Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][CH2:8][C:9]#[CH:10])[CH3:5])[CH3:2].C([Li])CCC.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:6][CH2:7][CH2:8][C:9]#[C:10][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH3:5])[CH3:2]
Reactant: C#CCCOC(C)OCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C)OCCC#CC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The product from Example 31A (79.99 g, 0.563 mole) in tetrahydrofuran (1 L) was treated dropwise at −78° C. with n-butyllithium (2.5 M in hexane, 0.563 mole, 225 mL). The reaction mixture was stirred at −78° C. for 30 minutes and then benzyl chloroformate (0.563 mole, 80.4 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hours, allowed to warm to ambient temperature and stirred overnight. After quenching with water, ethyl acetate was added and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and concentrated. Flash chromatography of the residue (silica, hexane to hexane:ethyl acetate, 30:1 to 4:1) provided the title compound as a colorless oil (155.5 g, 78%).
Reaction SMILES: C([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>Cl>[CH3:21][C:19]1[N:20]=[C:16]([NH:15][C:10]2[C:9]([OH:8])=[CH:14][CH:13]=[CH:12][N:11]=2)[S:17][CH:18]=1
Reactant: Cc1csc(Nc2ncccc2OCc2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1csc(Nc2ncccc2O)n1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A 250 mL round-bottomed flask was charged 3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (11.4 g, 38.3 mmol) in 6M HCl (100 mL), and the reaction mixture was heated to reflux for 10 hours. The reaction mixture was cooled to room temperature, poured onto ice and saturated sodium bicarbonate, filtered, dried under vacuum and triturated with hexanes to afford 2-(4-methylthiazol-2-ylamino)pyridin-3-ol (6.23 g, 78.5% yield) as a pale yellow solid. 1H NMR (CD3OD) δ 7.79 (dd, 1H), 7.07 (dd, 1H), 6.79 (dd, 1H), 6.46 (q, 1H), 2.28 (s, 3H). LCMS (5 to 95) Rt=2.69 min (apci) m/z=208 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C@@H:7]([NH:11][C:12]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)=[CH:21][C:20]=2[O:34][CH3:35])=[C:16]([CH3:36])[N:15]=[C:14]([NH2:37])[N:13]=1)[CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2].[F:38][CH:39]([F:48])[CH2:40][NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>>[C:1]([O:4][CH2:5][CH2:6][C@@H:7]([NH:11][C:12]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:41]([CH2:40][CH:39]([F:38])[F:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:21][C:20]=2[O:34][CH3:35])=[C:16]([CH3:36])[N:15]=[C:14]([NH2:37])[N:13]=1)[CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCOS(C)(=O)=O)cc1OC
Reactant: CCOC(=O)CNCC(F)F
Product: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCN(CC(=O)OCC)CC(F)F)cc1OC
Yield: 51.8 %

Procedure:
The sub-title compound was synthesized by the method of example 9 step (vi) from the product of example 9 step (v) (75 mg) and the product of example 3 step (i) (112 mg). The sub-title compound (44 mg) was obtained as a pale yellow oil; 1H NMR (300 MHz, CDCl3); 6.81 (1H, d), 6.44 (1H, d), 6.37 (1H, dd), 5.77 (1H, tt), 4.97 (2H, br s), 4.28-4.09 (3H, m), 4.00-3.85 (4H, m), 3.86 (3H, s), 3.58 (2H, s), 3.45 (2H, s), 3.11-2.86 (4H, m), 2.36 (3H, s), 1.97 (3H, s), 1.95-1.74 (3H, m), 1.63-1.50 (1H, m), 1.46-1.33 (1H, m), 1.30-1.15 (5H, m), 1.12-0.98 (2H, m), 0.77 (3H, t); LC-MS: m/z 610.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[N:13]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:22][C:21]1[CH:20]=[CH:19][C:18]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:25][CH:24]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccc(N2CCCC2)cc1
Product: S=C(NN=Cc1ccc(N2CCCC2)cc1)NC1CC2C=CC1C2

