Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[Br:31][C:32]1[CH:33]=[C:34]([CH2:41]Br)[C:35]2[O:39][CH:38]=[CH:37][C:36]=2[CH:40]=1>COCCOC.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([O:24][CH2:41][C:34]2[C:35]3[O:39][CH:38]=[CH:37][C:36]=3[CH:40]=[C:32]([Br:31])[CH:33]=2)[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: BrCc1cc(Br)cc2ccoc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](OCc2cc(Br)cc3ccoc23)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
Potassium bis(trimethylsilyl)amide (300 mg) was added to a stirred solution of [2S,3S]-N-tert-butoxycarbonyl-2-phenylpiperidine-3-ol (160 mg) in dry 1,2-dimethoxyethane (3.0 ml) under a dry nitrogen atmosphere. After 30 minutes 5-bromo-7-bromomethylbenzofuran (290 mg) was added, and the reaction stirred for 18 hours at room temperature. The resulting mixture was then diluted with water (50 ml), and extracted into ethyl acetate (2×50 ml). The organic layers were separated and washed with brine (20 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by MPLC (20% ethyl acetate/n-hexane), afforded [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[(5-bromobenzofuran-7-yl)methyloxy]piperidine as a yellow gum (136 mg). 1H NMR (360 MHz,CDCl3)δ1.43 (9H, s), 1.65 (2H, m), 1.92 (2H, m), 2.70 (1H, t d, J=7.2, 3.0 Hz), 3.74 (2H,m), 4.90 (2H, d, J=5.0 Hz), 5.74 (1H, br s), 6.71 (1H, d, J=1.0 Hz), 7.30-7.42 (4H, m), 7.58 (3H, m), 7.75 (1H, d, J=1.0 Hz); MS m/z CI+ 487 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]1[N:22]=[C:21]([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([CH2:30][OH:31])[CH2:25]2)[O:20][N:19]=1.[CH3:32][NH:33][C:34](=[O:37])[CH2:35]Cl.C(N(CC)C(C)C)(C)C.[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH:8]=[C:7]2[C:18]1[N:22]=[C:21]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH2:35][C:34](=[O:37])[NH:33][CH3:32])[C@H:26]([CH2:30][OH:31])[CH2:25]2)[O:20][N:19]=1
Reactant: CNC(=O)CCl
Reactant: OC[C@@H]1CN(Cc2nc(-c3cn(CC4CCOCC4)c4c(Cl)cccc34)no2)CCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)CN1CCN(Cc2nc(-c3cn(CC4CCOCC4)c4c(Cl)cccc34)no2)C[C@H]1CO
Yield: 93.9 %

Procedure:
A mixture of (S)-7-chloro-3-[5-(3-hydroxymethylpiperazin-1-ylmethyl)-[1,2,4]-oxadiazol-3-yl]-1-[(tetrahydropyran-4-yl)methyl]-1H-indole (22 mg, 0.049 mmol), N-methyl-2-chloroacetamide (11 mg, 0.098 mmol), N,N-diisopropylethylamine (19 mg, 0.15 mmol) and sodium iodide (7 mg, 0.049 mmol) in dimethylformamide (2.0 ml) was subjected to microwave irradiation at 160° C. for 5 minutes. The mixture was filtered through a 5 g Strata™ SCX giga tube, eluting with dichloromethane, methanol and then 2 M ammonia in methanol, and purified by flash column chromatography eluting with ethyl acetate to 33% (v/v) methanol in ethyl acetate to afford the title compound (23.9 mg, 0.046 mmol). EsIMS: m/z 539.8, 517.5 [M+H]+, 503.1, 200.6.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:23]4[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (76 mg, 86%), MS (ISP) m/z=356.5 [(M+H)+], mp 359° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1Br)[N:14]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[C:49]1[CH:50]=[CH:51][C:52]([CH3:55])=[N:53][CH:54]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[C:49]1[CH:54]=[N:53][C:52]([CH3:55])=[CH:51][CH:50]=1)[N:14]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cn1
Reactant: Brc1cc2c(cnn2C2CCCCO2)cc1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc3c(cnn3C3CCCCO3)cc2OCc2ccccc2)cn1
Yield: 46.2 %

