Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:32][CH2:31][CH2:30][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:29])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)=[O:11])=O)(C)(C)C.[CH2:33]([N:40]=C=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:6]([N:8]1[CH2:32][CH2:31][CH2:30][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](=[O:29])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)=[O:11])=[O:5])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc2c(c1)OCO2
Product: O=C(COc1ccc2c(c1)OCO2)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1

Procedure:
By the same procedure as in Example 21-C), while using (2S)1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-{1-hydroxy-2-[(3,4-methylenedioxy)phenoxy]ethyl} pyrrolidine (2.07 g) and benzyl isocyanate (0.63 ml), there was obtained 2.06 g of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.[CH3:15][S:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[CH:23][CH:24]=2)[NH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[N:10][C:11]([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([C:26]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:27])[CH:21]=3)[C:17]([S:16][CH3:15])=[CH:18]2)=[N:12][CH:13]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Potassium tert-butoxide (9.75 g, 86.95 mmol, 1.5 eq) and 5-bromo-2-chloropyrimidine (11.21 g, 57.97 mmol, 1.0 eq) were added to (3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (16.0 g, 57.97 mmol, 1.0 eq) in DMF (100 mL). The mixture was stirred at 120° C. for 16 h, then cooled to room temperature, diluted with ethyl acetate (100 mL), and filtered through a pad of celite. The filtrate was washed with water (2×100 mL) and brine (50 mL), and dried over sodium sulphate. The solvents were distilled off and the residue was purified by silica gel column chromatography [100-200 mesh; ethyl acetate/petrolether=1:1]. Yield: 8.0 g (32% over two steps).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(NC3C=CC(OC4C=CN=C(NCCCCN(C)C)N=4)=CC=3C)=O)=[CH:10][C:9]=2[C:40]([F:43])([F:42])[F:41])[CH:5]=[CH:6][CH:7]=1.[Br:44]C1C=C(B(O)O)C=CC=1>CCCCCC.CCOC(C)=O>[Br:44][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[C:40]([F:43])([F:42])[F:41])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(Oc2ccnc(NCCCCN(C)C)n2)ccc1NC(=O)Nc1ccc(-c2cccc(Cl)c2)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1ccc(-c2cccc(Br)c2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Ex. 3 (Step 3.1) for 1-(3′-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butylamino)-pyrimidin-4-yloxy]-2-methyl-phenyl}-urea but using 3-bromophenylboronic acid (Aldrich). The title compound: MS: 315.9 [M-1]−; HPLC DtRet=4.9; Rf=0.16 (Hexane/EtOAc, 4:1).
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[C:1]([NH:4][C:5](=[CH2:9])[C:6]([O:8][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: C=C(NC(C)=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(NC(C)=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-acetamidoacrylic acid (10.3 g, 80.0 mmol) and K2CO3 (10 g, 72.5 mmol) in N,N-dimethylformamide (50 mL) was added benzyl bromide (8.7 ml, 72.5 mmol) at room temperature then stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water (50 mL, 1:1), the aqueous layer was extracted with ethyl acetate (2×45 mL). The combined organic layers was washed with brine (2×25 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide titled compound. MS (ESI(+)) m/e 220(M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.43-7.30 (m, 5H), 6.13 (s, 1H), 5.70 (s, 1H), 5.23 (s, 2H), 2.01 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.[C:19]([O:23][C:24](OC([O-])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>[OH-].[Na+]>[C:19]([O:23][C:24](=[O:25])[NH:13][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)C1
Yield: 96.8 %

Procedure:
1-benzylpyrrolidin-3-ylamine (10 g, 57 mmol) was dissolved in 3M aqueous sodium hydroxide solution (21 ml) and t-butanol (114 ml) in a 500 ml vessel, and t-butyl-dicarbonate ((t-Boc)2O; 13.07 g, 59.9 mmol) was added thereto while stirring. The resulting mixture was reacted for 12 hrs. After the completion of the reaction, the reaction product was extracted with ethyl acetate twice. The organic layer was separated, washed with 0.1N hydrochloric acid solution and brine in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 15.25 g of the title compound as a white solid (yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH:10]([CH3:23])[N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:25])[CH:10]([CH3:23])[N:9]=1
Reactant: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=S

