Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:20]([C:25]#[N:26])([CH3:24])[C:21](O)=O)[C:13]([O:18][CH3:19])=[CH:14][C:15]=2[CH3:17])[CH:10]=[CH:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:60][C:61]1[CH:62]=[C:63]([NH2:68])[C:64]([NH2:67])=[CH:65][CH:66]=1>C(Cl)Cl>[Br:60][C:61]1[CH:66]=[CH:65][C:64]2[NH:67][C:21]([C:20]([C:12]3[C:13]([O:18][CH3:19])=[CH:14][C:15]([CH3:17])=[C:16]4[C:11]=3[CH:10]=[CH:9][NH:8]4)([CH3:24])[C:25]#[N:26])=[N:68][C:63]=2[CH:62]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(C#N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c2[nH]ccc2c1C(C)(C#N)c1nc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (±)-2-(1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)-2-cyanopropanoic acid (Example 155-E) (1.4 g, 3.91 mmol) in DCM (39.1 ml) at 0° C. was added DIPEA (2.05 ml, 11.72 mmol) followed by HBTU (1.926 g, 5.08 mmol) and 4-bromobenzene-1,2-diamine (1.096 g, 5.86 mmol) at 0° C. and stirred in the ice bath for 20 minutes. The ice bath was removed and the reaction was stirred at room temperature overnight. The reaction was diluted with water, the layers were separated and the organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in acetic acid (7 mL) and heated at 85° C. for 4 hours. The reaction was cooled to 0° C. and quenched with a saturated solution of sodium bicarbonate, diluted with water and EtOAc. The layers were separated and the organic layer was removed, dried over Na2SO4 and concentrated. The crude product was purified via FCC (0-50% EtOAc:heptanes) to obtain the title compound. MS (ESI+) m/z 409.3, 411.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:18]Br.O>C(O)(=O)C>[Br:18][C:12]1[S:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)cs1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(Br)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.01 ml (0.22 mmol) of bromine is provided in 1 ml of acetic acid, and 58.0 mg (0.22 mmol) of the compound from Example 13A, dissolved in 1 ml of acetic acid, are added dropwise. The mixture is stirred at 60° C. overnight. 0.01 ml (0.22 mmol) of bromine is a subsequently added, and the mixture is stirred at 60° C. for another 24 hours. Water is added to the reaction mixture, and the resulting precipitate is collected by suction filtration, washed with water and dried under high vacuum. 43.0 mg (54% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7][CH:8]=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[F-].[Cs+].Br[CH2:18][CH2:19][OH:20]>CN(C=O)C.CC#N>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[N:7]([CH2:18][CH2:19][OH:20])[CH:8]=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1
Reactant: OCCBr
Reactant: COc1ccc2c(c1)S(=O)(=O)N=CN2
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc2c(c1)S(=O)(=O)N=CN2CCO
Reaction time: 2 h

Procedure:
To a solution of 7-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide (4.0 g, 18.8 mmol) in a mixture of 30 ml of DMF and 30 ml of CH3CN there are added 8.6 g (56.6 mmol) of CsF and 1.47 ml (18.8 mmol) of 2-bromoethanol. Stirring is carried out for 2 hours at 75° C. and 1.47 ml (18.8 mmol) of 2-bromoethanol are added. After 6 more hours at 75° C., a further 1.47 ml (18.8 mmol) of 2-bromoethanol and then 2.8 g (18.8 mmol) of CsF are added and stirring is continued at 75° C. overnight. The salts are filtered off at ambient temperature and rinsed with CH3CN; the filtrate is evaporated to dryness. The residue is taken up in CH2Cl2, and the organic phase is washed with saturated NaCl solution and dried (MgSO4). After evaporation, the sticky residue is taken up in a mixture of ethyl ether/CH2Cl2. The gum is triturated until a solid is obtained, which is filtered off to obtain the title compound.
Reaction SMILES: II.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:14])C=CC=1)=O.[CH2:24]([O:26][C:27](=[O:60])[C@H:28]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[C:40]([O:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH:39]=1)[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH3:25]>ClCCl>[CH2:24]([O:26][C:27](=[O:60])[C@H:28]([CH2:37][C:38]1[C:43]([I:14])=[CH:42][C:41]([O:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[C:40]([O:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH:39]=1)[NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH3:25]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)c1)NC(=O)OC(C)(C)C
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Agent: II
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1I)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77 %

