Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[OH:11][C:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(O)n(-c2cccc(OC)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(-n2nc(C(=O)O)cc2O)c1

Procedure:
To a solution of 300 mg of 5-Hydroxy-1-(3-methoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester in 5 ml of THF, 1 ml of a 1 M aqueous NaOH solution was added. After 3 h the reaction was acidified to pH 1 with diluted aqueous hydrochloric acid and the organic solvents was removed under reduced pressure. The precipitated product was collected by filtration and was used in the subsequent reaction. Yield: 267 mg.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)/[CH:7]=[N:8]/[OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:22][CH:23]([C:26]#[N:27])[C:24]#[N:25]>CC(O)C>[NH2:27][C:26]1[C:23]([C:24]#[N:25])=[N:22][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][N+:8]=1[O-:9]
Reactant: O=C(/C=N/O)c1ccco1
Reactant: N#CC(N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: N#Cc1nc(-c2ccco2)c[n+]([O-])c1N
Temperature: 25 °C
Reaction time: 70 h
Yield: 92 %

Procedure:
A mixture of (E)-2-(furan-2-yl)-2-oxoacetaldehyde oxime 54 (2.52 g, 18.12 mmol) and aminomalononitrile p-toluenesulfonate (4.59 g, 18.12 mmol) in 2-Propanol (35 mL) was stirred at rt for 70 h. Cooled down with ice bad with stirring. The resulting precipitate was collected by filtration, washed with 2-propanol and dried to give 2-amino-3-cyano-5-(furan-2-yl)pyrazine 1-oxide 55 (3.37 g, 92%). NMR (400 MHz, DMSO-d6) 6.65 (m, 1H), 7.10 (m, 1H), 7.83 (m, 1H), 8.09 (br s, 2H), 8.87 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]#[N:26].[H-].[Na+]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]#[N:26])[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: N#CCCl
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC#N)C3=O)CC2)cc1
Temperature: 70 °C

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (1.65 mmol, 500 mg) and chloroacetonitrile (1.65 mmol, 0.125 g) in THF (30 mL) and DMF (5 mL) was added sodium hydride (60%, 2.48 mmol, 0.099 g) and heated to 70° C. for 30 min. The reaction was allowed to cool to ambient temperature and dried under vacuum. Flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate and provided the title compound as an off-white residue (125 mg, 22.1% yield). Calculated MS=341.4. found MS (ESI) m/e 342.9 (M+H+); HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.472 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1)[CH3:2].N1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:8][N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N)cn1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)OCc2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of ethyl(5-aminopyridin-2-yl)acetate (2.0 g) in tetrahydrofuran (30 mL) were successively added pyridine (2.7 mL) and benzyl chloroformate (1.9 mL) in an ice bath, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.6 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N:30]1[N:31]=[CH:32][N:33]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][N:41]([C:38]3[CH:37]=[CH:36][C:35]([N:33]4[CH:34]=[N:30][N:31]=[CH:32]4)=[CH:40][CH:39]=3)[C:42](=[O:44])[CH3:43])[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: CC(=O)Nc1ccc(-n2cnnc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(-n2cnnc2)cc1
Temperature: 50 °C

