Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8](O)[C:7]=2[CH:15]=1)#[N:2].C(N(CC)CC)C.CS([Cl:27])(=O)=O.O>ClCCl>[Cl:27][CH:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9]1
Reactant: CC1(C)CC(O)c2cc(C#N)ccc2O1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(Cl)c2cc(C#N)ccc2O1
Reaction time: 18 h

Procedure:
To a solution of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol (U.K. Patent Application GB 2 204 868A) (2.93 g) and triethylamine (4.04 ml) in dichloromethane (100 ml) was added methanesulphonylchloride (2.24 ml) over 30 min, under an atmosphere of nitrogen. The reaction mixture was stirred for 18 h, water was added and the organic phase separated, washed with aqueous sodium hydrogencarbonate and dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent in vacuo gave the title compound (3.03g) as a solid, which was used in the next step without further purification.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>C(Cl)Cl.CO>[CH3:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CCOCCOCCOC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: COCCOCCOCCP(=O)(O)O
Temperature: -35 °C
Reaction time: 2 h

Procedure:
{2-[2-(2-Methoxyethoxy)ethoxy]ethyl}phosphonic acid diethyl ester (1.00 g, 3.5 mmol) was dissolved in CH2Cl2 (20 ml) under N2. Bromotrimethylsilane (2.3 ml, 17.5 mmol) was added via syringe and the mixture was stirred for 2 hours. Volatiles were removed in vacuo to give a thick orange oil; this was dissolved in MeOH (100 ml) with fuming to give a give a yellow solution. The mixture was stirred for 2 hours and evaporated to dryness to give a thick yellow oil which was dissolved in CH2Cl2 and extracted with NaOH (3×50 ml, aq., 1M). HCl (conc.) was added to the yellow aqueous layer until the solution was acidic to pH paper. Removal of water in vacuo gave a yellow crystalline solid that was extracted with EtOH and filtered. Cooling the filtrate to −35° C. resulted in precipitation of further white solid which was removed by filtration. Removal of volatiles from the yellow supernatant under vacuum (0.01 torr) afforded the desired product as a thick yellow oil. Yield 0.60 g, 2.6 mmol, 74%. 1H NMR (d6-DMSO, 400 MHz, 298 K): δ 3.55 (ap. q. J=7 Hz, 2H), 3.48 (m, 6H), 3.41 (m, 2H), 3.23 (s, 3H), 1.83 (d of t, JH-P=19 Hz, JH-H=7 Hz, 2H). 13C{1H} NMR (d6-DMSO, 100 MHz, 298 K): δ 71.25, 69.69, 69.58, 69.27, 65.41, 58.05, 28.99 (d, JC-P=132 Hz). 31P{1H} NMR (d6-DMSO, 162 MHz, 298 K): δ 23.15. MS (ESI, m/z): 227 (44−, 100%), 229 ([M+H]+, 10%). Exact mass found (calculated for [M+H]+, m/z): 229.08490 (229.08410).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:18])[CH3:17])[CH:10]([C:25](=O)[NH:26][CH2:27][C:28]([C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:42]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:17])[CH3:18])[CH:10]([C:25]2[NH:26][CH:27]=[C:28]([C:30]3[CH:31]=[CH:32][C:33]([Br:36])=[CH:34][CH:35]=3)[N:42]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 3.43 mmol) was dissolved in m-xylenes (18 mL) and heated at 135° C. Solid ammonium acetate (1.70 g, 22.0 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w MeOH 10%/hexanes) to yield the product 3-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-1-carboxylic acid tert-butyl ester (674 mg, 1.19 mmol): LCMS-ESI+: calc'd for C25H34BrN5O5: 564.5 (M+); Found: 564.2/566.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N+:8]([O-])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[F:22][C:23]([F:34])([F:33])[C:24]([O:26]C(=O)C(F)(F)F)=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([O:26][C:24](=[O:25])[C:23]([F:34])([F:33])[F:22])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Br)ccc2N1
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1OC(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A 9.5-g (0.027 mole) portion of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide was added portion-wise to 50 ml of trifluoroacetic anhydride, and the reaction mixture was stirred for 90 minutes. The suspended solid that formed was collected on a filter, washed thoroughly with pentane and dried in a vacuum over KOH. There was obtained 9.72 g (80%) of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2one as an off-white crystalline powder: mp 175°-177° (dec.); 19F nmr (DMSO-d6) δ -74.6 ppm (s, 3F) and -112.7 ppm (m, 1F); 1H nmr (DMSO-d6) δ 6.34 ppm (s, 1H), 7.1-8.1 ppm (m, 7H), 11.5 ppm (NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].C1([C@H]2[O:40][CH:39]([CH2:41][O:42][NH2:43])[CH2:38][CH2:37][O:36]2)C=CC=CC=1>>[OH:40][C@H:39]([CH2:38][CH2:37][OH:36])[CH2:41][O:42][NH:43][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: NOCC1CCO[C@@H](c2ccccc2)O1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC[C@H](O)CCO)c(=O)n(C)c1=O
Yield: 60 %

