Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C([O:14][CH:15](OCC)[C:16]1[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])C.COB(OC)OC>C1COCC1>[CH2:2]([C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([CH:21]=1)[CH:15]=[O:14])[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(OCC)c1cc(Br)ccc1OC
Reactant: [Li]CCCC
Agent: COB(OC)OC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCc1ccc(OC)c(C=O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
n-BuLi in hexane (1.6M, 15.4 mL, 24.6 mmol) was added dropwise over 15 min to a -70° C. solution of 5-bromo-2-methoxybenzaldehyde diethylacetal in 50 mL of THF. Once the addition was complete, the mixture was stirred and allowed to warm up to 0° C. over 1.5 h. The mixture was then cooled to -70° C. and a solution of trimethylborate (5.4 mL, 48 mmol) in 25 mL of THF was added rapidly through a double-ended needle. The reaction was kept at -70° C. for 4 h and was then allowed to warm to 0° C. slowly before being quenched by the addition of 70 mL of 2.0N aqueous hydrochloric acid. After the mixture had been stirred for 1 h, the layers were separated and the aqueous layer was extracted with 3×100 mL of ethyl acetate. The combined organic layers were dried (sodium sulfate), decanted, and evaporated. The residue was then dissolved in ethyl acetate (100 mL) and extracted with 4×44 mL of 2.0N sodium hydroxide. The ethyl acetate layer was dried (sodium sulfate), decanted, and evaporated. The crude material was purified by flash column chromatography on silica gel, eluting with 10-20% dichloromethane in hexane to yield 5-butyl-2-methoxybenzaldehyde (1.87 g, 43% yield) as an amber liquid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)C(C)C)(C)C.[CH3:21][S@:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[NH:24])=[O:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([N:24]=[S@@:22]([CH3:21])(=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:6]
Reactant: C[S@](=N)(=O)c1ccccc1
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[S@@](=O)(=NC(=O)c1cc(Br)cnc1N)c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of 2-amino-5-bromonicotinic acid (189 mg, 0.87 mmol), N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (162 mg, 1.0 mmol) in 4.0 mL DMF at room temperature was added BOP (423 mg, 0.96 mmol). The solution was stirred 30 minutes, then heated at 60° C. for 30 minutes, and then cooled back to room temperature. After 19 hours, the mixture was dissolved in EtOAc, washed with Na2CO3 solution, H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The yellow foam was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a light yellow solid (260 mg, 84%).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([S:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:31])=O>CN(C)C=O>[ClH:31].[Cl:31][CH2:2][C:3]1[C:8]([S:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ncccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cl
Product: ClCc1ncccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 2 °C
Yield: 111.7 %

Procedure:
A thick suspension of 2-hydroxymethyl-3-triphenylmethylthiopyridine (90.3 g, 235 mmol) in N,N-dimethylformamide (270 mL) in a flask equipped with efficient mechanical stirring was chilled to 2° C. Thionyl chloride (25.8 mL, 354 mmol) was added in 5 mL portions over the period of 1 h while maintaining a temperature below 10° C. After completing the addition the reaction mixture was allowed to reach room temperature and was stirred for 30 min. The precipitate was filtered, washed with ethyl acetate (500 mL) and dried to give 86.7 g (84%) 2-chloromethyl-3-triphenylmethylthiopyridine hydrochloride