Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH:13]([F:16])[C:12]3[S:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:21]([C@:23]1([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29])#[CH:22]>>[F:16][CH:13]1[C:12]2[S:11][C:10]([C:17]([O:19][CH3:20])=[O:18])=[N:9][C:8]=2[C:6]2[CH:7]=[C:2]([C:22]#[C:21][C@:23]3([OH:30])[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[CH:3]=[CH:4][C:5]=2[O:15][CH2:14]1
Reactant: COC(=O)c1nc2c(s1)C(F)COc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: COC(=O)c1nc2c(s1)C(F)COc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Methyl 9-bromo-4-hydroxy-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate was reacted similarly to as described in General Procedure P with non-critical modifications to afford 142 mg (94%) of methyl 9-bromo-4-fluoro-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Methyl 9-bromo-4-fluoro-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford methyl 4-fluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4,5-dihydro-[1]benzoxepin o[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 29 mg and 30 mg (37% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-fluorine substitution position for each isomer was not determined.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH2:32])[N:17]=[C:16]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[S:44](Cl)(=[O:46])=[O:45]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:29][CH2:30][CH2:31][NH:32][S:44]([C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)(=[O:46])=[O:45])[N:17]=[C:16]([C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)[N:15]=2)(=[O:11])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ncccn2)nc1OCCN
Reactant: O=S(=O)(Cl)c1cccs1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ncccn2)nc1OCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 129 mg 5-isopropyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with thiophene-2-sulfonylchloride to give 105 mg 5-isopropyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=5.00 min, [M+1]+=684.60, [M−1]−=682.70.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24](O)=[O:25])[CH:17]=3)[O:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:41][O:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:11][C:10]2([CH2:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24]([NH:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)=[O:25])[CH:17]=3)[O:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Yield: 117673.3 %

Procedure:
A suspension of (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (490 g, 1.30 mmol) in DCM (6.5 ml) was treated with TEA (0.12 ml, 0.90 mmol) and then with EDC (172 mg, 0.900 mmol), HOBt (122 mg, 0.904 mmol) and NH2OTHP (82 mg, 0.72 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (380 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH2:32][CH3:33])[CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[C:4]([O:34]C)[CH:3]=1.BrB(Br)Br>>[ClH:1].[NH2:24][CH2:23][CH:22]([C:19]1[CH:18]=[CH:17][C:16]([C:5]2[C:6]3[C:7]4[CH:15]=[CH:14][S:13][C:8]=4[C:9](=[O:12])[NH:10][C:11]=3[C:2]([Cl:1])=[CH:3][C:4]=2[OH:34])=[CH:21][CH:20]=1)[CH2:32][CH3:33]
Reactant: CCC(CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Agent: BrB(Br)Br
Product: CCC(CN)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 98.9 %

Procedure:
