Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:27][CH:26]2[NH:28][CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:22][CH:23]2[N:28]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:8][CH2:7][C:6]3=[O:15])[CH:26]([CH2:25][CH2:24]2)[CH2:27]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Reactant: CCCCC1CC2CCC(C1)N2
Solvent: CC#N
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)CSc2ccccc21
Temperature: 40 °C
Reaction time: 120 h
Yield: 40.4 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl)-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.093 g, 0.269 mmol) and 3-butyl-8-aza-bicyclo[3.2.1]octane (104KS29) (0.054 g, 0.323 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 40° C. for 5 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:10) to give the title compound (108LM51-48) (0.042 g, 40%). 1H NMR (CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.00 (t, J=8.0 Hz, 1H), 4.18-4.10 (m, 2H), 3.38 (s, CH2), 3.15-3.00 (m, 2H), 2.30-2.22 (m, 1H), 2.20-2.10 (m, 1H), 1.90-1.75 (m, 3H), 1.60-1,40 (m, 5H), 1,40-1.15 (m, 8H), 0.90-0.82 (m, 6H); 13C NMR (CDCl3) δ 166.1, 139.2, 128.7, 127.2, 124.7, 123.5, 119.1, 61,4, 60.1, 57.3, 47.6, 38.3, 36.9, 32.1, 31.2, 29.9, 29.4, 28.2, 27.2, 26.5, 23.1, 16.7, 14.3; HPLC-MS (ammonium acetate) [M+H]+=387.3.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:33][C:20]3[C:21](=[O:32])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:41]([C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH2:45]Br)#[N:42]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:33]([CH2:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[C:41]#[N:42])[C:20]3[C:21](=[O:32])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCC(c2nc3ccn(Cc4ccccc4)c(=O)c3[nH]2)C1)OCc1ccccc1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Cn1c(C2CCCC(NC(=O)OCc3ccccc3)C2)nc2ccn(Cc3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 17 h
Yield: 66 %

Procedure:
To a solution of [3-(5-benzyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.1 g, 0.22 mmol) in DMF (3 mL) were added Cs2CO3 (0.14 g, 0.44 mmol) and a solution of 2-cyanobenzyl bromide (52 mg, 0.26 mmol) in 3 mL DMF. After stirring for 17 h at room temperature, the reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2. The combined extracts were dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 1% MeOH in CH2Cl2 to give {3-[5-benzyl-3-(2-cyano-benzyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (83 mg, 66% yield). 1H-NMR (CDCl3): δ 7.73 (m, 1H), 7.48 (m, 1H), 7.32 (m, 1H), 7.15 (d, 1H, J=7.2 Hz), 6.90 (d, 1H, J=8.0 Hz), 6.68 (d, 1H, J=7.6 Hz), 6.21 (m, 1H), 5.92 (m, 1H), 5.05 (s, 2H), 4.70 (m, 1H), 3.58 (m, 1H), 2.80 (m, 1H), 2.01 (m, 2H), 1.85 (m, 1H), 1.70 (m, 2H), 1.51 (m, 2H), 1.17 (m, 1H). MS: calculated for C35H33N5O3+H 572.3; found: 572.5.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][CH:25]2[N:28]=[N+]=[N-])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.[OH-].[Na+]>O>[Si:1]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][CH:25]2[NH2:28])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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
Reactant: CC(C)(C)[Si](Oc1ccc2c(c1)C(N=[N+]=[N-])CC2)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](Oc1ccc2c(c1)C(N)CC2)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-tert-butyldiphenylsilyloxy-1-indanyl azide, as described above in Step C, (6.10 g, 14.7 mmol) in TBF (150 mL) at 0° C. was added LiAlH4 (1.0 M in THF, 17.7 mL, 17.7 mmol), dropwise. The reaction mixture was stirred at 0° C. for 1 hour then EtOAc (0.7 mL) was added, followed by H2O (0.7 mL), then 15% aqueous NaOH (0.7 mL), then H2O (2.1 mL). The quenched mixture was stirred at ambient temperature for 18 hours, then filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with CHCl3—1% MeOH—0.1% NH4OH, to yield the titled product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:2]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[F:16][C:17]1[CH:24]=[CH:23][C:20](/[CH:21]=[N:15]/[NH:14][C:12](=[O:13])[CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NNC(=O)CCc1c[nH]c2ccccc12
Solvent: Cc1ccccc1
Product: O=C(CCc1c[nH]c2ccccc12)N/N=C/c1ccc(F)cc1
Yield: 98.7 %

