Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][CH2:9][CH2:10]Br)([O-:3])=[O:2].[CH3:15][N:16]1[C:21]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][C:19](=[O:28])[N:18]([CH3:29])[C:17]1=[O:30].C(N(CC)CC)C>O1CCOCC1>[CH3:15][N:16]1[C:21]([N:22]2[CH2:27][CH2:26][N:25]([CH2:10][CH2:9][CH2:8][O:7][C:6]3[CH:12]=[CH:13][CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:24][CH2:23]2)=[CH:20][C:19](=[O:28])[N:18]([CH3:29])[C:17]1=[O:30]
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])c1cccc(OCCCBr)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1c(N2CCN(CCCOc3cccc([N+](=O)[O-])c3)CC2)cc(=O)n(C)c1=O
Yield: 67 %

Procedure:
1.69 g of the above oily compound d, 1.12 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound b) and 1 ml of triethylamine were heated under reflux in 20 ml of dioxane for 4 hours to carry out reaction. After completion of the reaction, insolubles were removed from the reaction mixture by filtration, and the filtrate was then concentrated. Next, the resultant residue (concentrate) was dissolved in chloroform, and the resultant chloroform solution was washed with water. Afterward, the washed organic layer was dried over anhydrous magnesium sulfate and then treated with under reduced pressure to distill off the solvent. The residue was further purified through a silica gel column chromatography (chloroform/methanol=100/1 to 25/1 in volume ratio) and then recrystallized from ethanol. The resultant crystals were collected by filtration, washed, and then dried, thereby obtaining 1.35 g of 1,3-dimethyl-6-[4-(3-[3-nitrophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound c).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[N+:13]([O-])([OH:15])=[O:14].O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Nc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1ccc(C)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
100 ml of methylene chloride are introduced into a 2 l four-necked flask equipped with a stirrer, reflux condenser, thermometer and two dropping funnels, and 165.2 g (1 mol) of 4-tolylcarbamic acid methyl ester, dissolved in 400 ml of methylene chloride, and 109.3 g of 98% strength (1.7 mols) nitric acid dissolved in 150 ml of methylene chloride are added simultaneously in the course of 1 hour, at 20° C. and under normal pressure, the temperature being maintained by external cooling. After completion of the dropwise addition, the mixture is stirred for a further hour at 20° C., the resulting solution is extracted twice with 100 ml of water at a time, and the organic solvent is then distilled off. Yield: 209.3 g of crude product, of melting point 96° to 102° C. This crude product is introduced into dilute sodium hydroxide solution, consisting of 450 ml of water and 112 g (2.8 mols) of NaOH, and the mixture is heated to 95° C. and kept at this temperature for 3 hours, whilst distilling off the methanol formed during hydrolysis of the 2-nitro-4-tolylcarbamic acid methyl ester to the amino group. The mixture is cooled to 60° C. and stirred for a further 30 minutes at 60° C., and the product is filtered off and washed alkali-free with water. The moist product is dried to constant weight in vacuo at 60° C. Yield: 144.4 g of dry product (94.6% of theory); purity: 99.7%.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:30])[N:21]([CH3:29])[CH2:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][N:21]([CH2:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[C:20](=[O:30])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CN(CCc1cccs1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1cccs1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester (5.17 g, 11.4 mmol was dissolved in dichloromethane (12 ml). The solution was cooled to 0° C. Trifluoroacetic acid (12 ml) was added. The reaction mixture was stirred for 15 min at 0° C. The solvent was removed in vacuo at 20° C. The residue was codistilled with dichloromethane (3×60 ml). The crude product was purified by flash chromatography on silica (80 g), using dichloromethane/methanol/125% aqueous (100:10:1) ammonia as eluent, to give 1.91 g of (2R)-N-methyl-2-(methylamino)3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([N+:19]([O-])=O)=[CH:14][C:13]=2[Cl:22])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H][H]>CO.[Ni]>[Cl:18][C:17]1[CH:16]=[C:15]([CH:14]=[C:13]([Cl:22])[C:12]=1[CH:9]([C:10]#[N:11])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[NH2:19]
Reactant: [H][H]
Reactant: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CO
Product: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(N)cc1Cl
Yield: 95 %

Procedure:
In 100 ml of methanol were dissolved 7.6 g of α-(3,4-dichlorophenyl)-α-(2,6-dichloro-4-nitrophenyl)acetonitrile and 0.8 g (50%) of Raney's nickel. The solution was subjected to reduction with three times as much mol. of hydrogen gas. Insolubles were removed from the reaction mixture, then the remaining solution was concentrated to give the titled compound in a yield of 95%, m.p. 191-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[O:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: Oc1ccc2cn[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3cn[nH]c3c2)cc1Cl
Temperature: 90 °C