Procedure:
2.6 g of (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 40 ml of dioxane and treated with 1.6 g of phosphorus pentasulfide and 0.7 ml of triethylamine. The mixture is then heated to reflux for 20 minutes, cooled with ice and concentrated on a rotary evaporator. The residue is treated with 10% bicarbonate solution and ethyl acetate, and the ethyl acetate phase is washed twice with 10% bicarbonate solution, dried with sodium sulfate, filtered and concentrated. The residue is purified on a 60 g silica gel column using methylene chloride and methylene chloride/ethyl acetate (20:1) for the elution and then crystallised from methylene chloride/petroleum ether. There is obtained (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-thione which melts at 258°-260° C and which exhibits a rotation of [α]25D =+160,6° (in methylene chloride, 1%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([O:22][C:23]2[CH:24]=[CH:25][C:26]3[N:27]([CH:29]=[C:30]([NH:32][C:33]([CH:35]4[CH2:37][CH2:36]4)=[O:34])[N:31]=3)[CH:28]=2)=[C:20]([F:40])[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:18]([NH:17][C:7]([C:5]5[C:4](=[O:10])[N:3]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=6)[N:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:19][C:20]=4[F:40])=[CH:28][N:27]3[CH:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccccc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1
Yield: 14.4 %

Procedure:
Using 1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (220 mg, 0.99 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (220 mg, 0.66 mmol), HATU (380 mg, 0.99 mmol), diisopropylethylamine (260 mg, 2.0 mmol) and N,N-dimethylformamide (6 mL) as starting materials and in the same manner as in Example 35, the title compound (50 mg, 15%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>O1CCCC1.C(#N)C>[CH3:36][C:28]([NH:27][C:23](=[O:24])[CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1)([CH3:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NC(C)(C)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), tert-butyl 2-amino-2-methylpropanoate hydrochloride (27.8 mg, 0.142 mmol), and TEA (0.050 mL, 0.356 mmol) in tetrahydrofuran (1 mL) and acetonitrile (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction mixture was stirred at 60° C. for 1.5 h and 1M HCl was added to neutralize the reaction solution. The resulting mixture was purified by HPLC to give the title compound. LCMS m/z=479.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.9 Hz, 0.4H), 1.37 (s, 6H), 1.41 (s, 9H), 1.46 (d, J=6.5 Hz, 2.6H), 1.70-1.82 (m, 1H), 2.01-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.45 (t, J=7.8 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 3.05-3.22 (m, 4H), 3.39-3.48 (m, 1H), 3.53-3.62 (m, 1H), 3.72-3.82 (m, 1H), 6.60 (s, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H).
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[N:30]=[N:29][C:28]([CH3:31])=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[N:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[O:14])[N:33]=1
Reactant: Cc1nnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 23.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (203 mg, 0.302 mmol), DCM (3.0 mL) and TFA (1.39 mL, 18.1 mmol) for 2 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (37 mg, 24%) as a white powder. LCMS: Rt=0.35 min, m/z=518.1 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 7.03 (s, 1H), 5.37 (d, J=5.5 Hz, 1H), 5.08-4.97 (m, 1H), 4.90-4.80 (m, 2H), 2.35 (s, 3H), 1.32 (s, 3H), 1.31 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]([NH:7][N+]([O-])=O)=[O:6])(=[NH:3])[NH2:2].N[CH2:12][C:13]([OH:15])=[O:14].Cl>O>[C:1]([NH:4][C:5](=[O:6])[NH:7][CH2:12][C:13]([OH:15])=[O:14])(=[NH:3])[NH2:2]
Reactant: NCC(=O)O
Reactant: N=C(N)NC(=O)N[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: N=C(N)NC(=O)NCC(=O)O
Temperature: 10 °C