Procedure:
A solution of 3-(1H-Indol-3-yl)-propionic acid hydrazide (0.300 g, 1 eq) and 4-fluorobenzaldehyde (0.183 g, 1 eq) in toluene (7 ml) is refluxed overnight and then evaporated to dryness, to afford 0.450 g of white product that is purified by flash chromatography using neutral alumina and eluting with 1% methanol in chloroform (0.269 g, 59% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:36]1[CH:35]=[CH:34][C:33]([F:32])=[CH:38][C:37]=1[F:39])=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(F)cc2F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 2,4-difluorophenylboronic acid. A colorless powder (9 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12]O>>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: CO
Product: COC(=O)CCc1ccccc1
Yield: 96.3 %

Procedure:
A mixture of 3-phenylpropionic acid (118.2 g, 788 mmol) sulfuric acid (5.9 g), and 100 mL of methanol was heated to reflux overnight. TLC analysis indicated the absence of starting material and the reaction was concentrated in vacuo. The residue was dissolved in 200 mL of ethyl ether, washed with sodium bicarbonate (100 mL), dried over magnesium sulfate, filtered and concentrated to give 124.4 g (96.3%) of the ester as a tan oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:29]1([N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1nc(OCC(=O)N(C)C2CCN(C3CCCCC3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31, cyclohexanone and sodium triacetoxy-borohydride in the same manner as in Example 32.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:25](OC)=[O:26])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:8]2[C:17]=1[CH2:16][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:9]2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:7]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C:17]3=[C:5]([CH2:3][OH:2])[C:6]=2[CH2:25][OH:26])=[CH:23][CH:22]=1
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(Cl)cc2)n2c1Cc1ccccc1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Product: OCc1c(CO)c(-c2ccc(Cl)cc2)n2c1Cc1ccccc1C2
Reaction time: 2 h

Procedure:
A solution of the 3-(4-chlorophenyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline-1,2-dicarboxylic acid dimethyl ester (5.03 g, 15 mmol) in anhydrous dichloromethane (120 mL) was added dropwise into a stirred suspension of LiAlH4 (1.31 g, 34.5 mmol) in anhydrous diethyl ether (50 mL) at 10-15° C. The reaction mixture was further stirred for 2 hours after the addition was completed. The mixture was cooled in an ice bath and the excess hydride was destroyed by the sequential addition of water (2.0 mL), 15% aqueous NaOH (2.0 mL), and water (6.0 mL). The mixture was filtered to remove inorganic salt, the solid residue was washed with hot THF (300 mL). The combined filtrate and washings was evaporated in vacuo to dryness and the solid residue was recrystallized from dichloromethane/ether to give [3-(4-chlorophenyl)-2-hydroxymethyl-5,10-dihydro-pyrrolo[1,2-b]isoquinolin-1-yl]methanol (DA-1116), 3.12 g (61.4%); mp 170-171° C.; 1H NMR (DMSO-d6) δ 4.06 (2H, s, CH2), 4.28 (2H, d, J=5.1 Hz, CH2), 4.50 (2H, d, J=5.1 Hz, CH2), 4.55 (1H, t, J=5.1 Hz, exchangeable, OH), 4.57 (1H, t, J=5.1 Hz, exchangeable, OH), 4.98 (2H, s, CH2), 7.18-7.20 (1H, m, ArH), 7.25-7.30 (2H, m, ArH), 7.36-7.40 (1H, m, ArH), 7.49 (2H, d, J=8.5 Hz, 2×ArH), 7.54 (2H, d, J=8.5 Hz, 2×ArH); m/z 339.82 (M+H)+ Anal. Calcld. for C20H18CINO2: C, 70.69; H, 5.34; N, 4.12. Found: C, 70.42; H, 5.29; N, 4.19.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[CH:24][N:25]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[N:28]=2)=[CH:18][CH:17]=1.[O:41]1[CH:45]=[CH:44][C:43]([CH:46]=O)=[N:42]1.C(OCC)C>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[CH:24][N:25]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:46][C:43]4[CH:44]=[CH:45][O:41][N:42]=4)[CH2:37][CH2:36]3)[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[N:28]=2)=[CH:20][CH:21]=1
Reactant: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNCC2)n1
Reactant: O=Cc1ccon1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)CC2)n1
Reaction time: 1.5 h