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.6 mmol) and 4-pyrrolidinobenzaldehyde (126 mg, 0.72 mmol) similar to Example 3 and isolated as a white solid (60 mg, 29%). 1H NMR (CDCl3): 9.01 (s, 1H), 7.65 (s, 1H), 7.50-7.26 (m, 2H), 6.52 (d, J=8.8 Hz, 2H), 6.16 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 4.29 (t, J=8.1 Hz, 1H), 3.36-3.32 (m, 4H), 3.04 (s, 1H), 2.95 (s, 1H), 2.07-1.99 (m, 4H ), 1.87 (ddd, J=7.6, 7.0, 2.7 Hz, 1H), 1.63 (m, 1H), 1.53-1.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:28])[C:11]([CH3:27])([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[O:15][CH2:14]2)[CH3:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:31])[C:10](=[O:28])[C:11]([CH3:12])([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[O:15][CH2:14]2)[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CI
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(Cl)cc(Cl)c2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)N(C)c2cc(Cl)cc(Cl)c2)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A solution of N-(3,5-dichlorophenyl)-2-methyl-2-(6-methyl-5-phenyl-2,3-dihydro-4-oxo-4H-1,3-oxazin-3-yl)-propanamide (0.6 g) in 2 ml of DMF was cooled in an ice bath and 60% sodium hydride in oil (0.06 g) was added. The mixture was stirred at room temperature for 30 min. and subsequently methyl iodide (0.31 g) was added and the mixture was stirred at room temperature for 5 h. Then the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica gel column to get the captioned compound (0.51 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[C:23]([NH2:25])=[O:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:27]([CH3:29])[CH3:28].[OH-].[K+]>CC(C)=O>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH:27]([CH3:29])[CH3:28])[C:15]=2[C:23]([NH2:25])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2ccccc2c1N1CCC(Cc2ccccc2)CC1
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)n1c(C(N)=O)c(N2CCC(Cc3ccccc3)CC2)c2ccccc21

Procedure:
To a solution of 200 mg (0.63 mMol) of 4-benzylpiperidinyl-indole-2-carboxamide in 10 ml of acetone was added 321 mg (1.9 mMol) of 2-iodopropane and 106 mg (1.9 mMol) of powdered KOH. The mixture was refluxed for 3 h, then cooled, evaporated and the crude product was purified by silica gel column chromatography using EtOAc:hexane (1:4) to provide the 4-Benzylpiperidinyl-1-(2-propyl)-indole-2-carboxamide as white solids, NMR (DMSO-d6) δ=1.15 (m, 2H), 1.60 (d, 6H), 1.82 (m, 4H), 2.56 (d, 2H), 2.72 (m, 1H), 3.02 (m, 1H), 4.15 (m, 1H), 4.80 (m, 1H), 6.45 (s, 1H), 7.05-7.32 (m, 7H), 7.52 (d, 1H), 7.61 (d, 1H). MS (ESI) m/e 360 (M+).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:11])[S:5]([NH:8][O:9][CH3:10])(=[O:7])=[O:6].Cl[S:13]([NH:16][C:17](=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:15])=[O:14].Cl>CCCCCC.C1COCC1>[CH3:3][N:4]([CH3:11])[S:5]([N:8]([S:13]([NH:16][C:17](=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:14])=[O:15])[O:9][CH3:10])(=[O:7])=[O:6]
Reactant: O=C(NS(=O)(=O)Cl)Oc1ccccc1
Reactant: CONS(=O)(=O)N(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CON(S(=O)(=O)NC(=O)Oc1ccccc1)S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
2.69 g (61.5 mmol) of 55% sodium hydride was washed with n-hexane and then suspended in 100 ml of dry THF. Then, 4.62 g (30 mmol) of N,N-dimethyl-N'-methoxysulfamide dissolved in 20 ml of THF was dropwise added thereto under cooling with ice. The mixture is heated to room temperature and then stirred at room temperature for one hour. Then, this reaction mixture was again cooled with ice, and 7.07 g (30 mmol) of phenyl N-chlorosulfonylcarbamate dissolved in 30 ml of dry THF was dropwise added thereto. The mixture was heated to room temperature and then stirred at room temperature for 30 minutes. The reaction mixture was poured into 500 ml of ice water containing 6.4 g of 35% hydrochloric acid and extracted three times with 80 ml of diethyl ether. The extract solution was washed three times with 100 ml of water and once with 100 ml of a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 10.1 g of phenyl N-[(N-dimethylsulfamoyl-N-methoxyamino)sulfonyl]carbamate as slightly yellow oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>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.[Cu]I.C1COCC1>[CH2:12]([C:9]1[S:8][C:7]([C:5]2[S:6][C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:3][CH:4]=2)=[CH:11][CH:10]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCCc1ccc(-c2ccc(Br)s2)s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCc1ccc(-c2ccc(C#C[Si](C)(C)C)s2)s1
Yield: 62 %

