Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCS.[Li]CCCC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[C:18]=2[C:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37]C)=[CH:33][CH:32]=2)=[O:30])[CH:14]=[CH:15][CH:16]=1.C1(C)C=CC=CC=1.CCOC(C)=O>C(OCC)C.CN(C=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=3)[C:18]=2[C:29]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[O:30])[CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)C2=C(c3cccc(OC)c3)CCc3cc(OC)ccc32)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(C2=C(C(=O)c3ccc(O)cc3)c3ccc(OC)cc3CC2)c1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
To EtSH (12.5 g, 14.9 mL. 0.20 mol) in anhydrous ethyl ether (300 mL) at −78° C. under a dry nitrogen atmosphere in a 1 L single neck RB flask was added slowly via syringe 1.6M n-BuLi (113 mL, 0.180 mol) over 1 hour. After addition was complete, the ether was removed under vacuum and a solution of [2-(3-methoxyphenyl)-3,4-dihydro-6-methoxynaphthalen-1-yl][4-methoxyphenyl]methanone, (24.0 g, 0.065 mol) in anhydrous DMF (150 mL) was added. The reaction mixture was heated at 70-80° C. for 2.5 hours and then at 65° C. for 20 hr. TLC analysis (SiO2, Toluene-EtOAc 9-1) showed the starting material to be nearly gone. Two spots were present at lower Rf. These were attributed to the desired product and the corresponding diphenol (lowest spot). The reaction mixture was allowed to cool and was then poured into 500 mL iced 1N HCl solution. The crude product was extracted into EtOAc. The EtOAc phase was washed with saturated aq. NaCl solution, dried over anhydrous MgSO4, and evaporated to a yellow oil. The product was purified by chromatography over silica gel using a gradient consisting of chloroform changing linearly 95:5 chloroform: methanol. Following evaporation of the appropriate fractions, a yellow oil was obtained which was recrystallized from ethyl ether to yield 21.3 g, (54%) of the desired product, mp 197-8° C. 1H NMR (CDCl3) δ 7.76 (d, J=8.6 Hz, 2H), 7.10-7.00 (m, 1H), 6.90-6.70 (m, 4H), 6.70-6.60 (m, 4H), 6.07 (bs, 1H), 3.78 (s, 3H), 3.62 (s, 3H), 3.10-2.90 (m, 2H), 2.90-2.70 (m, 21H); MS (FD) m/e 386 (M+); Anal. Calc′d. for C25H22O4: C, 77.70; H. 5.74. Found: C, 77.45; H, 5.66.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromobenzene-1-sulfonamide [CAS 89599-01-9; commercially available] (236 mg, 1.0 mmol) according to
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](N1CCOCC1)=[CH:7][CH2:6][CH2:5]2.[OH:18][N:19]=[C:20](Cl)[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.ClC(Cl)C.C(O)(C(F)(F)F)=O>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1[O:18][N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH3:29])=[CH:23][CH:22]=3)[C:7]=1[CH2:6][CH2:5]2
Reactant: CCCc1ccc(C(Cl)=NO)cc1
Reactant: Brc1ccc2c(c1)CCC=C2N1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CCCc1ccc(-c2noc3c2CCc2cc(Br)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71 %

