Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][CH2:29]SC)[N:9]=2)[CH:7]=1.BrCC[N:39]1[CH:43]=[C:42](NC(C2C=NN3C=CC=NC=23)=O)[C:41]([C:56]2C=C(Cl)C=CC=2OC(F)F)=N1.N1C=CC=CC=1CN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][C:29]3[CH:56]=[CH:41][CH:42]=[CH:43][N:39]=3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: CSCCNCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: NCc1ccccn1
Product: O=C(Nc1cn(CCNCc2ccccn2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12

Procedure:
Using synthetic method analogous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and pyridin-2-ylmethanamine. LCMS (Method 20) [M+H]+=539.2, RT=2.53 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68 (dd, 1H, J=1.6, 4.0 Hz), 8.67 (s, 1H), 8.49 (d, 1H, J=4.0 Hz), 8.37 (s, 1H), 7.72 (dd, 1H, J=1.6, 7.6 Hz), 7.70-7.61 (m, 2H), 7.46-7.06 (m, 5H), 4.27 (t, 2H, J=6.0 Hz), 3.83 (s, 2H), 2.98 (t, 2H, J=6.0 Hz).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:23])=[C:7]([CH3:22])[C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]=2[C:20]=1[CH3:21])(=O)C.[OH-].[Na+]>O1CCCC1.CO>[CH3:13][C:11]1[O:12][C:8]2[C:7]([CH3:22])=[C:6]([CH3:23])[C:5]([OH:4])=[C:20]([CH3:21])[C:9]=2[C:10]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Oc1c(C)c(C)c2oc(C)c(-c3ccccc3)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc2c(C)c(C)c(O)c(C)c2c1-c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 2,4,6,7-tetramethyl-3-phenylbenzofuran-5-yl acetate (4.00 g, 13.0 mmol) in a mixture of tetrahydrofuran (32 mL) and methanol (8 mL) was added 8N sodium hydroxide solution (2.0 mL) dropwise and the mixture was stirred at 40° C. for 1 hour. The solvent was then distilled off under reduced pressure. To the residue was added 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether-hexane to obtain the title compound (3.0 g, yield 87%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=O)[CH:6]([CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:7]([NH:9][CH2:10][CH2:11][NH2:12])=O>C1COCC1>[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:9][CH2:10][CH2:11][NH2:12]
Reactant: NCCNC(=O)C(CCOCc1ccccc1)C(=O)NCCN
Solvent: C1CCOC1
Product: NCCNCC(CCOCc1ccccc1)CNCCN
Temperature: 40 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
N,N′-Bis-(2-aminoethyl)-2-(2-benzyloxy-ethyl)malonamide (3.80 g) was dissolved in THF (20 mL) and the flask was immersed in an ice bath. The flask was flushed with argon and THF borane complex (80 mL, 1 M in THF) was added through a syringe. The reaction mixture was allowed to warm up to room temp. and then stirred at 40° C. for 2 days and refluxed for 1 h. Methanol (50 mL) was added dropwise and the solution was stirred at 40 overnight. The solvents were removed by rotary evaporator and the residue was dissolved in methanol (20 mL). Sodium hydroxide (10 g in 15 mL of water) was added and the methanol was boiled away. A colourless oil separated that was extracted into CH2Cl2 (3×50 mL). The solution was dried over Na2SO4. Removal of the solvent gave 3.40 g of colourless oil.
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:3].[Li+].CC([N-]C(C)C)C.COB(OC)OC.[Cl:27][C:28]1[N:33]=[C:32](Cl)[CH:31]=[CH:30][N:29]=1.C(=O)(O)[O-].[Na+]>C1COCC1.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.COCCOC>[Cl:27][C:28]1[N:33]=[C:32]([C:8]2[S:7][C:6]([CH2:5][CH2:4][C:2]([CH3:1])([OH:11])[CH3:3])=[CH:10][CH:9]=2)[CH:31]=[CH:30][N:29]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(O)CCc1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: COB(OC)OC
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC(C)(O)CCc1ccc(-c2ccnc(Cl)n2)s1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution of 2-methyl-4-thiophen-2-yl-butan-2-ol (630 mg, 3.7 mmol) in 10 ml of THF was treated with LDA (4.6 ml of 2M solution in THF/heptane/ethylbenzene, 9.2 mmol) at −78° C. under nitrogen and the mixture was stirred for 5 minutes. Then, trimethylborate (1 ml, 9.2 mmol) was added in one portion and the cooling bath was removed. After 15 minutes, the mixture was quenched with 50 ml of saturated ammonium chloride solution and extracted twice with EtOAc. The combined organic extracts were washed with brine and evaporated under reduced pressure at room temperature. This crude boronic acid was redissolved in 10 ml of DME and added to a stirred suspension 2,4-dichloro-pyrimidine (275 mg, 1.85 mmol), Pd(PPh3)4 (64 mg, 0.037 mmol), 20 ml of DME and 5 ml of a 10% solution of sodium bicarbonate. This mixture was then kept at reflux (100° C. heat bath) for 90 minutes. After cooling, most of the DME was evaporated and the crude was partitioned between water and EtOAc. The organic layer was separated, washed with 0.2N-HCl, water and brine, dried over sodium sulfate and evaporated. The crude was purified by chromatography on silicagel (EtOAc/hexane:1/1). Yield: 390 mg (77%) of 4-[5-(2-Chloro-pyrimidin-4-yl)-thiophen-2-yl]-2-methyl-butan-2-ol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[OH-].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>CN(C=O)C.O>[CH:23]1([N:13]2[C:14]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15][S:16][C:12]2=[N:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: BrC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Temperature: 30 °C
Reaction time: 18 h
Yield: 26.6 %

