Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37]Br>CN(C=O)C>[C:17]([C:16]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:2]([CH3:4])([N:1]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH3:3])=[CH:6][CH:7]=2)=[N:12][C:13]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[N:14][CH:15]=1)#[N:18]
Reactant: BrCCCCBr
Reactant: CC(C)(N)c1ccc(-c2nc(Nc3ccc(F)cc3)ncc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(-c2nc(Nc3ccc(F)cc3)ncc2C#N)cc1)N1CCCC1
Reaction time: 12 h
Yield: 51.1 %

Procedure:
To a solution of the compound (1.0 g,2.88 mmol) of Example 20 in DMF (20 mL) was added potassium carbonate (786 mg, 5.7 mmol) and 1,4-dibromobutane (622 mg, 2.88 mmol) and the resulting mixture stirred at 60° for 12 h. The reaction was partitioned between brine and ethyl acetate then the organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to column chromatography to give the title compound (591 mg) as a yellow solid, m.p. 124°. δH (d6 DMSO) 8.58 (1H, s), 7.94 (2H, dapp, J 8.4 Hz), 7.63 (4H, m), 6.96 (2H, tapp, J 8.7 Hz), 3.23 (4H, s), 2.61 (4H, s) and 1.47 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[N:4]([CH3:8])[N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:6]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[Cl:9])[N:4]([CH3:8])[N:3]=1
Reactant: Cn1nc(Br)cc1Br
Reactant: OB(O)c1ccc(F)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1nc(Br)cc1-c1ccc(F)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of 3,5-dibromo-1-methyl-1H-pyrazole (i.e. the product of Step B) (2.00 g, 8.33 mmol) in toluene (40 mL) was sparged with a stream of argon for 45 minutes, and then 2-chloro-4-fluorophenylboronic acid (1.59 g, 9.11 mmol), potassium phosphate tribasic (5.30 g, 25.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.41 mmol) were added. The reaction mixture was heated at 90° C. for 3 h, and then cooled to room temperature and diluted with ethyl acetate (250 mL). The mixture was washed with water (25 mL) and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (5 to 40% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a white solid (620 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=O.C(O)(C(F)(F)F)=O>C(O)(C)C>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=[N:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8]
Reactant: O=Cc1cccs1
Reactant: N#Cc1ccsc1N
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccsc1N=Cc1cccs1
Yield: 69.4 %

Procedure:
2-Amino-thiophene-3-carbonitrile (50 mg) and thiophene-2-carboxaldehyde (54 mg) were mixed in isopropanol with TFA and refluxed for 20 hours. The reaction was then purified by flash chromatography, resulting in 61 mg (70%) of the title compound as an orange solid. M.p. 58°-60° C. 1H-NMR (300 MHz, [D] acetone): δ=8.49 (s, 1H), 7.90 (d, 1H, 3J=5.0 Hz), 7.82 (dd, 1H, 3J=3.7 Hz and 1.0 Hz), 7.42 (d, 1H, 3J=5.7 Hz), 7.27 (m, 2H, 3J=5.6 Hz). 13C-NMR (300 MHz, [D] acetone): δ=163.4, 155.4, 141.8, 136.2, 133.9, 129.0, 128.1, 122.5, 114.6, 105.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:15]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:16]=[O:17]>>[C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:12][N:13]([C:16](=[O:17])[NH:15][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC12CNC2
Product: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NCCCc1ccccc1)C2