Procedure:
Sonogashira cross coupling reaction was carried out using 5-bromo-5′-hexyl-2,2′-bithiophene (0.46 g, 1.39 mmol), trimethylsilyl acetylene (0.35 ml, 3.50 mmol), N-diisopropylethylamine (4.8 ml), Pd(PPh3)4 (80 mg, 0.070 mmol), CuI (13 mg, 0.070 mmol) and THF (10 ml), and the reaction was treated in accordance with a conventional method, thereby producing an intended product (yield: 62%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[Na+].Cl>O1CCCC1.O>[CH2:5]([O:4][C:2](=[O:3])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: NCCc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
Add dropwise via an addition funnel a solution of ethyl chloroformate (0.74 mL, 7.7 mmol) in tetrahydrofuran (7 mL) to a stirred solution of tyramine (1.0 g, 7.3 mmol), sodium hydroxide (0.7 g, 17.1 mmol), and water (7 mL). Stir at room temperature for 18 hours then pour the reaction into 1 N aqueous hydrochloric acid so the pH=1-2. Extract with ethyl acetate (3× 25 mL). Dry the combined ethyl acetate extracts over sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 1.3 g, 6.2 mmol of [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester: 1H NMR (CDCl3, 300.00 MHz): 7.01 (d, 2H); 6.78 (d, 2H); 6.26 (s, 1H); 4.78 (s, 1H); 4.14-4.09 (m, 2H); 3.40-3.38 (m, 2H); 2.74-2.69 (m, 2H); 1.24-1.19 (m, 3H).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.[C:18]([O:22][C:23](=[O:27])[C@H:24](Br)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>C(#N)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:18]([O:22][C:23](=[O:27])[C@@H:24]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])[CH3:25])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccccc1C1NCCc2ccccc21
Reactant: C[C@@H](Br)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccccc1C1c2ccccc2CCN1[C@@H](C)C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 16 h

Procedure:
Racemic 1-o-tolyl-3,4-dihydro-1H-isoquinoline (0.67 g, 3.00 mmol) is added to a solution of (R)-(+)-2-bromo-propionic acid tert-butyl ester (0.50 g, 2.39 mmol) in acetonitrile (10 mL) and the mixture was stirred at 85° C. for 16 hours. After cooling to room temperature the reaction is diluted with ethyl acetate (100 mL) and saturated sodium bicarbonate (100 mL) and the organic layer isolated, washed with water (2×100 mL), brine (1×100 mL), and dried over magnesium sulfate. Filtration and concentration are followed by flash chromatography on SiO2 using 40:1 hexane:ethyl ether to afford 2-(S)-(1-o-tolyl-3,4-dihydro-1H-isoquinolin-2-yl)-propionic acid tert-butyl ester as a colorless syrup. C. 2-(S)-[1-(S)-o-tolyl-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:25]4[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:20])[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2cccc(C#N)c2)cn1
Yield: 13 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 3-cyanophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (13 mg, 13%) which was obtained as an off-white solid. MS: m/e=345.6 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:1][CH:23]1[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]1)([O-:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCc1ccccc1[N+](=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2[N+](=O)[O-])CC1
Reaction time: 3 h

Procedure:
A solution of 2-(2-aminoethyl)nitrobenzene (8.00 g, 48.1 mmol) and 1-t-butoxycarbonyl-4-piperidinone (9.59 g, 48.1 mmol) in methanol (100 mL) was brought to pH 5 by the addition of acetic acid. Sodium cyanoborohydride (4.53 g, 72.2 mmol) was added and the reaction stirred for 3 h. Methanol was removed in vacuo, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated brine and dried over sodium sulfate. The title compound was obtained as an oil (19.27 g). MS 350 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]3[CH2:12][CH2:13][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]([Cl:14])=[N:4][N:3]=1.[Zn](C(C)C)[CH:16]([CH3:18])[CH3:17]>O1CCOCC1>[CH:16]([C:2]1[C:11]2[CH:10]3[CH2:12][CH2:13][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]([Cl:14])=[N:4][N:3]=1)([CH3:18])[CH3:17]
Reactant: Clc1nnc(Cl)c2c1C1CCC2CC1
Reactant: CC(C)[Zn]C(C)C
Solvent: C1COCCO1
Product: CC(C)c1nnc(Cl)c2c1C1CCC2CC1