Following General Procedure F, tert-butyl 2-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)butylcarbamate (65 mg, 0.13 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 0.76 mL, 0.76 mmol) to afford the desired product (28 mg, 56%) as a white solid: 1H NMR (500 MHz, MeOD) δ 7.60 (d, J=5.4 Hz, 1H), 7.54 (dd, J=7.9, 1.8 Hz, 1H), 7.44 (dd, J=7.7, 1.8 Hz, 1H), 7.39 (dd, J=7.9, 1.8 Hz, 1H), 7.35-7.30 (m, 2H), 6.08 (d, J=5.4 Hz, 1H), 3.38-3.22 (m, 2H), 2.98-2.89 (m, 1H), 1.97-1.85 (m, 1H), 1.85-1.72 (m, 1H), 0.98 (t, J=7.4 Hz, 3H); ESI MS m/z 399 [C21H19ClN2O2S+H]+; HPLC >99%, (AUC), tR=10.29 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]2[CH2:32][C@:33]4([CH2:43][C:27]=2[CH:26]=3)[C:41]2[C:36](=[N:37][CH:38]=[CH:39][CH:40]=2)[NH:35][C:34]4=[O:42])[CH2:10][CH2:11][C:12]([CH3:19])([CH3:18])[C:13](OCC)=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:20]([CH2:21][C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][C:28]3[CH2:32][C@:33]5([CH2:43][C:27]=3[CH:26]=4)[C:41]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]5=[O:42])[C:13](=[O:14])[C:12]([CH3:19])([CH3:18])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)C(C)(C)CC[C@H](NCc1cnc2cc3c(cc2c1)C[C@@]1(C3)C(=O)Nc2ncccc21)c1cc(F)cc(F)c1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(Cc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)C1=O
Temperature: 140 °C

Procedure:
A solution of ethyl (5S)-5-(3,5-difluorophenyl)-2,2-dimethyl-5-({[(7S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-3-yl]methyl}amino)pentanoate from Step B (131 mg, 0.224 mmol) in a 90/10 mixture of xylenes/HOAc (20 mL) was heated to 140° C. for ˜22 hours. After allowing the reaction mixture to cool, the bulk of the solvent was removed in vacuo to give a residue. This residue was diluted with chloroform (50 mL) and washed with saturated sodium bicarbonate (25 mL). This aqueous layer was then extracted twice with DCM (2×30 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue. This residue was applied to a silica gel column for purification, eluting with a gradient of CH2Cl2:MeOH—99:1 to 94:6. Clean product-containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=585 (M+1). HRMS: m/z=539.2264; calculated m/z=539.2253 for C32H29F2N4O2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:14])[CH2:8][C:7]=2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[CH3:1][O:2][C:3]1[C:13]2[CH:12]=[CH:11][N:10]([CH2:18][CH2:19][CH2:20][Cl:21])[C:9](=[O:14])[CH2:8][C:7]=2[C:6]([O:15][CH3:16])=[CH:5][CH:4]=1
Reactant: ClCCCBr
Reactant: COc1ccc(OC)c2c1C=CNC(=O)C2
Product: COc1ccc(OC)c2c1C=CN(CCCCl)C(=O)C2

Procedure:
This compound was prepared analogous to Example 1(a) by reacting 6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (m.p. 188°-191° C.) with 1-bromo-3-chloro-propane.
Reaction SMILES: [I:1][CH2:2][C:3]1([CH3:20])[O:8][CH2:7][C@@H:6]2[CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][N:5]2[CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:1][CH2:2][C:3]1([CH3:20])[O:8][CH2:7][C@@H:6]2[CH2:9][NH:10][CH2:11][CH2:12][N:5]2[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN2CC(C)(CI)OC[C@@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CI)CN2CCNC[C@H]2CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
(9aS)-tert-butyl 3-(iodomethyl)-3-methylhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (108 mg, 0.273 mmol) was taken up in DCM (3 mL) and TFA (0.42 mL, 5.45 mmol) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the material was taken up in MeOH. The solution was loaded onto an SCX column (5 g, benzenesulfonic acid sorbent) and rinsed with MeOH, then 7N NH3/MeOH solution to release the product. The solvent was removed in vacuo give (9aS)-3-(iodomethyl)-3-methyloctahydropyrazino[2,1-c][1,4]oxazine (79 mg) as an orange oil.
