Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][CH:11]([C:16]([CH3:18])=[CH2:17])[C:10]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28].[CH3:29][S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1>C(#N)C>[Cl:27][C:23]1[CH:22]=[C:21]2[NH:20][C:19](=[O:28])[C:10]3([CH:9]([C:3]4[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=4[NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:14][C:13](=[O:15])[NH:12][CH:11]3[C:16]([CH3:18])=[CH2:17])[C:26]2=[CH:25][CH:24]=1
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2N)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 16.2 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.1 mmol), methanesulfonyl chloride (0.0092 mL, 0.15 mmol), in acetonitrile (5 mL) was added pyridine (23 mg, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep. HPLC to give the title compound as a white solid (Yield: 8 mg).
Reaction SMILES: [C@@H:1]12[O:11][CH2:10][C@@H:8]([O:9]1)[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]2[OH:3].[OH2:12]>>[O:12]=[CH:10][C@H:8]([C@@H:6]([C@@H:4]([C@@H:2]([CH2:1][OH:11])[OH:3])[OH:5])[OH:7])[OH:9]
Reactant: O[C@H]1[C@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Reactant: O
Product: O=C[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO
Temperature: 100 °C
Reaction time: 8.5 h

Procedure:
0.16 g (1.00 mmol) of the compound (3) was dissolved in 50 ml of water, followed by adding 4.00 g of amberlight IR-120B (proton type cation exchange resin) to the resultant solution. The system thus prepared was kept stirred for 8.5 hours at 100° C. Then, the amberlight IR-120B was removed from the reaction system by means of filtration, followed by washing the cation exchange resin with water. Further, the solvent was removed from the filtrate and the washing water by means of distillation under reduced pressure. Formation of the desired compound of the present invention, i.e., D-altrose (compound 4), was confirmed by thin layer chromatography. It was also confirmed that the raw material compound (3) was mixed with the product compound (4). The mixing ratio of these compounds (3) and (4) was about 1:1.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:28][NH:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:35]4[CH2:36][CH2:37][N:32]([C:27]5[C:26]6[C:30](=[CH:31][C:23]([F:22])=[CH:24][CH:25]=6)[NH:29][N:28]=5)[CH2:33][CH2:34]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2n[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 6-fluoro-3-piperazin-1-yl-1H-indazole (Table No.1, SM 4) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=506.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][C@H:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20](=[O:27])[CH2:19][CH2:18]4)[C:13]([N+:28]([O-])=O)=[CH:12][N:11]=3)[C:6]=2[CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.C(Cl)Cl>[NH2:28][C:13]1[C:14]([NH:16][C@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[CH2:19][CH2:18]2)=[N:15][C:10]([N:7]2[C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[N:11][CH:12]=1
Reactant: O=C1CC[C@@H](Nc2nc(-n3cnc4ccc(F)cc43)ncc2[N+](=O)[O-])c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cnc(-n2cnc3ccc(F)cc32)nc1N[C@@H]1CCC(=O)c2ccccc21
Reaction time: 1.5 h

Procedure:
To the solution of (4R)-4-(2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-5-nitropyrimidin-4-ylamino)-3,4-dihydronaphthalen-1(2H)-one (80 mg) in THF (10 mL) was added Na2S2O4 (480 mg) and NaHCO3 (240 mg) in H2O (10 mL), and stirring continued at room temperature for 1.5 h. The reaction mixture was diluted with CH2Cl2, washed with saturated brine, dried over MgSO4, and concentrated in vacuo. The crude (32 mg) was subjected to the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][CH2:3]1.[CH2:20]([O:22][C:23](=[O:34])[C:24](=O)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:21].C([BH3-])#N.[Na+]>>[CH2:20]([O:22][C:23]([CH:24]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]2[CH2:16][CH:17]=[CH:18][CH:19]=[C:5]2[S:4][CH2:3]1)[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:34])[CH3:21]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CCOC(=O)CN1C(=O)C(N)CSc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCC)CSC2=CC=CCC21

Procedure:
(±)-3-Amino-3,4-dihydro-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester is reacted with ethyl-2-oxo-4-phenylbutyrate in the presence of sodium cyanoborohydride according to the procedure of Example 1(f) to yield (±)-dihydro-3-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid, ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]2[N:34]=[C:33]([CH2:35][OH:36])[NH:32][C:31]=2[CH:37]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:26][C:27]4[CH:28]=[CH:29][C:30]5[N:34]=[C:33]([CH2:35][OH:36])[NH:32][C:31]=5[CH:37]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5nc(CO)[nH]c5c4)nn23)cn1