Procedure:
In analogy to the experimental procedure of example 8) 1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of 1-benzyl-1,6-diaza-spiro[3.3]heptane was converted using (3-isocyanato-propyl)-benzene into the title compound which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:12]([CH3:19])[NH:13][C:14](=[O:18])[C:15](=[O:17])[N:16]=3)[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[CH:30]1([O:33][N:34]=[C:35]([C:39]2[N:40]=[C:41]([NH:44][CH:45]=[O:46])[S:42][CH:43]=2)[C:36](O)=[O:37])[CH2:32][CH2:31]1.Cl>O1CCCC1.O.C(OCC)(=O)C>[CH:30]1([O:33][N:34]=[C:35]([C:39]2[N:40]=[C:41]([NH:44][CH:45]=[O:46])[S:42][CH:43]=2)[C:36]([NH:1][C@@H:2]2[C:23](=[O:24])[N:4]3[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]4[N:12]([CH3:19])[NH:13][C:14](=[O:18])[C:15](=[O:17])[N:16]=4)[CH2:7][S:8][C@H:3]23)=[O:37])[CH2:32][CH2:31]1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)O)cs1
Reactant: Cn1[nH]c(=O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1[nH]c(=O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(NC=O)n3)[C@H]2SC1
Yield: 57.5 %

Procedure:
To a solution of 7β-amino-3-(5,6-dioxo-2-methyl-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (966 mg) and sodium bicarbonate (437 mg) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) was dropwise added the activated acid solution, prepared from 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (500 mg) according to a similar manner to that described in Example 1, with stirring and keeping pH 7.0 to 8.0 with saturated aqueous solution of sodium bicarbonate at 0° to 5° C. The mixture was stirred for 20 minutes at the same temperature. To the mixture was added ethyl acetate (40 ml) and the mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The resulting insoluble material was filtered off. The organic layer was separated from the filtrate, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β-[2-cyclopropyloxyimino-2 -(2-formamidothiazol-4-yl)acetamido]-3-(5,6-dioxo-2-methyl-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (685 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].[CH3:10][N:11]=[C:12]=[S:13]>C1COCC1>[C:2]1([C:6]([NH:8][NH:9][C:12]([NH:11][CH3:10])=[S:13])=[O:7])[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C=S
Reactant: NNC(=O)c1cccs1
Solvent: C1CCOC1
Product: CNC(=S)NNC(=O)c1cccs1
Reaction time: 14 h

Procedure:
A stirred mixture of 2-thiophene carboxylic acid hydrazide (4.75 g, 3.34×10-2 mole) and THF (115 ml) was warmed with a heat gun until homogeneous. A solution of freshly distilled methyl isothiocyanate (2.56 g, 3.51×10-2 mole) and THF (5 ml) was then added dropwise. After being stirred for about 14 hours the precipitate was collected by filtration, washed with a little Et2O, and dried by suction affording a colorless powder: 7.1 g (99%).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[NH:10][CH2:11][CH2:12][C:13]([O:15]C)=O>CO>[Br:9][C:6]1[CH:7]=[CH:8][C:3]2[NH:2][C:13](=[O:15])[CH2:12][CH2:11][NH:10][C:4]=2[CH:5]=1
Reactant: COC(=O)CCNc1cc(Br)ccc1N
Agent: [Na]
Solvent: CO
Product: O=C1CCNc2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Sodium (2.4 g, 104 mmol) was added in portions to 50 mL of methanol until it dissolved. The solution was then added dropwise to a cooled solution of methyl 3-((2-amino-5-bromophenyl)amino)propanoate (9.4 g, 34.6 mmol) in 50 mL of methanol at 0° C. After additional, the mixture was stirred at room temperature overnight. It was concentrated, added with water (50 mL), extracted with ethyl acetate (50 mL) and purified by CombiFlash (PE:EA=5:1) to give 7-bromo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (2 g, yield 24%). LRMS (M+H)+: 240 m/z. 1H NMR (300 MHz, CDCl3) δ 2.68-2.72 (t, J=6.0 Hz, 2H), 3.68-3.72 (t, J=6.0 Hz, 2H), 6.79-6.82 (d, J=8.7 Hz, 2H), 6.98-7.06 (m, 2H), 8.00 (br, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][C:7]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[O:17]=[C:7]1[NH:8][C:9](=[O:16])[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[N:6]1[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[S:25]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCCCn1c2c(c(=O)[nH]c1=O)CCCC2
Agent: Cl
Solvent: c1ccncc1
Product: CN(CCCn1c2c(c(=O)[nH]c1=O)CCCC2)S(=O)(=O)c1ccc(F)cc1
Yield: 34.1 %