Procedure:
A solution of 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (Method C2a; 33.2 g, 114 mmol) in DMF (1 L) was treated with NaOH (690 g, 17.3 mol) and cyclopentyl bromide (865 mL, 6.3 mol) and the resulting mixture was stirred at 20-40° C. for 18 h, then cooled to 4° C., and treated with water (1.5 L). A conc. HCl solution was added to adjust the pH to 0, and the mixture was extracted with EtOAc (80 mL). The organic phase was washed with a 1N HCl solution (1 L), dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (500 mL) and filtered through a pad of silica gel (9×4 cm). Hexane was added to the resulting solution and volatiles were slowly removed by partial vacuum until crystals formed. The solids were collected to yield 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane as yellow crystals (10.9 g, 26%): mp 118-9° C.; TLC (5% EtOAc/hex) Rf0.34.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6][CH:5]=2.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[H-].[Na+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:28][C:26]([C:23]1([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:3]3[C:4]4[C:9](=[CH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6][CH:5]=4)[C:10]([CH3:11])=[C:2]3[CH3:1])=[CH:22][CH:21]=2)[CH2:25][CH2:24]1)=[O:27]
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC1
Reactant: Cc1[nH]c2ccc(C(=O)O)cc2c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(Cn3c(C)c(C)c4cc(C(=O)O)ccc43)cc2)CC1
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a solution of 2,3-dimethyl-1H-indole-5-carboxylic acid (500 mg, 2.3 mmol) in anhydrous DMF (20 mL) was added methyl 1-(4-(bromomethyl)phenyl)cyclopropanecarboxylate (620 mg) followed by NaH (230 mg). The resulting solution was allowed to stir overnight under argon atmosphere. The remaining NaH was hydrolyzed by the careful addition of a 0.5 N HCl solution. The mixture was diluted with ethyl acetate, washed with a 0.5 N HCl solution and brine, dried on MgSO4, and concentrated. The crude residue was purified by chromatography on silica gel (Hexane/Ethyl acetate 5/5) to afford an orange powder (361 mg). ESI-MS (m/z): 378 [MH]+
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:51]([C:53]1[CH:54]=[C:55]([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH:56]=[CH:57][CH:58]=1)#[N:52]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([N:62]3[CH2:61][CH2:60][N:59]([C:55]4[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=4)[C:51]#[N:52])[CH2:64][CH2:63]3)=[O:17])[CH:12]=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: N#Cc1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(N2CCN(C(=O)c3cncc(CCc4ccccc4)c3)CC2)c1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.4 g, 1.8 mmol) in anhydrous dimethylformamide (3 ml) is treated with HATU (0.7 g, 1.8 mmol) and diisopropylethylamine (0.6 ml, 3.3 mmol). The reaction mixture