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of Example 2 by treatment of compound 2A with O—((R)-2-Phenyl-[1,3]dioxan-4-ylmethyl)-hydroxylamine, followed by acid hydrolysis of the resulting material (total yield 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (s, 1H) 11.97 (s, 1H) 7.80 (dd, J=10.11, 1.77 Hz, 1H) 7.58 (d, J=8.84 Hz, 1H) 7.15 (t, J=8.59 Hz, 1H) 4.90 (d, J=4.29 Hz, 1H) 4.38 (t, J=5.05 Hz, 1H) 3.71-3.90 (m, 2H) 3.56-3.67 (m, 1H) 3.44-3.53 (m, 2H) 3.21 (s, 3H) 2.96 (s, 3H) 1.30-1.59 (m, 2H). [M+H] calc'd for C17H20FIN4O6, 523; found, 523.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>O>[ClH:1].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CCCN(CCC)CC1CCCCN1CCN
Solvent: O
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Product: Cl
Yield: 87 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(dipropylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 87% of theory. Colourless crystals, m.p. 197°-199° C., not readily soluble in water.
Reaction SMILES: Cl.[CH3:2][C@:3]12[CH:16]3[CH2:17][CH:14]([C:15]3([CH3:19])[CH3:18])[CH2:13][C@H:4]1[O:5][B:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)[O:7]2.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[O:35]=[C:34]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[B:6]1[O:5][C@@H:4]2[CH2:13][CH:14]3[CH2:17][CH:16]([C@:3]2([CH3:2])[O:7]1)[C:15]3([CH3:19])[CH3:18])[CH2:33][NH:32][C:30]([C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]=[CH:21][CH:22]=1)=[O:31]
Reactant: O=C(O)CNC(=O)c1ccnc2ccccc12
Reactant: CC1(C)C2CC1[C@]1(C)OB([C@@H]3CCCN3)O[C@@H]1C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)C2CC1[C@]1(C)OB([C@@H]3CCCN3C(=O)CNC(=O)c3ccnc4ccccc34)O[C@@H]1C2
Reaction time: 3 h

Procedure:
(2R)-2-((3aS,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidine hydrochloride (0.190 g, 0.665 mmol) was added to a mixture of 2-(quinoline-4-carboxamido)acetic acid (0.153 g, 0.665 mmol), HATU (0.253 g, 0.665 mmol) and DIPEA (0.360 ml, 2.062 mmol) in dichloromethane (5 mL). The mixture was stirred for 3 h and washed with 0.5N citric acid, saturated sodium bicarbonate and brine, followed by filtration and evaporation. Purification was done using column chromatography DCM-MeOH 0-6% MeOH.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[C:8]2[C:16]=1[NH:15][C:14]1[CH2:13][CH:12]([C:17](O)=[O:18])[CH2:11][CH2:10][C:9]2=1)(=[O:3])[NH2:2].ClC(OCC(C)C)=O.Cl.[CH3:37][NH:38][O:39][CH3:40]>C1COCC1.O.C(Cl)Cl>[F:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([F:27])[C:20]=1[C:7]1[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[C:16]2[C:8]=1[C:9]1[CH2:10][CH2:11][CH:12]([C:17]([N:38]([O:39][CH3:40])[CH3:37])=[O:18])[CH2:13][C:14]=1[NH:15]2
Reactant: NC(=O)c1ccc(-c2c(F)cccc2F)c2c3c([nH]c12)CC(C(=O)O)CC3
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
A solution of 8-carbamoyl-5-(2,6-difluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylic acid (Intermediate 23-3, 720 mg, 1.944 mmol) and TEA (1.084 mL, 7.78 mmol) in THF (5 mL) was treated with isobutyl chloroformate (266 mg, 1.944 mmol) at 0° C. After stirring for 10 min, a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (190 mg, 1.944 mmol) in THF (2 mL) and water (0.5 mL) was added. The mixture was stirred for 30 min, then diluted with DCM, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc) to provide 5-(2,6-difluorophenyl)-N2-methoxy-N2-methyl-2,3,4,9-tetrahydro-1H-carbazole-2,8-dicarboxamide as a white solid (802 mg, 93%). 1H NMR (400 MHz, chloroform-d) δ1.70-1.82 (m, 1 H) 1.90-1.99 (m, 1 H) 2.19-2.25 (m, 2 H) 2.32-2.42 (m, 1 H) 2.84-2.92 (m, 1 H) 3.05-3.19 (m, 1 H) 3.23 (s, 3 H) 3.70 (s, 3 H) 6.98-7.06 (m, 3 H) 7.35-7.42 (m, 2 H) 10.10 (s, 1 H). Mass spectrum m/z 414.2 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)[C:12]=1[F:29])[CH2:9][CH3:10])(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.O>[NH2:7][C@@H:8]([C:11]1[C:12]([F:29])=[C:13]([C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:19]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]#[N:27])=[O:28])[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(OC)c(C(=O)c2cccc(C#N)c2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](N)c1ccc(OC)c(C(=O)c2cccc(C#N)c2)c1F
Reaction time: 5 h

