Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(Cl)(=O)C1C=CC=CC=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1>CC(C)=O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]([NH2:3])=[S:1])=[N:16][CH:17]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Br)cn1
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: NC(=S)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
1.1 Ammoniumthiocyanat (76 mmol, 1.2 eq.) is dissolved in acetone (75 ml) and benzoylchloride (1 eq.) is added dropwise. 20 min after stirring at RT, the reaction is heated to reflux. 2-Amino-5-bromopyridine (71 mmol) in acetone (50 ml) is added and 30 min heated to reflux. Afterwards, the reaction solution is poured onto ice. The precipitate is filtered and washed with water/methanol (1:1). The precipitate is dissolved in 2M NaOH (120 ml) at 80° C. and stirred 10 min at 80° C. The solution is poured into an HCl solution (5%) at 0° C. The pH of the solution is adjusted to 8 with a saturated Na2CO3 solution. The resulting precipitate is filtered and washed with water. (5-Bromo-pyridine-2-yl)-thiourea (“1”) is obtained after drying in vacuo at 40° C. as a pale yellow solid in a yield of 63%. HPLC (method C): 1.43 min; LC-MS (method A): 1.062 min, 231.95 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:23]([Cu])#[N:24]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:23]#[N:24])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Solvent: c1ccncc1
Product: N#Cc1cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2s1
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution of N-(4-chlorobenzyl)4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (Example No. 2) (0.500 g) in pyridine (5 mL) is added CuCN (0.201 g). The reaction is heated to reflux and stirred for 18 h. The reaction mixture is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale yellow solid which is recrystallized from methanol to yield 0.100 g (26%) of the title compound as an off-white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=C.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccccc1
Temperature: 100 °C
Yield: 66 %

Procedure:
3.51 g (0.025 mol) of benzoyl chloride, 3.125 g (0.03125 mol) of ethyl acrylate, 5.79 g (0.03125 mol) of tri-n-butylamine, 50 ml of toluene and 0.0561 g (0.00025 mol) of palladium acetate are introduced into a 100 ml glass flask and heated to 100° C., with stirring. A slight evolution of gas is observed. After the mixture has been stirred for 4 hours, it is cooled and the contents of the flask are extracted by shaking twice with 25 ml of 2 N hydrochloric acid at a time. The toluene phase is dried with magnesium sulfate and distilled. After the toluene has been distilled off, 2.9 g (0.0165 mol) of ethyl cinnamate are obtained, corresponding to a yield of 66% of theory; boiling point=135°-138° C./17×102Pa; nD20 =1.5592.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@@H:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:17](=[O:27])[C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[CH:19][CH:20]=[C:13]2[C:12]1=[O:28])[CH3:10].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[S:39]([F:44])([F:43])([F:42])([F:41])[F:40]>O1CCCC1.O>[CH3:26][C:24]1[N:23]=[CH:22][N:21]([C:18]2[C:17](=[O:27])[N:14]3[CH2:15][CH2:16][N:11]([C@@H:9]([CH3:10])[CH2:8][O:7][C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=4[S:39]([F:42])([F:43])([F:44])([F:40])[F:41])[C:12](=[O:28])[C:13]3=[CH:20][CH:19]=2)[CH:25]=1
Reactant: O=[N+]([O-])c1ccc(F)c(S(F)(F)(F)(F)F)c1
Reactant: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)CO)C3=O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)COc2ccc([N+](=O)[O-])cc2S(F)(F)(F)(F)F)C3=O)cn1
Reaction time: 0.17 h

