Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([CH:24]=[CH2:25])=[O:23]>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:22](=[O:23])[CH:24]([CH3:25])[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: C=CC=O
Product: CC1C(=O)Oc2[nH]c(-c3cc(F)ccc3F)nc2C1c1ccccc1
Reaction time: 72 h
Yield: 42 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and acrolein. After 72 h, the reaction only reached 63% conversion by 1H NMR. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 20 as an off-white solid (43 mg, 42%). Analytical data for 20: 1H NMR (500 MHz, CDCl3) δ 9.48 (br s, 1H), 7.91 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.37-7.27 (m, 3H), 7.12-7.03 (m, 3H), 7.02-6.95 (m, 1H), 4.21 (d, J=7.2 Hz, 1H), 3.36 (ap, J=7.0 Hz, 1H), 1.11 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3, 126 MHz) δ 169.6, 159.1 (d, JCF=243.9 Hz), 155.4 (dd, JCF=241.1, 2.5 Hz), 149.5, 137.0, 136.5, 129.2, 128.2, 127.8, 118.5 (dd, JCF=12.6, 9.0 Hz), 117.1 (dd, JCF=25.6, 8.7 Hz), 116.6 (dd, JCF=24.8, 9.4 Hz), 114.5 (dd, JCF−1 26.9, 3.9 Hz), 110.1 (d, JCF=3.7 Hz), 41.1, 40.7, 13.4; IR (film) cm−1 3083, 3029, 2987, 1773, 1758, 1636, 1618, 1529, 1482, 1464, 1411, 1236, 1173, 1132, 1084, 1062, 919, 873, 813, 766, 737, 700; LRMS (ESI): Mass calcd for [M+H]+ C19H15F2N2O2: 341.1. found 341.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 12% IPA/hexanes 1.0 mL/min, 280 nm), Rt1 (major)=14.4, Rt2 (minor)=27.6 min; er=>99:1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].O>CN(C)C=O.C(OCC)(=O)C>[O:7]=[C:2]1[CH2:3][O:4][CH2:5][CH2:6][N:1]1[CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C1COCCN1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCOCC1=O)OCc1ccccc1
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Under an argon atmosphere, to a solution of morpholin-3-one (220 mg, 2.2 mmol) in N,N-dimethylformamide (2.2 ml) was added sodium hydride (105 mg, 2.6 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then, benzyl bromoacetate (379 μl, 2.4 mmol) was added, and the mixture was stirred for 2 hr. To the reaction solution were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (321 mg, yield 59%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[C:10]=2Cl)=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[Cl:22]C1C=C(CC#N)C=CC=1Cl>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:22])=[C:11]([Cl:16])[CH:10]=2)=[C:4]([C:18]([F:20])([F:21])[F:19])[N:3]=1
Reactant: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(C(F)(F)F)n1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc(N)c(-c2ccc(Cl)c(Cl)c2)c(C(F)(F)F)n1

Procedure:
This compound was made in an analogous manner to the compound of Example 4, from 3,4-dichlorophenylacetonitrile (Aldrich) mp. 252°-254.5° C.: TLC (SiO2 ; methanol/chloroform, 1:9) Rf=0.38.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][CH2:8][O:9][C:10]([N:12]1[N:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:23][CH2:22][CH2:21]3)[CH:15]([CH3:40])[S:14][C:13]1=[O:41])=[O:11].N1C=CC=CC=1>ClCCl>[CH2:1]([N:3]([CH2:7][CH2:8][O:9][C:10]([N:12]1[N:17]=[C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:23][CH2:22][CH2:21]3)[CH:15]([CH3:40])[S:14][C:13]1=[O:41])=[O:11])[CH2:4][CH3:5])[CH3:2]
Reactant: CCNCC
Reactant: COc1ccc(C(=O)N2CCCc3cc(C4=NN(C(=O)OCCCl)C(=O)SC4C)ccc32)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)CCCN3C(=O)c2ccc(OC)c(OC)c2)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2.5 g of diethylamine dissolved in 30 ml of dichloromethane are added dropwise with stirring to a solution of 10 g of 3-[2-chloroethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 9 ml of pyridine in 100 ml of dichloromethane and the mixture is subsequently stirred at 20° C. for one hour. The solvent is removed and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; hydrochloride.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:27][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCCCNCc1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