Procedure:
Sodium triacetoxyborohydride (135 mg, 0.637 mmol) was added to a solution of 4-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]-N-methylpyrimidin-2-amine (C8) (150 mg, 0.426 mmol) and isoxazole-3-carbaldehyde (49.6 mg, 0.511 mmol) in THF (10 mL). After 90 minutes at room temperature, the reaction was concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a thick oil. Purification via silica gel chromatography (Eluants: ethyl acetate followed by 10% methanol in ethyl acetate) provided a viscous oil, which was reconcentrated from diethyl ether to afford the product as a white solid. Yield: 77 mg, 0.18 mmol, 42%. LCMS m/z 434.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.99-2.09 (m, 2H), 2.16-2.22 (m, 4H), 3.03 (m, 2H), 3.05 (d, J=5.1 Hz, 3H), 3.69 (s, 2H), 4.67 (br m, 1H), 5.17 (m, 1H), 6.41 (d, J=5.1 Hz, 1H), 6.41 (d, J=1.7 Hz, 1H), 7.00 (dd, J=8.7, 8.7 Hz, 2H), 7.46 (dd, J=8.7, 5.4 Hz, 2H), 7.77 (s, 1H), 8.16 (br d, J=4.5 Hz, 1H), 8.40 (d, J=1.6 Hz, 1H).
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[CH:6][CH:5]=1)=[N+]=[N-].C>CO.[Pd]>[NH2:1][C:4]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[CH:6][CH:5]=1
Reactant: Cn1c(=O)c2c(N=[N+]=[N-])ccnc2n(C)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)c2c(N)ccnc2n(C)c1=O
Yield: 73.7 %

Procedure:
1.33 g of Compound 3 was dissolved in 400 ml of methanol and reduced in the presence of 300 mg of Pd-C. Activated charcoal powder was added, and the solution was heated and filtered. The filtrate was distilled under reduced pressure and ethanol added thereto. The resulting crude crystals were separated by filtration and recrystallized from ethanol to give 0.87 g of 5-amino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 4).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[I-].[K+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][CH3:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][N:32]([CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=1)[CH3:33])(=[O:3])[CH3:2]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCBr
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2NC(C)=O)cc1OC
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A portion (440 mg, 1.46 mmol) of the 1-(2-acetamido-4-nitrophenoxy)-2-bromoethane produced in (2) above was dissolved in dimethylformamide (5 ml) and, thereafter, potassium iodide (267 mg, 1.608 mmol) and 2-(3,4-dimethoxyphenyl)-N-methylethylamine (0.81 ml, 4.36 mmol) were added to the solution, which was stirred at 70° C. for 1.5 h. Thereafter, the solvent was evaporated from the reaction mixture and the residue was subjected to extraction with ethyl acetate. The organic layer was washed with water four times and dried with sodium sulfate, followed by evaporation of the solvent, with the resulting residue being purified by being subjected to column chromatography on silica gel using, as an eluent, chloroform containing methanol (6%) to yield the end compound 1-(2-acetamido-4-nitrophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (590 ml) as a yellow caramel-like substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][C:24]#[N:25])[C@@H:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.S(C)C.CO>C1COCC1>[NH2:25][CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Temperature: 25 °C

Procedure:
(R)-tert-butyl 2-((S)-(3-chlorophenyl)(cyanomethoxy)methyl)morpholine-4-carboxylate (1.3 g, 3.55 mmol) was dissolved in anhydrous THF (25 mL), and the solution was heated to reflux under N2. A solution of BH3.Me2S in THF (5 mL) was added dropwise, and stirring was continued under reflux overnight. The resulting solution was cooled to rt, MeOH was added dropwise to quench the reaction until gas evolution ceased. After evaporation of the solution, the crude product was used for the next step.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(=O)([O-])[O-].[Ca+2:9]>O>[N+:1]([O-:4])([O-:3])=[O:2].[Ca+2:9].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=[N+]([O-])[O-]

Procedure:
1000 ml of nitric acid was added to 623.23 g of calcium carbonate in a very slow manner in increments of 5 ml to obtain calcium nitrate and water. The mixture was then thoroughly mixed for 30 minutes for the complete conversion of calcium carbonate to calcium nitrate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22](C)[CH2:23][CH:24](O)[CH:25]([NH:28][C:29]([O:31][C:32](C)(C)C)=[O:30])[CH2:26][OH:27])=[C:18]([Cl:38])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]3([CH2:26][OH:27])[CH2:32][O:31][C:29](=[O:30])[NH:28]3)=[C:18]([Cl:38])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CC(O)C(CO)NC(=O)OC(C)(C)C)c1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(CO)(CCCc2ccc(Sc3cccc(OCc4ccccc4)c3)cc2Cl)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]propyl-2-t-butoxycarbonylamino-1,3-propanediol (3.30 g) was dissolved in THF (80 mL). At 0° C., 60% sodium hydride (600 mg) was added and the mixture was stirred at room temperature for 24 hours. To the resulting reaction mixture, ice water was added and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated aqueous solution of sodium hydroxide, and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=1:1 and then ethyl acetate alone) to give the desired product as a pale yellow oil (2.37 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11](OC)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH2:11][OH:12])[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(CN2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 71.8 %