Procedure:
A solution of potassium tert-butoxide in tetrahydrofuran (1 M, 1.97 mL, 1.97 mmol) was added to a slurry of 2-[(2S)-1-hydroxypropan-2-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (C54) (541 mg, 1.79 mmol) in tetrahydrofuran (6 mL), and the mixture was allowed to stir for 10 minutes. A solution of 1-fluoro-4-nitro-2-(pentafluoro-λ6-sulfanyl)benzene (P15) (478 mg, 1.79 mmol) in tetrahydrofuran (4 mL) was added, and the reaction mixture was stirred at room temperature for 18 hours. At that point, it was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluents: ethyl acetate, then 10% methanol in ethyl acetate) afforded the product as a yellow foam. Yield: 695 mg, 1.26 mmol, 70%. LCMS m/z 550.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.53 (d, J=7.1 Hz, 3H), 2.34 (d, J=1.0 Hz, 3H), 3.73-3.85 (m, 2H), 4.30-4.47 (m, 4H), 4.99-5.08 (m, 1H), 7.16-7.21 (m, 2H), 7.28 (d, J=7.7 Hz, 1H), 7.52 (d, J=7.7 Hz, 1H), 8.40 (dd, J=9.2, 2.7 Hz, 1H), 8.44 (br s, 1H), 8.71 (d, J=2.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].[N:13]1[C:22]2[C:17](=[CH:18][C:19]([NH2:23])=[CH:20][CH:21]=2)[CH:16]=[N:15][CH:14]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:13]=[CH:14][N:15]=[CH:16]2)[CH3:2]
Reactant: CCOC(=O)c1ccccc1Br
Reactant: Nc1ccc2ncncc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1Nc1ccc2ncncc2c1

Procedure:
A mixture of 2-bromo-benzoic acid ethyl ester (7.9 g), quinazolin-6-ylamine (5.0 g), Pd(OAc)2 (387 mg), BINAP (714 mg), and K2CO3 (26 g) in toluene (100 mL was heated at reflux for 12 h. The mixture was diluted with EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified with flash chromatography (SiO2 50% EtOAc/hexane) to obtain 2-(quinazolin-6-ylamino)-benzoic acid ethyl ester. MS (ES+): 294.0 (M+H)+. Calc'd for C17H15N3O2: 293.32.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14]C)=O)[CH2:4]1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:12](=[O:14])[CH2:11][C@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:8][C:7]([CH3:9])([CH3:10])[O:6]1)[CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: CCCCN
Product: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1

Procedure:
A mixture of methyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (110 grams) and n-butylamine (370 grams) was heated to reflux and stirred. After completion of the reaction, the reaction mixture was distilled under reduced pressure. Water (500 ml) was added to the obtained residue followed by sodium bicarbonate and washed it with petroleum ether. The reaction mixture was extracted into methylene chloride. The solvent from the reaction mixture was distilled off under reduced pressure to get the title compound.
Reaction SMILES: CO.[OH:3][C:4]1[CH:27]=[C:26]([O:28]COC)[CH:25]=[C:24]([O:32]COC)[C:5]=1[C:6](=[O:23])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]COC)=[C:11]([O:19]COC)[CH:10]=1.Cl.CO.O>CCCCCC.C(OCC)(=O)C>[OH:3][C:4]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([OH:32])[C:5]=1[C:6](=[O:23])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:19])[CH:10]=1
Reactant: COCOc1cc(O)c(C(=O)C=Cc2ccc(OCOC)c(OCOC)c2)c(OCOC)c1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: O=C(C=Cc1ccc(O)c(O)c1)c1c(O)cc(O)cc1O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 32.9 %

Procedure:
Then, 20 ml of methanol was added to 5.19 g of the so-obtained 2'-hydroxy-3,4,4',6'-tetrakis(methoxymethoxy)chalcone, and 40 ml of a hydrochloric acid/methanol reagent was added to the formed suspension and the mixture was stirred at 60° C. for 15 minutes. After the reaction, the reaction liquid was poured into water, and the precipitated crystal was recovered by filtration, washed with water and dried to obtain 2.81 g (yield=87.2%) of a crude crystal. The crude crystal was subjected to the column chromatography (200 g of 240-400 mesh Kieselgel 60; 0.3 kg/cm2 ; eluting solvent hexane/ethyl acetate=2/1, 2700 ml, hexane/ethyl acetate=1/1). Fractions of 50 ml were collected and the 92nd to 149th fractions were combined and concentrated to dryness to obtain 1.06 g (yield=32.9%) of 2',3,4,4',6'-pentahydroxychalcone.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:17]2[CH:16]=[C:15]([CH:18]([CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:19]([NH:21][C:22]3[S:23][CH:24]=[C:25]([CH2:27][C:28]([O:30]CC)=[O:29])[N:26]=3)=[O:20])[CH:14]=[CH:13][C:12]=2[S:11](=[O:41])(=[O:40])[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.Cl>O1CCCC1.O>[CH3:3][N:4]1[C:17]2[CH:16]=[C:15]([CH:18]([CH2:33][CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[C:19]([NH:21][C:22]3[S:23][CH:24]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[N:26]=3)=[O:20])[CH:14]=[CH:13][C:12]=2[S:11](=[O:40])(=[O:41])[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCOCC2)c2ccc3c(c2)N(C)c2ccccc2S3(=O)=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCOCC3)C(=O)Nc3nc(CC(=O)O)cs3)cc21
Temperature: 25 °C

