Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:46])[NH:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:47])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.Cl.Cl.Cl.[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:57][N:56]([CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C>CN(C)C=O>[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:55][N:56]([CH:58]2[CH2:63][CH2:62][N:61]([C:10]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)=[O:46])[CH2:36][CH2:37]5)=[O:34])=[C:28]([F:47])[CH:27]=4)[CH:22]=[CH:21][N:20]=3)=[O:11])[CH2:60][CH2:59]2)[CH2:57]1
Reactant: CN(C)C1CN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccccc6)CC5)c(F)c4)ccn3)CC2)C1
Reaction time: 120 h
Yield: 25.2 %

Procedure:
To a solution of [4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) in N,N-dimethylformamide (2.0 ml) were added 4-(3-dimethylaminoazetidin-1-yl)piperidine trihydrochloride (181 mg) and triethylamine (0.259 ml) at room temperature, followed by stirring for 5 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (24.0 mg, 25%).
Reaction SMILES: [CH3:1][C:2](=[CH2:31])[CH2:3][C@:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1>[Pd].O1CCCC1.[H][H]>[CH2:3]([C@:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]([CH3:31])[CH3:1]
Reactant: C=C(C)C[C@@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3nnc(C)o3)cc2)C(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc(C(C)N3CC[C@@](CC(C)C)(c4ccccc4)OC3=O)cc2)o1

Procedure:
A mixture of (S)-6-(2-methyl-allyl)-3-{(S)-1-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one (48 mg; isomeric mixture from Intermediate X) and palladium on carbon (10 mg) in tetrahydrofuran (10 mL) was shaken in hydrogen atmosphere (50 psi) at room temperature for 6 h. Then, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 99:1->95:5) to afford the title compound as a colorless resin-like solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[S:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[S:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: O=Cc1cc2c(cn1)OCCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccc2ncc(=O)n3c2n1C[C@@H]3CN1CCC(NCc2cc3c(cn2)OCCS3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
Racemic 2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j)) (360 mg, 1.195 mmol) was stirred with 2,3-dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 60) (195 mg, 0.9 eq.) in chloroform:methanol (9:1, v:v, 15 ml) at room temperature for 30 mins; the mixture was then treated with sodium triacetoxyborohydride (760 mg, 3.0 eq.) with vigorous stirring at room temperature for 30 mins. The reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 5 mins. The organic phase was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica (eluting with 0-12% (2M ammonia in methanol) in DCM, appropriate fractions were combined and evaporated under reduced pressure to give the free base of the title compound as a pale yellow foam (235 mg, 42%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[CH2:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: CCn1nc2c(c1-c1ccc(C(C)C)cc1)CCNCC2
Yield: 93.2 %

Procedure:
The title compound (131 mg) was prepared according to Example 193 using 205 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 245 mg of 4-isopropylphenylboronic acid. MS (ESI): exact mass calculated for C18H25N3, 283.20; found, m/z 284.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.48-7.46 (m, 2H), 7.34-7.33 (m, 2H), 4.12 (q, J=7.3 Hz, 2H), 3.50-3.45 (m, 2H), 3.36-3.33 (m, 2H), 3.27-3.25 (m, 2H), 3.01 (m, 1H), 2.87-2.85 (m, 2H), 1.34 (t, J=7.3 Hz, 3H), 1.31 (d, J=6.9 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:24](OC)(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[SH:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:32]=[C:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[S:27][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])=[O:16])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: C[Si](C)(C)CCOC(=O)CCCCCCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)CCCCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 50.7 %