Procedure:
A solution of 75 mg (0.32 mmol) of 1-[3-(methylamino)propyl]-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione and 61.5 mg (0.32 mmol) of 4-fluorophenylsulphonyl chloride in 3 ml of pyridine is stirred at room temperature overnight. The reaction mixture is then adjusted to pH 1 using 2-molar hydrochloric acid and extracted twice with in each case 20 ml of ethyl acetate. The organic phase is concentrated under reduced pressure and the resulting residue is purified by preparative HPLC (RP-C18, acetonitrile/water gradient). This gives 43.1 mg (34% yield) of the product as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:9][CH2:8]1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([F:49])=[C:31]([C:33]2[S:34][C:35]([NH:41]C(OC(C)(C)C)=O)=[C:36]([C:38](O)=[O:39])[N:37]=2)[CH:32]=1>>[NH2:41][C:35]1[S:34][C:33]([C:31]2[CH:32]=[C:27]([Br:26])[CH:28]=[CH:29][C:30]=2[F:49])=[N:37][C:36]=1[C:38]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9][CH2:8]1)=[O:39]
Reactant: Cn1ncc(N)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(Br)ccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3cc(Br)ccc3F)sc2N)c1N1CCC[C@@H](N)CC1

Procedure:
Following procedures from Examples 140, (R)-benzyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16 and the product of Example 27, 2-(5-bromo-2-fluorophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid, were converted to 308. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 8.45 (dd, J=6.7, 2.5 Hz, 1H), 7.66-7.55 (m, 1H), 7.48 (s, 2H), 7.43 (s, 1H), 7.36 (dd, J=11.2, 8.9 Hz, 1H), 3.65 (s, 4H), 3.21-2.93 (m, 7H), 1.84 (dd, J=8.2, 3.6 Hz, 3H), 1.72-1.39 (m, 3H). MS (ESI) m/z: 508.1/510.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.Br>[Br:21][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OC)cc1
Yield: 101.8 %

Procedure:
To a mixture of methyl 4-methoxyphenylacetate (20 g, 0.11 mol) and NBS (0.11 mol) in CCl4 (0.2 I) were added 3 drops of 48% HBr and this mixture was heated to reflux for 8 h. The cooled solution was filtered through a pad of silica gel and the filtrate was evaporated in vacuo to give 29 g of the title compound as pale yellow oil, which was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[F:1][C:2]1[CH:8]=[CH:7][C:6]([S:9][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc(S)ccc1F
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1cc(SCc2ccccc2F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-fluoro-5-mercaptoaniline (0.13 g) and 2-fluorobenzyl bromide (0.12 mL) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.25 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with water twice and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =6/1) to give the title compound (0.17 g).
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10](=[O:18])[C@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:12][OH:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH3:21]I>>[N:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10](=[O:18])[C@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:12][O:13][CH3:21])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: CC(=O)N[C@H](CO)C(=O)NCc1ccc(N=[N+]=[N-])cc1
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccc(N=[N+]=[N-])cc1
Yield: 80.3 %