Procedure:
To a solution of 5-(benzyloxy)-6-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4 g, 10.3 mmol) in 1,4-dioxane (25 mL) is added bis(pinacolato)diboron (3 g, 11.8 mmol), dppf (0.3 g, 541 μmol), PdCl2(dppf) (0.42 g, 514 μmol) and KOAc (2 g, 20.4 mmol) under N2. After the reaction mixture is stirred at reflux for 5 hours, 5-bromo-2-methylpyridine (2.1 g, 12.2 mmol), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (0.6 g, 519 μmol) and Cs2CO3 (4 g, 12.3 mmol) are added and the mixture is stirred at reflux overnight. The reaction mixture is cooled and filtered, the filtrate is concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (2:1) to give the product (1.9 g, 46.0% yield). MS (m/z): 400.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:25])[C@H:13]([CH3:24])[NH:14][CH:15]([C:20]([O:22][CH3:23])=[O:21])[C:16]([O:18][CH3:19])=[O:17])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:30][CH2:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)=[O:33].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:26])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:25])[C@H:13]([CH3:24])[NH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])([C:20]([O:22][CH3:23])=[O:21])[CH2:30][CH2:31][C:32](=[O:33])[C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)C(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OC
Reactant: CN(C)CCC(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C(CCC(=O)c1cccs1)(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OC

Procedure:
A-mixture of N-(dimethoxycarbonylmethyl)-L-alanyl-L-proline t-butyl ester (2.0 g.), 3-dimethylamino-1-(2-thienyl)propan-1-one hydrochloride (1.8 g.), potassium carbonate (2.0 g.) and methanol (15 ml.) was stirred at laboratory temperature for 16 hours and then evaporated to dryness under reduced pressure. The residue was stirred with dichloromethane, the mixture was filtered through a filter-aid and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column using a 19:1 v/v mixture of dichloromethane and ethyl acetate as eluant. There was thus obtained as an oil N-[1,1-dimethoxycarbonyl-4-oxo-4-(2-thienyl)butyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: P(OCC)(OCC)(O[C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:11]=2)[C:7]([C:33]#[N:34])=[CH:6][N:5]=1)=O.[NH2:41][C@@H:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1)[CH3:43].C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[C:33]([C:7]1[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=3)(=[O:24])=[O:25])[CH:11]=2)=[N:9][C:4]([NH:41][C@@H:42]([CH:44]2[CH2:45][CH2:46][N:47]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[CH2:48][CH2:49]2)[CH3:43])=[N:5][CH:6]=1)#[N:34]
Reactant: C[C@@H](N)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOP(=O)(OCC)Oc1ncc(C#N)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(C(F)(F)F)cc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCN(C(=O)OC(C)(C)C)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
5-cyano-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl diethyl phosphate (200 mg, 0.3359 mmol) was treated with a solution of (R)-tert-butyl 4-(1-aminoethyl)piperidine-1-carboxylate (76.70 mg, 0.3359 mmol) in THF (2 mL), and diisopropylethylamine (70.22 μL, 0.4031 mmol). The reaction mixture was stirred at room temperature for 24 hours. The crude mixture was diluted with ethyl acetate and washed with aqueous NaHCO3. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography to afford the title compound as a colourless glass (188 mg, 84% yield).
Reaction SMILES: [OH:1][C:2]1[C:18]([CH3:19])=[C:17]([CH3:20])[CH:16]=[C:15]([CH3:21])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](OCC)=[O:11])=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:1][C:2]1[C:18]([CH3:19])=[C:17]([CH3:20])[CH:16]=[C:15]([CH3:21])[C:3]=1[CH:4]([OH:5])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: CCOC(=O)CCCCC(=O)c1c(C)cc(C)c(C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(O)CCCCCO)c(O)c1C

