Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:40][C:41]1[CH:74]=[CH:73][C:44]([O:45][C:46]2[C:55]3[C:50](=[CH:51][C:52]([O:58][CH2:59][CH:60]4[CH2:65][CH2:64][N:63]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:62][CH2:61]4)=[C:53]([O:56][CH3:57])[CH:54]=3)[N:49]=[CH:48][CH:47]=2)=[C:43]([F:75])[CH:42]=1>CN(C=O)C>[F:75][C:43]1[CH:42]=[C:41]([NH:40][C:14]([C:10]2[C:9](=[O:17])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:74]=[CH:73][C:44]=1[O:45][C:46]1[C:55]2[C:50](=[CH:51][C:52]([O:58][CH2:59][CH:60]3[CH2:65][CH2:64][N:63]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:62][CH2:61]3)=[C:53]([O:56][CH3:57])[CH:54]=2)[N:49]=[CH:48][CH:47]=1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (15 mg, 0.06 mmol), HOBt (10 mg) and EDCI.HCl (20 mg, 0.10 mmol) in DMF (2 mL) was added a solution of tert-butyl 4-((4-(4-amino-2-fluorophenoxy)-6-methoxyquinolin-7-yloxy)methyl)piperidine-1-carboxylate (35 mg, 0.07 mmol) in DMF (1 mL) at rt, and the reaction mixture was stirred overnight at rt. It was directly purified by preparative HPLC to afford the product (24 mg, 56%) as a white TFA salt solid. 1H NMR (CDCl3) δ 12.16 (s, 1H), 8.75 (d, 1H, J=7.7 Hz), 8.64 (d, 1H, J=5.5 Hz), 8.05 (d, 1H, J=12.1 Hz), 7.83 (s, 1H), 7.67-7.24 (m, 8H), 6.72 (d, 1H, J=6.1 Hz), 6.65 (t, 1H, J=6.6 Hz), 4.22-4.11 (m, 2H), 4.07 (s, 3H), 3.48 (s, 2H), 2.78 (m, 2H), 2.13 (m, 1H), 1.87 (m, 2H), 1.47 (s, 9H), 1.35 (m, 2H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[Na+]>CN(C)C=O>[CH2:8]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(C)O
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)OCc1ccccc1
Temperature: 30 °C
Reaction time: 6 h

Procedure:
To a pre-cooled solution of racemic methyl lactate (200 g) in dimethyl formamide (400 ml) at 0-10° C., added benzyl chloride (218.8 g). Sodium tertiary butoxide (224.6 g) was added to the reaction mixture at 0-10° C. and stirred for 6 hours at 25-35° C. After completion of the reaction, the reaction mixture was quenched with water and extracted with toluene. The toluene layer was washed with water followed by 10% sodium chloride solution. The obtained toluene layer containing title compound was taken to next step.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7]I)(=[O:3])[CH3:2].Cl.[CH3:31][NH:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([NH2:28])[C:18]=3[C:19](=[O:21])[CH:20]=2)=[CH:11][C:10]=1[F:29])[CH2:5][CH2:6][CH2:7][N:32]([CH3:33])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCI)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CCCN(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.6 %

Procedure:
7.16 g (13.9 mmol) of the above 2-[4-[N-acetyl-N-(3-iodopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 150 mL of dimethylformamide under argon atmosphere, 5.68 g (69.5 mmol) of dimethylamine hydrochloride and 9.61 g (69.5 mmol) of potassium carbonate were added and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1-6:1-chloroform:methanol:aqueous ammonia=9:1:1) to give 4.13 g of 2-[4-[N-acetyl-N-(3-dimethylaminopropyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one (yield: 69%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:21]=[C:20]([O:38][CH3:39])[N:19]=1>CN1C(=O)CCC1>[CH3:34][N:30]1[C:29]2[C:35]([CH3:37])=[CH:36][C:26]([C:24]([C:22]3[CH:21]=[C:20]([O:38][CH3:39])[N:19]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:23]=3)=[O:25])=[CH:27][C:28]=2[O:32][C:31]1=[O:33]
Reactant: COc1cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(Cl)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
785 mg (3.60 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 420 mg (1.26 mmol) 6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were combined in 3 mL NMP and stirred for 12 h at 120° C. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the acetonitrile was eliminated i. vac. The residue was diluted with water, the precipitated solid was suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([I:26])[S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([I:26])[S:25][C:16]=12
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (380 mg, 2.0 mmol) and 60% sodium hydride (80 mg, 2.0 mmol) in 20 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (320 mg, 1.0 mmol) is added and the reaction mixture is heated at reflux overnight. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 2% methanol in chloroform to provide 240 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 233-234° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.38 (s, 1H), 7.77 (s, 1H), 7.79 (s, 1H), 8.56 (s, 1H), 9.74 (s, 1H); MS 475.9 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-:3])=[O:2].Br[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:12]([S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccccc1S
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Sc1ccccc1[N+](=O)[O-]