Procedure:
To 4-(6-bromo-3,4-dihydronaphthalen-1-yl)morpholine (Preparation 20A, 0.36 g, 1.224 mmol) in dichloromethane (4 mL) was added N-hydroxy-4-propylbenzimidoyl chloride (Preparation 20B, 0.242 g, 1.224 mmol) dissolved in 1 mL of dichloromethane at room temperature. Next, triethylamine was added dropwise over a period of 5 min. at room temperature. The reaction mixture was stirred at room temperature for 14 h. and concentrated. The reaction mixture was partitioned between ethyl acetate (15 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to yield an oil. To the oil was added dichloroethane (4.00 mL) followed by TFA (0.141 mL, 1.836 mmol) at room temperature. The reaction mixture was heated at 70° C. for 45 min., stirred at room temperature for 2 h, and partitioned between dichloromethane (10 mL) and sat. aq. sodium bicarbonate (10 mL). The dichloromethane layer was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography employing hexane/ethyl acetate. The desired fractions were collected and concentrated to yield 7-bromo-3-(4-propylphenyl)-4,5-dihydronaphtho[2,1-d]isoxazole (0.32 g, 0.869 mmol, 71.0% yield) as a white solid. LCMS M+1=369.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[F:24])[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2ccccc2F)c1
Yield: 51.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(2-fluorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 2-fluorophenylboronic acid (0.028 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.036 g (51%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:6]([C:8](O)=[O:9])[CH:7]=1.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:8]([C:6]1[CH:7]=[C:2]([F:1])[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:9])=[CH2:24]
Reactant: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (0.20 g, 0.48 mmol), O-(2-vinyloxyethyl)-hydroxylamine (55 mg, 0.53 mmol), EDCI (102 mg, 0.53 mmol), HOBt (72 mg, 0.53 mmol) and DIPEA (90 μL, 0.53 mmol) were dissolved in DMF (10 mL) and the reaction mixture stirred at room temperature for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (200 mg, 83%). LCMS (Method B): RT=3.41 min, [M+H]+=501.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]#[C:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)=[CH:36][N:35]=3)=[CH:26][CH:25]=2)[CH3:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([C:37]2[CH:38]=[CH:39][C:34]([C:33]#[C:32][CH2:31][CH2:30][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][N:21]([CH3:22])[CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)=[CH:29][CH:28]=3)=[N:35][CH:36]=2)=[CH:41][CH:42]=1
Reactant: CN(Cc1ccc(CCC#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccc(CCC#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 mL trifluoroacetic acid are added to a solution of 35 mg (0.06 mmol) tert-butyl4-[(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-methyl-amino]-piperidin-1-carboxylate in 3 mL DCM and the reaction mixture is stirred for 3 h at RT. The mixture is evaporated down i. vac., the residue is combined with 10 mL NaHCO3 solution, extracted with 20 mL DCM and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the desired product is obtained.
Reaction SMILES: [CH:1]([N:4]([CH:25]=[CH:26][CH3:27])[C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH:12]=[N:11][C:10]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)=[CH:9][C:8]2=1)=[CH:2][CH3:3].[H-].[Na+].Br[CH2:31][CH2:32][CH2:33][Cl:34]>CN(C=O)C>[Cl:34][CH2:33][CH2:32][CH2:31][N:14]1[C:13]2[CH:12]=[N:11][C:10]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:16][CH:17]=[C:5]([N:4]([CH:1]=[CH:2][CH3:3])[CH:25]=[CH:26][CH3:27])[CH:6]=2
Reactant: ClCCCBr
Reactant: CC=CN(C=CC)c1ccc2[nH]c3cnc(-c4nc(CC)no4)cc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CN(C=CC)c1ccc2c(c1)c1cc(-c3nc(CC)no3)ncc1n2CCCCl
Yield: 28 %

Procedure:
The compound was synthesized by mixing (Compound 18) (1 g, 2.8 mmol), NaH (50% in oil) (0.075 g, 3.1 mmol) and 1-bromo-3-chloropropane (0.44 g, 3.1 mmol) in DMF in the same manner as illustrated in example 3 to give the title compound (0.35 g, 28%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:30][S:31]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[C:6]2[C:4]([OH:3])=[O:5])=[CH:26][CH:25]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc([N+](=O)[O-])cc1
Product: CS(=O)(=O)Nc1ccc(Cn2c(C(=O)O)c(-c3cccs3)c3ccccc32)cc1

Procedure:
The title compound was prepared from 1-(4-nitro-benzyl)-3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester and methanesulfonyl chloride followed the procedure of Example 3 Step 2 as a light yellow solid: 1H NMR (DMSO-d6) δ 2.94 (s, 3H), 5.76 (s, 2H), 7.08-7.24 (m, 7H), 7.34 (td, J=8.4, 1.2 Hz, 1H), 7.60-7.70 (m, 3H), 9.69 (br s, 1H), 13.25 (br s, 1H); MS (ESI) m/z 427 (MH+); MS (ESI) m/z 425 ([M−H]−); HRMS calcd for C21H19N2O4S2: 427.0784; found (ESI+): 427.0779.
Reaction SMILES: N1(O[C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[Si:20]([O:19][C@@H:18]1[C@@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:31])[CH3:32])[O:37][C@@H:16]([N:15]2[C:38]3[N:39]=[CH:40][N:41]=[C:11]([NH:49][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:12]=3[N:13]=[CH:14]2)[CH2:17]1)([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NCc4ccccc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 61.4 %