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate (60 mg, 0.14 mmol) from Example 5 step 1 and N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide (30.6 mg, 0.15 mmol) were added in DMF (0.7 mL), then cesium carbonate (224 mg, 0.69 mmol) was added and the reaction was heated to 50° C. overnight. The reaction was cooled to room temperature, water (10 mL) was added and extracted with ethyl acetate (20 mL), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™silica gel cartridge eluting with 50% acetone/hexanes to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:52]=[CH:51][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28](=[O:35])[N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][C:19]=3[N:18]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([N:45]4[CH2:49][CH:48]=[CH:47][CH2:46]4)=[O:44])=[CH:39][CH:38]=3)[C:17](=[O:50])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.C=O.[C:55](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([N:29]4[CH2:34][CH2:33][N:32]([CH3:55])[CH2:31][CH2:30]4)=[O:35])=[CH:25][C:19]=3[N:18]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([N:45]4[CH2:46][CH:47]=[CH:48][CH2:49]4)=[O:44])=[CH:39][CH:38]=3)[C:17](=[O:50])[CH2:16]2)=[O:14])=[CH:51][CH:52]=1
Reactant: CC(=O)O
Reactant: O=C(CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2)N1CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C(=O)CCc2ccc3c(c2)N(Cc2ccc(C(=O)N4CC=CC4)cc2)C(=O)CN(C(=O)c2ccc(Cl)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mg (0.014 mmol) of 4-(4-chlorobenzoyl)-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-8-[3-oxo-3-(1-piperazinyl)propyl]-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on trifluoroacetate was dissolved in 2 ml of dichloromethane. 5 mg of paraformaldehyde and 0.005 ml (0.09 mmol) of acetic acid were added to the obtained solution and they were stirred at room temperature for 30 minutes. 24 mg (0.12 mmol) of sodium triacetoxyborohydride was added to the obtained mixture and they were stirred at room temperature overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: O1C=CC=C1C=O.[OH-].[K+].[N+](C[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=O)#[C-].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C@@H:25]1[O:29][CH:28]=[N:27][C@H:26]1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>CO>[CH:16]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:19][CH:18]=2)[C:21]([C@@H:25]2[O:29][CH:28]=[N:27][C@H:26]2[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:13][N:15]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C@@H:25]1[O:29][CH:28]=[N:27][C@H:26]1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: O=C([C@@H]1N=CO[C@H]1c1ccco1)N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O=Cc1ccco1
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1cncc2ccccc12)N1CCCC1

Procedure:
BLE 04136C was prepared in accordance with method D using 2-furaldehyde (0.449 mL, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue was purified by column chromatography on silica (cyclohexane:EtOAc=100:0 to 0:100) to led, after evaporation, to trans-(5-(furan-2-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin-1-yl)methanone BLE 04136D as a yellow pale oil (0.742 g, 58.5% yield).
Reaction SMILES: [CH:1]1([CH:4]2[CH2:8][CH:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[CH:6]([CH3:16])[NH:5]2)[CH2:3][CH2:2]1.Br[CH:18]([OH:20])[CH3:19]>>[ClH:15].[OH:20][CH2:18][CH2:19][N:5]1[CH:6]([CH3:16])[CH:7]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH2:8][CH:4]1[CH:1]1[CH2:3][CH2:2]1
Reactant: CC(O)Br
Reactant: CC1NC(C2CC2)CC1c1ccc(Cl)cc1
Product: CC1C(c2ccc(Cl)cc2)CC(C2CC2)N1CCO
Product: Cl
Yield: 65.6 %

Procedure:
The procedure of Example XXXV using 15 g of 2-cyclopropyl-4-(p-chlorophenyl)-5-methyl-pyrrolidine and 8.8 g of bromoethanol gives 6.6 g of N-hydroxyethyl-2-cyclopropyl-4-(p-chlorophenyl)-5-methylpyrrolidine hydrochloride as white crystals after recrystallisation from ethyl acetate -- acetone (50:50). Melting point = 175°-180° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]1[O:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:6].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:38]([O:37][C:35]([CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]1[O:14][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:6])=[O:36])[CH3:39]
Reactant: O=C(c1cccc(O)c1)N1CCCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc(C(=O)N2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of 1-(3-hydroxybenzoyl)-2-(4,5-diphenyl-2-oxazolyl)piperidine (100 mg), ethyl bromoacetate (61 mg), and K2CO3 (84 mg) in acetonitrile (1.0 ml) was stirred at room temperature overnight and partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 1-[3-(ethoxycarbonylmethoxy)benzoyl]-2-(4,5-diphenyl-2-oxazolyl)piperidine (90 mg) as a colorless oil.
Reaction SMILES: C([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([O:30][CH3:31])=[C:14]([O:19][CH:20]3[CH2:29][CH2:28][C:23]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:22][CH2:21]3)[CH:15]=2)[N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[O:18]=[C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:30][CH3:31])=[C:14]([O:19][CH:20]3[CH2:21][CH2:22][C:23]4([O:24][CH2:25][CH2:26][O:27]4)[CH2:28][CH2:29]3)[CH:15]=2)[N:10]=[CH:9][NH:8]1
Reactant: [H][H]
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1OC1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2nc[nH]c(=O)c2cc1OC1CCC2(CC1)OCCO2