Procedure:
{6-[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-1H-benzoimidazol-2-yl}-methanol was prepared from trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1061. Product isolated as a yellow solid (35 mg, 34%). m.p.=182-187° C.; LCMS (m/e) 388 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 12.16 (bs, 1H), 9.36 (s, 1H), 8.97 (s, 1H), 8.92 (s, 1H), 8.60 (dd, 1H, J=1.8 and 8.7 Hz), 7.87 (bs, 1H), 7.50-7.35 (m, 2H), 7.18 (d, 1H, J=4.6 Hz), 6.99 (d, 1H, J=8.7 Hz), 6.94 (d, 1H, J=4.6 Hz), 5.63 (bs, 1H), 4.66 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([NH2:13])=O)[N:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11](=[S:23])[NH2:13])[N:4]=1
Reactant: COc1cc(OC)nc(C(N)=O)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(C(N)=S)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred solution of compound 286 (21.86 g, 1 eq.) in dry THF (200 mL) was added Lawesson's reagent (29 g, 0.6 eq.) under nitrogen. The mixture was then stirred at 90° C. for 1 hr and then concentrated in vacuo. The residue obtained was triturated in a DCM/diisopropyl ether mixture to yield compound 287 as an orange solid in 72% yield. MS (ESI, EI+): m/z=200 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH:10]([CH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1)[C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[N+]=[N-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[CH3:16][C:13]1[O:12][C:11]([CH:10]([NH2:7])[CH:17]2[CH2:18][CH2:19][S:20][CH2:21][CH2:22]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(N=[N+]=[N-])C2CCSCC2)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(N)C2CCSCC2)o1
Temperature: -10 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
304 mg (8 mmol, 2 eq) of lithium aluminum hydride were added to a solution of 968 mg (4 mmol, 1 eq) of 2-[azido(tetrahydrothiopyran-4-yl)methyl]-5-methylfuran in 10 ml of tetrahydrofuran cooled to −10° C. The reaction medium was stirred at ambient temperature for 2 hours. The reaction medium was cooled to 0° C. and water with a solution of sodium hydroxide at 2 N and diethyl ether were added (precipitation of the aluminum and lithium salts). The reaction medium was filtered through celite and then the filtrate was treated with a 3 N hydrochloric acid solution. The aqueous phase was recovered and basified with a 15 N sodium hydroxide solution and then extracted with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. 728 mg of C-(5-methylfuran-2-yl)-C-(tetrahydrothiopyran-4-yl)methylamine were obtained. Yield=86%.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[C:6](=[C:8]1[S:12]C(=S)N[C:9]1=[O:14])[CH3:7])([OH:3])=O.C([OH:21])C.O>>[CH3:7][C:6]1[C:5]2[C:4](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1](=[O:3])[S:12][C:8]=1[C:9]([OH:21])=[O:14]
Reactant: CC(=C1SC(=S)NC1=O)c1ccccc1C(=O)O
Reactant: CCO
Solvent: O
Product: Cc1c(C(=O)O)sc(=O)c2ccccc12

Procedure:
4-Methyl -2- thiaisocoumarin -3- carboxylic acid mp. (EtOH-H2O) 250.5°-251.5° (lit mp. 243°-5°), (Found: C, 60.40; H, 3.98; S, 14.80 C11H8SO3 requires C, 59.99; H, 3.66; S, 14.56) was prepared from 5- (o-carboxy-α-methylbenzylidene) rhodanine by an analogous procedure to that described in Example 12.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[N:17]=[CH:18][CH:19]=[CH:20][N:21]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2ncccn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: C(#CC1CCNCC1)c1ncccn1