Procedure:
As described for the synthesis of 6-(morpholin-1-yl)-9-[2-deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuranosyl]purine, the benzyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol) and benzylamine (21.8 μL, 0.200 mmol) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) in dry DME (1.0 mL) at room temperature over 6 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes followed by 50% EtOAc in hexanes) afforded 35.0 mg (84% yield) of the title compound as a clear gum. Rf (3% MeOH in CH2Cl2)=0.07. 1H NMR (500 MHz, CDCl3): δ 8.41 (s, 1H, Ar—H), 8.11 (s, 1H, Ar—H), 7.38 (d, 2H, Ar—H, J=7.5), 7.33 (t, 2H, Ar—H, J=7.6), 7.28 (m, 1H, Ar—H), 6.45 (t, 1H, H-1′, J=6.6), 5.98 (br s, 1H, NH), 4.87 (br s, 2H, CH2), 4.61 (m, 1, H-3′), 4.01 (q, 1H, H-4′, J=3.4), 3.87 (dd, 1H, H-5′, J=5.9, 4.4), 3.77 (dd, 1H, H-5′, J=5.9, 4.4), 2.64 (quint, 1H, H-2′. J=6.3), 2.43 (ddd, 1H, H-2′, J=13.2, 6.4, 3.9), 0.91 (s, 18H, tert-Bu), 0.10, 0.09, 0.08 (3 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 154.6, 153.1, 138.4, 128.6, 127.8, 127.5, 120.2, 87.8, 84.3, 71.2, 62.8, 41.2, 25.9, 25.8, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C29H48N5O3Si2 (M++H) 570.3296. found 570.3279.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][C:10]=1[NH:19][C:20]([NH2:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:30][CH:31]([CH3:43])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(#N)C>CCOCC>[CH2:23]([N:30]([CH:31]([CH3:43])[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:38]=1)[CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([NH:19][C:20]([NH2:22])=[O:21])[CH:11]=1)=[O:18])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(CC(C)NCc2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1ccc(CC(C)N(CC(=O)c2ccc(OCc3ccccc3)c(NC(N)=O)c2)Cc2ccccc2)cc1

Procedure:
1-(4-Benzyloxy-3-ureidophenyl)-2-bromoethanone (3.1 g) and N-benzyl-(2-[4-carbomethoxyphenyl]-1-methylethanamine) (4.85 g) were heated in refluxing acetonitrile (50 ml) for 2 hours. The solution was diluted with an equal volume of ether, filtered and the filtrate diluted further with ether (200 ml). The solution was washed with water, dried and evaporated to give the title compound, mp 140°-145° (ethyl acetate). τ(CDCl3) 9.00 (3H, d, J=6Hz), 6.70-7.60 (3H, m), 6.0-6.4 (4H, m), 6.20 (3H, s), 4.90 (2H, s), 6.32 (2H, b), 2.1-3.3 (17H, m), 1.20 (1H, d, J=2Hz).
Reaction SMILES: FCC[N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1.[F:39][CH2:40]N=[N+]=[N-]>>[F:39][CH2:40][N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1
Reactant: [N-]=[N+]=NCF
Reactant: O=C1C(=O)N(Cc2cn(CCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Product: O=C1C(=O)N(Cc2cn(CF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
was prepared according to the procedure for compound 11, with the exception that fluoromethylazide was used in place of the 2-fluoroethylazide.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[CH:14]=4)=[CH:9][N:8]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:5]2=[N:6][CH:7]=1.[C:40]([NH:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)(=[O:43])[CH:41]=[CH2:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:20][C:15]1[CH:14]=[C:13]2[C:18]([CH:19]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:47]5[CH:46]=[C:45]([NH:44][C:40](=[O:43])[CH:41]=[CH2:42])[CH:50]=[CH:49][CH:48]=5)[N:3]=4)[N:8]([C:21]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:9]=3)[NH:12]2)=[CH:17][CH:16]=1
Reactant: Cc1ccc2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ncc(Br)nc34)[nH]c2c1
Reactant: C=CC(=O)Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1cccc(-c2cnc3c(n2)c(-c2cc4ccc(C)cc4[nH]2)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A solution of 2-bromo-7-(6-methyl-1H-indol-2-yl)-5-trityl-5H-pyrrolo[2,3-b]pyrazine 8 (30 mg, 0.0528 mmol) and (3-acrylamidophenyl)boronic acid 2 (10.9 mg, 0.0528 mmol) in DMF was added cesium carbonate (34.74 mg, 0.1056 mmol). The reaction was degassed and purged with nitrogen for 10 min. Pd(PPh3)Cl2 (2.06 mg, 0.00264 mmol) was added to the reaction and again degassed for 15 min. The reaction was stirred for 2 h at 90° C. The reaction mixture was allowed to cool to rt. The reaction was diluted with DCM filtered through Celite. The organic layer was concentrated to get the crude. The resulting oil was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 40% ethyl acetate in hexane to afford off white colour solid compound N-(3-(7-(6-methyl-1H-indol-2-yl)-5-trityl-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)acrylamide 9.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[N:13]2[C:14]3[CH:20]=[C:19]([CH3:21])[N:18]([CH2:22][C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26](N)=[O:27])[C:15]=3[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.Cl.[NH2:33][OH:34].C(N(C(C)C)CC)(C)C.CC#N>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[N:13]2[C:14]3[CH:20]=[C:19]([CH3:21])[N:18]([CH2:22][C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([NH:33][OH:34])=[O:27])[C:15]=3[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: NO
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(C(N)=O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(C(=O)NO)c1
Reaction time: 8 h