To a solution of 4-[(4-butylphenyl)ethynyl]benzaldehyde (334 mg, 1.27 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) and hexylamine (Aldrich, 98 μL, 1.53 mmol) in DCE (15.00 mL) was added acetic acid (110 mL) and sodium triacetoxyborohydride (405 mg, 1.91 mmol) and the resulting mixture was stirred at rt for 3 hrs. The reaction mixture was then diluted with DCM and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by flash chromatography on silicagel (DCM, DCM/MeOH/NH4OH 98:2:1 then 95:5:1) to give 144 mg (32%) of the title compound. HPLC, Rt: 4.59 min (purity: 98.7%). 1H NMR (CD3Cl3) δ: 0.87 (t, J=6.9 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.28-1.64 (m, 13H), 2.6 (t, J=7.3 Hz, 4H), 3.78 (s, 2H), 7.14 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Cl[CH2:14][O:15][CH2:16][O:17][CH2:18][P:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].C([O:28]P([O-])(OCC)=O)C.ClCOCOCCl>CN(C=O)C>[CH2:21]([O:20][P:19]([CH2:18][O:17][CH:16]([O:15][CH3:14])[N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12])([O:23][CH2:24][CH3:25])=[O:28])[CH3:22]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: CCOP(=O)([O-])OCC
Reactant: CCOP(COCOCCl)OCC
Agent: ClCOCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COC(OC)n1cnc2c(N)ncnc21)OCC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride in mineral oil (1.4 g, 34.5 mmol) in DMF (100 mL) was added adenine (4.7 g, 34.5 mmol) and the mixture was stirred at 80° C. for 1 hr. To the resulting yellow solution was added dropwise a solution of chloromethoxy-(diethoxyphosphinomethoxy)methane [(prepared from diethylphosphate (4.4 mL, 34.5 mmol) and bis-(chloromethoxy)methane (25 g, 172 mmol)] in DMF (20 mL) under nitrogen. After stirring at 25° C. for 15 hr, volatiles were removed in vacuo, and the resulting oily residue was purified by silica gel column chromatography using CH2Cl2 /10% MeOH as eluent to obtain the title compound as a colorless oil: yield 6.0 g (50%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].C(Br)(Br)Br.[OH-].[K+].Cl.C([OH:20])C.[O:21]1[CH2:26][CH2:25][O:24][CH2:23]C1>O.C(O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH2:23][O:24][CH2:25][C:26]([OH:21])=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCO
Reactant: C1COCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: BrC(Br)Br
Product: N#Cc1ccc(CCOCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Cyanobenzaldehyde (3.0 g) was dissolved in a 1:1 mixed solution of ethanol/1,4-dioxane (80 mL), and bromoform (7.0 g) was added thereto under ice cooling. Subsequently, an ethanol solution (40 mL) of potassium hydroxide (7.6 g) was carefully added thereto, and the mixture was stirred for 6 hours at room temperature. After distilling off the solvent under reduced pressure, the residue thus obtained was diluted with water. The mixture was acidified with a 2 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (50% to 100% ethyl acetate/hexane), and the title compound (2.6 g) was obtained as a crude product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH:39]([N:42]=[C:43]=[O:44])([CH3:41])[CH3:40]>C(Cl)Cl.CO>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][C:43]([NH:42][CH:39]([CH3:41])[CH3:40])=[O:44])[CH:5]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(C)N=C=O
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)NC(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
To a suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (52 mg, 0.10 mmol) in dry DCM (0.5 mL) was added triethylamine (15 μL, 0.11 mmol), followed with isopropyl isocyanate (11 μL, 0.11 mmol). The reaction mixture was stirred at room temperature for 45 min. LCMS showed mainly product. The reaction mixture was diluted with DCM and methanol and then concentrated in vacuo. The resultant residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was evaporated in vacuo to give the title compound (43 mg, 75%) as a white powder. LCMS (System A) RT=1.11 min, ES+ve m/z 548/550 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.CCN(C(C)C)C(C)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([NH:1][C:2]1[O:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1oc(N)nc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1oc(NC(C)=O)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2 g (11.8 mmol) ethyl 2-amino-4-methyl-oxazole-5-carboxylate in 50 ml DCM are added 6.1 ml (35.3 mmol) DIPEA. To this mixture 0.92 ml (12.9 mmol) acetyl chloride are added and the reaction mixture is stirred at r.t. for 2 h. The mixture is diluted with further DCM and washed with water. The organic layer is separated, dried and the solvent is removed in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC(OC)=CC=2)=[CH:12][C:11]=1[CH:26](O)[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29].FC1C(B(C2C(F)=C(F)C(F)=C(F)C=2F)C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.C[Si]([C:71]#[N:72])(C)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH:26]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:71]#[N:72]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)CC(C)(C)C)c2)cc1