Procedure:
2-(Trimethylsilyl)ethyl 7-(6-cyano-2-pyridyl)heptanoate (0.52 g, 1.6 mmol) and methyl thiosalicylate (0.43 g, 2.5 mmol) were dissolved in toluene (2 ml), and triethylamine (0.44 ml, 2.3 mmol) was added thereto. The reaction mixture was refluxed for 16 hrs and subjected to a silica gel (35 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (0.38 g, 27%) as a yellow oil.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[N:20][C:19]=2[C:18]([O:25]C)=[C:17]2[CH:27]([OH:39])[N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:29](=O)[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:28]2[C:27](=[O:39])[C:17]3[C:16](=[C:15]([O:14][CH3:1])[C:24]4[N:23]=[CH:22][CH:21]=[N:20][C:19]=4[C:18]=3[OH:25])[CH2:29]2)=[CH:33][CH:34]=1
Reactant: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Into a flask containing 5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one 247a (20 mg, 0.038 mmol, 1 equiv.) was added CH2Cl2 (1 mL) under a nitrogen atmosphere. Triethylsilane (200 μL) was added followed by trifluoroacetic acid (200 μL). The reaction was allowed to stir for 1 hour and then concentrated in vacuo until thoroughly dried. To the oil was Hexanes/Ethyl ether (15 mL, 1/1 ratio) and sonicated. The resulting solid was then filtered, washed in hexanes, and air dried to give 7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one 248 (38%, 7.2 mg, 0.0.14 mmol). 1H NMR (300 MHz) CDCl3 δ 8.95 (d, J=13.8 Hz, 2 H), 7.23-7.27 (m, 2 H), 6.96-7.05 (s, 2 H), 4.79 (2 H), 4.55 (s, 2 H), 4.14 (s, 3 H). 19F NMR (300 MHz) CDCl3 δ 62.80. MS: 340.1 (M+1)
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(OC(OCC)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=1)C.O>C(O)CCC.Cl>[ClH:1].[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:17]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[CH:20][CH:21]=1)[CH:27]=[CH2:28]
Reactant: C=CCOc1ccc(OCC(OCC)OCC)cc1
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: C=CCOc1ccc(OC2NCCc3cc(O)c(O)cc32)cc1
Yield: 98.6 %

Procedure:
A solution of 3,4-dihydroxyphenethylamine hydrochloride (3.3 g) and (4-allyloxyphenoxy)acetaldehyde diethyl acetal (5.2 g) in a mixture of n-butanol (45 ml), water (12 ml) and concentrated hydrochloric acid (2 drops) was refluxed for 4 hours. After the reaction, the reaction mixture was concentrated to dryness. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixed solvent of 99% ethanol and ether to give 1-(4-allyloxyphenoxy)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (6.0 g), mp 114° to 116°C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[O:64])[C:27]([NH:29][CH:30]2[C:62](=[O:63])[N:32]3[C:33]([C:46]([O:48][CH:49]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[O:47])=[C:34]([CH:37]=[CH:38][S:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.O1CCCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]([OH:64])[C:27]([NH:29][CH:30]2[C:62](=[O:63])[N:32]3[C:33]([C:46]([O:48][CH:49]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[O:47])=[C:34]([CH:37]=[CH:38][S:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cccnc3)CS[C@H]12)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C=CSc2cccnc2)CS[C@@H]2C(NC(=O)C(O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
To a solution of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)glyoxylamido]-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (3.1 g) in a mixture of methanol (16 ml) and tetrahydrofuran (16 ml) was added sodium borohydride (0.033 g) under ice-cooling and the mixture was stirred for 10 minutes. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid and extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-hydroxyacetamido]-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate (trans isomer) (2.84 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[C:5]([N:7]([C:21]([CH3:25])([CH3:24])[CH:22]=[O:23])[NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH2:18][CH3:19])=[O:6].[O-:30][Mn](=O)(=O)=O.[K+].[OH-].[Na+].CCO>>[CH3:29][C:27]1[CH:26]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:28]=1)[C:5]([N:7]([C:21]([CH3:24])([CH3:25])[C:22]([OH:30])=[O:23])[NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[CH2:18][CH3:19])=[O:6]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCc1c(OC)cccc1C(=O)NN(C(=O)c1cc(C)cc(C)c1)C(C)(C)C=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(OC)cccc1C(=O)NN(C(=O)c1cc(C)cc(C)c1)C(C)(C)C(=O)O