Procedure:
4-Pyrimidin-2-ylethynyl-piperidine-1-carboxylic acid tert-butyl ester was treated with TFA for 10 minutes and concentrated, lyophilized to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl[C:14]([N:18](C)[CH3:19])=C(C)C.C(N(CC)CC)C.CNC.C1COCC1>C(Cl)Cl.Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:18]([CH3:19])[CH3:14])=[O:5]
Reactant: CC(C)=C(Cl)N(C)C
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(F)c(F)cc1Cl
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of 2-chloro-4,5-difluorobenzoic acid (385 mg, 2.0 mmol) in DCM (5 mL) was treated with (1-chloro-2-methylprop-1-en-1-yl)dimethylamine (293 mg, 2.2 mmol) and stirred under argon for 1 hour. The mixture was then treated with triethylamine (0.56 mL, 4.0 mmol) and a 2M solution of dimethylamine in THF (1.2 mL, 2.4 mmol), and stirred for 18 hours. The mixture was diluted with DCM (5 mL) and 2M hydrochloric acid (4 mL) and separated. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (425 mg). The residue was used without further purification.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([Cl:34])[CH:20]=[C:21]([C:23]([N:25]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:26][CH:27]=[CH2:28])=[O:24])[CH:22]=1.CN>C(O)C>[NH2:3][O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([Cl:34])[CH:20]=[C:21]([C:23]([N:25]([CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:26][CH:27]=[CH2:28])=[O:24])[CH:22]=1
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCCON2C(=O)c3ccccc3C2=O)c1)C1CCCC1
Agent: CN
Solvent: CCO
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCCON)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
To a solution of ethanol (50 mL) and phthalimide 18 (1.8 g, 3.7 mmol) was added 40% aqueous methylamine (25 mL). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo and then chromatographed on silica gel to provide hydroxylamine 19 (0.5 g; 15% from 16). 1H NMR (300 MHz, CDCl3) δ 6.92 (s, 2H), 6.79 (s, 1H), 5.92 (bs, 1H), 5.40 (s, 2H), 5.17 (m, 2H), 4.04 (t, 2H), 3.88-4.03 (m, 3H), 3.82 (t, 2H), 2.01-2.12 (m, 2H), 1.4-1.9 (m, 8H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:14])([F:13])[CH2:11][NH2:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:9][C:10]([F:14])([F:13])[CH2:11][NH:12][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1cccs1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NCC(F)(F)F)c1cccs1

Procedure:
Thiophene-2-carboxylic acid was coupled to trifluoroethyl amine using HBTU utilizing a procedure described in Example 1, Step 2 below except substituting HOBt with HBTU to give thiophene-2-carboxylic acid (2,2,2-trifluoroethyl)amide.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:31])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:23][CH2:22][N:21]([CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20]4)=[CH:14][CH:13]=3)=[C:9]([C:32]3[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][CH:33]=3)[S:8][C:7]=2[CH:40]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:31])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:19]4[CH2:23][CH2:22][N:21]([CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20]4)=[CH:16][CH:17]=3)=[C:9]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)[S:8][C:7]=2[CH:40]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCN(Cc4ccccc4)C3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: O=C(c1ccc(OC2CCN(Cc3ccccc3)C2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Yield: 37.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[1-benzylpyrrolidin-3-oxy]benzoyl)benzo[b]thiophene (1.57 g, 2.86 mmol), ethane thiol (14.3 mmol), and aluminum chloride (2.29 g, 17.2 mmol) were converted to 566 mg (38%) of the title compound by the procedure of Example 16. MS(FD) 521(M+). IR (CHCl3) ν max 3300, 3027, 3012, 2981, 1732, 1599, 1469, 1257, 1167.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C(=O)([O-])[O-].[Na+].[Na+]>CO>[O:6]=[C:1]1[CH2:5][CH2:4][CH:3]([N:11]2[C:7](=[O:17])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:12])[CH2:2]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1C=CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)C1
Reaction time: 22 h
Yield: 63.9 %

