Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:7]=1)[O:8][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 110 °C
Yield: 90.3 %

Procedure:
To a solution of 5-bromo-2-methylphenol (1.0 g, 0.005 mol) in DMF (10 mL) was added K2CO3 (1.38 g, 0.01 mol) at RT. 2-Chloro-5-(trifluoromethyl)pyridine (908 mg, 0.005 mol) was added and the reaction was refluxed at 110° C. for 12 h. The reaction mixture was quenched with water and extracted with EtOAc three times. The organic extract was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.5 g, 88%). 1H NMR (500 MHz, CDCl3): δ 8.42 (s, 1H), 7.92 (d, J=2.15 Hz, 1H), 7.32 (t, J=6.45 1H), 7.23 (d, J=1.5 Hz, 1H), 7.17 (d, J=8.05 Hz, 1H), 7.03 (d, J=8.65 Hz, 1H), 2.12 (s, 3H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH3:13]S(C)=O.OO>O>[CH3:13][O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: CS(C)=O
Agent: OO
Solvent: O
Product: CON1C(C)(C)CC(=O)CC1(C)C
Temperature: 30.5 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A 5.0 L 4 neck mechanically stirred flask is charged with 1oxyl-2,2,6,6-tetramethyl-4-piperidone (300 g, 1.76 moles), ferrous sulfate heptahydrate (513.7 g, 1.85 moles) and dimethylsulfoxide (1450 g). Hydrogen peroxide, 30% (279.2 g, 2.46 moles), is added over a 1 hour 45 min span. The temperature is maintained at 29-32° C. The Content is stirred for an additional 30 min at 25-30° C. and then chilled below 10° C. Water (1250 ml) is added and the mixture is extracted with four 750 ml portions of ethyl acetate. The combined extracts are washed, 2×1.0 L of H2O, then 1×500 ml of saturated NaCl and then dried over anhydrous MgSO4. Ethyl acetate is evaporated and the product is distilled (82-84° C./0.33×10−2 bar), yielding 254 g of a pale yellow oil (yield: 78% of theory; IR-spectrum: Ketone carbonyl, 1710 cm−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][CH:38]([OH:40])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][CH:38]([OH:40])[CH3:39])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: CC(O)CCN
Product: CC(O)CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-amino-2-butanol using methods similar to Example 563 to provide a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06-1.12 (m, 3 H), 1.53-1.68 (m, 6 H), 2.04 (t, J=5.90 Hz, 2 H), 3.22-3.30 (m, 2 H), 3.48 (dt, J=13.48, 6.74 Hz, 4 H), 3.62-3.76 (m, 1 H), 4.16 (s, 2 H), 4.39 (t, J=6.21 Hz, 2 H), 4.64 (d, J=4.63 Hz, 1 H), 7.11-7.18 (m, 2 H), 7.38-7.44 (m, 2 H), 8.19 (s, 1 H), 8.56 (d, J=1.26 Hz, 1 H), 10.33 (t, J=5.48 Hz, 1 H), 17.27 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[C:9]([O:12][CH:13]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:14][NH:15][C:16]([C:18]1[C:23]([I:24])=[C:22]([NH2:25])[C:21]([I:26])=[C:20]([C:27]([NH:29][CH2:30][CH:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:28])[C:19]=1[I:41])=[O:17])(=[O:11])[CH3:10]>>[C:9]([O:12][CH:13]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:14][NH:15][C:16]([C:18]1[C:23]([I:24])=[C:22]([NH:25][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:21]([I:26])=[C:20]([C:27]([NH:29][CH2:30][CH:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:28])[C:19]=1[I:41])=[O:17])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: O=C(Cl)CCCCCl
Product: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)CCCCCl)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reaction time: 1 h
Yield: 97 %

Procedure:
5-Chloropentanoyl chloride (5.1 g, 33 mmol) was added dropwise to a stirred solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (20.5 g, 23 mmol) in N,N'-dimethylacetamide (75 ml) at 0°-5°. The reaction mixture was stirred at 5° for 1 hour, and then at room temperature for 30 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (250 ml). The solution was washed with water (2×50 ml), followed by saturated aqueous NaCl (50 ml), and then dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[(5-chloro-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide as an off-white fluffy solid (22.1 g, yield 97%, purity 98.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][CH2:13]O>>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)[CH3:13]
Reactant: CCO
Reactant: Nc1cccc(CC(=O)O)c1
Product: CCOC(=O)Cc1cccc(N)c1