Procedure:
2-[N-(3,5-Dimethyl-benzoyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazino]-2-methyl-propionic acid was prepared by oxidation of 2-ethyl-3-methoxy-benzoic acid N′-(3,5-dimethyl-benzoyl)-N′-(1,1-dimethyl-2-oxo-ethyl)-hydrazide with KMnO4. The corresponding ester could not be saponified to the acid shown, even with 40% NaO/CH3OH, or 50% aqueous NaOH+EtOH with reflux.
Reaction SMILES: Cl[CH2:2][CH:3]=O.C([O:9][C:10](=[O:27])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[CH:15][C:14]([NH2:26])=[N:13][CH:12]=1)(C)(C)C>CCO.CCOC(C)=O>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:16]2[C:11]([C:10]([OH:9])=[O:27])=[CH:12][N:13]3[CH:2]=[CH:3][N:26]=[C:14]3[CH:15]=2)=[C:19]([Cl:25])[CH:20]=1
Reactant: O=CCCl
Reactant: CC(C)(C)OC(=O)c1cnc(N)cc1Nc1ccc(Br)cc1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1cn2ccnc2cc1Nc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
Chloroacetaldehyde (12 μL, 0.188 mmol) was added to a mixture of 6-amino-4-(4-bromo-2-chlorophenylamino)-nicotinic acid tert-butyl ester (42) (50 mg, 0.125 mmol) in EtOH (630 μL). After stirring the reaction mixture at 80° C. for 5 hours, an additional 12 μL of chloroacetaldehyde were added and heating was continued for 10 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc to give a cloudy semi-solution. The organic layer was washed with water, saturated NaHCO3 and brine. The organic layer contains a precipitate, which was collected by filtration to give the desired product (43) (15 mg, 33%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:9]([CH3:10])[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[N:6]=2)[CH2:2]1.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O.CCOC(C)=O>[Cl:15][C:16]1[N:17]=[C:18]([CH3:23])[N:19]=[C:20]([N:1]2[CH2:4][CH:3]([C:5]3[N:9]([CH3:10])[C:8]4[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=4[N:6]=3)[CH2:2]2)[CH:21]=1
Reactant: Cn1c(C2CNC2)nc2ccccc21
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
Intermediate 1 (8.2 g, 43.8 mmol), 4,6-dichloro-2-methylpyrimidine 2-1 (8.2 g, 50.4 mmol) and Cs2CO3 (21.4 g, 65.7 mmol) were suspended in DMA (100 mL) and the mixture was stirred at 50° C. for 3 h. The mixture was cooled to rt, diluted with EtOAc (200 mL), and washed sequentially with water, brine, and water (150 mL each). The combined aqueous phase was back extracted with EtOAc (2×100 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to give a brownish solid. The solid was triturated with a diethyl ether/DCM mixture (95/5) and then filtered and dried under vacuum to give Intermediate 3 as a light brown solid (10.2 g, 74%). MS: m/z=314.2 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][CH:5]2[O:9][CH2:8][CH2:7][O:6]2)[CH2:20][CH2:19]1
Reactant: ClCCCC1OCCO1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCC2OCCO2)CC1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A solution of 5.4 g of 2-(3-chloropropyl)-dioxolan and 15.9 g of 1-(2-methoxyphenyl)-piperazine in 60 ml of dimethylformamide was stirred at 80° C. for 4 hours. After cooling to 20°-25° C., the reaction mixture was poured into 500 ml of ice cold 0.5N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and dried on anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane:ethanol (95:5). 9.8 g of 2-{3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl}-dioxolan was obtained as an oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1/[CH:11]=[N:12]\[S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14].C1(C)C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:32]=1[Cl:33]>O>[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:11]([C@H:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[O:1]2)[NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: CC(C)(C)[S@](=O)/N=C\[C@H]1COC2(CCCCC2)O1
Reactant: Clc1ccc([Mg]Br)cc1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Cl)c(Cl)c1)[C@H]1COC2(CCCCC2)O1
Temperature: 0 °C
Yield: 58.7 %