Procedure:
2-Nitrothiophenol, 2-bromopropane, potassium carbonate and acetone were refluxed for several hours. The solvent then was removed by rotary evaporation. The crude product was partitioned between methylene chloride and a 10% sodium carbonate solution. The organic phase was distilled to yield 2-isopropylmercaptonitrobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.C(P(CCCC)(CCCC)[CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1)CCC.CC([O-])(C)C.[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[CH:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1
Reactant: O=Cc1cccn1-c1ccccc1Br
Reactant: CCCC[PH](CCCC)(CCCC)CC1OCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccccc1-n1cccc1C=CC1OCCO1
Temperature: 47 °C

Procedure:
3.12 g (12.5 mmol) of 1-(2-Bromo-phenyl)-1H-pyrrole-2-carbaldehyde and 1.2 eqv. of tributyl-[1,3]dioxolan-2-ylmethyl-λ5-phosphane and 1.5 eqv. KOtBu in 20 ml DMSO was stirred for 2 hours. The reaction mixture was heated to 47° C. and stirred over night. The reaction mixture was cooled down to room temperature and poured into 200 ml of water and extracted with diethyl ether, dried over Na2SO4 and the solvent was evaporated. An oily residue was obtained which crystallised over night. The precipitate was washed with diethyl ether, filtered and dried. A mixture of E and Z isomers was obtained. Purification by column chromatography yielded 2 g (50%) of the E isomer 3b.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[C:13]=2[N+]([O-])=O)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:20]([NH:23][CH2:24][CH:25]=[CH2:26])[CH:21]=[CH2:22]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[CH:13]=2)[N:8]=[C:7]([N:23]([CH2:24][CH:25]=[CH2:26])[CH2:20][CH:21]=[CH2:22])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: C=CCNc1nc(Cl)nc2ccc(Cl)c([N+](=O)[O-])c12
Solvent: O
Product: C=CCNc1nc(N(CC=C)CC=C)nc2ccc(Cl)cc12
Yield: 85.1 %

Procedure:
In a sealed tube were stirred 268 mg (1.06 mmol) of 4-allylamino-2,6-dichloronitroquinazoline and 787 mg (8.10 mmol) of diallylamine at 120° C. for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column to give 284 mg (yield: 85.1%) of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[F:9][C:10]([F:34])([F:33])[CH2:11][N:12]1[C:16]([C:17]2[CH:18]=[C:19]3[N:25]([N:26]=2)[C:24]2[CH:27]=[C:28]([CH:31]=O)[CH:29]=[CH:30][C:23]=2[O:22][CH2:21][CH2:20]3)=[N:15][CH:14]=[N:13]1>C(OCC)C>[F:33][C:10]([F:9])([F:34])[CH2:11][N:12]1[C:16]([C:17]2[CH:18]=[C:19]3[N:25]([C:24]4[CH:27]=[C:28]([CH2:31][NH:2][C:3]5[CH:8]=[N:7][CH:6]=[CH:5][N:4]=5)[CH:29]=[CH:30][C:23]=4[O:22][CH2:21][CH2:20]3)[N:26]=2)=[N:15][CH:14]=[N:13]1
Reactant: O=Cc1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Reactant: Nc1cnccn1
Agent: Cl
Solvent: CCOCC
Product: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(CNc3cnccn3)ccc1OCC2