Procedure:
3-Aminophenylacetic acid (2 g, 13 mmol) was esterified with EtOH using Method B to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28]>>[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN)c2F)c1
Product: Cc1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(Cl)n3)c2F)[nH]1
Yield: 98.6 %

Procedure:
The previously described 2-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (0.040 g, 0.13 mmol) and 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.064 g, 0.14 mmol) were employed in a similar process described herein to prepare the title compound (0.064 g, quant.) as a white solid after purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) followed by neutralization. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.11 (br. s., 1H) 7.36 (t, J=5.84 Hz, 1H) 7.18-7.31 (m, 4H) 4.73 (d, J=5.91 Hz, 2H) 2.37 (s, 3H). ES-LCMS: m/z 497.9, 499.9, 501.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]3[CH2:16][CH:15]([NH:17][OH:18])[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C[Si]([N:25]=[C:26]=[O:27])(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]3[CH2:16][CH:15]([N:17]([OH:18])[C:26]([NH2:25])=[O:27])[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:20]=1
Reactant: ONC1CC(c2cccc(Oc3ccc(F)cc3)c2)C1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: NC(=O)N(O)C1CC(c2cccc(Oc3ccc(F)cc3)c2)C1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of 3-(3-(4-fluorophenoxy)phenyl)-1-cyclobutylhydroxylamine from above in THF (50 mL) was added trimethylsilylisocyanate (1.64 g of 85% purity, 12.12 mmol) and the reaction was stirred for 10 min. It was then concentrated in vacuo. The resulting residue was chromatographed (silica gel; ether, methanol 96:4 to 90:10) to afford 1.60 g (50% over three steps) of N-[3-(3-(4-fluorophenoxy)phenyl)-cyclobutyl]-N-hydroxyurea as a 1:1 mixture of diastereomers.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[N:9][CH:10]=2)[CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[N:9][CH:10]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc2cnnn2c1
Product: C(#Cc1ccc2cnnn2c1)c1ccccc1

Procedure:
The title compound, light brown solid, MS: m/e=220.3 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-[1,2,3]triazolo[1,5-a]pyridine (example 34, step 1) and phenylacetylene.
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[NH2:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>[Ni]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH2:9][OH:10])[CH2:2][NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [Ni]
Product: O=C(O)[C@H](Cc1ccc(O)cc1)NCC(O)C(O)C(O)CO

Procedure:
The product was made from D-ribose and L-(-)-tyrosine using Raney nickel as a catalyst and heating for 2 hours to 50° C. and for 4 hours to 70° C. The reaction product was yellowish, wax-like mass with an RF -value of 0.65 (determined as indicated under Example M).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)=[CH:4][CH:5]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(C(=O)c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure AJ and Scheme AV using [4-(bromomethyl)phenyl](phenyl)methanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.0 (M+H)+.
Reaction SMILES: C[O-].[Na+].Cl.Cl[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[SH:26])[CH3:14].O>CO>[CH2:13]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[S:26][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:14]
Reactant: CCn1c(S)nc2ccccc2c1=O
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1c(SCc2ccccn2)nc2ccccc2c1=O
Reaction time: 4 h
Yield: 48.3 %

Procedure:
7.0 ml of 28% methanolic solution of sodium methoxide and 2.82 g of 2-chloromethylpyridine hydrochloride were added, in turn, to a solution of 3.56 g of 3-ethyl-2mercapto-4(3H)-quinazolinone in 50 ml of methanol, and the stirring was continued at room temperature for 4 hours. The reaction solution was poured into about 300 ml of water and extracted with chloroform. The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether, to give 2.47 g of the title compound.
Reaction SMILES: CC([NH:9][S:10](/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:12])=[O:11])(C)CC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15](/[CH:14]=[CH:13]/[S:10]([NH2:9])(=[O:11])=[O:12])=[CH:20][CH:19]=1
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)/C=C/c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
To (E)-2-(4-chloro-phenyl)-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (5.0 g, 15.2 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (10 ml) and the mixture was stirred for 15 min. The mixture was concentrated in vacuo to afford a solid. The solid was washed with dichloromethane (5 ml) and heptane (150 ml). The resultant solid was collected by suction filtration. The solid was dried under vacuum at room temperature to afford (E)-2-(4-chloro-phenyl)-ethenesulfonic acid amide (2.95 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:35]=[CH:34][C:23]([O:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([OH:30])=[O:29])=[C:22]([F:36])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:37])[CH:3]=1.Cl.[NH2:39][OH:40].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:35]=[CH:34][C:23]([O:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([OH:30])=[O:29])=[C:22]([F:36])[CH:21]=2)[CH2:9]/[C:10](=[N:39]\[OH:40])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:37])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2cccc(C(=O)O)c2)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2cccc(C(=O)O)c2)c(F)c1

