Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:12]2[C:13]([OH:15])=O)=[CH:6][CH:5]=1>CCOCC>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:10][N:11]3[CH:12]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:13](=[O:15])[C:8]=2[CH:9]=1
Reactant: COc1ccc(CN2CCCCC2C(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=O)C1CCCCN1C2

Procedure:
By the above procedure, N-(4-methoxyphenylmethyl)pipecolinic acid hydrochloride (2.98 g) was converted to 1,3,4,11a-tetrahydro-9-methoxy-2H-benzo[b]quinolizin-11(6R)-one (950 mg): mp 117-119° C. (ether); 1H NMR (300 MHz) δ 7.48 (d, J=2.7 Hz, 1 H), 7.14 (d, J=8.4 Hz, 1 H), 7.08 (dd, J=8.4, 2.7 Hz, 1 H), 3.84 (s, Me), 3.84(d, J=14.8 Hz, 1 H), 3.61 (d, J=14.8 Hz, 1 H), 3.08 (br d, J=11.1 Hz, 1 H), 2.74 (br d, J=10.1 Hz, 1 H), 2.42 (m 1 H), 2.34 (td, J=11.3, 3.6 Hz, 1 H), 1.90 (m, 1 H), 1.15-1.80 (m); 13C NMR (75 MHz) δ 195.89, 158.84, 134.60, 131.02, 127.51, 121.88, 108.96, 69.01, 56.61, 56.13, 55.52, 26.74, 25.03, 23.87; MS (EI) 231 (64, M), 203 (53), 202 (53), 174 (10), 161 (83), 148 (27), 121 (100), 120 (31); Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06; found C, 72.47; H, 7.47; N, 5.91.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:20]([C:22]1[C:23](=[C:33]([C:36]#[N:37])[C:34]#[N:35])[O:24][C:25]([CH3:32])([C:28]([F:31])([F:30])[F:29])[C:26]=1[CH3:27])#[N:21]>C(O)C>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:27][C:26]2[C:25]([CH3:32])([C:28]([F:31])([F:29])[F:30])[O:24][C:23](=[C:33]([C:36]#[N:37])[C:34]#[N:35])[C:22]=2[C:20]#[N:21])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
In 5 ml of ethanol were dissolved 149 mg (0.57 mmol) of 4-dibutylamino-2-methoxybenzaldehyde and 158 mg (0.62 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred at 50° C. for 2 hours, ethanol was evaporated off. The residue was purified by silica gel column chromatography to give 262 mg of a dark brown crystal (yield: 92.9%; mp: 211-213° C.)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:18][C:19]([F:32])([F:31])[C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[NH2:23]>>[F:18][C:19]([F:31])([F:32])[C:20]1[CH:21]=[C:22]([NH:23][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][C:2]=2[OH:1])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(C(F)(F)C(F)(F)F)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)C(F)(F)F)ccc1O

Procedure:
Using 2-hydroxy-5-(pentafluoroethyl)benzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. (2-Hydroxy-5-(pentafluoroethyl)benzoic acid: refer to Chem. Pharm. Bull., 1996, 44, 734.)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:16]([F:19])([F:18])[F:17])([CH3:15])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[I-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][C:24]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(COC)OC>[CH2:3]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:16]([F:17])([F:18])[F:19])([CH3:15])[CH2:13][O:14][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[C:24]([O:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:25]=2)=[CH:10][CH:11]=1)[CH3:4]
Reactant: CCOc1ccc(C(C)(CO)C(F)(F)F)cc1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1ccc(C(C)(COCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
Sodium hydride (144 mg; 6 mmol) was suspended in dimethoxyethane (16 ml) and then in turn, with stirring, there was added 2-(4-ethoxyphenyl)-2-trifluoromethyl-1-propanol (1.25 g; 5.044 mmol), a spatula of sodium iodide and 4-fluoro-3-phenoxybenzyl bromide (1.4 g; 5.04 mmol). After stirring for 5 hours at room temperature, the mixture was added to ice-water, extracted 3 times with ether and the extracts washed with water dried over sodium sulphate and evaporated. After chromatography on silica gel using a mixture of ethyl acetate and hexane, there was obtained 2.06 g of product (=91.1% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:11]=[CH:10][CH:17]=[CH:16][C:13]=2[CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=Cc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A heterogeneous mixture of 4-chlorophenol (14.1 g, 0.11 mmol), 4-fluorobenzaldehyde 12.4 g, 0.1 mmol) and CS2CO3 (65.0 g, 0.20 mmol) in DMF (400 mL) was stirred at 90° C. for 6 h. The reaction mixture was poured into water (1.2 L) and extracted with ethyl acetate (2×200 mL). The organic phase was washed with water (2×100 mL), dried over magnesium sulfate and concentrated to give essentially pure 4-chlorophenoxybenzaldehyde, which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[CH:11]1[O:15][CH:7]2[CH2:8][N:9]([CH2:16][C:17]#[CH:18])[CH2:10]1)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:16]([N:9]1[CH2:8][CH:7]2[O:15][CH:11]([C:12]3[C:6]2=[CH:5][C:4]([NH2:1])=[CH:14][CH:13]=3)[CH2:10]1)[C:17]#[CH:18]
Reactant: C#CCN1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCN1CC2OC(C1)c1cc(N)ccc12