Procedure:
To a stirred solution of 2-chloro-4-fluoro-1-nitrobenzene (3 mmol) in DMF (5 mL) was added 6-hydroxyindazole (3 mmol) and K2CO3 (6 mmol). The contents were heated at 90° C. for 6 h. The reaction mixture was cooled to RT, and the contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 6-(3-chloro-4-nitrophenoxy)-1H-indazole as a yellow solid, which was used for further transformation without any purification.
Reaction SMILES: [ClH:1].C(N([CH:7]([C:9]1[C:10]([CH3:21])=[C:11]2[C:15](=[C:16]([CH3:18])[CH:17]=1)[NH:14][C:13](=O)[C:12]2=O)[CH3:8])CC)C.[F:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][C:28]2[N:29]([NH2:34])[C:30]([NH2:33])=[N:31][N:32]=2)=[CH:25][CH:24]=1>C(O)CO.O.C(NCC)C>[ClH:1].[CH2:13]([N:14]([CH2:15][CH3:11])[CH2:8][CH2:7][C:9]1[C:10]([CH3:21])=[C:11]2[C:15](=[C:16]([CH3:18])[CH:17]=1)[NH:14][C:13]1[C:12]2=[N:34][N:29]2[C:28]([CH2:27][C:26]3[CH:35]=[CH:36][C:23]([F:22])=[CH:24][CH:25]=3)=[N:32][N:31]=[C:30]2[N:33]=1)[CH3:12]
Reactant: CCN(CC)C(C)c1cc(C)c2c(c1C)C(=O)C(=O)N2
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Agent: Cl
Solvent: OCCO
Solvent: CCNCC
Solvent: O
Product: CCN(CC)CCc1cc(C)c2[nH]c3nc4nnc(Cc5ccc(F)cc5)n4nc3c2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.60 mmol of 5-(N,N-diethylamino-2-ethyl)-4,7-dimethyl-1H-indole-2,3-dione hydrochloride (186.5 mg) and 0.70 mmol of (4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine (145 mg) in 1.5 mL of ethylene glycol was stirred at 125° C. for 1 day. The mixture was cooled to room temperature, diluted with water (5 mL), and neat diethylamine 0.5 mL was added. Stirred for 3 hours, the precipitate was collected by filtration, washed with water and dried on highvac. The obtained free base was suspended in water (10 mL), 2M HCl 0.5 mL was added, heated to boil, sonicated briefly while hot and then allowed to crystallize in a refrigerator (+5° C.) overnight. The precipitate was collected by filtration, washed with ice-cold water (2×1 mL) and dried on high vacuum.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[C:23]2[N:19]([C:20]([C:27]([C:29]3[CH:30]=[CH:31][C:32]([NH:39]C(=O)C(F)(F)F)=[C:33]([CH:38]=3)[C:34]([O:36][CH3:37])=[O:35])=[O:28])=[C:21]([CH3:26])[C:22]=2[O:24][CH3:25])[CH:18]=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.ClCCl>[NH2:39][C:32]1[CH:31]=[CH:30][C:29]([C:27]([C:20]2[N:19]3[C:23]([C:15]([O:14][CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:16][CH:17]=[CH:18]3)=[C:22]([O:24][CH3:25])[C:21]=2[CH3:26])=[O:28])=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCc4ccccc4)cccn23)ccc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCc4ccccc4)cccn23)ccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.2 %