Procedure:
At room temperature and with stirring, 0.25 ml of 2M NaOH are added to a suspension of 25.0 mg of ethyl {2-[2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionylamino]thiazol-4-yl}acetate in 5 ml of tetrahydrofuran and 2 ml of water, and the mixture is stirred at room temperature for 12 hours. The reaction mixture is then neutralized by addition of 1M HCl. The solvents are removed under reduced pressure, and the residue is taken up in 20 ml of ethyl acetate and washed three times with in each case 10 ml of water. The organic phase is dried with MgSO4 and concentrated under reduced pressure. The residue is purified by RP-HPLC. This gives 22.5 mg of {2-[2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(tetrahydropyran-4-yl)propionylamino]thiazol-4-yl}acetic acid as a lyophilisate.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[C:8]([C:14]1[NH:18][N:17]=[N:16][N:15]=1)[C:7]2=[O:19])[CH3:3].CC(C)=O.S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].O>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]=[C:8]([C:14]1[NH:15][N:16]=[N:17][N:18]=1)[C:7]2=[O:19])(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1

Procedure:
To a solution of 2.58 parts of 6-(1-hydroxyethyl)-3-(1H-tetrazol-5-yl)chromone in 700 parts by volume of acetone kept at 9°-15° C there is added dropwise over a period of 30 minutes 4.5 parts by volume of a solution which is prepared from chromium trioxide, 97% sulfuric acid and water in a ratio of 6.0 parts: 3.6 parts by volume: 18 parts by volume. The reaction mixture is concentrated at a temperature lower than 30° C to a one-tenth volume and then admixed with 700 parts by volume of water to give precipitates. The precipitates are recovered by filtration and recrystallized from dimethylformamide. The procedure yields 1.70 parts of 6-acetyl-3-(1H-tetrazol-5-yl)chromone as colorless crystals.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[C:50]1([C:56]2[CH:61]=[C:60]([CH:62]3[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)[CH:59]=[CH:58][C:57]=2[NH:68][C:69]([C:71]2[NH:72][CH:73]=[C:74]([C:76]#[N:77])[N:75]=2)=[O:70])[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]([N:65]1[CH2:66][CH2:67][CH:62]([C:60]2[CH:59]=[CH:58][C:57]([NH:68][C:69]([C:71]3[NH:72][CH:73]=[C:74]([C:76]#[N:77])[N:75]=3)=[O:70])=[C:56]([C:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]=3)[CH:61]=2)[CH2:63][CH2:64]1)=[O:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
A solution of N-BOC-glycine (0.29 g, 1.63 mmol) in CH2Cl2 (10 mL) was treated with DIEA (0.85 mL, 4.90 mmol), HOBt (0.26 g, 1.96 mmol), and EDCI (0.38 g, 1.96 mmol). The mixture was stirred at room temperature for 10 min and added to a suspension of 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (as prepared in Example 14, step (b), 0.80 g, 1.63 mmol) in CH2Cl2 (20 mL). The solution was stirred at room temperature for 17 h. Solvents were evaporated in vacuo. Silica gel chromatography (50% EtOAc in hexanes) afforded the title compound (0.41 g, 47%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.53 (s, 1H), 8.26 (d, 1H, J=8.4 Hz), 7.80-7.78 (m, 1H), 7.71 (s, 1H), 7.45-7.43 (m, 1H), 7.06 (d, 1H, J=8.4 Hz), 7.00 (s, 1H), 5.83 (br s, 1H), 5.76 (br s, 1H), 4.78-4.68 (m, 1H), 3.96-3.85 (m, 2H), 3.17-3.03 (m, 1H), 2.78-2.63 (m, 2H), 2.29 (br s, 2H), 2.22 (br s, 2H), 1.95-1.87 (m, 2H), 1.86-1.72 (m, 4H), 1.70-1.55 (m, 2H), 1.44 (s, 9H). LC-MS (ESI, m/z): Calcd. for C29H36N6O4 533.3 (M+H). found 532.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH2:22]([N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:22][CH3:23])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2cccc(N3CCOCC3)c2)n1
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cccc(N5CCOCC5)c4)n3)cc2CC1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(3-morpholin-4-yl-phenyl)-amine (96 mg, 0.29 mmol) was added into a vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (52 mg, 0.27 mmol) in 2-Methoxyethanol (2.7 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.10 mL) was added and the reaction was heated at 120° C. After 6 h, the reaction was cooled and Macroporous carbonate resin (3.16 mmol/g loading; 400 mg, 1.25 mmol) was added and the reaction was stirred overnight, then was concentrated in vacuo onto Celite, and chromatographed (24 g alumina column, EtOAC-5% MeOH: EtOAC-5% MeOH:DCM). 5-Chloro-N*2*-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo-[d]azepin-7-yl)-N*4*-(3-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was isolated as a yellow foam (64 mg, 49%). LCMS (m/e) 479 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.47 (m, 2H), 7.37 (d, 1H, J=2.0 Hz), 7.14 (dd, 1H, J=2.3, 8.1 Hz), 6.96 (d, 1H, J=7.9 Hz), 6.92 (m, 3H), 6.82 (s, 1H), 3.89 (t, 4H, J=4.8 Hz), 3.16 (t, 4H, J=4.8 Hz), 2.85 (m, 4H), 2.63 (m, 4H), 2.57 (q, 2H, J=7 Hz), 1.10 (t, 1H, J=7 Hz).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@@H:11]1[C:15]2[NH:16][C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[C:26]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:25]([CH3:34])[C:24]4=[O:35])=[CH:18][C:14]=2[C:13](=[O:36])[NH:12]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:30]([NH:29][C:26]1[N:25]([CH3:34])[C:24](=[O:35])[C:23]2[C:28](=[C:19]([C:17]3[NH:16][C:15]4[C@@H:11]([CH2:10][CH2:9][OH:8])[NH:12][C:13](=[O:36])[C:14]=4[CH:18]=3)[CH:20]=[CH:21][CH:22]=2)[N:27]=1)([CH3:32])([CH3:33])[CH3:31]
Reactant: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](CCOCc3ccccc3)NC4=O)cccc2c1=O
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](CCO)NC4=O)cccc2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 51.7 %