Procedure:
The pH of a mixture of 29.4 g (0.2 mole) of N-guanyl-N'-nitrourea and 7.5 g. (0.1 mole) of glycine in 200 ml. of water is adjusted to 6.0 and the resulting solution heated to reflux. During the 2 hrs. of reflux (95°-97° C.) the pH of the reaction is maintained between 6 and 7 by the addition of 10% hydrochloric acid. The reaction, after 2 hours reflux, is cooled to 10° C. and the pH adjusted to 6.9. The precipitate is filtered, washed with 500 ml. of water and dried to give 14 g. of the desired intermediate, m.p. 202° C. (dec.).
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[S:9][CH:10]=1)C.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:4](=[O:21])[CH2:5][C:6]2[N:7]=[C:8]([NH:11][C:12](=[O:20])[C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[S:9][CH:10]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1

Procedure:
54.1 Using general method A, with THF instead of DMF as solvent, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid ethyl ester (example 1.1) was coupled with tert-butyl-1-piperazine carboxylate to give 4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester. White solid. MS 465.1 ([M+H]+)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1(NS(C)(=O)=O)[CH:11]=[C:10]([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH:9]=[CH:8][NH:7]1)(=[O:4])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH:9]=[CH:8][N:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NC1(NS(C)(=O)=O)C=C(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)C=CN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 1 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid(2,2-bismethanesulfonylamino-pyridin-4-ylmethyl)-amide (36 mg, 0.069 mmol) in THF (1 mL) was added a 1 M solution of tetra-n-butylammonium fluoride (347 μL, 0.347 mmol) in THF and the mixture was warmed at reflux. After 1 hour, the mixture was quenched with saturated aqueous ammonium chloride (15 mL) and diluted with EtOAc (15 mL). The organic phase was separated and washed with NaHCO3 (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to afford the title compound as a solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN(C)CCN(C)C.[CH3:21][Si:22]([CH3:32])([CH3:31])[O:23][C:24]([CH3:30])=[CH:25][C:26]([O:28][CH3:29])=[O:27].[CH3:33][Si:34](Cl)([CH3:36])[CH3:35]>C1COCC1>[CH3:29][O:28][C:26]([O:27][Si:34]([CH3:36])([CH3:35])[CH3:33])=[CH:25][C:24]([O:23][Si:22]([CH3:31])([CH3:21])[CH3:32])=[CH2:30]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)C=C(C)O[Si](C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C(C=C(OC)O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To diisopropylamine (6.8 ml, 48 mm) in THF at 0° C. is added 30 ml of 1.6 M n-butyllithium (48 mm), then 6.5 ml tetramethylethylenediamine (TMEDA, 48 mm) cooled to -78° C. Then 7.6 g (40 mm) of methyl 3-trimethylsilyloxybut-2-enoate is added over 5 minutes at -70° C. The mixture is stirred at -75° for 10 minutes, then 8 ml (48 mm) trimethylsilylchloride is added over 5 minutes at -75° C. The solution is warmed to room temperature and concentrated in vacuo. The residue is slurried in 500 ml of n-hexane, and solids filtered off. The filtrate is concentrated in vacuo, B.P.=75°-76° C. at 0.3 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][CH:14]([OH:26])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[C:27](Cl)(=O)C.C(=O)(O)[O-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][CH:14]([O:26][CH3:27])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: CC(=O)Cl
Reactant: COc1cc(C2CC(O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CC(OC)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of 4-(3-bromo-4,5-dimethoxyphenyl)-2-hydroxy-7-methyl-pyrrolo[2,3-h]chroman (5 mg; 0.012 mmol ) in methanol (0.5 ml) at 0° C. was added acetyl chloride (10 μl). The mixture was warmed to room temperature and stirred at this temperature for 3 h. Saturated sodium bicarbonate solution was added and the reaction mixture was extracted with dichloromethane. The extract was washed with saturated sodium chloride solution, dried and evaporated. The crude product was passed through bond-elute (hexane:ethyl acetate=9:1 as eluent), giving the title compound (3 mg; 58%). 