Procedure:
A solution of ethyl 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoate (formula II-1 wherein R=H3C, X=H, Y=OH, n=4, in the form of ethyl ester) (0.4 part) in tetrahydrofuran (100 volume parts) was reduced with lithium aluminum hydride (0.5 part) under warming for 1 hour. The reaction mixture was quenched with ethyl acetate followed by the addition of saturated aqueous sodium sulfate (5 volume parts) solution. After removal of the resulting inorganic salt by filtration, the filtrate was condensed in vacuo to dryness. The residue was crystallized from diethyl ether to give 1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol (formula III-3 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.32 part) as colorless needles melting at 135°-136° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:15]([CH2:14][CH:13]([N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[N:7]=2)[CH:9]=[N:10]1)[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)#[N:16]
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Cl)n2)cn1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (500.0 mg, 0.001657 mol), p-aminobenzoic acid (341 mg, 0.00248 mol), and p-toluenesulfonic acid (240 mg, 0.0014 mol) in dry 1,4-dioxane (10 mL) was refluxed overnight. The mixture was cooled to room temperature. The resulting solid was filtered, washed with dioxane, and air dried to yield the desired product as a racemic mixture (460 mg, 69%). LCMS (M+H) 403.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[N:12]=[C:13]([Cl:15])[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:15][C:13]1[CH:14]=[C:9]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)[C:10](=[O:17])[N:11]([CH3:16])[N:12]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: Nc1ccncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Yield: 69.9 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (150 mL), pyrimidin-4-amine (1.7 g, 18.0 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (4.0 g, 18.0 mmol), and cesium carbonate (11.74 g, 36.0 mmol). After bubbling nitrogen through the suspension for 30 minutes, Xantphos (1.04 g, 1.8 mmol) and tris(dibenzylideneacetone)dipalladium(0) (823 mg, 0.9 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 15 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×50 mL). The combined filtrate was concentrated and the residue was washed with acetonitrile (5 mL) to afford 263a (2.99 g, 70%) as a yellow solid. MS: [M+H]+ 238
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:21](N)=[NH:22]>C(O)C>[N:11]1([C:9]2[CH:10]=[C:2]3[C:3]([C:4](=[O:6])[NH:22][CH:21]=[N:1]3)=[CH:7][CH:8]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Nc1cc(N2CCOCC2)ccc1C(=O)O
Reactant: N=CN
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(N3CCOCC3)ccc12
Yield: 50.1 %

Procedure:
4.22 g (0.019 mol) of 2-amino-4-morpholin-4-ylbenzoic acid and 4.0 g (0.038 mol) of formamidine acetate were suspended in 40 ml of ethanol. The reaction mixture was subsequently stirred under reflux for 16 h. Conventional work-up gave 2.2 g (Y=50%) of 7-morpholin-4-yl-3H-quinazolin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10](O)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:12])[CH3:11])=[C:4]([F:9])[CH:3]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(Cl)cc1F
Product: CC(=O)Nc1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 94 %

Procedure:
As presented in the following reaction formula, anhydrous acetic acid (Ac2O; 1.7 mL) was added several times in a divided manner to a mixture of 4-chloro-2-fluoroaniline (2 g, 13.8 mmol) in acetic acid (2 mL) at room temperature (about 25° C.). The resulting reaction mixture was stirred for 2 hours. After the completion of reaction, the mixture was filtered to obtain a crude product, which was washed with hexane to obtain N-(4-chloro-2-fluorophenyl)acetamide (2.4 g, yield: 94%).
Reaction SMILES: [N:1]1C=NC=N[CH:2]=1.[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[N:11]=[CH:10][C:9]=1[C:20](O)=O.B(F)(F)F.CCOCC>CS(C)=O.CCOC(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]3=[N:7][CH:2]=[N:1][CH:20]=[C:9]3[CH:10]=[N:11]2)=[CH:14][CH:15]=1
Reactant: Nc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Reactant: c1ncncn1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Brc1ccc(-n2ncc3cncnc32)cc1
Temperature: 120 °C