Procedure:
Iodine (7.4 mmol) and bis(trifluoroacetoxy)iodobenzene (8.16 mmol) were added to a solution of the tri-boc protected dopa ester analog 16 (5.7 mmol) in anhydrous dichloromethane (60 mL) under argon. The reaction mixture was stirred at room temperature for 40 min and then quenched with a saturated solution of sodium thiosulfate. The organic layer was washed with water (3×10 mL), dried with anhydrous sodium sulfate, filtered and evaporated in a rotary evaporator. The product was purified by silica gel column chromatography using 15-20% ethyl acetate in hexane as the mobile phase to give the iodo analog 17 as white foam in 77% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([OH:18])=O)=[O:5])[CH3:2].[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:21])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:20])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:19])[C:16]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CC(C)NC(C)C
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)C(=O)N(C(C)C)C(C)C

Procedure:
Starting materials: 11-ethoxycarbonyl-2,6,10-trimethyl-2,6,10-undecatrienoic acid and diisopropylamine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[CH3:18][C:19]([CH3:35])([CH3:34])[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28](O)=[C:29]([CH2:30][CH2:31][CH3:32])[C:24]=2[O:23][N:22]=1>>[CH3:18][C:19]([CH3:34])([CH3:35])[CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:1][CH2:2][CH2:3][C:4]3[NH:5][C:6]4[C:11]([CH:12]=3)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=4)=[C:29]([CH2:30][CH2:31][CH3:32])[C:24]=2[O:23][N:22]=1
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Reactant: CCCc1c(O)ccc2c(CC(C)(C)C)noc12
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3[nH]2)ccc2c(CC(C)(C)C)noc12

Procedure:
Using the procedures in Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and 3-(2,2-dimethylpropyl)-7-propyl-6-hydroxybenz[4,5]isoxazole.
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:29]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([Br:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=[S:32])[NH:7][C:6]=2[CH:29]=1
Reactant: O=C1Nc2cc(Br)c(Br)cc2N(C(=O)CN2CCN(CCO)CC2)c2ncccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: O=C(CN1CCN(CCO)CC1)N1c2cc(Br)c(Br)cc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 8,9-dibromo-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 8,9-dibromo-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [CH2:1]([Si:3]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:4][CH2:5][C:6]1([CH2:12][CH2:13][CH2:14][OH:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:15][CH2:14][CH2:13][CH2:12][C:6]1([CH2:5][O:4][Si:3]([CH2:1][CH3:2])([CH2:16][CH3:17])[CH2:18][CH3:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:22])[CH3:21]
Reactant: CC[Si](CC)(CC)OCC1(CCCO)CCCCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)OCC1(CCCOC(C)=O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-[1-(triethylsiloxymethyl)cyclohexyl]propan-1-ol (410 mg) were added acetic anhydride (3 mL) and pyridine (3 mL) at room temperature. The solution was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was distilled with toluene azeotropically to give the title compound (480 mg). This product was subjected to the subsequent step without further pirification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:25])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCCCCBr
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCCCCCCCCCBr

Procedure:
A solution of 30 mmols (8.4 g) of 12-bromododecanoic acid and 10 ml of toluene in 5 ml of thionyl chloride was stirred at 80° C. for 1 hour. Excess thionyl chloride and toluene were distilled out under reduced pressure to obtain 12-bromododecanoyl chloride (acid chloride 11e). 25 mmols (10.1 g) of hydroxy ester 11d obtained in said (11-5) and 30 mmols (3.0 g) of triethylamine were stirred in 100 ml of THF for 2 hours. Thereto was added dropwise a solution of said acid chloride 11e in THF, followed by stirring for 8 hours. The reaction mixture was extracted with ether, washed with dilute aqueous hydrochloric acid solution, dried, concentrated and then purified by column chromatography to obtain the objective bromo ester 11f (13.3 g, yield 80% [α]23D=+2.29 (chloroform)).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>S(=O)(=O)(O)O.O>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)(=[O:17])[CH3:16]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
In a 30 ml-round-bottomed flask, 2.00 g (10.6 mM) of 6-hydroxy-2-naphthoic acid, 4.0 ml of acetic anhydride and two drops of concentrated sulfuric acid were placed, followed by heat-stirring for 1 hour at about 90° C. The reaction mixture was cooled to room temperature and poured into 100 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and recrystallization from ethanol to obtain 1.48 g of 6-acetoxy-2-naphthoic acid (Yield: 60.5%).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.ClC(Cl)(Cl)C(=N)O[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1>C(Cl)Cl>[C:1]([O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[O:16][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCOC(=N)C(Cl)(Cl)Cl)cc1OC
Reactant: O=C(OC1CCCCC1O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CCO[C@H]2CCCC[C@H]2OC(=O)c2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 72 h
Yield: 67.3 %

Procedure:
A 250 mL round bottom flask equipped with an argon inlet and magnetic stir bar was charged with 2-hydroxycyclohexyl benzoate (7.39 g, 33.6 mmol) in anhydrous CH2Cl2 (50 mL). The solution was cooled to 0° C. prior to the successive addition of trimethylsilyl trifluoromethanesulfonate (3.0 mL, 1.9.4 mmol) and 3,4-dimethoxyphenethyl 2,2,2-trichloroacetimidate (16.5 g, 50.4 mmol) dissolved in anhydrous CH2Cl2 (30 mL). The reaction mixture was stirred at r.t. for 3 days. The reaction was then quenched by the addition of H2O (100 mL). The aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed successively with brine (2×100 mL) and distilled water (100 mL), dried over anhydrous MgSO4, and concentrated under vacuum. The crude material was purified by flash column chromatography (EtOAc-hexanes, 1:7, v/v,) to afford a yellow oil (8.69 g, 67%). Rf 0.77 (EtOAc-hexanes, 1:2, v/v,); 1H-NMR (300 MHz, CDCl3) δ 1.36 (m, 2H), 1.62 (m, 4H), 1.85-2.03 (m, 2H), 2.75 (t, 2H), 3.53 (m, 1H), 3.62 (m, 1H), 3.72 (m, 2H), 3.79 (s, 6H, OCH3), 6.76 (m, 3H, Ar), 7.38 (m, 2H, Ar), 7.53 (m, 1H, Ar), 8.00 (m, 2H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:28]2([CH2:33][NH:34][C:13]([C:11]3[N:12]=[C:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=4)[S:9][CH:10]=3)=[O:15])[CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(Cc2nc(C(=O)O)cs2)cc1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cc2nc(C(=O)NCC3(c4ccc(OC)c(OC)c4)CCCC3)cs2)cc1
Reaction time: 16 h
Yield: 44.4 %