Procedure:
In analogy to example 151, step 3, 3-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=532.9 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[C:4](Cl)[C:5](Cl)=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>C(Cl)CCl>[C:16]1([C:17]2[NH:18][C:19]3[C:24]([C:25]=2[C:8]([C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:11]([OH:10])=[O:12])=[O:9])=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Cc1cc2ccccc2[nH]1
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
Employing a procedure similar to that described in part A of Example 10 above, 7.15 g (0.025 mole) of tetrachlorophthalic anhydride and 3.65 g (0.028 mole) of 2-methylindole were interacted in 100 ml of ethylene dichloride to obtain 2-[(2-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrachlorobenzoic acid (Formula VIII: R0 =R1 =R2 =R3 =Cl; R5 =CH3 ; R6 =Y1 =H), an orange solid melting at 200°-201° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[CH:14](=O)[C:15]1[CH:22]=[CH:21][CH:20]=[C:17]([CH:18]=[O:19])[CH:16]=1>[Cl-].[Zn+2].[Cl-]>[C:8]1([C:4]2[N:3]=[C:2]([CH:1]=[CH:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[CH:18]=[O:19])[CH:7]=[CH:6][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(-c2ccccc2)n1
Reactant: O=Cc1cccc(C=O)c1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=Cc1cccc(C=Cc2cccc(-c3ccccc3)n2)c1
Temperature: 160 °C

Procedure:
A mixture of 2-methyl-6-phenylpyridine (525 mg) (step 2), isophthalaldehyde (630 mg) and dry zinc chloride (40 mg) was heated at 160° C. under N2 for 3 hours. The resulting mixture was partitioned between 25% aqueous NH40Ac (20 cc) and ethyl acetate (20 cc) The organic layer was washed with H2O (10 cc), brine and solvent as removed in vacuo. The residue was purified by chromatography to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[NH3:21]>>[OH:17][CH2:18][CH2:19][CH:15]([C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:16]([NH2:21])=[O:20]
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Reactant: N
Product: CC1(C(CCO)C(N)=O)OCCc2c1[nH]c1ccccc21
Temperature: 90 °C

Procedure:
A suspension of 4,5-dihydro-3-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indol-1-yl)-2(3H)-furanone (described in Example 1, 20 g, 0.073 mole) in liquid ammonia is heated at 90° C. in a pressure apparatus for three hours. The apparatus is rinsed with ethanol and the yellow solution is evaporated. The residue is crystallized from methanol to afford α-(2-hydroxyethyl)-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetamide (16.15 g), mp 159°-161° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cccnc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Fc1ncccc1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (2-fluoropyridin-3-yl)methanol was dissolved in dichloromethane (30 mL) at 0° C. under nitrogen. Phosphorus tribromide (4.2 mL, 42 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by addition of 10% NaHCO3 solution (5 mL). After 10 minutes, Na2SO4 (30 g) was added. The solvent was filtered and evaporated to provide 3-(bromomethyl)-2-fluoropyridine, which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=[C:12]([OH:22])[CH:11]=2)=[N:4]1)[CH3:2].[N:24]1([C:28]([C:30]2[CH:31]=[C:32]([Cl:37])[C:33](Cl)=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:24]1([C:28]([C:30]2[CH:31]=[C:32]([Cl:37])[C:33]([O:22][C:12]3[CH:11]=[C:10]([CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=3)[C:9]([NH:8][C:5]3[CH:6]=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[O:23])=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)COC)c2)n1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)COC)c2)n1
Temperature: 160 °C
Yield: 85.6 %