Reaction SMILES: [N:1]1([C:6]2[CH2:10][CH2:9][O:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][I:12]>CO>[I-:12].[O:8]1[CH2:9][CH2:10][C:6]([N+:1]2([CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:7]1
Reactant: CI
Reactant: C1CCN(C2=NOCC2)C1
Solvent: CO
Product: C[N+]1(C2=NOCC2)CCCC1
Product: [I-]
Reaction time: 72 h

Procedure:
1-(4,5-Dihydroisoxazol-3-yl)-1-methylpyrrolidinium iodide III-60 was synthesized according to the following procedure: 3-(pyrrolidin-1-yl)-4,5-dihydroisoxazole III-59 was dissolved in methanol (0.044 M) followed by the addition of methyl iodide (0.022 M). The reaction was allowed to sit for 72 h after which it was concentrated and purified using high pressure liquid chromatography (0.1% formic acid). The desired fractions were lyophilized to provide the desired product plus some impurities which were removed by washing the solid with hexanes. Activity: C
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:16][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(#N)C>[S:17]([C:15]1[S:16][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:13][N:14]=1)(=[O:18])(=[O:19])[NH2:20]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(S(N)(=O)=O)s2)cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
5-(4-Aminophenylsulfonamido)-1,3,4-thiadiazole-2-sulfonamide (7, 50 mg, 0.15 mmol) was suspended in anhydrous acetonitrile (5 mL). Triethylamine (17.1 mg, 0.17 mmol) was added with stirring at 0° C. A solution of decanoyl chloride (32.4 mg, 0.17 mmol) dissolved in anhydrous acetonitrile (1 mL) was added dropwise, and the reaction mixture was stirred at 0° C. for 2 h and overnight at room temperature. Volatiles were removed in vacuo and the residue was washed with water (5 mL). The residue was subjected to chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1, giving the pure product as a solid (42 mg, 0.09 mmol, 60% yield), mp 242-243° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, 3H, J=6.9 Hz), 1.24 (m, 12H), 1.56 (m, 2H), 2.32 (t, 2H, J=7.5 Hz), 7.66 (s, 4H), 7.91 (s, 2H), 10.13 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.1, 22.3, 25.2, 28.8, 29.0, 31.5, 36.6, 118.6, 127.0, 137.4, 142.2, 157.8, 170.8, 172.1; LRMS (LCQ, ESI) calcd for C18H26N5O5S3 488.1, found 488.1 (M−H)−; HRMS (ESI−, m/z) calcd for C18H26N5O5S3 488.1102, found 487.1101 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])/[C:9](/[N+:10]([O-:12])=[O:11])=[CH:16]\[N:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(C[N+](=O)[O-])c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CN(C)/C=C(\C(=O)c1ccc(Br)cc1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 1-(4-bromophenyl)-2-nitroethanone (5.38 g, 0.022 mol, Seter J. et al., Isr. J. Chem., 4, 7 (1966)) and N,N-dimethylformamide dimethylacetal (2.9 g, 0.024 mol) and catalytic amount of p-TsOH in THF (100 mL) was refluxed for 10 h. The mixture was cooled to room temperature and concentrated in vacuo. The reaction mixture was purified by flash chromatography eluting with ethyl acetate/hexane (1/1) to give title compound (2.8 g, 43%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2CC(F)(F)F)N1CCN(C2CCCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a light yellow solid (60%).
Reaction SMILES: [N:1]1([CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:12](Cl)([Cl:14])=[O:13]>C(Cl)Cl>[ClH:14].[O:13]=[S:12]1[O:11][CH:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:9][O:10]1
Reactant: OCC(O)CN1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: O=S1OCC(CN2CCOCC2)O1
Temperature: 0 °C
Yield: 113.1 %

Procedure:
3-Morpholin-4-ylpropane-1,2-diol (2.1 g, 9.07 mmol) was dissolved in DCM (15 mL) and cooled to 0° C. The cooled solution was treated with thionyl chloride (1.81 mL, 24.8 mmol) and then heated at the reflux temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to give a solid (2.5 g, 97%): 1H NMR (DMSO-d6) δ: 11.4 (1H, br s), 5.64-5.55 (1H, m) 4.82 (1H, dd), 4.50 (1H, dd), 4.02-3.71 (4H, m), 3.55-3.33 (4H, m), 3.26-3.06 (2H, br s).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12]2[C:13]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12]2[C:13]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccc(F)cc43)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccc(F)cc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of methyl 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (120 mg, 0.28 mmol) in methanol (20 ml) was added a solution of sodium hydroxide (44 mg, 1.10 mmol) in water (3 ml). The reaction was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo to give a residue, which was dissolved in water (20 ml) and adjusted to pH 4 with hydrogen chloride (3 N). The solids were collected by filtration to afford 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (101 mg, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16](NCCOCC)[CH3:17])=[CH:6][CH:5]=1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH3:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOCCNC(C)c1ccccc1-c1ccc(OCC)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(-c2ccccc2CC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 13.5 mg [1-(4′-ethoxy-biphenyl-2-yl)-ethyl]-(2-ethoxy-ethyl)-amine (43.1 μmol, 1.00 equiv), 10.5 mg 4′-(trifluoromethyl)phenylacetic acid (51.7 μmol, 1.20 equiv), 9.9 mg EDC (51.7 μmol, 1.20 equiv), and 1.0 mg HOBT (7.4 μmol, 0.18 equiv) dissolved in 2.0 mL dichloromethane was stirred at room temperature for 2 h. To the reaction solution was added 5 mL aqueous saturated sodium bicarbonate solution. The aqueous layer was diluted with water to 15 mL and extracted with dichloromethane (2×20 mL). The combined organic separations were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a yellow oil. The crude product was adsorbed onto a column of silica gel (3.5 cm o.d.×10 cm h) and eluted with 17% to 25% ethyl acetate gradient in hexane. Fractions containing product were combined and concentrated in vacuo to afford 12.8 mg purified product as a colorless oil. 1H NMR (d6-DMSO; T=140° C.) δ1.04 (t, 3H, J=6.8 Hz), 1.34 (t, 3H, J=6.8 Hz), 1.44 (d, 3H, J=7.2 Hz), 3.00-3.06 (m, 1H), 3.17-3.36 (m, 6H), 3.49 (d, 1H, J=16.0 Hz), 4.07 (q, 2H, J=6.8 Hz), 5.43 (q, 1H, J=7.2 Hz), 6.92-6.96 (m, 2H), 7.13-7.18 (m, 3H), 7.22-7.26 (m, 2H), 7.34 (ddd, 1H, J1=1.2 Hz, J2=7.6 Hz, J3=8.4 Hz), 7.39 (ddd, 1H, J1=2.0 Hz, J2=7.6 Hz, J3=9.2 Hz), 7.53-7.59 (m, 3H) ppm. At room temperature, compound exists as a mixture of cis/trans amide rotamers in ca. 2:1 ratio as determined by integration of characteristic 1H NMR signals (CDCl3; T=25° C.) δmajor 5.19 (q, 2.1H, J=7.2 Hz) and δminor 5.89 (q, 1.0H, J=7.6 Hz) ppm. MS (ESI, positive mode) 500.1 [MH]+
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:15][CH2:16]I.[Li+].CC([N-]C(C)C)C.C(O)(=O)C>C1COCC1>[Cl:15][CH2:16][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1OCCO2
Reactant: ClCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(CCl)c1cccc2c1OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester (100 mg, 0.515 mmol) and chloroiodomethane (0.075 ml, 1.03 mmol) in 1 ml of THF was added a solution of LDA in THF (2M, 0.57 ml, 1.13 mmol) dropwise at −78° C. over 15 min. The reaction mixture was stirred at −78° C. for 10 min. A solution of acetic acid (0.75 ml) in THF (5 ml) was added dropwise over 5 min at −78° C. The resulting solution was stirred at the same temperature for additional 10 min. and was then partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo to give the crude 2-chloro-1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethanone as a light brown liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]#[N:27])[CH:20]=1)[C:8]1[C:13]([CH:14]([CH3:16])[CH3:15])=[C:12](Cl)[N:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][O-:30].[Na+].[CH3:32][OH:33]>>[C:1]([O:5][C:6](=[O:28])[N:7]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]#[N:27])[CH:20]=1)[C:8]1[C:13]([CH:14]([CH3:16])[CH3:15])=[C:12]([O:30][CH3:29])[N:11]=[C:10]([O:33][CH3:32])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: Cc1cc(C#N)cc(N(C(=O)OC(C)(C)C)c2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: CO