Procedure:
2-(4-Methoxy-benzyl)-thiazole-4-carboxylic acid (101 mg, 0.405 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (96.5 mg, 0.410 mmol) were dissolved in acetonitrile (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (171 mg, 0.450 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 5-30% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a yellow solid (84.0 mg, 0.180 mmol, 43.9%). ESI-MS m/z calc. 466.6, found 467.2 (M+1)+. Retention time of 8.32 minutes. 1H NMR (400 MHz, CD3CN) δ 1.68-2.07 (m, 8H), 3.50 (d, J=6.3 Hz, 2H), 3.82 (s, 9H), 4.20 (s, 2H), 6.83-7.29 (m, 8H), 7.87 (s, 1H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.[O-]S([O-])(=O)=O.[Mg+2].[CH3:15][NH:16][NH2:17]>C(Cl)(Cl)Cl>[CH3:15][NH:16][N:17]=[C:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=O
Reactant: CNN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)=NNC
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
To a suspension of ethyl pyruvate (37.8 mL, 338 mmol) and MgSO4 (40.8 g, 339 mmol) in CHCl3 (500 mL) was added a solution or methylhydrazine (18.0 mL, 332 mmol) in CHCl3 (100 mL) at 0° C. The reaction mixture was warmed to room temperature. After stirring for 24 hours at room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 44 g (94%) of the desired product that was used directly without further purification.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[CH:9]([Si:12](Cl)([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].N1C=CN=C1>C(Cl)Cl.CCOCC>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[CH:1][CH:2]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a stirred solution of p-bromophenol (5) (4.0 g, 23.1 mmol) in DCM (40 ml) was added triisopropylsilyl chloride (5 ml, 23.4 mmol). The reaction mixture was cooled to 0° C. and imidazole (3.94 g, 57.9 mmol) was added and the mixture was stirred at 0° C. for 30 minutes then allowed to warm to ambient temperature over 12 hours. The reaction mixture was diluted with ether and sequentially washed with 0.5 M HCl (2×), sat. aq. NaHCO3, water and brine then dried over MgSO4. The crude product was purified by bulb to bulb distillation (boiling point: 149-150° C. at 2.0 mmHg) to give 6 as a clear oil (6.23 g, 82% yield): 1H-NMR (400 MHz, chloroform-d) δ 7.30 (d, J=8.8 Hz, 2 H), 6.75 (d, J=8.8 Hz, 2 H), 1.24 (septet, J=7.2 Hz, 3 H), 1.09 (d, J=7.2 Hz, 18 H); 3C-NMR (100 MHz, chloroform-d) δ 155.2, 132.2, 121.7, 113.2, 17.8, 12.6; FTIR (thin film) 2945, 2892, 2867, 1586, 1487, 1274, 909, 883, 828, 732 cm−1; HRMS (EI+) for C15H25BrOSi calcd. 328.0858 found 328.0844.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][C@@H:22]([NH:25][C:26]([C:28]4[NH:29][C:30]([CH3:35])=[C:31]([Cl:34])[C:32]=4[Cl:33])=[O:27])[C@@H:21]([O:36][CH3:37])[CH2:20]3)[S:12][C:13]=2[C:14]([O:16]CC)=[O:15])=[O:8])[CH2:5][CH2:4]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[C:1]([C:3]1([NH:6][C:7]([C:9]2[N:10]=[C:11]([N:19]3[CH2:24][CH2:23][C@@H:22]([NH:25][C:26]([C:28]4[NH:29][C:30]([CH3:35])=[C:31]([Cl:34])[C:32]=4[Cl:33])=[O:27])[C@@H:21]([O:36][CH3:37])[CH2:20]3)[S:12][C:13]=2[C:14]([OH:16])=[O:15])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1C(=O)NC1(C#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CO[C@H]1CN(c2nc(C(=O)NC3(C#N)CC3)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl

Procedure:
To a solution of ethyl 4-{[(1-cyanocyclopropyl)amino]carbonyl}-2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate (0.09 g, 0.16 mmol, Example 230) in methanol (2 mL) was added potassium carbonate (0.022 g, 0.16 mmol) and water (0.5 mL). After heating in the microwave for 30 min at 80°, reaction was complete by LCMS analysis. The reaction mixture was diluted with water and acidified with 1N HCl. After concentrating to remove methanol, the resulting white precipitate was filtered, washed with water and dried (0.071 g). MS (ES) M+H+: 541 for C21H22Cl2N6O5S; NMR: 1.33-1.41 (m, 2 H) 1.64 (s, 2 H) 1.75 (s, 2 H) 2.19 (s, 3 H) 3.37 (s, 3H) 3.43 (s, 1 H) 3.57 (s, 1 H) 4.08 (s, 1 H) 4.27 (d, 2 H) 4.40 (s, 1 H) 7.16 (d, 1 H) 9.87 (s, 1 H) 12.17 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12][NH:11]1)([O-])=O.[CH3:23][O:24]CCOC>[Pd]>[C:17]1([N:14]2[CH2:15][CH2:16][N:10]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[NH:1][C:23](=[O:24])[N:11]3[CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCOC
Reactant: O=[N+]([O-])c1ccccc1N1CCN(c2ccccc2)CCN1
Agent: [Pd]
Product: O=C1Nc2ccccc2N2CCN(c3ccccc3)CCN12