Procedure:
A solution of 1,4-dichloro-5,6,7,8-tetrahydro-5,8-ethanophthalazine (Alfa Aesar) (0.109 g, 0.474 mmol), iPr2Zn (1 M in toluene, 0.50 mL, 0.50 mmol), PdCl2dppf CH2Cl2 (19.3 mg, 0.024 mmol) in dioxane (1.5 mL) was stirred at 80° C. for 2.5 hours, quenched with 1 N HCl, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (10% Et2O/CH2Cl2 to 5% MeOH/CH2Cl2) to give impure title compound as a tacky solid (34.9 mg). LC/MS (APCI) M/Z 237.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=O)[CH2:7][CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][NH2:25])[CH3:21]>Cl.C(O)C>[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][CH2:24][N:25]1[C:6]([C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=2
Reactant: O=C(CC1CCCCCC1=O)c1ccc(Br)cc1
Reactant: CN(C)CCCN
Agent: Cl
Solvent: CCO
Product: CN(C)CCCn1c(-c2ccc(Br)cc2)cc2c1CCCCC2

Procedure:
A mixture of 18.6 (0.06 mole) of 2-(p-bromophenacyl)cycloheptanone and 6.19 g (0.06 mole) of dimethylaminopropylamine is dissolved in 200 ml. of absolute ethanol. A few drops of concentrated hydrochloric acid are added and the mixture is refluxed for 4 hours. The ethanol is evaporated, and the residue is dissolved in dilute hydrochloric acid and washed with ether. The aqueous solution is basified with sodium carbonate solution and extracted with ether. The ether solution is washed with water, dried, and concentrated to a brown oil which solidifies upon cooling. The resulting solid is recrystallized from petroleum ether to give 1-(3-dimethylaminopropyl)-2-(p-bromophenyl)-1,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole, m.p. 69°-70° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=3)[O:14][CH2:13][C:12]2([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=2)[CH3:25])=[CH:7][CH:6]=1.[C:36]([C:40]1[CH:41]=[C:42]([CH2:50][N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:43]=[C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:45]=1)([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+].CCCCCC>CC(C)=O.CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:36]([C:40]1[CH:41]=[C:42]([CH2:50][N:51]2[CH2:52][CH2:53][N:54]([CH2:2][CH2:3][O:4][C:5]3[CH:10]=[CH:9][C:8]([CH:11]4[C:20]5[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=5)[O:14][CH2:13][C:12]4([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=4)[CH3:25])=[CH:7][CH:6]=3)[CH2:55][CH2:56]2)[CH:43]=[C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:45]=1)([CH3:37])([CH3:38])[CH3:39]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OCCCl)cc2)cc1
Reactant: CC(C)(C)c1cc(CN2CCNCC2)cc(C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OCCN3CCN(Cc4cc(C(C)(C)C)cc(C(C)(C)C)c4)CC3)cc2)cc1
Yield: 50.7 %