Procedure:
16.0 g 3-benzyl-3,4-dihydro-4-oxo-6-(1,4-dioxa-spiro[4,5]decan-8-yl-oxy)-7-methoxy-quinazoline in 150 ml glacial acetic acid are hydrogenated in the presence of 1.6 g palladium on activated charcoal (10% Pd) at 60° C. and at a hydrogen pressure of 50 psi. The catalyst is filtered off and the filtrate is evaporated down, combined with toluene and evaporated down again. The residue is mixed with water and made slightly alkaline with saturated sodium hydrogen carbonate solution. The precipitate is suction filtered and dried.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:27]=2[S:28][C:29]=1[CH2:30][CH3:31])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:35]=[CH:34][C:33]([O:36][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=34)=[CH:32][C:27]=2[S:28][C:29]=1[CH2:30][CH3:31])=[O:24]
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@H]5COC)sc34)ccc2c1C(=O)NC
Yield: 9.8 %

Procedure:
This material was prepared by reacting 7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 2a (155 mg, 0.5 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (141 mg, 0.60 mmole) and Cs2CO3 (488 mg, 1.5 mmole) in a manner analogous to that described for example 1 to give a yellow solid (25 mg, 10%). 1H NMR (DMSO-d6, 300 MHz), δ 8.59 (1H, d, J=5.56 Hz), 8.33 (1H, d, J=4.55 Hz), 8.03 (1H, s), 7.99 (1H, d, J=2.02 Hz), 7.81 (1H, d, J=8.59 Hz), 7.33 (1H, dd, J=2.27, 8.84 Hz), 6.77 (1H, d, J=5.56 Hz), 4.31 (1H, br s), 3.90–3.81 (2H, m), 3.37–3.15 (2H, m), 3.37 (3H, s), 3.00 (2H, q, J=7.41 Hz), 2.83 (3H, d, J=4.55 Hz), 2.09–1.84 (4H, m), 1.28 (3H, t, J=7.58 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([N+:15]([O-])=O)[CH:14]=[C:8]2[CH2:7]1)[CH3:5].[H][H]>CCO.[Pd]>[CH3:1][O:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][N:9]2[N:12]=[C:13]([NH2:15])[CH:14]=[C:8]2[CH2:7]1)[CH3:5]
Reactant: [H][H]
Reactant: COCC(C)N1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: COCC(C)N1CCn2nc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of 300a (600 mg, 2.5 mmol) in EtOH (40 mL) was added Pd/C (10%, 60 mg). The reaction mixture was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE®. The filtrate was concentrated reduced pressure to afford 300b as a yellow solid (467 mg, 89%), which was used without further purification. MS-ESI: [M+H]+ 211.1
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10](=[O:26])[N:11]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:13][CH:14]=1.Cl[C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29].[Cl-].[O:41]=[C:42]1[NH:46][C:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:44][N:43]1[CH:53]1[CH2:58][CH2:57][NH2+:56][CH2:55][CH2:54]1>O1CCCC1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[N:11]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:26])[C:9]([NH:8][C:28]([N:56]2[CH2:57][CH2:58][CH:53]([N:43]3[CH:44]=[C:45]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[NH:46][C:42]3=[O:41])[CH2:54][CH2:55]2)=[O:29])=[CH:14][CH:13]=1
Reactant: Nc1ccc(-c2ccccc2Cl)n(CC2CC2)c1=O
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CC[NH2+]CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccccc2Cl)n(CC2CC2)c1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
Triethylamine (9 μL, 0.062 mmol) was added to a solution of amino-6-(2-chlorophenyl)-1-(cyclopropylmethyl)pyridin-2(1H)one (17 mg, 0.062 mmol) and 4-nitrophenyl chloroformate (13 mg, 0.062 mmol) in tetrahydrofuran (2 mL) at 0° C. After 0.5 h, 4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidinium chloride (20 mg, 0.071 mmol) and triethylamine (0.030 mL, 0.215 mmol) were added and the mixture allowed to warm to ambient temperature. After 2 h, the mixture was concentrated in vacuo. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) followed by reverse phase HPLC(C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (5 mg). MS 544.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15]([CH3:22])([CH3:21])[CH:14]=[C:13]4[CH3:23])[CH:10]([OH:24])[O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1.[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>>[CH2:27]([O:24][CH:10]1[C:11]2=[C:12]3[C:17](=[CH:18][CH:19]=[C:20]2[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9]1)[NH:16][C:15]([CH3:21])([CH3:22])[CH:14]=[C:13]3[CH3:23])[CH:26]=[CH2:25]
Reactant: C=CC[Si](C)(C)C
Reactant: COc1cccc2c1-c1ccc3c(c1C(O)O2)C(C)=CC(C)(C)N3
Product: C=CCOC1Oc2cccc(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3