Procedure:
Step 5 {(R)-1-[3-(3-Cyano-benzoyl)-2-fluoro-4-methoxy-phenyl]-propyl}-carbamic acid tert-butyl ester (200 mg) was dissolved in DCM (5 mL), 4M HCl in dioxane (485 uL, 1.94 mmol, 4 eq) was added and the reaction mixture was stirred for 5 hours. Water was then added and the mixture was made basic with 1M NaOH. The organic phase was isolated by phase separator and combined and concentrated to give 3-[3-((R)-1-amino-propyl)-2-fluoro-6-methoxy-benzoyl]-benzonitrile.
Reaction SMILES: [F:1]/[CH:2]=[C:3](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl.O>C(O)C>[C:16]1(/[C:3](=[CH:2]/[F:1])/[CH2:4][NH2:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1C/C(=C\F)c1ccccc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NC/C(=C\F)c1ccccc1

Procedure:
(Z)-1-Fluoro-2-phenyl-3-phthalimidopropene (0.25 g) is treated with hydrazine hydrate (50 mg) in ethanol (2 ml), and then concentrated hydrochloric acid (2 ml) and water (2 ml). Recrystallization of the resulting product (0.19 g) from ethanol/ether affords pure (Z)-2-phenyl-3-fluoroallylamine, as the hydrochloride: m.p. 145°;
Reaction SMILES: C[O-].[Na+].[C:4](O)(=[S:6])[CH3:5].BrCC([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH2:18]([OH:20])[CH3:19]>CCOCC>[C:18]([CH2:5][C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:6])(=[O:20])[CH3:19]
Reactant: CC(O)=S
Reactant: O=C(CBr)c1ccccc1
Reactant: CCO
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)CC(=S)c1ccccc1

Procedure:
To a solution of 54.0 g (1.0M) sodium methoxide in 100 ml absolute ethanol stirring under nitrogen at reflux temperature 74 ml (76.1 g, 1.0M) thioacetic acid is added dropwise over a period of 0.5 hours. Upon complete addition the solution is refluxed for 15 minutes. To the yellow solution stirring under nitrogen atmosphere at reflux temperature, a solution of 199.1 g (1.0M) α-bromoacetophenone in 800 ml absolute ethanol is added rapidly dropwise over a period of 70 minutes. After complete addition, the suspension formed is refluxed for 3 hours. The reaction mixture is cooled and the precipitated NaBr is removed by vacuum filtration. The filtrate is concentrated in vacuo to give a brown oil with some solid present. This mixture is suspended in 500 ml of ether and is filtered to remove insoluble NaBr. The filtrate is stirred with activated charcoal for 0.5 hours, filtered, and concentrated in vacuo to give a red-brown oil. This oil is purified by vacuum distillation and the fraction is collected at 133°-137°/0.2-0.05 mm Hg and characterized by NMR as α-acetylthioacetophenone.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:15]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[N:14]=1)=[O:12])[CH2:6][CH:7]([CH3:9])[CH3:8])=[N+]=[N-].C(N(CC)CC)C.C(S)CCS.[BH4-].[Na+]>CC(O)C>[NH2:1][CH2:4][C@@H:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)=[C:15]([O:24][CH2:25][CH:26]2[CH2:27][CH2:28]2)[N:14]=1)=[O:12])[CH2:6][CH:7]([CH3:8])[CH3:9]
Reactant: CC(C)C[C@@H](CN=[N+]=[N-])NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Agent: SCCCS
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](CN)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-azidomethyl-3-methyl-butyl)-amide (107 mg, 277 μmol) was combined with 2-propanol (725 μl) to give an off-white suspension. To this suspension was added triethylamine (56.0 mg, 77.2 μl, 554 μmol), 1,3-propanedithiol (3.00 mg, 2.8 μl, 27.7 μmol) and sodium borohydride (15.7 mg, 415 μmol). The resulting reaction mixture was stirred at room temperature for 20 hours. Volatiles were removed in vacuo and the residue was stirred with 10% citric acid solution (5 mL) and a mixture of ethyl acetate/heptane (5 mL, 1:1). The aqueous layer was brought with 2N NaOH to pH=12 and extracted twice with ethyl acetate. The organic phases were combined, dried with Na2SO4, and concentrated in vacuo to give the title compound (32 mg, 32%) as colorless, viscous oil that was used without further purification in the next step; MS (ESI) 361.3 (M+H)+.
Reaction SMILES: N1C=CC=CC=1C1C=CC=CN=1.Cl[C:14]1[C:15]([C:23]([OH:25])=[O:24])=[N:16][C:17]([Cl:22])=[C:18]([Cl:21])[C:19]=1[Cl:20]>[Zn].C(#N)C>[Cl:20][C:19]1[C:18]([Cl:21])=[C:17]([Cl:22])[N:16]=[C:15]([C:23]([OH:25])=[O:24])[CH:14]=1
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC#N
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reaction time: 0.08 h