Procedure:
(3RS,4SR)-4-[4-(2-Chloroethoxy)phenyl]-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]-3-methylchroman (210 mg, 0.42 mmol) and {(3,5-bis(t-butyl)phenyl]methyl}piperazine (243 mg, 0.84 mmol) were dissolved in a solvent mixture of acetone (4 ml) and DMF (0.4 ml). To the mixture potassium carbonate (116 mg, 0.84 mmol) and tetrabutylammonium iodide (16 mg, 0.04 mmol) added were, and the mixture was stirred while heated under reflux for 3 days. The reaction solution was extracted with ethyl acetate, dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the concentrate thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 160 mg (yield: 51%) of a white foamy solid.
Reaction SMILES: N#N.[NH2:3][CH2:4][C:5]([OH:7])=O.[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)C(=O)[O:15][C:16](=O)[C:11]=2[CH:10]=1>CC(O)=O>[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:5](=[O:7])[CH2:4][NH:3][C:16](=[O:15])[C:11]=2[CH:10]=1
Reactant: NCC(=O)O
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3cc(Cl)ccc32)cc1
Agent: N#N
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)CNC(=O)c3cc(Cl)ccc32)cc1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
In a 2 L RBF equipped with mechanical stir, condenser and N2 inlet, glycine (34 g, 0.45 mol) was added to B2 (280 g) followed by the addition of AcOH (500 mL). Reaction flask was heated in a 130° C. oil bath for 8 h. Solvent was removed on the rotary evaporator at 50-60° C. To the thick syrupy crude product was added heptane (1 L) and H2O (1 L) followed by the addition of NaHCO3 to adjust the pH to ˜8-9. The mixture gave a solid along with organic and aqueous layers. The organic and aqueous layers were decanted and the solid was slurried with 500 mL of 5% NaHCO3 solution. NaHCO3 layer was decant and sticky solid was suspended in 700 mL ethylacetate (EtOAc) and 300 mL of dichloromethane (DCM). The mixture was stirred for 20 min, filtered and the filter cake was washed with 1 L of DCM. The filtrate was concentrated and residue was pass through 330 g silica gel plug using 25/75 to 75/25 EtOAc/heptane (total of 8 L). Clean fractions were combined to give 58 g of pure product. An additional 13 g of ˜70% pure product was obtained from less pure fractions. Yield was 47% over two steps. 1H NMR (300 MHz, DMSO-d6) δ 3.45 (m, 1H), 3.6 (s, 3H), 3.8 (m, 1H), 4.8 (d, 1H), 5.3 (d, 1H), 6.8 (d, 2H), 7.1 (d, 2H), 7.7-7.5 (m, 3H), 8.9 (t, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH2:20][C@H:21]([OH:33])[CH2:22][N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>CCO>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:11]([C:12](=[O:14])[NH:19][CH2:20][C@H:21]([OH:33])[CH2:22][N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NC[C@H](O)CN2CCc3ccccc3C2)c1
Temperature: 120 °C
Yield: 58.8 %

Procedure:
A mixture of methyl 3-((tert-butoxycarbonyl)amino)benzoate (500 mg, 2 mmol) and (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (618 mg, 3 mmol) in EtOH (1 mL) was heated at 120° C. for 3 h in a microwave reactor under N2. The reaction solution was concentrated and the residue was purified by column chromatography to give the title product (500 mg, Yield 58.8%). LCMS (m/z): 426.2 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[C:10]([CH3:11])=[C:9]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][SH:17])[CH:8]=[CH:7][N:6]=1.Cl[CH2:19][CH2:20][N:21]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]1[CH3:29]>CN(C=O)C.C(O)(=O)C>[OH:3][CH2:4][C:5]1[C:10]([CH3:11])=[C:9]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][CH2:19][CH2:20][N:21]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]2[CH3:29])[CH:8]=[CH:7][N:6]=1
Reactant: Cc1c(SCCCCS)ccnc1CO
Reactant: Cc1ncc([N+](=O)[O-])n1CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1c(SCCCCSCCn2c([N+](=O)[O-])cnc2C)ccnc1CO
Temperature: 0 °C

Procedure:
0.43 g (15 mmol) of sodium hydride are initially introduced in 25 ml of DMF with ice-cooling. 3.33 g (13.7 mmol) of 2-hydroxymethyl-4-(4-mercaptobutylthio)-3-methylpyridine are added. After the evolution of gas has ended, 2.62 g (13.7 mmol) of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole in 10 ml of DMF are added dropwise. The mixture is stirred with ice- cooling for 1 h. It is then diluted with 200 ml of ice-water and neutralized with acetic acid. The mixture is extracted 3 times with dichloromethane. The combined organic phases are washed 4 times with water, dried over magnesium sulfate, filtered and concentrated. The crude product is chromatographed on silica gel using ethyl acetate/methanol/conc. ammonia=89/10/1. The title compound is obtained on concentrating as a yellow crystallizate which is washed by stirring with diethyl ether. M.p. 86°-87° C.; yield 4 g (75% of theory).