Procedure:
treating 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol with allyltrimethylsilane and a Lewis acid to provide 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline; and
Reaction SMILES: C(OC(=O)[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27](=[O:42])[N:28]=[C:29]3[NH:34][C:33]([C:35]4[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=4)=[CH:32][N:30]3[CH:31]=2)=[CH:22][CH:21]=1)[CH2:8][CH2:9][CH2:10][NH:11]C(OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:52]>>[ClH:52].[NH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:27](=[O:42])[N:28]=[C:29]3[NH:34][C:33]([C:35]4[CH:36]=[CH:37][C:38]([Br:41])=[CH:39][CH:40]=4)=[CH:32][N:30]3[CH:31]=2)=[CH:24][CH:25]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1ccc(-c2cn3cc(-c4ccc(Br)cc4)[nH]c3nc2=O)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCCNCc1ccc(-c2cn3cc(-c4ccc(Br)cc4)[nH]c3nc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
{4-[2-(4-Bromo-phenyl)-7-oxo-1,7-dihydro-imidazo[1,2-a]pyrimidin-6-yl]-benzyl}-(3-tert-butoxycarbonylamino-propyl)-carbamic acid tert-butyl ester (100 mg, 0.153 mmol) was dissolved in CH2Cl2 (5 mL), TFA (1 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated and 3 mL of 0.6 N HCl and 2 mL of acetonitrile were added and stirred for 0.5 h, concentrated to a ca. 3 mL and lyophilized to give the title compound (80 mg, 100%). 1NMR (300 MHz, CD3OD): δ 8.99 (s, 1H), 8.24 (s, 1H), 7.75 (m, 8H), 4.30 (s, 2H), 3.32 (t, J=8.1 Hz, 2H), 3.09 (t, J=7.5 Hz, 2H), 2.17 (m, 2H). LCMS (EI) m/z: 454 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:13])[CH:9]=2)[CH2:4]1.CCCCCC.C(O)(C)C.C(NCC)C>>[CH3:1][N:2]([CH3:14])[C@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:13])[CH:9]=2)[CH2:4]1.[CH3:1][N:2]([CH3:14])[C@@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:13])[CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CCc2cc(N)ccc2C1
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: CCNCC
Product: CN(C)[C@@H]1CCc2cc(N)ccc2C1
Product: CN(C)[C@H]1CCc2cc(N)ccc2C1