as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:19]([Si:23]([CH3:47])([CH3:46])[O:24][CH2:25][CH2:26][CH2:27][CH:28]([C:30]1[S:34][C:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH3:45])O)([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:28]([C:30]3[S:34][C:33]([C:35]4[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=4)=[N:32][C:31]=3[CH3:45])[CH2:27][CH2:26][CH2:25][O:24][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:47])[CH3:46])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCCO[Si](C)(C)C(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCCO[Si](C)(C)C(C)(C)C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with [rac]-4-(tert-butyl-dimethyl-silanyloxy)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butan-1-ol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to obtain [rac]-(6-[4-(tert-butyl-dimethyl-silanyloxy)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butoxy}-indol-1-yl)-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][OH:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:35][OH:36])[CH2:22][CH2:21]4)=[N:18][CH:19]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3cnc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3cnc(N4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 54.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 0.114 mmol) and 2-bromo ethanol (25 mg, 0.20 mmol) to give 7-cyclopentyl-2-[4-(2-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 54%). MS(ESI) m/z 480.6 (M+H)+
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[C:33]([CH2:39][NH:40]C(OC(C)(C)C)=O)[CH:32]=2)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]=2[F:29])=[N:11]1)=[O:4].CO.[OH-].[Na+]>C(O)(=O)C>[F:29][C:18]1[C:19]([O:25][CH2:26][CH2:27][OH:28])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[CH:16]([NH:30][C:31]1[CH:32]=[C:33]2[C:34](=[CH:35][CH:36]=1)[C:37](=[NH:38])[NH:40][CH2:39]2)[C:12]1[NH:13][C:14](=[O:15])[N:10]([C:6]2[N:7]=[CH:8][O:9][C:5]=2[C:3]([OH:2])=[O:4])[N:11]=1
Reactant: COC(=O)c1ocnc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc(OC)cc(OCCO)c2F)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ncoc3C(=O)O)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a mixture of 4-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)oxazole-5-carboxylic acid methyl ester (39 mg) and methanol (2.0 mL) there was added a 5 M sodium hydroxide aqueous solution (28 μL), and the mixture was stirred overnight at room temperature. After neutralizing the mixture with acetic acid, the solvent in the mixture was distilled off under reduced pressure. Dichloromethane (2.0 mL) was added to the residue, and then a 4M hydrogen chloride-ethyl acetate solution (500 μL) was added to the solution prior to stirring at room temperature for 15 minutes. Toluene (10 mL) was added to the mixture, and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (8.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:24])=[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C([N:27]([CH2:30]C)CC)C.C(Cl)(Cl)=[O:33].C1C=CC=CC=1.[OH-].[NH4+]>ClCCl>[C:30]([N:8]1[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]([C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])=[C:5]([CH3:24])[N:4]=[C:3]1[O:2][CH3:1])(=[O:33])[NH2:27]
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Reactant: O=C(Cl)Cl
Reactant: CCN(CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC1=NC(C)=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N1C(N)=O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A soluton of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester (5.00 g, 15.0 mmol; see Example 2A) and triethylamine (5.88 g; 45.0 mmol) in dichloromethane (45 ml) at 0° C. under argon was treated via syringe with a 1.2M solution of phosgene in benzene (15.0 ml, 18.0 mmol). After stirring at 0° C. for 3.5 hours, the reaction was treated with concentrated ammonium hydroxide (1.52 ml, 22.5 mmol). After two hours at room temperature, the reaction was treated with more concentrated ammonium hydroxide (0.5 ml, 7.5 mmol) and stirred at room temperature overnight. The reaction was then diluted with dichloromethane and washed with water and saturated sodium chloride. The organic phase was concentrated and flash chromatographed to give the title compound as a brittle yellow foam (2.83 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH2:7]1.O1CCCC1.C(Br)CCC>CCCCCC>[CH2:1]([CH:7]1[S:8][CH2:9][CH2:10][CH2:11][S:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CSCSC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCCCBr
Product: CCCCC1SCCCS1
Reaction time: 2 h

Procedure:
30 ml. of a 1.6M solution of n-butyllithium in n-hexane were added dropwise to a solution of 4.8 g. of 1,3-dithiane in 150 ml. of tetrahydrofuran under an atmosphere of nitrogen at -20° to -25° C. After 2 hours stirring, 6 g. of n-butyl bromide in 60 ml. of tetrahydrofuran were added dropwise to the reaction mixture, which was stirred for 1 hour at -20° to -25° C. and for a further 30 minutes at room temperture and then concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 6.8 g. of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[C:5]([CH3:19])[O:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][CH:45]1[CH2:52][CH:51]2[N:53]([CH3:54])[CH:47]([CH2:48][CH2:49][CH2:50]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:54][N:53]1[CH:47]2[CH2:48][CH2:49][CH2:50][CH:51]1[CH2:52][CH:45]([NH:44][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:19])=[N:11][C:10]=13)=[O:18])[CH2:46]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: Cc1noc(C)c1-c1nc2c(C(=O)O)cccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1nc2c(C(=O)NC3CC4CCCC(C3)N4C)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
A mixture of 2-(3,5-dimethylisoxazol-4-yl)benzoxazole-4-carboxylic acid (136 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (201 mg, 1.05 mmol), 1-hydroxybenzotriazole (142 mg, 1.05 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (150 mg, 0.66 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.29 mL, 2.11 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3,5-dimethylisoxazole-4-yl)benzoxazole-4-carboxamide (99 mg, 48%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=6.6 Hz, 1H), 8.22 (dd, J=7.7, 1.0 Hz, 1H), 7.69 (dd, J=8.0, 0.9 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 4.66-4.60 (m, 1H), 4.22-4.15 (m, 2H), 2.90 (s, 3H), 2.71 (s, 3H), 2.68-2.60 (m, 2H), 2.57 (s, 3H), 2.07-1.96 (m, 3H), 1.90-1.61 (m, 3H), 1.15-1.05 (m, 2H); MS (ESI+) m/z 395 (M+H); HPLC>99% (AUC), tR=12.33 min.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][N:14]=[C:15]=[S:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:14]([CH2:13][C:12]2[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=2)[C:15]1=[S:16])[CH3:2]
Reactant: Fc1ccc(CN=C=S)cc1
Reactant: CCNCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(Cc2ccc(F)cc2)C1=S
Yield: 38.3 %

Procedure:
The title compound was prepared by the procedure described in Example 4 using 9.2 g of N-ethyl glycine, 8.4 g of 4-fluorobenzyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethyl acetate/hexane mixture. Title compound (4.85 g) was obtained as a white solid, m.p. 73°-76° C. Anal. Calcd. for. C12H13F N2O S: C, 57.12; H, 5.19; N, 11.10 Found: C, 56.97; H,5.15; N, 11.06. Mass spectrum (EI, M.+) m/z 252.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][CH2:9][CH:10]([OH:21])[C@H:11]([NH:13]C(=O)OC(C)(C)C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Cl:8][CH2:9][C@H:10]([OH:21])[CH2:11][NH3+:13]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(O)CCl
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Product: [NH3+]C[C@@H](O)CCl