Procedure:
Hexahydro-1-(2-nitrophenyl)-5-phenyl-1H-1,2,5-triazepine (10.0 g) in 1,2-dimethoxyethane (500 ml) was hydrogenated over 10% palladium on carbon (2 g) at atmospheric pressure and room temperature until theoretical uptake was achieved. The mixture was filtered through Celite and the filter pad was washed with 1,2-dimethoxyethane. The filtrate was evaporated to approximately 100 ml and 1,1'-carbonyl-dimidazole (11 g) was added. The mixture, protected from moisture, was swirled and heated under reflux on a steam bath for 4 hours. The solution was evaporated to dryness. The residue in chloroform was applied to a column (75×5.4 cm) of dry column grade neutral alumina prepacked in chloroform. Elution was with chloroform and monitoring of fractions was by t.l.c. on Alox-25 uv254 plates (Brinkmann) with chloroform-methanol (9:1) as developer. The fractions containing the major component were evaporated to dryness and the residue was crystallized from chloroform-ether; wt. 7.45 g (75%), mp=196°-198°. Three crystallizations from the same solvent system gave titled product, mp=198°-199°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH:16]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][NH:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCC1CCCCN1Cc1ccccc1
Reactant: NC1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(CN2CCCCC2CCCNC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 23 (820 mg, 3.55 mmol) in DCM (15 mL) was added 2-amino-indane (472 mg, 3.55 mmol) drop-wise at ice cold conditions. Acetic acid (0.2 mL) was added to the reaction mixture, followed by sodium triacetoxy borohydride (2.2 g, 10.65 mmol) portion-wise at ice cold conditions. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted with DCM, washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by 230-400 silica gel column chromatography using 1-3% MeOH-DCM as eluent to yield compound 24.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[CH:6][N:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:4]=1[NH:18][C:19](=O)[CH3:20])#[N:2].P(=O)(O)(O)[OH:23]>>[CH3:20][C:19]1[NH:2][C:1](=[O:23])[C:3]2[C:7]([CH3:8])=[CH:6][N:5]([C:9]3[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[CH3:17])[C:4]=2[N:18]=1
Reactant: CC(=O)Nc1c(C#N)c(C)cn1-c1c(C)cc(C)cc1C
Reactant: O=P(O)(O)O
Product: Cc1cc(C)c(-n2cc(C)c3c(=O)[nH]c(C)nc32)c(C)c1
Reaction time: 0.5 h

Procedure:
A suspension of the compound of step B (3.200 g, 11.38 mmol) in 3 ml of 85% phosphoric acid was immersed in an oil bath preheated to 130° C. for 30 minutes. The reaction mixtures was cooled and poured onto crushed ice and stirred until solid formed and ice melted. The solid was filtered, washed with water to give a tan solid, the title compound, which was purified through silica gel column chromatography to give a tan solid. 1H NMR (CDCl3) δ 1.92(s, 6H), 2.32(s, 3H), 2.41(s, 3H), 2.45(s, 3H), 2.46(s, 3H), 6.42(d, 1H), 6.95(s, 2H) ppm.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[NH:5][N:4]=[CH:3]1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(OCC)(=O)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:4]1[CH:3]=[C:2]([CH3:1])[C:6](=[O:7])[NH:5]1)[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: CC1C=NNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1cc(C)c(=O)[nH]1
Yield: 16 %

Procedure:
As described for example 320a, 4-methyl-2-pyrazolin-5-one was reacted with ethyl bromoacetate and potassium carbonate. Extractive workup followed by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound as a white solid (yield: 16%). MS: m/e=185.0 [M+H]+.