Procedure:
To a solution of 248 (2.0 g, 7.3 mmol) and toluene (30 mL) cooled to −78° C. was added (3,4-dichlorophenyl)magnesium bromide (29 mL, 15 mmol) and warmed to 0° C. for 30 min. The reaction was poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a hexane/EtOAc gradient (4:1 to 1:1) to afford 1.8 g (59%) of (S)—N—((S)-(3,4-dichlorophenyl)((S)-1,4-dioxaspiro[4.5]decan-2-yl)methyl)-2-methylpropane-2-sulfinamide (250) which appears to be a ca. 10:1 mixture of diastereomers by 1H NMR.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([N:9]([CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(NCCCn1ccnc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N(CCCn1ccnc1)Cc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 4.58 g. of N-[3-(1H-imidazol-1-yl)propyl]benzamide, 40 ml. of dimethylformamide, and 0.96 g. of 50% sodium hydride in oil was stirred for 2 hours and 2.62 g. of benzyl bromide was added. The mixture was stirred for 24 hours, concentrated to remove the dimethyl formamide, diluted with water and methylene chloride, and the layers separated. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The oil was twice washed with hexane and again concentrated. The desired product was obtained as an oil.
Reaction SMILES: Cl.[NH2:2]O.[Br:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH:16]=O)=[CH:10]2>CS(C)=O.C(OCC)(=O)C>[Br:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([C:16]#[N:2])=[CH:10]2
Reactant: NO
Reactant: O=Cc1ccc2c(Br)cc(F)cc2c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(Br)cc(F)cc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
Hydroxylamine hydrochloride (0.5 g, 7.9 mmol) was added to a solution of 32 (1.0 g, 4.0 mmol) in DMSO (5.0 mL), and the mixture was stirred for 16 h at 100° C. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL), and washed with saturated NaHCO3 aqueous solution (2×50 mL). The organic was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, and purified by column chromatography to give 5-bromo-7-fluoro-2-naphthonitrile (33) (28%). 1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.29 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.77 (dd, J=8.0, 2.3 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H). GC-MS (ES) for C11H5BrFN [M+1]+ 250.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)C(C)(C)C)CC1
Temperature: 60 °C

Procedure:
To 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butylester (480 mg, 2.1 mmol) dissolved in dry DMF (10 ml) was added NaH (120 mg, 3.0 mmol, 55-65% in mineral oil) and the mixture was warmed to 60° C. for 2 h. The mixture was allowed to cool to rt and then pivaloyl chloride (0.1.6 ml, 1.3 mmol) was added. The reaction was allowed to stir over night and then poured into water and the mixture was extracted with ether. The combined organic phases were washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and the oily residue was purified by Flash column chromatography (SiO2; heptane/EtOAc 70:30) to yield 4-(2,2-dimethylpropionyloxymethyl)piperidine-1-carboxylic acid t-butyl ester as an oil. Deprotection of 4-(2,2-dimethylpropionyloxymethyl)piperidine-1-carboxylic acid t-butyl ester was conducted using the method (CH2Cl2:TFA; 1:1) to yield the title compound as an oil (85 mg, 0.43 mmol, 33 %). This crude was used without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1=[O:9].C(N(CC)C(C)C)(C)C.[CH3:19][C:20]([O:23][C:24]([N:26]1C(C2C=CC(C#N)=CC=2)O1)=[O:25])([CH3:22])[CH3:21]>ClCCl>[C:20]([O:23][C:24](=[O:25])[NH:26][N:6]1[CH2:7][CH2:8][N:3]([CH3:2])[C:4](=[O:9])[CH2:5]1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Reactant: CN1CCNCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(NC(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
Methyl-2-piperazinone hydrochloride (1:1) (300 mg, 1.99 mmol) was combined with dichloromethane (20 mL) to give a light yellow suspension. N,N-Diisopropylethylamine (309 mg, 417 μl, 2.39 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (441 mg, 1.79 mmol) in dichloromethane (10 mL) was added during 35 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 5 g, ethyl acetate/n-heptane 1/1) to give the title compound (67 mg, 15%) as white solid; GC-MS (EI) 229.0 (M)+.