Procedure:
Utilizing Method B, (R)—N-(4-azidobenzyl)-2-acetamido-3-hydroxypropanamide (1.16 g, 4.19 mmol), Ag2O (4.85 g, 20.94 mmol), and MeI (2.61 mL, 41.89 mmol) gave crude (R)-5 after 4 d. The product was purified by column chromatography (SiO2; 1/9 MeOH/CHCl3) to obtain 0.98 g (80%) of (R)-5 as a white solid: mp 149-150° C.; [α]26D −15.2° (c 1.0, MeOH); Rf=0.5 (1/9 MeOH/CHCl3); IR (nujol mull) 3285, 2931, 2113, 1635, 1560, 1456 cm−1; 1H NMR (CDCl3) δ 2.03 (s, CH3C(O)), 3.38 (s, OCH3), 3.44 (dd, J=7.5, 9.3 Hz, CHH′OCH3), 3.80 (dd, J=4.2, 9.3 Hz, CHH′OCH3), 4.40 (½HH′q, J=6.2, 15.0 Hz, CHH′Ar), 4.46 (½HH′q, J=6.2, 15.0 Hz, CHH′Ar), 4.52-4.58 (m, CH), 6.48 (br d, J=6.3 Hz, NHCH), 6.82-6.85 (br m, NHCH2), 6.96-7.01 (m, 2 ArH), 7.23-7.28 (m, 2 ArH), addition of excess (R)-(−)-mandelic acid to a CDCl3 solution of (R)-5 gave only a single signal for the acetyl methyl protons and the ether methyl protons, addition of excess (R)-(−)-mandelic acid to a CDCl3 solution of (R)-5 and (S)-5 (1:2 ratio) gave two signals for the acetyl methyl protons (δ 1.995 (R) and 2.010 (S) (Δppm=0.015)), and two signals for the ether methyl protons (δ 3.302 (S) and 3.342 (R) (Δppm=0.040)); 13C NMR (CDCl3) δ 23.4 (CH3C(O)), 43.1 (CH2Ph), 52.7 (CH), 59.3 (CH2OCH3), 71.8 (CH2OCH3), 119.5, 129.1, 134.9, 139.5 (C6H5), 170.2, 170.5 (2C(O)); HRMS (ESI) 292.1406 [M+H+] (calcd. for C13H18N5O3 292.1410); Anal. (C13H17N5O3) Calcd.: C, 53.60%; H, 5.88%; N, 24.04%. Found: C, 53.72%; H, 5.91%; N, 23.84%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])(=[O:27])[CH3:26].CC1C(C)=CC=CC=1C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1OC)=O>>[C:25]([C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:31])(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccccc1C(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1NC(=O)c1cccc(C)c1C
Product: CC(=O)c1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 27 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-acetylbenzoyl chloride, the title compound (yield 27%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C([O:24][C:25]([C@H:27]1[C@@H:32]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C@H:31]2[CH2:42][C@@H:28]1[CH2:29][CH2:30]2)=O)C.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:33]2[C:17](=[O:18])[C:16]([C:11]3[NH:10][C:9]4[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=4[S:13](=[O:14])(=[O:15])[N:12]=3)=[C:25]([OH:24])[C@H:27]3[C@@H:32]2[C@H:31]2[CH2:42][C@@H:28]3[CH2:29][CH2:30]2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 23 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 1.88 kg, 5.63 mol) and (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6l, 1.72 kg, 5.91 mol) were dissolved in acetonitrile (18.8 L) at 23° C. N-Methylmorpholine (1.25 kg, 12.4 mol) was added and the resulting suspension was stirred at 23° C. for 1 h. The suspension was cooled to 0° C. and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.19 kg, 6.20 mol) was added in one portion. The mixture was stirred at 0° C. for 3 h, and was then allowed to warm to 23° C. and stirred overnight. Triethylamine (1.88 kg, 18.6 mol) was added and the mixture was then heated at 50° C. for 3 h. The mixture was partially concentrated in vacuo at 45° C., and was then diluted with ethyl acetate (22.5 L) and washed with 2.0M aqueous hydrochloric acid solution (22.6 L). The resulting aqueous fraction was extracted with ethyl acetate (2×9.4 L). The combined organic extracts were washed with 1.0M aqueous hydrochloric acid solution (10.4 L) and then with water (18.8 L). The resulting organic fraction was filtered through Celite (600 g), and the filtrate was then partially concentrated in vacuo at 45° C. Absolute ethanol (5.6 L) was added to the residue, and the mixture was then heated at 50° C. with stirring. Dichloromethane (400 mL) was added in portions until crystallization initiated. Absolute ethanol (20.7 L) was added in portions over 1 h, and the resulting mixture was stirred at 23° C. overnight. The mixture was filtered and the solid was then washed with absolute ethanol (1.9 L). The solid was further dried in vacuo at 45° C. to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (2.46 kg, 4.39 mol, 78%), as an off-white crystalline solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:41]=[CH:40][C:29]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:41]=[CH:40][C:29]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 88.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (780 mg, 2.5 mmol) was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethylcarbamate (1.5 g, 4.3 mmol) to afford the desired product (1.0 g, 90%) as a brown solid: ESI MS m/z 451 [C25H26N2O4S+H]+.
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:6]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:7][S:8][CH:9]=1)[CH2:2][CH3:3].C([Li])CCC.[C:23](=[O:25])=[O:24].Cl>C1COCC1.CCCCCC>[CH2:1]([S:4][C:5]1[C:6]([S:10]([NH:13][C:14]([CH3:16])([CH3:15])[CH3:17])(=[O:12])=[O:11])=[C:7]([C:23]([OH:25])=[O:24])[S:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: O=C=O
Reactant: CCCSc1cscc1S(=O)(=O)NC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCSc1csc(C(=O)O)c1S(=O)(=O)NC(C)(C)C
Temperature: 20 °C

