylimino)-2,3,4,5-tetrahydro-1,3-thiazine Method C3a) was reacted with isobutyl bromide in a manner analogous to Method D2a to yield (4R)-3-isobutyl-4-isopropyl-2-(2-methyl-4-nitrophenylimino)tetrahydro-2H-1,3-thiazine (0.081 g, 32%). TLC (33% EtOAc/hex) Rf0.76.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH2:8][CH2:9][CH:10]([C:14]#[N:15])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2].O1CCCC1.B#B.[BH4-].[Na+]>COCCOCCOC>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH2:8][CH2:9][CH:10]([CH2:14][NH2:15])[CH2:11][CH:12]([OH:13])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: N#CC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1
Agent: B#B
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOCCOC
Product: NCC1CCc2ccc([N+](=O)[O-])cc2C(O)C1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
20 g of 3-nitro-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene-7-carbonitrile were added under nitrogen to 200 ml of anhydrous tetrahydrofuran and diborane [prepared by introducing a solution of 23 g of sodium borohydride in 640 ml of diglyme at 20° C. over 4 hours into a solution of 118 g of a ether-boron trifluoride complex in 250 ml of diglyme (J.A.C.S., Vol. 82 (1960), p. 685] was bubbled into the mixture for 30 minutes at room temperature. The mixture was then heated for 31/2 hours on a bath at 50° C. and was then cooled to 20° C. 100 ml of water were added thereto dropwise over 10 minutes followed by 50 ml of fuming hydrochloric acid. The mixture was refluxed for an hour and was cooled to 20° C. after which 100 ml of water were added. The mixture was extracted with ethyl acetate and the organic phase was washed with water. The combined aqueous phases were made alkaline at 10° C. with concentrated sodium hydroxide and was iced. The mixture was vacuum filtered and the white product was washed with water. The wash waters were washed with methylene chloride containing 20% of methanol and the organic phase was washed with water. The while precipitate from the aqueous phase was dissolved in 100 ml of water and the solution was added to the organic extracts. The mixture was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 14 g of a yellow oil which was crystallized from ethyl acetate to finally obtain 13 g of a mixture of cis and trans isomers of 3-nitro-7-aminomethyl-6,7,8,9-tetrahydro [5H] benzocycloheptene-5-ol melting at ≃150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][C@H:6]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:7]([OH:11])[CH2:8][CH:9]=[CH2:10].[NH+]1C=C[CH:27]=[CH:26][CH:25]=1.COC(OC)(C)C>C(Cl)(Cl)Cl>[CH2:8]([C@H:7]1[O:11][C:26]([CH3:27])([CH3:25])[N:12]([C:13]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:19])[C@H:6]1[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:22]=[C:21]([F:23])[CH:20]=1)[CH:9]=[CH2:10]
Reactant: C=CC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reactant: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)OC
Product: C=CC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1Cc1cc(F)cc(F)c1

Procedure:
Alcohol 13 was stirred in chloroform with pyridinium p-toulenesulfonate and 2,2-dimethoxypropane while heating to afford (14) as a tan solid after workup.
Reaction SMILES: C1O[C:4]2([CH2:21][CH2:20][C@@:19]3([CH3:22])[C:6](=[CH:7][CH2:8][C@@H:9]4[C:18]3=[CH:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][C@@H:12]([CH3:35])[C@@H:13]3[C:23](=[O:34])[CH2:24][CH2:25][CH2:26][O:27]C3CCOCC3)[CH2:5]2)[O:3]C1.Cl.C(=O)(O)[O-].[K+]>CC(C)=O>[CH3:35][C@@H:12]1[CH2:11][C@H:10]2[C@H:9]3[C:18](=[CH:17][CH2:16][C@:14]2([CH3:15])[C@H:13]1[C:23](=[O:34])[CH2:24][CH2:25][CH2:26][OH:27])[C@:19]1([CH3:22])[C:6](=[CH:5][C:4](=[O:3])[CH2:21][CH2:20]1)[CH2:7][CH2:8]3
Reactant: C[C@@H]1C[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CCCOC1CCOCC1)OCCO5
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CCCO

Procedure:
16α-Methyl-17β-(1-oxo-[4-tetrahydropyranyloxy]-butyl)-androsta-5,9(11)-dien-3-one 3-ethylene ketal, step (D), is dissolved in acetone (90 ml) and hydrochloric acid (1 N, 10 ml) and allowed to stand at 20°-25° for several hours. Following addition of potassium bicarbonate (1N, 25 ml), the mixture is concentrated and extracted with ethyl acetate. The concentrate is chromatographed on silica gel eluting with acetone/methylene chloride. The appropriate fractions are pooled and concentrated to give 16α-methyl-17β-(1-oxo-[4-hydroxy]butyl)androsta-4,9(11)-dien-3-one.