Procedure:
An 8 mL scintillation vial was charged with NiCl2.6H2O (12.0 mg, 0.051 mmol) and 2,2′-bipyridine (17.0 mg, 0.109 mmol). The vial was closed and purged with nitrogen for 5 min, after which the vial was charged with DMF (4.5 mL) and isopropyl alcohol (iPrOH; 0.5 mL). The mixture was allowed to stir for 5 min. To the vial was added zinc dust (0.2194 g, 3.4 mmol), and the mixture was allowed to stir under nitrogen for 35 min. Solid 3,4,5,6-tetrachloropicolinic acid (0.1076 g, 0.4 mmol) was added through the top of the reactor. The reaction mixture was allowed to stir at 14° C. and samples were removed periodically to determine reaction kinetics. The samples (˜0.01 mL of reaction mixture diluted to 1.5 mL with acetonitrile) were analyzed by a calibrated HPLC method.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][O:6][CH2:7][C:8](=[N:10][OH:11])[NH2:9].[CH3:12][N:13]1[CH2:18][C:17]([C:19]([O:21]C)=O)=[CH:16][CH2:15][CH2:14]1.Br.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)C.CCOCC>[C:24]([O-:29])(=[O:28])[C:25]([O-:27])=[O:26].[CH3:12][NH+:13]1[CH2:14][CH2:15][CH:16]=[C:17]([C:19]2[O:11][N:10]=[C:8]([CH2:7][O:6][CH3:5])[N:9]=2)[CH2:18]1.[CH3:12][NH+:13]1[CH2:14][CH2:15][CH:16]=[C:17]([C:19]2[O:21][N:10]=[C:8]([CH2:7][O:6][CH3:5])[N:9]=2)[CH2:18]1
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: O=C(O)C(=O)O
Reactant: COCC(N)=NO
Agent: Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COCc1noc(C2=CCC[NH+](C)C2)n1
Product: O=C([O-])C(=O)[O-]
Temperature: 80 °C