Reactant: C[Si](C)(C)C#N
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(F)c(-c2ccc(O)cc2C(C#N)CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)-3,3-dimethylbutan-1-ol (160 mg) and tris(pentafluorophenyl)borane (20 mg) in acetonitrile (3 mL) was added trimethylsilyl cyanide (81 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (97 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:25][CH3:26])=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:33][C:34](Br)=[O:35].[NH2:37][CH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:25][CH3:26])=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:33][C:34]([NH:37][CH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1)=[O:35]
Reactant: O=C(Br)CBr
Reactant: NC1CCc2ccccc21
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OCc4ccccc4)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OCc4ccccc4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.C(N(CC)CC)C.[O:27]=[C:28]1[C:37]2[C:32](=[CH:33][C:34]([CH2:38][CH:39]=O)=[CH:35][CH:36]=2)[CH2:31][CH2:30][O:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[O:1]=[C:2]1[CH2:7][N:6]([CH2:39][CH2:38][C:34]2[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=2)[C:28](=[O:27])[O:29][CH2:30][CH2:31]3)[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: O=CCc1ccc2c(c1)CCOC2=O
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4c(c3)CCOC4=O)CC1=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (51 mg, 0.17 mmol) and triethylamine (65 mg, 0.64 mmol) was dissolved in dichloroethane then (1-oxo-3,4-dihydro-1H-isochromen-6-yl) acetaldehyde (60 mg, 0.26 mmol) was added followed by sodium triacetoxyborohydride (270 mg, 1.28 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was poured into water then extracted with dichloromethane. The organic layer was washed with brine then dried over Na2SO4, filtered and concentrated. The compound was purified by preparative TLC plate to yield the title product. 1H-NMR (500 MHz, CDCl3) δ ppm 8.07 (d, J=7.8 Hz, 1H), 7.43 (s, 1H), 7.42 (d, J=7.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.18 (d, J=7.61 Hz, 1H), 7.14 (s, 1H), 4.90 (b, 1H), 4.57 (t, J=5.7 Hz, 2H), 3.27-3.36 (m, 4H), 3.08 (t, J=5.8 Hz, 2H), 3.02-2.74 (m, 10H), 2.01 (b, 1H), 1.92-1.95 (m, 1H).
Reaction SMILES: CN1CCC/C/1=C1/C=NC2C/1=CC=C(C(O)=O)C=2.[ClH:19].C[O:21][C:22]([C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH:33]3[CH2:37][CH2:36][CH2:35][N:34]3[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:29][NH:30]2)=[CH:26][CH:25]=1)=[O:23].O[Li].O>>[ClH:19].[CH2:38]([N:34]1[CH2:35][CH2:36][CH2:37][CH:33]1[C:28]1[C:27]2[C:31](=[CH:32][C:24]([C:22]([OH:23])=[O:21])=[CH:25][CH:26]=2)[NH:30][CH:29]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)c1ccc2c(C3CCCN3Cc3ccccc3)c[nH]c2c1
Agent: CN1CCC/C1=C1/C=Nc2cc(C(=O)O)ccc21
Agent: Cl
Agent: [Li]O
Solvent: O
Product: O=C(O)c1ccc2c(C3CCCN3Cc3ccccc3)c[nH]c2c1

Procedure:
According to the procedure described for synthesis of 3-[1-methyl-pyrrolidin-(2Z)-ylidene]-3H-indole-6-carboxylic acid; hydrochloride (example 35, step 2) the title compound was prepared from 3-(1-benzyl-pyrrolidin-2-yl)-1H-indole-6-carboxylic acid methyl ester and LiOH.H2O. MS (m/e): 321.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].C(O)(=O)C.[OH-].[Na+]>C(O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[CH:11][C:3]([CH2:4][N:5]2[CH2:9][CH2:8][O:7][C:6]2=[O:10])=[C:2]([F:1])[CH:14]=1
Reactant: O=C1OCCN1Cc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(CN2CCOC2=O)c(F)c1
Reaction time: 0.17 h

Procedure:
To a solution of the compound obtained in Step B (10.37 mmoles) in ethanol (25 ml) there are added 122 microliters of acetic acid. The solution is heated at reflux and stirred for 10 minutes. Powdered iron (2.08 g) and 75 mg of FeCl3.6H2O are added. After stiffing for 2 hours at reflux, the mixture is brought to ambient temperature and then concentrated to dryness. 50 ml of water are added to the residue obtained, and the pH is made alkaline using sodium hydroxide. The solution is extracted 4 times with AcOEt. The organic phases are combined and washed with saturated aqueous NaCl solution and then dried with MgSO4. After filtration, the organic phase is evaporated to dryness to yield the title product, which is used directly in the next Step.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][CH:6]([CH2:11][C:12]([OH:14])=O)[C:7]([O:9][CH3:10])=[O:8]>ClCCl.CN(C)C=O>[Br:5][CH:6]([CH2:11][C:12]([Cl:3])=[O:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(Br)CC(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(Br)CC(=O)Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