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(N(C(=O)OC(C)(C)C)c2cc(C)cc(C#N)c2)n1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
(3-Cyano-5-methyl-phenyl)-(2,6-dichloro-5-isopropyl-pyrimidin-4-yl)-carbamic acid tert-butyl ester (469 mg, 1.113 mmol) was dissolved in methanol (4 mL) at room temperature. Sodium methoxide solution (25% in methanol, 1.18 g, 5.56 mmol) was added and the reaction was heated at 75° C. After 4 hours, the reaction was stopped by the evaporation of solvents. The crude material was purified via flash chromatography on silica gel (eluent: ethyl acetate in hexanes) to yield (3-Cyano-5-methyl-phenyl)-(2,6-dimethoxy-5-isopropyl-pyrimidin-4-yl)-carbamic acid tert-butyl ester (336.8 mg, 0.816 mmol). 1H (CDCl3): δ=7.36 (s, 1H), 7.31 (s, 1H), 7.20 (s, 1H), 4.02 (s, 3H), 3.92 (s, 3H), 3.01 (m, 1H), 2.32 (s, 3H), 1.41 (s, 9H), 1.20-1.10 (m, 6H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5]N=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:10]2=[N:9][N:8]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[Cl:29].Br[CH2:31]C1C=CC=C(Cl)C=1Cl>>[Cl:29][C:20]1[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:14]1[CH2:13][CH2:12][N:11]2[C:7]([C:2]3[CH:3]=[CH:31][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=[C:10]2[C:15]1=[O:16]
Reactant: FC(F)(F)c1cccc(CBr)c1Cl
Reactant: Clc1cccc(CBr)c1Cl
Reactant: O=C1NCCn2c1nnc2-c1cnccn1
Product: O=C1c2nnc(-c3ccccn3)n2CCN1Cc1cccc(C(F)(F)F)c1Cl
Yield: 89 %

Procedure:
Example 9 was made in a manner analogous to Example 2 substituting Intermediate 2 for Intermediate 1 and 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene for 1-(bromomethyl)-2,3-dichlorobenzene to provide the desired compound as a white solid (66 mg, 89%). MS (ESI): mass calcd. for C18H13ClF3N5O, 407.1; m/z found, 408.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.75 (ddd, J=4.8, 1.6, 0.9 Hz, 1H), 8.29 (dt, J=8.0, 0.9 Hz, 1H), 8.05 (dt, J=7.8, 1.7 Hz, 1H), 7.82 (dd, J=12.7, 7.8 Hz, 2H), 7.64-7.49 (m, 2H), 4.97-4.90 (m, 2H), 4.88 (s, 2H), 3.98-3.88 (m, 2H).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.Cl.[SH:44][C@@H:45]1[CH2:49][N:48](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:47]([CH:63]2[CH2:68][CH2:67][N:66]([CH3:69])[CH2:65][CH2:64]2)[CH2:46]1>>[CH:36]([N:21]([CH2:20][CH3:19])[CH:22]([CH3:18])[CH3:23])([CH3:37])[CH3:45].[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[CH:18][C@@:19]([CH3:42])([S:44][C@@H:45]3[CH2:49][NH:48][C@H:47]([CH:63]4[CH2:68][CH2:67][N:66]([CH3:69])[CH2:65][CH2:64]4)[CH2:46]3)[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: CN1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Product: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C[C@@](C)(S[C@@H]3CN[C@H](C4CCN(C)CC4)C3)[C@H]12
Yield: 79.5 %

Procedure:
The same procedure as in Example 49-1) was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (3.86 g, 6.5 mmol), (2S,4S)-4-mercapto-2-(N-methylpiperidin-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride (2.88 g, 6.9 mmol, the compound of Reference Example 38 and N,N-diisopropylethylamine (2.61 ml, 15 mmol) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-1-[(2S,4S)-2-(N-methylpiperidin-4-yl)pyrrolidin-4-yl-thio]-1-carbapen-2-em-3-carboxylate (3.74 g, yield: 79.5%). Various spectra data of this compound agreed to the data of the compound obtained in Example 49-1). ##STR1223##