Procedure:
To a solution of (R)-8-(6-(2-(benzyloxy)ethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (503b, 555 mg, 1.14 mmol) in DCM (30 mL) at 0° C. was added boron trichloride (1.0 M in DCM, 1.71 mL, 1.71 mmol) slowly dropwise. The resulting tan suspension was stirred at 0° C. for 5 min, then RT for 15 min. LC-MS indicated only unreacted starting material. The reaction mixture was treated with additional BCl3 solution (0.5 mL) at RT and stirred 10 min. LC-MS indicated product formation. The reaction was cooled to 0° C. in an ice bath and treated with MeOH (ca. 3 mL) and ca. 500 mg of powdered NaHCO3 and stirred for 5 min. The reaction mixture was then treated with silica gel and purified on an ISCO Combiflash RF (40 g Silicycle column, using a gradient of 0-20% MeOH in DCM) affording (R)-2-(tert-butylamino)-8-(6-(2-hydroxyethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrolo-2-yl)-3-methylquinazolin-4(3H)-one (503) (233 mg, 0.589 mmol, 51.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (1H, s), 7.88 (2H, dd, J=7.6, 2.5 Hz), 7.66 (1H, br. s.), 7.18 (1H, t, J=7.7 Hz), 6.72 (1H, d, J=1.4 Hz), 5.93 (1H, s), 4.54 (1H, dd, J=8.8, 3.9 Hz), 3.52-3.83 (6H, m), 1.95-2.09 (1H, m), 1.55-1.67 (1H, m), 1.45-1.54 (9H, s). m/z (ESI, +ve) 396.0 (M+1)+.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CC(C)([O-])C.[K+].CS(O[CH2:16][CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]2[O:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[C:27](=[O:28])[C:21]=2[CH:20]=1)(=O)=O>C(O)C>[O:28]=[C:27]1[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[CH2:24][O:23][C:22]2[CH:33]=[CH:34][C:19]([CH2:18][CH2:17][CH2:16][N:3]([OH:4])[CH3:2])=[CH:20][C:21]1=2
Reactant: CS(=O)(=O)OCCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CNO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CN(O)CCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To a stirring solution of 13.06 g of N-methylhydroxylamine hydrochloride in 250 ml of absolute ethanol was added 17.48 g of potassium tert-butoxide. To the resulting suspension was added 9.0 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propanol methanesulfonate. The resulting product suspension was allowed to reflux for 24 hours and was then cooled to room temperature. The suspension was filtered to remove potassium chloride, and the mother liquor was then treated with 200 ml of water and concentrated in vacuo to remove ethanol. The resulting mixture was partitioned against a total of 450 ml of methylene chloride and 250 ml of water. The organic phase was washed with 250 ml of saturated sodium chloride solution, dried (Na2SO4), filtered, and concentrated in vacuo to a viscous oil which solidified upon triturating the oil, with 10 ml of ethyl acetate and 3 drops of hexane and refrigerating. Thin layer analysis of the solids indicated a mixture, which was separated via HPLC (silica gel). The purified oil solidified upon standing to give 4.03 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methyl-1-propylamine m.p. 113°-114.5° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1(C(OC(C)(C)C)=O)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCNCC1
Temperature: -20 °C