Thionyl chloride (6.54 g, 54.9 mmol) in dichloromethane (7 mL) was added dropwise over 30 minutes to a mixture of 1-methyl hydrogen bromobutanedioate (i.e. the product of Step A) (10 g, 47.4 mmol) and N,N-dimethylformamide (5 drops) in dichloromethane (20 mL) heated at reflux. The mixture was heated at reflux for an additional 60 minutes and then allowed to cool to room temperature. The solvent was removed under reduced pressure to leave the title product as an oil (11 g, about 100% yield).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:17]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:16]=3)=[O:14])[CH:10]=[CH:11][C:6]=2S[CH2:4][C:3]1=[O:34].[Cl:35]C1C=CC=C(C(OO)=O)C=1.[S:46]([O-:49])(O)=[O:47].[Na+].Cl>CN(C)C(=O)C.C(OCC)(=O)C.O>[ClH:35].[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:17]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:16]=3)=[O:14])[CH:10]=[CH:11][C:6]=2[S:46](=[O:49])(=[O:47])[CH2:4][C:3]1=[O:34]
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1C(=O)CSc2ccc(NC(=O)c3ccc(-c4ccccc4)c(CN4CCCCC4)c3)cc21
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1C(=O)CS(=O)(=O)c2ccc(NC(=O)c3ccc(-c4ccccc4)c(CN4CCCCC4)c3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.2 %

Procedure:
In 5 ml of N,N-dimethylacetamide was dissolved 230 mg of N-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide, and then 252 mg of m-chloroperbenzoic acid was added under ice cooling, followed by 24 hours of stirring at room temperature. To the reaction solution was added 5 ml of water and 1016 mg of sodium hydrogen sulfite as two divided portions, followed by 2 hours of stirring at room temperature. Water was added to the reaction system, the organic layer was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia) to obtain a yellow oil. It was dissolved in 5 ml of ethyl acetate and then 1 ml of a 4M ethyl acetate solution of hydrochloric acid was added thereto. The solvent was removed by evaporation and the resulting solid was recrystallized from ethanol to obtain 61 mg of N-(4-methyl-1,1-dioxo-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl)-2-(piperidin-1-ylmethyl)biphenyl-4-carboxamide hydrochloride as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(O)(=O)C>[C:9]([O:8][C:7](=[O:13])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:22]([CH3:21])(=[O:24])=[O:23])([CH3:10])([CH3:12])[CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl N-(4-aminobutyl)carbamate (13.8 g, 73.4 mmol) and triethylamine (15.3 mL, 110 mmol) was cooled to 0° C. Methanesulfonyl chloride (6.3 mL, 81 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Aqueous acetic acid (200 mL of 10%) was added. The organic layer was then separated and washed with water (200 mL), saturated aqueous sodium bicarbonate (200 mL), water (200 mL), and brine; dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 18.9 g of tert-butyl[4-(methanesulfonylamino)butyl]carbamate as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36](=[O:46])[C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-])=O)[CH:38]=5)[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>CCOC(C)=O.CCO.[Pt]=O>[NH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[C:36]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:47])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])[CH:30]=1)=[O:46]
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)c5cccc([N+](=O)[O-])c5)c4)C(=O)O3)ccc2O1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)c5cccc(N)c5)c4)C(=O)O3)ccc2O1
Yield: 97.2 %

Procedure:
A solution of N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-3-nitrobenzamide (2.11 g) in EtOAc (30 ml) and EtOH (30 ml) was hydrogenated over platinum oxide (100 mg). After 1.25 h the mixture was filtered through celite and the filtrate evaporated in vacuo to give the title compound (1.955 g). LCMS RT=3.49 min, ES+ve 618 (MH)+.