Procedure:
A solution of N-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide (128 mg, 0.4 mmol) and the 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (111 mg, 0.48 mmol) in acetonitrile (2 mL) containing potassium carbonate (111 mg, 0.8 mmol) was heated in a microwave reactor at 160° C. for 6 hours. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure and purified by chromatography on silica, eluting with 50-100% ethyl acetate in hexane to give the required product as a white foam (176 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH:32]1[C:29]1[CH:28]=[CH:27][N:26]=[CH:31][CH:30]=1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1cc(C2CCCN2)ccn1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2c2ccncc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(pyridin-4-yl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.87 minutes; C26H23Cl2N5O2 (508.41); mass spectrum: (M−H)−=507/509/511 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Product: Fc1ccc(-c2noc(-c3cccnc3)n2)cc1
Temperature: 25 °C

Procedure:
4-Fluoro-N′-hydroxybenzimidamide (0.154 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.47 (t, J=6.8 Hz, 2 H), 7.74-7.70 (m, 1 H), 8.20-8.15 (m, 2 H), 8.58-8.54 (m, 1 H), 8.91-8.89 (dd, J=1.7, 1.7 Hz, 1 H), 9.35 (d, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]=[C:8]([CH3:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:18](Cl)([Cl:20])=[O:19]>C(Cl)(Cl)(Cl)Cl>[C:8]([N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:18]([Cl:20])=[O:19])([CH3:10])=[CH2:9]
Reactant: CC(C)=NC1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)N(C(=O)Cl)C1CCCCC1

Procedure:
139 parts of acetone cyclohexylimine and 111 parts of triethylamine are dissolved in 500 parts of carbon tetrachloride, and the whole reacted with 110 parts of phosgene as described in Example 1. 123 parts (61% of the theory) of N-isopropenyl-N-cyclohexylcarbamyl chloride is obtained having a boiling point of 85° C. at 0.01 mm.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:23]([CH2:36][CH2:37][CH3:38])[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1)[CH2:21][CH3:22].C(OC(C)C)(C)C>>[CH2:36]([N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH:35][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3=[CH:16][S:17][C:18]([CH3:19])=[C:5]23)=[O:3])[CH2:29][CH2:28]1)[CH2:37][CH3:38]
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CCCN(CCC)CCCC1CCN(CCN)CC1
Solvent: CC(C)OC(C)C
Product: CCCN(CCC)CCCC1CCN(CCNC(=O)N2c3ccccc3NC(=O)c3csc(C)c32)CC1
Yield: 42 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[4-[3-(dipropylamino)propyl]-piperidin-l-yl]ethanamine in a yield of 42% of theory. Colourless crystals, m.p. 114°-115° C. (diisopropyl ether).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[H][H]>C(O)C.[NH4+].[OH-].[Rh]>[NH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[N:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: N#CCc1c[nH]c2ccncc12
Reactant: [H][H]
Agent: [Rh]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCCc1c[nH]c2ccncc12
Reaction time: 24 h

Procedure:
A mixture of (1H-pyrrolo[3,2-c]pyridin-3-yl)-acetonitrile (0.260 g, 1.66 mmol) and 5% rhodium on alumina (0.26 g) in ethanol (10 mL) and concentrated NH4OH (5 mL) is placed under 55 psi hydrogen pressure on a Parr shaker. After 24 h at ambient temperature, the reaction mixture is filtered through Celite and concentrated in vacuo to afford the title amine, identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21]I>C(#N)C>[Cl:18][CH2:19][CH2:20][CH2:21][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: ClCCCI
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])ccc1OCCCCl
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a stirred solution of 2-methyl-4-nitrophenol (1.0 g, 6.5 mmol) and potassium carbonate (1.8 g, 13.0 mmol) in acetonitrile was added 1-chloro-3-iodopropane (1.2 g, 5.9 mmol). The mixture was heated at reflux overnight then cooled to r.t. and filtered, the solids being further washed with acetonitrile. The combined filtrates were evaporated to dryness. The crude residue was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and brine solution. The organic phase was dried over sodium sulfate, filtered and concentrated to afford 1-(3-chloro-propoxy)-2-methyl-4-nitro-benzene (700 mg, 52%) as an oil.