Procedure:
1.15 g (8.33 mmol) of potassium carbonate are added to the solution of 0.90 g (1.67 mmol) of methyl 5-{[8-(benzyloxy)-1-methoxy-2-methylindolizin-3-yl]carbonyl}-2-[(trifluoroacetyl)amino]benzoate in 100 ml of methanol and 100 ml of dichloromethane. The mixture is stirred at ambient temperature for 20 hours. The yellow precipitate formed is filtered, washed thoroughly with water and dried, to give 0.61 g (83%) of a yellow powder.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.Cl[C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30]2)[CH:26]=[N:25][CH:24]=1>C1COCC1>[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:30]2)[CH:26]=[N:25][CH:24]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2cncc(Cl)n2)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCCC(NC(=O)OC(C)(C)C)C2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a solution of tri-n-butyltin hydride (1.686 mL, 6.39 mmol) in THF (10 mL) at 0° C. was added LDA (1.8 M solution in heptane/THF/ethylbenzene, 3.55 mL, 6.39 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min and tert-butyl 1-(6-chloropyrazin-2-yl)piperidin-3-ylcarbamate (1.00 g, 3.20 mmol) was added. The reaction mixture was kept at 0° C. for 2 h, then quenched with 10% KF solution. The mixture was extracted with DCM and the combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-25% EtOAc in Hexanes) to give tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-3-ylcarbamate (400 mg, 22.1% yield). MS (ESI, pos. ion) m/z: 569 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH:16]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][NH:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1Cc2ccccc2C1
Reactant: O=CCCC1CCCCN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CN2CCCCC2CCCNC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 23 (820 mg, 3.55 mmol) in DCM (15 mL) was added 2-amino-indane (472 mg, 3.55 mmol) drop-wise at ice cold conditions. Acetic acid (0.2 mL) was added to the reaction mixture, followed by sodium triacetoxy borohydride (2.2 g, 10.65 mmol) portion-wise at ice cold conditions. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted with DCM, washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by 230-400 silica gel column chromatography using 1-3% MeOH-DCM as eluent to yield compound 24.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[C:2]#[CH:3].[ClH:18]>O1CCOCC1>[ClH:18].[CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[C:2]#[CH:3]
Reactant: C#CCOC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C#CCOC1CCNCC1
Reaction time: 1 h

Procedure:
To a RT solution of tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (0.826 g, 3.45 mmol) in 1,4-dioxane (10 mL) was added 4.0M HCl solution in 1,4-dioxane (1.80 mL, 7.20 mmol). After 2 h an additional amount of 4.0M HCl solution in 1,4-dioxane (1.80 mL, 7.20 mmol) was added and the reaction was stirred for 1 h. The solvent was removed in vacuo to yield the titled compound as a white crystalline solid (632 mg, quant).
Reaction SMILES: N/[C:2](=[CH:5]\[CH3:6])/[C:3]#[N:4].[ClH:7].Cl.[NH:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[NH2:10].Cl>O>[ClH:7].[ClH:7].[CH3:6][C:5]1[CH:2]=[C:3]([NH2:4])[N:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:10]=1
Reactant: C/C=C(\N)C#N
Reactant: NNc1cccnc1
Agent: Cl
Solvent: O
Product: Cc1cc(N)n(-c2cccnc2)n1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A solution of aminocrotononitrile (8.21 g, 100 mmol) and 3-hydrazinopyridine dihydrochloride (20.7 g, 114 mmol) in water (50 mL) was mixed with conc. hydrochloric acid (15 mL), and the mixture was heated under reflux for 30 minutes. The solution was allowed to cool to room temperature, and the reaction solvent was evaporated under reduced pressure, and the resulting crystals were collected by filtration. The crystals obtained were washed with water and air dried to give the title compound (13.6 g, 55% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([OH:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[N:21]=[C:22]([NH2:24])[CH3:23].CN1CCOCC1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([O:19][N:21]=[C:22]([NH2:24])[CH3:23])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(N)=NO
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN1CCOCC1
Product: CC(N)=NOC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by a similar method to Preparation 39 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparation 38], N′1-hydroxyethanimidamide [La Manna, et al, Theochem (1990), 69, 161-68], N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford N′1-[((2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonyl)oxy]ethanimidamide as a colourless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.C1C(=O)N([Br:22])C(=O)C1>>[Br:22][C:8]1[CH:7]=[C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CCCC(=O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1ccc(CCCC(=O)O)cc1Br
Reaction time: 20 h
Yield: 99.6 %

Procedure:
According to the procedure described in the synthesis method of Intermediate 3 in Reference Example 1 (Step g) with the modifications that the reaction was carried out under ice cooling for 30 minutes and at room temperature for 20 hours, 4-(4-methoxyphenyl)butyric acid (11.64 g, Ald) and NBS (11.21 g) were reacted and treated to obtain the title compound (Intermediate 11, 16.30 g).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:48]([C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[N:52][CH:51]=1)=[CH2:49]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([CH:49]=[CH:48][C:50]4[C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH:53]=[N:52][CH:51]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: C=Cc1cncc2ccccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)CC[C@]2(C)c3ccc(C=Cc4cncc5ccccc45)cc3CC[C@@H]12
Reaction time: 20 h