Procedure:
A mixture of 3-(1-piperidinylmethyl)benzoic acid, methyl ester (17.56 g) and lithium aluminium hydride (2.68 g) in tetrahydrofuran (500 ml) was stirred at room temperature for 30 h and quenched with water. The solid was removed by filtration and the filtrate distilled to give the title compound as a colourless oil (11.1 g) b.p. 135° (10-1 mm). TLC silica; ether; Rf 0.2.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]#[N:13])(=[O:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH2:11][Br:14])[CH:8]=[CH:7][C:6]=1[C:12]#[N:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)ccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(=O)Oc1cc(CBr)ccc1C#N
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a solution of (2-cyano-5-methyl-phenyl) acetate (0.72 g, 4.11 mmol) in CCl4 (10 mL) was added recrystallized N-bromosuccinimide (0.767 g, 4.31 mmol) followed by benzoyl peroxide (56 mg, 0.23 mmol). The resultant mixture was heated to reflux for 2.5 hours then cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (6:1 hexanes-EtOAc) provided 0.31 g (30%) of (5-bromomethyl-2-cyano-phenyl) acetate as a colorless oil. 1H NMR (CDCl3) δ 2.40 (s, 3H), 4.45 (s, 2H), 7.33 (s, 1H), 7.35 (d, 1H, J=9 Hz), 7.65 (d, 1H, J=9 Hz).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH:19][CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH2:20][CH:21]([O:22][CH3:23])[O:24][CH3:25])[C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:35])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(CNCCN1CCN(c2cccc3c2OCCO3)CC1)OC
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: COC(CN(CCN1CCN(c2cccc3c2OCCO3)CC1)C(=O)Nc1ccc(F)cc1)OC

Procedure:
A solution of 1-(1,4-benzodioxan-5-yl)-4-(2-(2,2-dimethoxy-1-ethylamino)-1-ethyl)piperazine (2.3 g) and 4-fluorophenyl isocyanate (0.9 g) in methylene chloride (100 ml) was refluxed for 2 h. Removal of solvent in vacuo gave an oil which was purified on a silica gel column (eluent: ethyl acetate/methanol=3:1). The product, 1-(1,4-benzodioxan5-yl)-4-(2-(N-(2,2-dimethoxy 1-ethyl)-N-(4-fluorophenylaminocarbonyl)-amino)-1-ethyl)piperazine, was obtained as a solid (2.5 g).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([N+:12]2[C:17]([NH2:18])=[C:16](Cl)[C:15]([NH2:20])=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].[H][H]>[Ni].O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([N+:12]2[C:17]([NH2:18])=[CH:16][C:15]([NH2:20])=[CH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: Nc1cn[n+](-c2ccccc2)c(N)c1Cl
Agent: [Ni]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1cn[n+](-c2ccccc2)c(N)c1
Yield: 76.8 %

Procedure:
32 parts of 1-phenyl-4,6-diamino-5-chloropyridazinium perchlorate in 200 parts of water in a stirred autoclave is stirred with 10 parts of sodium bicarbonate and 2 parts of Raney nickel for 3 hours at 100° C and 200 atmospheres gauge of hydrogen pressure. The discharge is filtered free from nickel and 20 parts of a 70% by weight perchloric acid is added to it. 22 parts (76.8% of theory) of 1-phenyl-4,6-diaminopyridazinium perchlorate is obtained; C10H11O4N4Cl, melting point 105° to 107° C after having been recrystallized from water.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:16]1[C:28]2[NH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[CH:25]1[C:26]2[N:27]([C:2]3[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])[C:28]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(C(=O)O)c(Br)cc1C(=O)O
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)c(-n2c3ccccc3c3ccccc32)cc1C(=O)O
Yield: 50 %

Procedure:
Into a three-neck flask, 10 g (3.6×10−2 mol) of 2-bromo-5-methoxyterephthalic acid prepared in the above step (2), 12.04 g (7×10−2 mmol, 2 eq) of carbazole, 12.94 g (9.4×10−2 mmol, 1.3 eq) of K2CO3 and 0.3 g (3% w/w) of Cu were introduced and reacted in the presence of 300 ml of DMF for 48 hours, then cooled to room temeparature. The used solvent was distilled off under reduced pressure and the aqueous solution was washed with water and diethyl ether several times. To the aqueous solution so obtained, 5 N HCl was slowly added to produce yellow precipitates, which were then recrystallized with CHCl3. Yield: 50% (6.5 g); m.p.: 298° C.