Procedure:
A solution of 12.15 g 4-propylthio-3-N-(1,1-dimethylethyl)-3-thiophenesulfonamide in 150 mL THF was cooled to -30° C. and treated dropwise with 31.6 mL 2.69M n-butyllithium in hexane. The solution was warmed to 20° C. for 1.5 hours and then cooled to -80° C. 8.8 g Solid carbon dioxide was added in one portion, the mixture was warmed to 20° C. and poured over ice and hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to a solid. The product was purified by recrystallization from butyl chloride to give 10.4 g of light yellow solid; m.p. 123°-126° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.[OH:20][C@@H:21]([CH3:30])[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].B.N1C=CC=CC=1C.B.C(C1C=CC(C)=NC=1)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:26][CH2:25][N:24]([C:22](=[O:23])[C@@H:21]([OH:20])[CH3:30])[CH2:29][CH2:28]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C[C@H](O)C(=O)N1CCNCC1
Agent: B
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCc1ccc(C)nc1
Solvent: Cc1ccccn1
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
Scheme 2 shows the synthesis of intermediate (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II from 4-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholino VI. Treatment of VI with isopropylmagnesium chloride Grignard reagent followed by n-butyllithium at −10° C. was followed by addition of dimethylformamide and quenching with aqueous acid gave formylated intermediate 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (Example 4). Reductive amination of IV was effected by mixing IV with the oxalate salt of (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V followed by a reducing agent, such as sodium triacetoxyborohydride (Method A), 2-picoline borane (Method B) or 5-Ethyl-2-methylpyridine borane to give II which was crystallized in toluene/heptane (Example 5) or Me-THF/heptane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[C:9]([Mg]Cl)#[CH:10]>C1COCC1>[OH:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]#[CH:10]
Reactant: O=Cc1ccccn1
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1ccccn1

Procedure:
3-Hydroxy-3-(2-pyridinyl)-1-propyne was prepared according to Method A above from 2-pyridine carboxaldehyde (1.0 g, 9.3 mmol) (Aldrich) in THF (50 mL) and ethynylmagnesium chloride (10 mmol, 20 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 956 mg, 77%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][N:11]=[CH:12][C:13]1[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1.[N+:21](C1OC(C=O)=CC=1)([O-:23])=[O:22].N(C1SC2C=C([N+]([O-])=O)C=CC=2N=1)N>>[N+:21]([C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[C:2]([NH:10][N:11]=[CH:12][C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[S:1][C:5]=2[CH:6]=1)([O-:23])=[O:22]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Agent: NNc1nc2ccc([N+](=O)[O-])cc2s1
Product: O=[N+]([O-])c1ccc2nc(NN=Cc3ccc([N+](=O)[O-])o3)sc2c1

Procedure:
The compound 3o was prepared according procedure described for 3a by employing 5-nitrofuran aldehyde (141 mg, 1 mmol) and 2-hydrazino-6-nitro-benzothiazole (210 mg, 1 mmol) at 70° C. for 2 h (yield 283 mg, 85%).