Procedure:
A 508 mg portion of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one, 4 mg of palladium acetate, 20 mg of tri-o-tolylphosphine, 0.34 mL of triethylamine and 5 mL of dimethylformamide were combined in a sealable tube with a stir bar, and the mixture was warmed to 50° under argon. An 0.26 g portion of 4-ethenylisoquinoline was added. Then the vessel was blanketed with argon and sealed and the mixture was heated with stirring at 120° for 20 hours. It was then cooled, and concentrated under vacuum and the residue was purified by chromatography on silica gel, eluting with 5% isopropanol in chloroform. An 0.29 g portion of an oil was obtained, which was recrystallized from ethyl acetate/hexane to obtain the desired product in crystalline form. mp 183°-185°; FDMS 382 M+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:16][C:17]([C:19]1[NH:23][C:22]2[S:24][C:25](Br)=[CH:26][C:21]=2[CH:20]=1)=[O:18])[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37].O>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@H:8]([NH:16][C:17]([C:19]1[NH:23][C:22]2[S:24][C:25]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])=[CH:26][C:21]=2[CH:20]=1)=[O:18])[C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1)c1cc2cc(Br)sc2[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc2cc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CC(O)C3)[nH]c2s1
Reaction time: 8 h
Yield: 4 %

Procedure:
Using a modified procedure of J. M. Tour et al. (J. Org. Chem., 61: 6906-6921 (1996)), to a degassed solution of 2-bromo-6H-thieno[2,3-b]pyrrole-5-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide (106 mg, 0.24 mmol) in tetrahydrofuran (5 ml) was sequentially added diisopropylamine (36 μl, 0.26 mmol), a mixture of copper(1) iodide (9 mg, 0.05 mmol) and dichlorobis(triphenylphosphine)palladium(II) (68 mg, 0.1 mmol), and (trimethylsilyl)acetylene (41 μl, 0.29 mmol). The mixture was stirred overnight, poured into water, and extracted with dichloromethane. The combined organic phases were washed with saturated NaCl, dried over MgSO4, and concentrated. The product was purified by Chromatotron-chromatography (dichloromethane; 20:1 dichloromethane:methanol) to give the title product (4.5 mg, 4%).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]([C:9]([O:11]C)=[O:10])[CH:7]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]([CH3:21])[C:5](=[O:22])[O:4]1>C(O)C>[CH3:2][CH:3]1[CH:8]([C:9]([OH:11])=[O:10])[CH:7]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]([CH3:21])[C:5](=[O:22])[O:4]1
Reactant: COC(=O)C1C(C)OC(=O)C(C)C1NCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC1OC(=O)C(C)C(NCc2ccccc2)C1C(=O)O

Procedure:
Methyl (2SR,3SR,4RS,5RS)-tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyrane-3-carboxylate hydrochloride (110 mg) was dissolved in conc. hydrochliric acid (0.9 ml), and the resultant mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with ethanol and distilled under reduced pressure. The residue was purified by thin layer chromatography to give (2SR,3SR,4RS,5RS)-tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyrane-3-carboxylic acid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18](C)=[CH:17][CH:16]=2>C(Cl)CCl>[C:12]1([C:13]2[NH:14][C:15]3[C:20]([C:21]=2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc2[nH]c(C)cc2c1
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Yield: 65.5 %

Procedure:
A mixture of 5.0 g (0.034 mole) of phthalic anhydride and 5.0 g (0.034 mole) of 2,5-dimethylindole in 30 ml of ethylene dichloride was refluxed for 20 hours, cooled and the separated solid filtered off and dried to obtain 3.8 g of 2-[(2,5-dimethyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R0 =R1 =R2 =R3 =R6 =H; R5 =CH3 ; Y1 =CH3) as a pink-colored solid melting at 198°-200° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CSCCN1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C#N)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A10) (2.00 g, 7.11 mmol) and thiomorpholine (3.38 ml, 35.6 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a light yellow solid (2.20 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[CH:21][N:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.BrBr.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[CH:16]=[C:15]3[C:10]([C:11]4[CH:22]=[CH:21][N:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2N=C3c4ccncc4CCC3CC2=O)cc1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(-n2nc3c(cc2=O)CCc2cnccc2-3)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 25.2 %

Procedure:
4,4a,5,6-Tetrahydro-2-(4-methylphenyl)pyrido[3,4-h]cinnolin-3(2H)-one (0.14 g; from Example 1 above) was dissolved in acetic acid (2 ml) and heated to 80° C. Bromine (0.027 ml) was added dropwise and the solution stirred for 16 hours. The reaction was cooled to room temperature, poured into aqueous sodium hydrogen carbonate and extracted thrice with dichloromethane. The organics were washed with sodium thiosulphate solution and brine, dried, filtered and concentrated. The product was adsorbed onto silica then chromatographed eluting with 1:1 dichloromethane:ethyl acetate then recrystallised from isopropanol twice to give the title compound (35 mg).