Procedure:
To a solution of 1,3,5-triazine (0.575 g, 7.09 mmol) and compound 21A (2 g, 7.09 mmol) in DMSO (30 mL) was added boron trifluoride etherate (1.078 mL, 8.51 mmol). The resulting mixture was heated at 120° C. for 20 h, cooled, diluted with EtOAc and washed with 1% NaOH and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was triturated with small amount of EtOAc and the precipitate was collected to provide the desired product: 1H NMR (400 MHz, DMSO-D6) δ ppm 9.47 (1H, s), 9.16 (1H, s), 8.68 (1H, s), 8.22 (2H, d), 7.80 (2H, d).
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH3:5][C:6]1([CH3:13])[O:10][CH:9]([CH2:11][OH:12])[CH2:8][O:7]1>C1C=CC=CC=1.C(Cl)Cl>[Cl:3][C:1]([O:12][CH2:11][CH:9]1[CH2:8][O:7][C:6]([CH3:13])([CH3:5])[O:10]1)=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC1(C)OCC(CO)O1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC1(C)OCC(COC(=O)Cl)O1

Procedure:
10 ml of a 10% w/v solution of phosgene in benzene were added to a solution of 1.0 g of 2,3-isopropylideneglycerol in 5 ml of methylene chloride, and the mixture was allowed to react overnight at room temperature. The mixture was then concentrated by evaporation under reduced pressure, giving 1.47 g of the title compound as a liquid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)CCCCCBr
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of 1-(3-chlorophenyl)piperazine hydrochloride (12 g, 0.051 mol) in anhydrous toluene (250 ml) was added triethylamine (TEA) (15.6 ml, 0.112 mol) and ethyl 6-bromohexanoate (13.6 g, 0.061 mol) and the mixture heated at reflux for 4 hours. The mixture was then cooled to room temperature, washed with water (2×100 ml), brine (100 ml), dried over Na2SO4, filtered and concentrated to dryness. The residue obtained was purified by flash chromatography on silica gel using ethyl acetate/hexane (1/1) to give ethyl 6-[N′-(3-chlorophenyl)-N-piperazinyl]hexanoate (10.3 g) as a clear oil.
Reaction SMILES: C([NH:3][C@@H:4]1[C:30](=[O:31])[N:6]2[C:7]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:8]([CH2:11][S:12][CH3:13])[CH2:9][S:10][C@H:5]12)=O.[ClH:32]>>[ClH:32].[NH2:3][C@@H:4]1[C:30](=[O:31])[N:6]2[C:7]([C:14]([O:16][CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:8]([CH2:11][S:12][CH3:13])[CH2:9][S:10][C@H:5]12
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: Cl
Product: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The oil was digested in a mixture of peroxide-free tetrahydrofuran (120 ml.) and concentrated hydrochloric acid (30 ml.), and stirred at room temperature until thin-layer examination revealed that no diphenylmethyl 7β-formamido-3-methylthiomethylceph-3-em-4-carboxylate remained. This occurred after ~5 hours, during which time the hydrochloride salt crystallised out. The solution was refrigerated overnight, filtered, and the solid dried to give diphenylmethyl 7β-amino-3-methylthiomethylceph-3-em-4-carboxlate, hydrochloride (2.4 g.), m.p. 185°-192° (decomp.), λmax. (EtOH) 265 nm. (ε 6,850), [α]D - 24.9° (C 1.0, DMSO), νmax. (Nujol) 2620 (--N+H3), 1770 (β-lactam), 1711 (ester), and 702 cm-1 (phenyl), τ (DMSO-d6) 8.1 (3-proton singlet; --S--CH3), 6.25 (2-proton singlet; C-2 protons), 6.05, 6.35 (two 1-proton doublets, J = 18 Hz; 3-CH2 --S--), 4.70 (1-proton doublet, J = 5 Hz; 7-H), 4.5 (1-proton doublet, J = 5 Hz; 6-H), 2.9 (1-proton singlet; CHPh2), 2.45 (10-proton multiplet; aromatic protons). (Found: C, 57.3; H, 5.0; Cl, 7.9; N, 5.8; S, 13.1. C22H23ClN2O3S2 requires C, 57.2; H, 5.0; Cl, 7.7; N, 6.0; S, 13.8%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][O:14][C@@H:13]([CH2:16][O:17]C(=O)C3C=CC=CC=3)[O:12]2)=[C:4]([Cl:26])[N:3]=1.CO[Na].CO>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][O:14][C@@H:13]([CH2:16][OH:17])[O:12]2)=[C:4]([Cl:26])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3CO[C@@H](COC(=O)c4ccccc4)O3)c2n1
Agent: CO[Na]
Solvent: CO
Product: Nc1nc(Cl)c2ncn([C@H]3CO[C@@H](CO)O3)c2n1
Temperature: 2 °C
Reaction time: 20 h
Yield: 70.1 %