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (0.70 mL, 9.0 mmol) was added to a mixture of tert-butyl ((2R)-4-chloro-3-hydroxybutan-2-yl)carbamate (200 mg, 0.89 mmol) in dichloromethane (1.4 mL) and the mixture was stirred for one hour. The mixture was concentrated to afford (R)-3-chloro-2-hydroxypropan-1-aminium 2,2,2-trifluoroacetate. 1H NMR (500 MHz, DMSO-d6) δ 7.80 (s, 3H), 3.84 (td, J=6.8, 3.2 Hz, 1H), 3.76-3.63 (m, 1H), 3.61 (dd, J=11.3, 6.0 Hz, 1H), 3.51 (dd, J=11.2, 7.1 Hz, 1H), 3.39-3.30 (m, 1H), 1.08 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][S:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[C:22]([F:25])([F:24])[F:23])=[N:15][CH:16]=2)[N:6]=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:41]1([C:52](=[O:53])[C:51]2[N:50]([CH2:54][C:55](O)=[O:56])[CH:49]=[N:48][C:47]=2[N:45]([CH3:46])[C:43]1=[O:44])[CH3:42]>N1C=CC=CC=1.C(Cl)Cl>[CH3:42][N:41]1[C:52](=[O:53])[C:51]2[N:50]([CH2:54][C:55]([N:4]([CH2:3][S:2][CH3:1])[C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]4[CH:16]=[N:15][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C@H:18]5[C:22]([F:25])([F:23])[F:24])=[N:13][CH:12]=4)[N:6]=3)=[O:56])[CH:49]=[N:48][C:47]=2[N:45]([CH3:46])[C:43]1=[O:44]
Reactant: CSCNc1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSCN(C(=O)Cn1cnc2c1c(=O)n(C)c(=O)n2C)c1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of (S)—N-((methylthio)methyl)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 4.17 g, 46.0 mmol) and DCC (18.99 g, 92 mmol) in pyridine (230 mL) was heated for 30 minutes at 60° C. before theophylline 7-acetic acid (21.92 g, 92 mmol) was added in one portion. The reaction mixture was stirred at 60° C. and monitored by LCMS. After 2 hours, additional theophylline 7-acetic acid (21.92 g, 92 mmol) and DCC (18.99 g, 92 mmol) were added to drive the reaction to completion. The reaction mixture was diluted with CH2Cl2. The resulting precipitate (DCC urea) was filtered over Celite® and washed with CH2Cl2 (3×). The mixture was diluted with water and adjusted to pH 3 with aqueous 3M HCl. The organic and aqueous layers were separated and the aqueous layer was extracted with additional CH2Cl2 (3×). The combined organic layers were washed with aqueous 1M HCl (2×), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified using silica gel chromatography, eluting with EtOAc:Hex (70:30) to yield 18.5 g (31.4 mmol, 68%) of the title product as a thick oil; 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.16-8.03 (m, 2H), 7.99 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 5.33 (s, 2H), 5.12 (m, 3H), 3.82-3.65 (m, 2H), 3.43 (s, 3H), 3.18 (s, 3H), 2.31-2.09 (m, 4H), 2.06 (s, 3H); m/z found [M+H]+=590.37.
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]2[N:28]([CH:29]([CH3:31])[CH3:30])[C:27]([CH3:32])=[N:26][CH:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)C)[CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1>C(O)(C)C.O.Cl>[NH2:20][C@H:17]1[CH2:18][CH2:19][N:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:5]3[N:4]=[C:3]([C:24]4[N:28]([CH:29]([CH3:30])[CH3:31])[C:27]([CH3:32])=[N:26][CH:25]=4)[C:2]([F:1])=[CH:7][N:6]=3)=[CH:14][CH:13]=2)[CH2:16]1
Reactant: CC(=O)N[C@H]1CCN(c2ccc(Nc3ncc(F)c(-c4cnc(C)n4C(C)C)n3)cc2)C1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](N)C4)cc3)ncc2F)n1C(C)C
Yield: 94.8 %

Procedure:
N-[(3S)-1-(4-{[5-Fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl]amino}phenyl)pyrrolidin-3-yl]acetamide (Example 152; 0.49 g, 1.12 mmol) in isopropanol (20 ml), water (5 ml) and hydrochloric acid (2 ml) was heated at reflux under nitrogen for 18 hours. After evaporation under reduced pressure, the mixture was dissolved in water (15 ml) and adjusted to pH 9 with aqueous ammonium hydroxide solution. The solution was extracted with DCM (3×15 ml), dried and after evaporation under reduced pressure to give the title compound as a solid (0.42 g, 95%). NMR: 1.38 (d, 6H), 1.61-1.73 (m, 1H), 2.00-2.13 (m, 1H), 2.44 (s, 3H), 2.80-2.88 (m, 1H), 3.12-3.20 (m, 1H), 3.20-3.42 (m, 2H), 3.49-3.60 (m, 1H), 5.40-5.51 (m, 1H), 6.46 (d, 2H), 7.30 (d, 2H), 7.33 (s, 1H), 8.40 (s, 1H), 9.00 (s, 1H); m/z 396.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[C:15]([OH:16])=[CH:14][C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=1.[CH3:21][N:22]1CCCC1=O>>[C:21]([C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[C:15]([OH:16])=[CH:14][C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=1)#[N:22]