Procedure:
Methanesulphonyl chloride (18.3 mL, 0.236 mol) was added dropwise to a solution of tert-butyl piperazine-1-carboxylate (40 g, 0.214 mol) and triethylamine (60 mL, 0.43 mol) in CH2Cl2 (300 mL) in argon under stirring at −20° C. The mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The layers were separated, and the water layer was extracted with chloroform (2×200 mL). The organic fraction were washed with the 1 N NaHSO4 solution (100 mL), the saturated NaHCO3 solution (100 mL), dried over Na2SO4, filtered through SiO2 (50 g, 40-63 μm), and evaporated to dryness. The residue (white crystals) was dissolved in isopropanol (200 mL), concentrated HCl (35 mL) was added, and the mixture was refluxed for 1 h and evaporated. Chloroform (200 mL), the saturated K2CO3 solution (50 mL), and water (50 mL) were added to the residue under stirring. The organic layer was separated, and the water layer was extracted with chloroform (2×100 mL). The organic layers were dried over Na2SO4, filtered through SiO2 (50 g, 40-63 μm), and evaporated to dryness. The residue (white crystals) was dried to give the title compound in 94% (33 g) yield. LCMS data: M+H 165.0 (Calculated for C5H12N2O2S 164.23), 97.2%, r.t. 0.913 min. 1H-NMR data (dmso-d6): 2.99 (m, 4H), 2.83 (s, 3H), 2.74 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:33][CH2:34][CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27]([O:29]C)=[O:28])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[C:1]1([C:7]2[O:8][C:9]([CH2:33][CH2:34][CH3:35])=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH2:26][C:27]([OH:29])=[O:28])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a mixture of methyl 2-[2-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.40 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added a 1N aqueous sodium hydroxide solution (1.7 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.30 g, 77%) of 2-[2-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[C:13]([CH:14]=[CH:15][N+:16]([O-])=O)=[CH:12][CH:11]=[CH:10][C:9]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1.O.[OH-].[Na+]>C1COCC1>[Br:7][C:8]1[C:9]([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][NH2:16]
Reactant: O=[N+]([O-])C=Cc1cccc(OCC2CC2)c1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCCc1cccc(OCC2CC2)c1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 0.92 mL (2.2 mmol) lithium aluminum hydride solution (2.4 M in THF) are added dropwise 300 mg (1.01 mmol) 2-bromo-1-cyclopropylmethoxy-3-(2-nitro-vinyl)-benzene (example XX) in 5 mL THF at 0° C. After stirring at 0° C. for 2 h the reaction mixture is quenched by the addition of 36 μL (2.0 mmol) water, 0.50 mL (2.0 mmol) aq. NaOH solution (c=4 mol/L) and 0.11 mL (6.0 mmol) water. The resulting mixture is stirred for 20 min, filtered over celite/Na2SO4 and the filtrate is concentrated by evaporation. The residue is purified by HPLC (ACN/H2O/NH4OH).