Procedure:
To a solution of sodium ethoxide (prepared from sodium (180 mg;7.8 mmol)), distilled ethanol (20 ml), molecular sieves (5 g), and methoxymethylcarboxamide oxime (832 mg; 8 mmol) were added. The mixture was stirred at room temperature for 10 min. whereafter arecoline, HBr (1.0 g; 4.23 mmol) was added. The mixture was heated at 80° C. for 12 hours, filtered, and evaporated in vacuo. To the residue was added water (10 ml) and the mixture was extracted with ether (3×25 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo. Upon disolving the residue in ethanol (99.9%)(5 ml) a solution of oxalic acid (350 mg;3.9 mmol) in ethanol (99.9%)(10 ml) was added. Addition of ether gave an analytically pure product in a yield of 500 mg (40%). M.P. 153°-154° C.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:2]1([C:1]2[NH:8][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][C:16](=[O:25])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)c1ccccc1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1CC(c2ccccc2)NC(c2ccccc2)=N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
To a stirred suspension of 8.42 g (70.2 mmol) of benzamidine and 8 mL (99.2 mmol) of pyridine in 150 mL of toluene was added dropwise over 10 min a solution of 7.68 g (46.1 mmol) of cinnamoyl chloride in 20 mL of toluene. The mixture was stirred for 10 min at room temperature and heated at reflux for 2 days. The mixture was cooled, diluted with 150 mL of ethyl acetate and extracted with two 125 mL portions of 5% aqueous HCl. The combined aqueous HCl extracts were neutralized by careful addition of 50% aqueous NaOH and extracted with two 250 mL portions of ethyl acetate. These ethyl acetate extracts were combined, dried over MgSO4 and rotovaped to afford 7.80 g of 5,6-dihydro-2,6-diphenylpyrimidin-4-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[NH:7][CH:6]=[CH:5]2.BrC1C=C2C(=CC=1)C(=O)N([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)C=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH:6]=[CH:5]2
Reactant: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Reactant: O=c1[nH]ccc2cc(Br)c(Cl)cc12
Product: COc1ccc(Cn2ccc3cc(Br)c(Cl)cc3c2=O)cc1

Procedure:
Starting from 6-Bromo-7-chloro-2H-isoquinolin-1-one (12), the title compound was prepared by the method described for 6-Bromo-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (compound 13). Rt=2.12 min (Method B). Detected mass: 378.1/380.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]1([CH2:14]Br)[CH2:13][CH2:12]1>CN(C=O)C>[CH:11]1([CH2:14][O:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: BrCC1CC1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 28.8 %

Procedure:
To a cold solution of 2-hydroxy-5-nitro pyridine (0.500 g, 3.57 mmol) in DMF (4.0 mL) was added cyclopropyl methyl bromide (0.481 g, 3.57 mmol) at 0° C. The reaction mass was stirred at RT for 5-6 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on neutral alumina eluting with 10% EtOAc: Pet.ether to afford 0.200 g of the desired product. 1HNMR (DMSO-d6): δ 0.45-0.48 (m, 2H), 0.70-0.75 (m, 2H), 1.10-1.28 (m, 1H), 3.87 (d, J=7.2 Hz, 2H), 6.57 (d, J=10.2 Hz, 1H), 8.10 (dd, J=3.0 Hz & 2.4 Hz, 1H), 8.77 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:35][C:36]1[N:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([NH:43][CH2:42][C:39]1[CH:40]=[N:41][C:36]([CH3:35])=[CH:37][CH:38]=1)=[O:7]
Reactant: Cc1ccc(CN)cn1
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNC(=O)c2cc(Br)cc(I)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 3-bromo-5-iodo-benzoic acid (1.4 g, 4.4 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.7 g, 8.8 mmol), 1-hydroxybenzotriazole hydrate (0.20 g, 1.3 mmol), and CH2Cl2 (50 mL) were added (6-methylpyridin-3-yl)methanamine (0.65 g, 5.3 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.8 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The precipitated solid was washed with water and ethyl ether and dried to afford the product as a white solid. LC-MS: 432.7 [M+l].
Reaction SMILES: C([O:4][CH2:5][CH3:6])(=O)C.[CH:7](OCC)=O.[O-]CC.[Na+].[NH:16]1[C:20]([NH2:21])=[CH:19][CH:18]=[N:17]1>C1(C)C=CC=CC=1>[N:17]1[N:16]2[C:5]([OH:4])=[CH:6][CH:7]=[N:21][C:20]2=[CH:19][CH:18]=1
Reactant: Nc1ccn[nH]1
Reactant: CCOC(C)=O
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1ccnc2ccnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl acetate (88 g, 1.0 mol, 1.0 eq) and ethyl formate (74 g, 1.0 mol, 1.0 eq) in toluene (100 mL), sodium ethoxide (68 g, 1.0 mol, 1.0 eq) is added and the resulting mixture is stirred at RT overnight. The reaction mixture is concentrated in vacuo to remove the solvent. The resulting residue is suspended in EtOH (100 mL) and then 1H-pyrazol-5-amine (41.5 g, 0.5 mol, 0.5 eq) is added in portions to the mixture. The resulting mixture is stirred at reflux for 5 h and concentrated in vacuo. The residue is suspended in ice-water (200 mL) and neutralized with conc. HCl to adjust pH to 1. The resulting solid is collected by filtration and dried in vacuo to afford the product, pyrazolo[1,5-a]pyrimidin-7-ol (C-1).