Procedure:
4-Nitro-10-prop-2-ynyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (120 mg, 0.49 mmol) and tin chloride dihydrate (554 mg, 2.45 mmol) were heated at reflux in EtOAc (10 mL) for 2 h. The resulting mixture was then diluted with saturated aqueous NaHCO3 (10 mL), extracted with EtOAc (2×15 mL), dried over MgSO4, filtered and concentrated to obtain 10-Prop-2-ynyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine as a brown, viscous oil (71 mg, 68%). MS (m/e) 215 (M+1)
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[N:4]1.[I-].[Na+].Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[C:32]([CH3:42])=[N:33][N:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:35]=4)[CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][N:23]=2)=[CH:14][CH:13]=1>CN(C=O)C>[CH3:42][C:32]1[C:31]([CH2:30][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH2:11][N:4]5[N:5]=[CH:6][CH:7]=[N:3]5)=[CH:13][CH:14]=4)=[N:23][CH:22]=[CH:21][N:20]=3)[CH2:29][CH2:28]2)=[CH:35][N:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:33]=1
Reactant: Cc1nn(-c2ccccc2)cc1CN1CCN(c2nccnc2-c2ccc(CCl)cc2)CC1
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)cc1CN1CCN(c2nccnc2-c2ccc(Cn3nccn3)cc2)CC1
Reaction time: 1 h
Yield: 18.5 %

Procedure:
Add sodium hydride (173 mg, 4.33 mmol) to a solution of 1H-1,2,3-triazole (308 mg, 4.33 mmol) in DMF (3 mL). Maintain stirring under nitrogen for 1 hr then add sodium iodide (162 mg, 1.08 mmol) and a solution of 3′-(4-Chloromethyl-phenyl)-4-(3-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (495 mg, 1.08 mmol) in DMF (8 mL). Maintain stirring under nitrogen for 20 hr. Quench by adding water (10 mL), wash with DCM (3×10 mL) and discard the aq. phase. Concentrate to dryness to give a mixture of 4-(3-Methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3′-(4-[1,2,3]triazol-1-ylmethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl and 4-(3-Methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3′-(4-[1,2,3]triazol-2-ylmethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl. Purify first by preparative HPLC then by SCX-2® ion exchange chromatography, eluting with 2 M NH3 in MeOH. to give 4-(3-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3′-(4-[1,2,3]triazol-2-ylmethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (98 mg). MS (ES): m/z=492 [M+H]+ 2 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:26]=1)[C:21](O)=[O:22]>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:21](=[O:22])[C:20]1[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[N:26]=[C:18]([C:17]([F:32])([F:16])[F:31])[CH:19]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.). The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of CH2Cl2: EtOAc (100:0 to 70:30). Light yellow foam (61%). MS (ESI): m/z=440.118 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([NH:14][C@@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16]I)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1>CN(C=O)C>[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:16][CH:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=1)[C:30](=[O:32])[CH3:31])[C:18]([O:20][CH3:21])=[O:19])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(=O)Cc1cccc(Cl)c1
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C(C)=O)c1cccc(Cl)c1)NC(=O)OC(C)(C)C
Reaction time: 2.5 h

Procedure:
A mixture of cesium carbonate (9.80 g, 30.1 mmol) and methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (9.90 g, 30.1 mmol) in DMF (75 mL) was stirred at 23° C. for 45 min before 1-(3-chlorophenyl)propan-2-one (6.09 g, 36.1 mmol) and additional cesium carbonate (9.80 g, 30.1 mmol) were added. The resulting mixture was stirred for 2.5 h. The majority of the DMF was then removed under reduced pressure at a bath temperature of <40° C. The concentrated mixture was partitioned between water (100 mL) and ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the title compound as a 1:1 racemic mixture of cis and trans diastereomers, which was used without further purification. MS: m/z=392.1 (M+Na).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][C:4]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)=[O:5]
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: O=C(Cl)CCBr
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCBr)N1CC(c2ccccc2)c2ccccc21
Temperature: 10 °C