Procedure:
A slurry of methanol (88 mL), 2-cyclopenten-1-one (10.2 mL, 122 mmol), and phthalimide (17.9 g, 122 mmol) was stirred at ambient temperature and sodium carbonate (2M in water, 7.92 mL, 15.8 mmol) was added. After 22 hours, the thick white slurry was filtered and washed with MeOH (100 mL). Water (100 mL) was added to the wet cake, stirred for 1 hour, and filtered. The solid was washed with water (50 mL) and dried in a vacuum oven at 50° C. for 14 hours to provide the title compound (17.8 g, 78.0 mmol, 64% yield). MS (DCI) M/Z 247 [M+NH4]+.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1.[N+:18]([O-])([OH:20])=[O:19]>O>[Cl:6][C:7]1[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([OH:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
224.5 g of sulphuric acid (50% w/w) was dissolved in 300 ml of water and cooled to 25° C. while stirring under a mild nitrogen purge. 185.1 g (1 mole) of N-(5-chloro-2-hydroxyphenyl)acetamide prepared according to Example 1a was added to the diluted sulphuric acid and mixed intensively. 4 ml of nitric acid 65% w/w was added to the foam formed on top of the reaction mixture at low stirring speed. The stirring speed was increased and 75 ml of nitric acid 65% w/w was added in 45 minutes, while maintaining the temperature between 23 and 26° C. The mixture was stirred vigorously for an additional 1 hour at 23-26° C. Then the mixture was cooled to 0-5° C. and vigorously stirred at this temperature for 1 hour. The solid was filtered off quickly, washed three times with 300 ml of cold water, sucked for at least 30 minutes and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry.
Reaction SMILES: OCC(N[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][C:16]2[CH:17]=[C:18]([C@H:23]3[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]3)[CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:13][CH:12]=1)(C)C.[NH2:36][C:37]([CH2:42][OH:43])([CH2:40][OH:41])[CH2:38][OH:39]>>[OH:39][CH2:38][C:37]([NH:36][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[CH:17]=[C:18]([C@H:23]3[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]3)[CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:34][CH:35]=1)([CH2:42][OH:43])[CH2:40][OH:41]
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC(C)(C)CO)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: NC(CO)(CO)CO
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCNC(CO)(CO)CO)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The same procedure was employed as for amine 24, using 2-amino-2-(hydroxyl-methyl)propane-1,3-diol, to provide the product 25 as the bisformate salt. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.53 (s, 2 H), 6.98-7.23 (m, 7 H), 4.39 (d, J=9.3 Hz, 1 H), 4.13 (d, J=9.1 Hz, 1H), 3.94-4.03 (m, 2 H), 3.69 (s, 6 H), 3.34-3.50 (m, 3 H), 3.03-3.13 (m, 2 H), 2.58-2.69 (m, 2 H), 2.20 (s, 3 H), 2.12-2.18 (m, 3 H), 1.70 (m, 4 H). [M+H]+=537.
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][C@H:6]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O>[C:44]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A mixture of 30 ml chloroform and 30 ml water containing 1.0 g of phenylalanyl-valyl-tryptophan and 0.6 g of sodium carbonate is cooled to 0° and treated with 0.20 ml of benzoyl chloride. The reaction mixture was allowed to warm to room temperature and stirred overnight. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to give 0.47 g (53 percent) of the title compound. Analysis calculated for C32H34N4O5.H2O: C, 67.11; H, 6.34; N, 9.79. Found: C, 67.00; H, 6.23; N, 9.13.
Reaction SMILES: [CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][CH:11]([CH2:18][CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:10][CH:11]([CH:12]([C:2]([OH:9])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][CH3:19]
Reactant: CCCCCCC(C)=O
Reactant: CCOC(=O)CC(C)CC
Product: CCCCCCC(C)(O)C(C(=O)OCC)C(C)CC

Procedure:
A sample of the prepared hydroxy-ester pyrolyzes at 230° C. to a 1:1 mixture of 2-octanone and ethyl 3-methylvalerate.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[O:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]=1[CH:11]=[O:12].C(O)=O>O>[O:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([CH:11]=[O:12])=[C:6]1[CH:2]=[O:1]
Reactant: O=Cc1c(C2OCCO2)oc2ccccc12
Solvent: O
Solvent: O=CO
Product: O=Cc1oc2ccccc2c1C=O
Reaction time: 2 h
Yield: 92 %

Procedure:
2-(1,3-Dioxolan-2-yl)-1-benzofuran-3-carbaldehyde (3.63 g, 16.6 mmol) is dissolved in formic acid (16.3 ml, 433 mmol) with water (4.1 ml). After 2 hours, additional formic acid (10 ml) and water (2.5 ml) are added to alleviate the slurry. The reaction stirred 12 h and is diluted with water (30 ml). The resulting slurry is filtered, dried in an air stream, affording 2.66 g (92%) of 1-benzofuran-2,3-dicarbaldehyde as an orange solid. MS (EI) m/z: 174 (M+).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[C:14]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[C:13]([F:23])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35](Cl)[N:34]=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35]([NH:3][C@H:4]([C:6]2[N:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:8]3[C:14]([C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[O:16])=[C:13]([F:23])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[N:34]=[CH:33][N:32]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 41.7 %

Procedure:
To a solution of [2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazol-4-yl]-morpholin-4-ylmethanone dihydrochloride (300 mg, 0.69 mmol) in IPA (5 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (108 mg, 0.69 mmol) and DIPEA (353 mL, 2.07 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-4% methanol in EtOAc). The product was triturated with diethyl ether. The solid obtained was purified by prep HPLC (C18 Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give the title compound as a white solid (140 mg, 42%). 1H NMR 400 MHz δ (DMSO-d6) (mixture of rotamers): 7.80 (0.5H, s), 7.76 (0.5H, s), 7.73 (1H, dd, J=8.8, 4.8 Hz), 7.67 (0.5H, d, J=7.5 Hz), 7.54 (0.5H, d, J=7.2 Hz), 7.50-7.31 (5H, m), 7.19-7.07 (3H, m), 5.28 (0.5H, quin, J=7.1 Hz), 5.21 (0.5H, quin, J=7.0 Hz), 3.48-3.35 (1H, m), 3.34-3.18 (4H, m), 3.10-2.87 (2H, m), 2.56-2.47 (1H, m), 1.47-1.40 (3H, m), LCMS (Method K): RT=2.96 min, [M+H]+=487, RT=3.00 min, [M+H]+=487 (mixture of rotamers)