Procedure:
Following the procedure for 128 without the use of HCl in diethyl ether, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carbaldehyde was reacted with 2-amino pyrazine to give 131 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 3H); 7.87 (d, J=2.6 Hz, 1H); 7.84 (d, J=2.2 Hz, 1H); 7.31 (dd, J=8.3, 2.2 Hz, 1H); 7.20 (d, J=8.3 Hz, 1H); 6.92 (s, 1H); 5.49 (q, J=8.2 Hz, 2H); 5.42 (br s, 1H); 4.66 (d, J=5.4 Hz, 2H); 4.55 (t, J=6.0 Hz, 2H); 3.16 (t, J=6.0 Hz, 2H). LCMS: RT=9.93 min, M+H+=443
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][O:41][CH2:40][CH2:39][OH:38])[CH2:49][CH2:48]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCOCCN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCOCCO)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-[2-(2-hydroxyethoxy)-ethyl]-piperazine (Aldrich) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H46N6O4Cl2 [(M+H)+] 697.3031, observed 697.3026.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:18]([NH:17][CH:14]([CH3:16])[CH3:15])=[O:19])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CC(C)N=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 53.8 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg, 0.67 mmol) and isopropyl isocyanate (80 μL, 0.81 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), followed by recrystallization from acetone and hexane, gave the desired product (111 mg, 54%). LC-MS (m/z) 308.0 (M+).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][C:16]1[N:25]2[CH2:26][CH2:27][N:28]=[C:24]2[C:23]2[CH:22]=[CH:21][C:20]([OH:29])=[C:19]([O:30][CH3:31])[C:18]=2[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:43][C@@H:44]1[O:46][CH2:45]1)(=O)=O>CN(C=O)C>[CH3:31][O:30][C:19]1[C:18]2[N:17]=[C:16]([NH2:15])[N:25]3[CH2:26][CH2:27][N:28]=[C:24]3[C:23]=2[CH:22]=[CH:21][C:20]=1[O:29][CH2:43][C@H:44]1[CH2:45][O:46]1
Reactant: CS(=O)(=O)OC[C@H]1CO1
Reactant: COc1c(O)ccc2c1N=C(N)N1CCN=C21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.7 %

Procedure:
To a solution of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bis(trifluoroacetate) (Intermediate E, 0.30 g, 0.65 mmol) in DMF (8 mL) was added caesium carbonate to generate a white suspension. The suspension was stirred at room temperature for 1.5 hr, then (R)-glycidyl methanesulfonate (Intermediate F, Step 1, 3.9 mL of 0.34 M solution in DMF, 1.30 mmol, 2.0 equiv.) was added, and the resulting solution was stirred at 60° C. for 20 h. The resulting suspension was concentrated under reduced pressure and the residue was treated separated between a saturated sodium bicarbonate solution (30 mL) and a 4:1 CH2Cl2/isopropanol solution (30 mL). The aqueous phase was extracted with a 4:1 CH2Cl2/isopropanol solution (30 mL). The combined organic phases were dried (anh. sodium sulfate) and concentrated under reduced pressure. The residue was purified using MPLC (Isolute Flash NH2 reverse phase column; 100% CH2Cl2 for 5 min., gradient to 95% CH2Cl2: 5% MeOH over 15 minutes; gradient to 90% CH2Cl2: 10% MeOH over 15 min.; gradient to 80% CH2Cl2: 20% MeOH over 15 min.; and gradient to 75% CH2Cl2: 25% MeOH over 15 min.) to give 7-methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (0.080 g, 43%): 1H NMR (DMSO-d6+1 drop TFA-d) δ 2.71 (dd, J=2.5, 4.8 Hz, 1H), 2.85, (t, J=4.6 Hz, 1H), 3.34-3.40 (br m, 1H), 3.75 (s, 3H), 3.82 (s, 3H), 4.30 (dd, J=6.6, 11.4 Hz, 1H), 4.10 (br t, J=9.7 Hz, 2H), 4.31 (br t, J=9.7 Hz, 2H), 4.54 (dd, J=2.3, 11.6 Hz, 1H), 7.26 (d, J=9.4 Hz, 1H), 7.84 (d, J=9.1 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Br[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[C:37]#[N:38]>>[CH3:1][N:2]([CH3:32])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20]([C:34]4[CH:41]=[CH:40][CH:39]=[C:36]([C:37]#[N:38])[CH:35]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: N#Cc1cccc(Br)c1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)N3CC=C(B4OC(C)(C)C(C)(C)O4)CC3)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)N3CC=C(c4cccc(C#N)c4)CC3)cc2)C1

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 3-bromobenzonitrile by method O-a. This resulted in the product with the molecular weight of 415.54 (C25H29N5O); MS (ESI): 416 (M+H+)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[S:12]([O-:15])([O-:14])=[O:13].[Na+].[Na+].O>C(O)C>[CH3:11][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[S:12]([OH:15])(=[O:14])=[O:13]
Reactant: O=S([O-])[O-]
Reactant: Cc1ccc(C(=O)O)nc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)O)nc1S(=O)(=O)O
Temperature: 180 °C
Yield: 111.2 %