Procedure:
N2,N2-dimethyl-1,2,3,4-tetrahydronaphthalene-2,6-diamine was optically resolved with CHIRALPAK AD-H (20 mm×250 mm) (hexane/isopropanol/diethylamine=80/20/0.1) to obtain 57.4 mg of (2S*)—N2,N2-dimethyl-1,2,3,4-tetrahydronaphthalene-2,6-diamine as a white solid, and 52.9 mg of (2R*)—N2,N2-dimethyl-1,2,3,4-tetrahydronaphthalene-2,6-diamine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=S)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1>CC(C)=O.[Ni]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=S)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ni]
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A suspension of Raney® 2800 nickel (3 big spatula, pre-washed with H2O, MeOH and acetone) in acetone (50 mL) was stirred at refluxing for 1 h. Triacetate 77 (0.93 g, 2.03 mmol) was subsequently added into the above suspension at reflux. The mixture was stirred for 5 min, cooled to room temperature over 30 min. The reaction was quenched by bubbling H2S (g) into the mixture for 2 h. The resulting mixture was filtered through a short pad of Celite® and washed with EtOH. The filtrate was concentrated and purified by flash column chromatography (silica, MeOH/CHCl3=1-2%) to afford 0.52 g (60%) of 78 as a white solid: mp 121-123° C.; 1H (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 6.93 (s, 2H), 6.03 (d, J=3.6 Hz, 1H), 5.93 (dd, J=6.4, 3.6 Hz, 1H), 5.58 (t, J=6.0 Hz, 1H), 4.38 (dd, J=11.6, 3.6 Hz, 1H), 4.26 (m, 1H), 4.11 (q, J=6.0 Hz, 1H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+ m/z 427.2. Elemental Analysis calc'd for C16H18N4O8S.0.5 CH3OH.0.25H2O: C, 44.34; H, 4.62; N, 12.54; S 7.17. Found: C, 44.54; H, 4.88; N, 12.16; S, 7.17.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][C:32]=3[CH3:33])=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[C:34]([C:36]1[CH:37]=[C:38]([CH:55]=[CH:56][C:57]=1B1OC(C)(C)C(C)(C)O1)[C:39]([N:41]1[CH2:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:43][CH2:42]1)=[O:40])#[N:35].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.O>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([C:57]2[CH:56]=[CH:55][C:38]([C:39]([N:41]3[CH2:47][CH2:46][CH2:45][N:44]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:43][CH2:42]3)=[O:40])=[CH:37][C:36]=2[C:34]#[N:35])=[N:3][C:4]=1[C:23]1[O:24][C:25]([C:28]2[S:29][CH:30]=[CH:31][C:32]=2[CH3:33])=[N:26][N:27]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccsc1-c1nnc(-c2nc(Br)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C#N)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccsc1-c1nnc(-c2nc(-c3ccc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)cc3C#N)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o1
Temperature: 75 °C
Yield: 60.2 %

Procedure:
tert-Butyl N-[5-bromo-3-[5-(3-methyl-2-thienyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (13.52 g, 25.12 mmol) and tert-butyl 4-[3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-1,4-diazepane-1-carboxylate (11.44 g, 25.12 mmol) were taken up in DMF (160 mL) and Na2CO3 (37.68 mL of 2 M, 75.36 mmol) (4:1 mixture) and reaction mixture degassed with nitrogen and Pd (tBu3P)2 (1.027 g, 2.010 mmol) added in one portion. The resulting mixture was heated at 75° C. 2.5 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The organic extracts were washed with water (1×100 mL) and brine (1×100 mL) and then the aqueous layers back extracted with ethyl acetate (3×100 mL), dried over MgSO4, filtered and concentrated in vacuo. The material was passed through a silica pad eluting with 50-100% EtOAc/Petroleum ether. The material was purified further by column chromatography on silica (500 mL) eluting with 30-100% EtOAc/petroleum ether. Product fractions were combined and concentrated in vacuo to leave the product as a yellow solid (11.9 g, 55% yield)