is stirred 10 mins. at ambient temperature before being treated with a solution of 1-(3-cyanophenyl)piperazine (0.3 g, 1.6 mmol) in dimethylformamide (5 ml). The reaction mixture is stirred at ambient temperature for 18 hours, concentrated under vacuum and the residue partitioned between dichloromethane (2×40 ml) and saturated aqueous sodium bicarbonate (40 ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chromatographed on silica gel (ethyl acetate) to give the title compound as a yellow oil (0.33 g). 1H NMR (CDCl3, 500 MHz) δ8.82 (s, 1H), 8.61 (s, 1H), 7.90 (s, 1H), 7.58 (m, 2H), 7.39 (m, 4H), 7.16 (m, 3H), 3.95 (br m, 2H), 3.63 (br m, 2H), 3.30 (br m, 4H), EI MS M++H: 393.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH3:10][C:11]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].[Cl-].[NH4+]>C1COCC1.II.BrC1C=CC(F)=CC=1>[CH3:10][C:11]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:12]=1[CH:13]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[OH:14]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: Fc1ccc(Br)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2ccc(F)cc2)c(C)c1
Temperature: 39 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere, turnings of magnesium (16.8 g) were dispersed in THF (46 ml), and iodine (0.1 g) was added. Then, 4-bromofluorobenzene (2.1 g) was added dropwise. After confirmation of the start of the reaction, THF (242 ml) was flown in. 4-Bromofluorobenzene (113.9 g) was added dropwise at 31.8-48.9° C., and the mixture was stirred at 38-40° C. for 2 hr. The obtained mixture with a Grignard reagent was cooled and thereto was added dropwise 2,4-dimethylbenzaldehyde (81 g) at: 5-29.9° C. After the dropwise addition, the reaction mixture was stirred at 21.3-28.3° C. for 1.5 hr. A saturated aqueous ammonium chloride solution was added to stop the reaction. The reaction mixture was partitioned and the obtained organic layer was washed with saturated brine. The solvent was evaporated from the organic layer under reduced pressure to give (2,4-dimethylphenyl)-(4′-fluorophenyl)methanol (139.2 g, 100%) as a colorless oil. The obtained colorless oil was measured for 1H-NMR and found to be the same as in Example 1.
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:38]=[CH:37][C:32]([CH2:33][N:34]=[C:35]=[O:36])=[CH:31][CH:30]=1.O.C(OCC)(=O)C>CN(C)C=O.C(OCC)C.C(OCC)(=O)C.C(O)(C)C>[CH3:28][C:29]1[CH:38]=[CH:37][C:32]([CH2:33][NH:34][C:35]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]3[CH:26]=[CH:27][C:14]([C:12]4[N:13]=[C:9]([CH2:8][O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[NH:10][CH:11]=4)=[CH:15][CH:16]=3)=[CH:25][CH:24]=2)=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(CN=C=O)cc1
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CCOCC
Product: Cc1ccc(CNC(=O)Nc2ccc(Oc3ccc(-c4c[nH]c(COc5ccccc5)n4)cc3)cc2)cc1
Temperature: 100 °C
Yield: 21 %