Procedure:
6-chloro-5-methyl-pyridine-2-carboxylic acid (0.85 g, 4.97 mmol) and sodium sulfite (CAN 7757-83-7, 1.5 g, 11.9 mmol) were added to water (3 mL) and ethanol (3 mL). The mixture was heated to 180° C. for 4 h in a sealed tube. After that the mixture was cooled to room temperature and a solid precipitated that was removed by filtration. The filtrate was concentrated and added to water (20 mL). The aqueous phase was washed with ethyl acetate (2×20 mL). Subsequently the aqueous phase was adjusted to pH=2 with 2 N hydrochloric acid. Water was removed in vacuo to give the product as solid (1.2 g); MS (EI): m/e=218.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[O:26][C:25]3[C:16](=[CH:17][C:18]4[CH2:19][C@@H:20]([C:36](O)=[O:37])[N:21]([C@H:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28][CH3:29])[CH2:22][C:23]=4[CH:24]=3)[N:15]([CH3:39])[C:14]2=[O:40])=[CH:9][CH:8]=1.[CH3:45][O:46][C:47](=[O:65])[C@H:48]([NH2:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:65])[C@H:48]([NH:64][C:36]([C@@H:20]1[CH2:19][C:18]2[CH:17]=[C:16]3[C:25]([O:26][C@H:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]5[CH:41]=[CH:42][C:43]([Cl:44])=[C:2]([Cl:1])[CH:3]=5)=[CH:12][CH:11]=4)[C:14](=[O:40])[N:15]3[CH3:39])=[CH:24][C:23]=2[CH2:22][N:21]1[C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])=[O:37])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1
Reactant: COC(=O)[C@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid was coupled to (R)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester following general procedure 0 to provide (R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester. Title compound was prepared from (R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (267 mg) following general procedure B. LC-MS (m/z): 880.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH2:4]([O:6][C:7]([C:9]1[C:10]([CH3:24])=[N:11][S:12][C:13]=1[NH:14][C:15](OC1C=CC=CC=1)=[O:16])=[O:8])[CH3:5].O>C(O)C>[CH2:1]([NH:3][C:15](=[O:16])[NH:14][C:13]1[S:12][N:11]=[C:10]([CH3:24])[C:9]=1[C:7]([O:6][CH2:4][CH3:5])=[O:8])[CH3:2]
Reactant: CCOC(=O)c1c(C)nsc1NC(=O)Oc1ccccc1
Reactant: CCN
Solvent: CCO
Solvent: O
Product: CCNC(=O)Nc1snc(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 50% w/v solution of ethylamine in ethanol (30 ml.) was added to a solution of 4-ethoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole (prepared according to the method of Goerdeler and Horn, Chemische Berichte, 1963, 96, 1551; 30.6 g.) in warm ethanol (120 ml.). The mixture was then heated under reflux for 1 minute, and allowed to cool to ambient temperature and stand for 2 days. The mixture was then heated under reflux for 5 minutes, allowed to cool to ambient temperature and stand for 1 day and poured into cold water (1 liter). The precipitated solid was filtered off, dried and recrystallised from benzene (300 ml.) to give 3-ethyl-1-(4-ethoxycarbonyl-3-methylisothiazol-5-yl)urea (24.8 g.), m.p. 141° C.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:9].C[OH:11]>>[ClH:9].[C:1](=[NH:8])([OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: N#Cc1ccccc1
Agent: Cl
Product: N=C(O)c1ccccc1
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of benzonitrile (20 g, 0.194 mol) in methanol (8 ml) was bubbled with gaseous HCl to saturation. The solution was allowed to stand overnight, and then a pale yellow solid was found. The solid was triturated with ether, filtered, washed with ether, and dried to yield beige solid product (32 g, 96%).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:37])[CH2:10][C@@:11]1([C:27]2[S:28][C:29]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)=[CH:30][CH:31]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:38]>CO.C(OCC)(=O)C>[ClH:38].[OH:7][NH:8][C:9](=[O:37])[CH2:10][C@@:11]1([C:27]2[S:28][C:29]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)=[CH:30][CH:31]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(-c3ccco3)s2)S(=O)(=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(C[C@]1(c2ccc(-c3ccco3)s2)CCNCCS1(=O)=O)NO
Reaction time: 1 h

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-(2-furyl)-2-thienyl)-4-tert-butoxycarbonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (160 mg) in methanol (5 ml) was added 4M hydrogen chloride in ethyl acetate (5 ml) at room temperature. After being stirred for 1 hour, the mixture was concentrated in vacuo. The resulting residue was triturated with diethyl ether to afford N-hydroxy-2-[(S)-7-(5-(2-furyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide hydrochloride (75 mg) as a powder.