Procedure:
Benzoic acid 4(R)-(2-amino-6-chloro-purin-9-yl)-[1,3]dioxolan-2(R)-ylmethyl ester (2.4 kg, 6.3 moles) and methanol (6.24 L) were combined under inert atmosphere. 25% MeONa/MeOH (33.6 g) was added at room temperature and the reaction mixture was stirred for 16-24 hours. The reaction was monitored by HPLC for complete deprotection of the benzoate ester. The reaction mixture was cooled to 2° C. for 2 hours. The solids were collected by filtration and dried in vacuo to give the desired compound (1.2 kg, 71% yield).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][N:22]3[C:26]([CH3:27])=[N:25][N:24]=[N:23]3)[C:18]3[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.I.[OH-].[Na+]>C(O)C>[N:11]1([C:15]2[N:19]([CH2:20][CH2:21][N:22]3[C:26]([CH3:27])=[N:25][N:24]=[N:23]3)[C:18]3[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=3[N:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: Cc1nnnn1CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1CCn1c(N2CCCNCC2)nc2ccccc21
Yield: 84.4 %

Procedure:
Reflux 4-{1-[2-(5-methyl-tetrazol-1-yl)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.42 g, 0.98 mmol) in ethanol (15 mL) with 57% hydroiodic acid (5 mL) for one hour. Cool, treat with sodium hydroxide solution (final pH 13) and extract with dichloromethane (10×50 mL). Dry the combined organic phases (Na2SO4), filter and concentrate the filtrate in vacuo to afford 2-[1,4]diazepan-1-yl-1-[2-(5-methyl-tetrazol-1-yl)-ethyl]-1H-benzoimidazole (0.27 g), Rf=0.60 (silica gel, dichloromethane:methanol:ammonium hydroxide solution, 80:20:0.2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(Cl)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 4-chlorophenylboronic acid (269 mg, 1.71 mmol) the subtitle compound was obtained (323 mg, 74%). The product was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:6]3[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:5]=3[C:4]=2[CH:3]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([N:25]3[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]3)=[O:15])[C:6]3[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1CCNCC1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1CCN(C(=O)CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
A mixture of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoic acid (50 mg, 0.17 mmol), 4-methyl Piperidine (0.02 mL, 0.17 mmol), DCC (38 mg, 0.18 mmol), and DMAP (23 mg, 0.18 mmol) in dry DCM (2 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated to obtain 12 mg of 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(4-methylpiperidin-1-yl)propan-1-one as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).