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and 4-methylbenzylisocyanate (0.17 g, 1.12 mmol) in 3 ml of dimethylformamide is heated at 100° C. for two hours. After returning to ambient temperature 20 ml of water and 30 ml of ethyl acetate are added, followed by extraction then the organic phase is washed with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The solid obtained is stirred in 5 ml of a mixture of solvents such as ethyl ether/ethyl acetate/isopropanol 6/3/1. The solid obtained is filtered then dried. A cream-coloured powder is obtained with a yield of 21%.
Reaction SMILES: Cl[CH:2]([C:10]1[CH:22]=[C:21]2[C:13]([CH:14]=[CH:15][C:16]3[O:17][C:18](=[O:25])[C:19](C)(C)[C:20]=32)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:22]=[C:21]3[C:13]([CH:14]=[CH:15][C:16]4[O:17][C:18](=[O:25])[CH2:19][C:20]=43)=[CH:12][CH:11]=2)[N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)=[CH:4][CH:5]=1
Reactant: c1nc[nH]n1
Reactant: CC1(C)C(=O)Oc2ccc3ccc(C(Cl)c4ccc(Cl)cc4)cc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1Cc2c(ccc3ccc(C(c4ccc(Cl)cc4)n4cncn4)cc23)O1

Procedure:
A mixture of 8-(α,4-dichlorobenzyl)-1,1-dimethyl-2(1H)-naphtho[2,1-b]furanone, 1,2,4-triazole (0.3 g), potassium carbonate (0.3 g) and acetonitrile (5 ml) was heated under reflux for 18 h. The mixture was treated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried and then evaporated to dryness, and the residue was purified by flash chromatography eluting with methanol:chloroform, 1:99 v/v, to give 8-[4-chloro-α-(1H-1,2,4-triazol-1-yl)benzyl]-2(1H)-naphtho[2,1-b]furanone. Nmr in deuteriochloroform: δ8.12(2H,s); 7.94(1H,d); 7.36-7.46(4H,m); 7.15-7.25(3H,m); 6.92(1H,s); 1.62(3H,s); 1.60(3H,s).
Reaction SMILES: [BH4-].[Na+].[C:3]1([C@@H:9]([N:11]=[C:12]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH2:14][CH2:13]2)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+]>CO>[C:3]1([C@@H:9]([NH:11][C@@H:12]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:15]3([CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH2:14][CH2:13]2)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](N=C1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21)c1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](N[C@H]1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21)c1ccccc1
Temperature: 0 °C

Procedure:
At −78° C., NaBH4 (760 mg, 20 mmol) was added to a solution of the imine (B1) (7.82 g, 20 mmol) in methanol (100 ml). The reaction mixture was allowed to warm to 0° C. over 2-3 hours then treated with saturated NaHCO3 (ca. 100 ml), concentrated under reduced pressure at <30° C. to remove the solvent. The residue was extracted with ethyl acetate. The organic phase washed with water, dried over Na2SO4 and concentrated to give (S)-tert-butyl 4-((S)-1-phenylethylamino)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B2) as a solid. LC-MS: m/e=421.32 (M+H). Rt=2.20 min.
Reaction SMILES: C([O-])(=O)C.[Na+:5].[CH:6]1[CH:7]=[CH:8][C:9]([CH:12]([S:38]([OH:41])(=[O:40])=[O:39])[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]3[C:21]([C:35]([OH:37])=[O:36])=[C:22]([CH2:25][N+:26]4[CH:27]=[CH:28][C:29]([C:32]([NH2:34])=[O:33])=[CH:30][CH:31]=4)[CH2:23][S:24][C@H:17]23)=[O:14])=[CH:10][CH:11]=1>>[CH:6]1[CH:7]=[CH:8][C:9]([CH:12]([S:38]([O-:41])(=[O:39])=[O:40])[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]3[C:21]([C:35]([O-:37])=[O:36])=[C:22]([CH2:25][N+:26]4[CH:31]=[CH:30][C:29]([C:32]([NH2:34])=[O:33])=[CH:28][CH:27]=4)[CH2:23][S:24][C@H:17]23)=[O:14])=[CH:10][CH:11]=1.[Na+:5]
Reactant: NC(=O)c1cc[n+](CC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(c4ccccc4)S(=O)(=O)O)[C@H]3SC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: NC(=O)c1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(c4ccccc4)S(=O)(=O)[O-])[C@H]3SC2)cc1