1H NMR (acetone-d6): 7.14 (d, J=2.7 Hz) and 7.13 (d, J=2.9 Hz) (1H), 6.94-7.02 (m, 2H), 6.89 and 6.88 (d each, J=8.5 Hz, 1H), 6.50-6.57 (m, 2H), 5.32 (t, J=2.6 Hz) and 5.27 (dd, J=2.3, 7.6 Hz) (1H), 4.34 (dd, J=6.6, 9.5 Hz) and 4.27 (dd, J=6.0, 11.3 Hz) (1H), 3.85, 3.82, 3.81, 3.80, 3.79, 3.78 (s each, 9H), 3.59 and 3.50 (s each, 3H), 2.43 (ddd, J=2.3, 6.6, 13.3 Hz) and 2.12-2.30 (m) (2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([OH:16])[C:14]#[CH:15].[O-]Cl.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH:15]=[C:14]([CH2:13][OH:16])[O:10][N:9]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Reactant: C#CCO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2cc(CO)on2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-nitro-benzaldehyde oxime (2.40 g, 14.4 mmol) was dissolved in methylene chloride (70 ml, 0.2 M), and then propargyl alcohol (2.51 ml, 43.2 mmol) was added to the solution. To the resulting solution was slowly added dropwise 10% NaOCl (17.8 ml, 28.8 mmol) using a dropping funnel. After the addition of NaOCl was completed, the mixture was stirred for about 5 hours while increasing the temperature slowly to room temperature. The completion of the reaction was confirmed by liquid chromatography, and then the mixture was distilled under reduced pressure to remove methylene chloride. Water (200 ml) was added to the residue and the resulting solid was filtered off. The filtered compound was washed with excess of water and finally washed with diethyl ether. The thus-obtained solid compound was recrystallized from ethyl acetate/hexane (1:2) to obtain [3-(4-nitro-phenyl)-isoxazol-5-yl]-methanol in a white sold phase.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH:24]=O)([O-:14])=[O:13].Cl>C(O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:24]/[C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=4)[NH:20][CH:19]=3)/[O:8][C:4]=2[CH:3]=1
Reactant: O=Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CCO
Product: O=C1/C(=C/c2c[nH]c3ccc([N+](=O)[O-])cc23)Oc2cc(O)ccc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (0.400 g, 2.7 mmol) and 5-nitro-1H-indole-3-carboxaldehyde (0.56 g, 2.9 mmol) in ethanol (5.0 mL) was added with concentrated hydrochloric acid (1.0 mL), and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain (Z)-6-hydroxy-2-[(5-nitro-1H-indol-3-yl)methylene]benzofuran-3(2H)-one (0.77 g, 90%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:10]([CH:22]([CH:30]([CH3:32])[CH3:31])[C:23]([O:25]C(C)(C)C)=[O:24])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:10]([CH:22]([CH:30]([CH3:31])[CH3:32])[C:23]([OH:25])=[O:24])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CC2CN(Cc3ccccc3)C(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC2CN(Cc3ccccc3)C(=O)N2C(C(=O)O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
t-Butyl 2-(3-benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (0.22 g; 0.48 mmol) was dissolved in CH2Cl2 (2 ml), and the reaction solution was cooled to 0° C. Then TFA (2 ml) was added. The reaction mixture was stirred at 0° C. for 3 h. It was then concentrated in a rotary evaporator, and the residue was taken up with water and extracted with CH2Cl2 (3×). The organic phase was dried over Na2SO4 and concentrated in a rotary evaporator. 2-(3-Benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyric acid (0.18 g; 0.45 mmol) was obtained as a yellow oil. MS: 397.20 (M+H); Rt: 1.52 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.FC1C=C([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[CH3:32][C:27]1([CH3:33])[C:28]([CH3:31])([CH3:30])[O:29][B:25]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)[O:26]1
Reactant: Brc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Product: CC1(C)OB(c2ccc(Nc3nc4ccccc4s3)cc2)OC1(C)C

Procedure:
N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzothiazol-2-amine was prepared from N2-(4-bromophenyl)-1,3-benzothiazol-2-amine (0.909 g, 2.98 mmol) in a manner similar to that used for N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as an off-white powder (0.321 g, 31%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=13.82 min., 92%; m/z 351 (MH+).