Reactant: Oc1cc2c(cc1CC=Cc1ccccc1Br)OCC2
Reactant: CN1CCCC1=O
Product: N#Cc1ccccc1C=CCc1cc2c(cc1O)CCO2
Temperature: 25 °C

Procedure:
6-(o-Bromocinnamyl)-2,3-dihydro-5-hydroxybenzofuran (1.49 g; 4.5 mM) and cuprous cyanide (1.37 g; 15.3 mM) were suspended in 18 ml of anhydrous N-methyl-2-pyrollidinone. Nitrogen was bubbled through this suspension for approximately 15 minutes and the reaction mixture was then heated to 175° under nitrogen for 2 hours. After cooling to ambient temperature the reaction was poured into 60 ml of water containing 60 ml of concentrated ammonium hydroxide. This emulsion was extracted three times with ether, dried over magnesium sulfate and stripped to a brown oil. Flash chromatography of this material on a 30 mm by 51/2" column of silica gel eluted with 500 ml of 35% ethyl acetate in hexane gave a solid which was recrystallized from ethyl acetate/hexane producing 0.95 g (76%) of white crystals identified as 6-(o-cyanocinnamyl)-2,3-dihydro-5-hydroxy-benzofuran.
Reaction SMILES: ClCC([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@H:11]1[CH2:30][C@@:29]2([CH3:31])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:25]2([CH3:33])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[CH2:13][C@@H:12]1[OH:34])=O.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+].O>CO>[OH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@H:11]1[CH2:30][C@@:29]2([CH3:31])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:25]2([CH3:33])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[CH2:13][C@@H:12]1[OH:34]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCOC(=O)CCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCO)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 50 °C
Reaction time: 5 h
Yield: 52.9 %

Procedure:
2β-(4'-Chloroacetoxy-n-butoxy)-3α-hydroxy-5α-pregnane-11,20-dione (380 mg.) was dissolved in methanol (40 ml.) and the stirred solution heated to 50°C. Perchloric acid (0.5 ml.) was added and the mixture stirred at 50°C for 5 hours. The mixture was neutralised with sodium bicarbonate solution, poured into water and extracted with ether (2 × 100 ml.). The combined extracts were washed with water (200 ml.), dried over anhydrous sodium sulphate and evaporated in vacuo to a white foam (270 mg.) which was purified by preparative tlc in acetone/petroleum ether 1/1 to give the title compound (170 mg.) [α]D + 79.5°
Reaction SMILES: CO.[CH:3]1([C:9]2[C:17]3[C:16](=[O:18])[NH:15][C:14]([C:19]4[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:21][C:20]=4[O:31][CH3:32])=[N:13][C:12]=3[N:11]([CH3:33])[N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH-].[Na+].Cl>O>[CH:3]1([C:9]2[C:17]3[C:16](=[O:18])[NH:15][C:14]([C:19]4[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][C:20]=4[O:31][CH3:32])=[N:13][C:12]=3[N:11]([CH3:33])[N:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)COc1ccc(-c2nc3c(c(C4CCCCC4)nn3C)c(=O)[nH]2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OCC(=O)O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a 2 ml methanol solution of 127 mg (0.298 mmol) of the compound obtained in Example 40, 372 μl (0.372 mmol) of 1M sodium hydroxide was added, and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was returned to room temperature, and diluted with 5 ml of water. Then, 0.4 ml of 1M hydrochloric acid was slowly added. Precipitated solids were collected by filtration to obtain 85 mg (69%) of the captioned compound.