Procedure:
adding about 1 equivalent of sodium acetate to the solution of cefsulodin to provide a solution of cefsulodin sodium, and
Reaction SMILES: [Br-:1].[CH2:2]([N+:5]1([CH2:12][CH:13]=[CH2:14])[CH2:11][CH2:10][CH2:9][CH2:8]C[CH2:6]1)[CH:3]=[CH2:4].[Cl-:15].[CH2:16]([NH2+:19][CH2:20][CH:21]=[CH2:22])[CH:17]=[CH2:18].[OH2:23]>Cl.Cl.N(C(C(=N)N)(C)C)=NC(C(=N)N)(C)C>[Br-:1].[CH2:12]([N+:5]1([CH2:2][CH:3]=[CH2:4])[CH2:6][CH2:8][CH:9]([OH:23])[CH2:10][CH2:11]1)[CH:13]=[CH2:14].[Cl-:15].[CH2:16]([NH2+:19][CH2:20][CH:21]=[CH2:22])[CH:17]=[CH2:18]
Reactant: C=CC[N+]1(CC=C)CCCCCC1
Reactant: O
Agent: C=CC[NH2+]CC=C
Agent: CC(C)(N=NC(C)(C)C(=N)N)C(=N)N
Agent: Cl
Product: C=CC[N+]1(CC=C)CCC(O)CC1
Temperature: 70 °C

Procedure:
N,N-diallylhomopiperidinium bromide (13.0 g, EXAMPLE 4) and diallylammonium chloride (2.7 g, EXAMPLE 7) were dissolved in 15.0 g deionized water. To this aqueous solution was added 0.5 g of 2,2′-azobis(2-amidinopropane) dihydrochloride, the reaction mixture was bubbled with a slow stream of nitrogen gas for 45 minutes. While stirring, the temperature was raised to 70° C. The reaction mixture was stirred at 70° C. for 48 hours. After cooling to room temperature, 30.0 g of viscous polymer solution was obtained.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][NH:3][CH2:2]2.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=1>>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([N:3]2[CH2:4][CH:5]3[CH2:9][CH:1]([CH2:8][NH:7][CH2:6]3)[CH2:2]2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(I)cn1
Reactant: C1NCC2CNCC1C2
Product: Clc1ccc(N2CC3CNCC(C3)C2)cn1
Yield: 10 %

Procedure:
3,7-Diazabicyclo[3.3.1]nonane, prepared as described in (Garrison, G. L. et. al., J. Org. Chem. 58, 27, (1993) 7670), and 2-chloro-5-iodopyridine were processed as described in Example 57A. The crude was purified by flash chromatography (silica gel; CHCl3:MeOH:NH4OH; 90:5:1) to provide the title compound (10% yield). MS (DCI/NH3) m/z 238 (M+H)+.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][C:6]=2Br)[CH2:4][CH2:3][CH2:2]1.[C:26]([Zn]C#N)#[N:27].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(#N)C.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]>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][C:6]=2[C:26]#[N:27])[CH2:4][CH2:3][CH2:2]1
Reactant: N#C[Zn]C#N
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(Br)cc2c1=O
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(C#N)cc2c1=O

Procedure:
A solution of EXAMPLE 82A (0.50 g), dicyanozinc (0.29 g), 2-(di-tert-butylphosphino)biphenyl (0.15 g), and tris(dibenzylideneacetone)dipalladium(0) (0.11 g) in acetonitrile (20 mL) was refluxed for 1 hour then cooled and filtered; and the filtrate was diluted with water and filtered.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.[CH:34](N(C(C)C)CC)(C)[CH3:35].C(Cl)(=O)C=C>O1CCOCC1.C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([NH:7][C:6](=[O:5])[CH:34]=[CH2:35])[CH2:13][CH2:12]2)=[CH:16][CH:17]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CC(=O)NC1CCN(Cc2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.5 %

Procedure:
[1-(4-Benzyloxycarbonylamino-benzyl)piperidin-4-yl]-carbamic acid tert-butyl ester (0.14 g, 0.32 mmol) was suspended in a 4M solution of HCl in Dioxane (5 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum and the resulting residue dissolved in THF (10 ml). To this solution was added diisopropylethylamine (0.28 ml, 1.6 mmol) was added in one portion, followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 100% DCM to 90% DCM, 10% Methanol) to give the title compound (0.012 g, 10% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:38]1[C:27]2=[CH:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])=[CH:40][CH:39]=3)=[O:24])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]2[CH:36]=[CH:37]1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2C=C3CC=CN3Cc3ccccc32)cc1)c1ccccc1F
Reaction time: 0.05 h
Yield: 88.4 %

Procedure:
To a solution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo-[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give 620 mg of the desired product as a crystalline solid, m.p. 257°-260° C.