Procedure:
One-third portion of the crude acid chloride (0.077 mmol) from Example 30, Step 2 was added to a solution of hydroxylamine HCl (0.048 g, 0.69 mmol, Aldrich) and diisopropylethylamine (0.12 mL, 0.69 mmol) in DCM (1 mL). MeCN (1 mL) was added and the reaction was stirred overnight. DCM was removed in vacuo and the reaction mixture was diluted with MeOH, filtered and purified by preparative HPLC-MS (Waters SunFire C18, eluting with a gradient of MeCN/H2O containing 0.1% TFA) (10 mg, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C@@H:7]([C:16](O)=[O:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C@H:7]([NH:8][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:16][OH:17])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 4-bromo-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (72.6 mmol), in anhydrous diethyl ether (550 mL) at 0° C. was added slowly lithium aluminum hydride, 95% (108.9 mmol). The resulting solution was stirred for an additional 2 h at 0° C. The reaction was then carefully quenched with a saturated aqueous solution of sodium bicarbonate (73 mL) which stirred at RT for half an hour. Lithium aluminium salts crashed out of solution which were removed by filtration. The filtrate was concentrated and vacuum pumped for 24 h to afford the title product as a white solid (97%). ESMS [M+H]+: 331.2.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N:15]1[C:20]([CH3:21])=[C:19]([Cl:22])[CH:18]=[C:17]([CH3:23])[C:16]1=[NH2+:24].[CH:25]([CH:27]1[CH2:29][CH:28]1[C:30]([O:32]CC)=[O:31])=O.[OH-].[K+].[Li+].[OH-]>CO.O1CCCC1>[Cl:22][C:19]1[CH:18]=[C:17]([CH3:23])[C:16]2[N:15]([N:14]=[C:25]([CH:27]3[CH2:29][CH:28]3[C:30]([OH:32])=[O:31])[N:24]=2)[C:20]=1[CH3:21]
Reactant: CCOC(=O)C1CC1C=O
Reactant: Cc1cc(Cl)c(C)n(N)c1=[NH2+]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)c(C)n2nc(C3CC3C(=O)O)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
1-Amino-5-chloro-3,6-dimethylpyridin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (100 mg, 269 μmol, Eq: 1.00) was added to a solution of ethyl 2-formylcyclopropanecarboxylate (38.2 mg, 269 μmol, Eq: 1.00) in methanol (2 ml). 2 N KOH aq (200 μl, 400 μmol, Eq: 1.49) was added and the yellow mixture was stirred for 1 h at room temperature under air. 1 N LiOH aq (4 mL, 4 mmol, Eq: 14.9) and tetrahydrofuran (8 ml) were added and the mixture was stirred for 30 min at room temperature. Volatile organic solvents were evaporated, water (10 ml) was added and the mixture was washed with diethyl ether (10 ml). The aqueous phase was acidified with 2 N HCl aq and then extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over sodium sulfate and then concentrated to give the desired product (70 mg, 98%) as a white solid. MS: m/z=266.1 (M+H+)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:36])[C:32](=[O:33])[CH2:31][CH2:30][C@@:29]2([CH3:34])[C:9]1=[CH:10][CH2:11][C@@H:12]1[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:35])[C@H:13]1[CH2:14][CH:15]=[C:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22].O>C(OCC)C>[OH:33][C@H:32]1[CH2:31][CH2:30][C@@:29]2([CH3:34])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:35])[C@H:13]3[CH2:14][CH:15]=[C:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:8]1([CH3:36])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1.5 h
Yield: 106.6 %

Procedure:
To a suspension of lithium aluminium hydride (80 mg, 2 mmol) in diethyl ether (15 mL) was added 4,4-dimethylcholesta-5,16-dien-3-one (220 mg, 0.5 mmol) in 10 mL ether and the whole was stirred for 1.5 hours. Water was added and the solution filtered through a plug of Celite. The aqueous phase was extracted with ether, washed with 4N HCl, brine, dried over magnesium sulphate and concentrated under reduced pressure to give 3β-hydroxy-4,4-dimethylcholesta-5,16-diene (220 mg).