Procedure:
A solution of 9.1 ml of 3-bromopropionylchloride in 10 ml of dry benzene was added dropwise to a solution of 10.0 g of 3-phenylindoline and 10 ml of triethylamine in 100 ml of dry benzene cooled to 10° C. The precipitated triethylamine hydrochloride was separated by filtration, the benzene was removed from the filtrate in vacuo at room temperature and the residue recrystallized from ethanol to give 5.6 g of the desired N-(3-bromopropionyl)-3-phenylindoline having a melting point of 98°-9° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:13])[C:5]2[C:10]([N:11]=1)=[CH:9][N:8]=[C:7]([CH3:12])[N:6]=2.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)[N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:14][C:15]1[N:16]=[C:17]([C:21]2[N:25]([CH2:2][C:3]3[N:4]([CH3:13])[C:5]4[C:10]([N:11]=3)=[CH:9][N:8]=[C:7]([CH3:12])[N:6]=4)[CH:24]=[CH:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: Cc1ncc2nc(CCl)n(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc2nc(Cn3ccnc3-c3cccc(F)n3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 8-Chloromethyl-2,9-dimethyl-9H-purine (40 mg, 0.2 mmol), 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine (40 mg, 0.25 mmol) and K2CO3 (55 mg, 0.4 mmol) in 2 mL of DMF is stirred at room temperature for four hours. The mixture is diluted with water (10 mL), and extracted with ethyl acetate three times. The combined extract is washed with brine, dried and concentrated. The residue is purified by preparative thin layer chromatography to give the title compound. 1H NMR (CDCl3): δ 8.92 (s, 1H), 8.18 (dd, 1H), 7.88 (q, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 6.83 (dd, 1H), 6.22 (s, 2H), 3.89 (s, 3H), 2.8 (s, 3H). LRMS calcd 323. found 324 (MH+).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH:13]1[C:14]2[N:15]([CH2:18][CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)[C:16]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a suspension of sodium hydride (60% mineral oil, 0.13 g, 3.24 mmol) in dimethyl formamide (3 ml) was added phenoxazine (0.5 g, 2.7 mmol) in dimethyl formamide (5 mL). The reaction mixture was stirred at 25° C. for 0.5 h and a solution of 4-(2-bromoethoxy)benzaldehyde (0.74 g, 3.24 mmol) in dimethyl formamide (3 mL) was added. The reaction mixture was stirred at 25° C. for 6 h. Water (25 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (50 ml), brine solution (50 ml) and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (3:7) as eluent to afford the title compound (0.52 g, 57%) as a syrupy liquid.
Reaction SMILES: [I:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7](=[O:17])[CH2:8][CH:9](C(OCC)=O)[C:10](=[O:11])[C:4]=2[CH:3]=1.[Na+].[Cl-].O>CS(C)=O>[I:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7](=[O:17])[CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CC(=O)Nc2ccc(I)cc2C1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCC(=O)c2cc(I)ccc2N1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 7-iodo-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate (iii-a) (4.84 g, 13.2 mmol) in dimethyl sulfoxide (66 mL) was added a solution of NaCl (81 mg, 15.9 mmol) in H2O (475 μL, 26.4 mmol). The reaction mixture was heated to 150° C. for 2 h, and subsequently cooled to 0° C. for 30 min. H2O (120 mL) was added and the solution was allowed to stir for an additional 1.5 h at 0° C. The resulting precipitate was filtered to provide iv-a (3.2 g, 81%) as a purple/brown solid: MS m/z═302 (M+H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[S:9]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]1.[CH:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20].O>O1CCCC1>[CH3:20][CH:19]([CH3:21])[CH2:18][C:17]([C:10]1[S:9][CH:13]=[CH:12][C:11]=1[C:14]([OH:16])=[O:15])=[O:22]
Reactant: O=C(O)c1ccsc1
Reactant: CC(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1sccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lithium diisopropylamide (86 mmol) in tetrahydrofuran (30 ml) was added at 0° C. to a solution of thiophene-3-carboxylic acid (5 g) in tetrahydrofuran (50 ml). Isovaleraldehyde (4.6 ml) was added as a solution in tetrahydrofuran (30 ml) at 0° C. The reaction mixture was stirred at 25° C. for 3 hours and then water (100 ml) was added and the tetrahydrofuran was removed in vacuo. The aqueous residue obtained was extracted with ethyl acetate and the aqueous phase added to potassium permanganate (12.3 g) and warmed to 60° C. for 1.5 hours. The mixture was filtered, allowed to cool to ambient temperature, and then acidified with dilute hydrochloric acid. The acidic aqueous mixture was extracted with ethyl acetate and the organic extract dried and evaporated to give the sub-title compound as an oil (5.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13](CC1C=CC(Br)=CC=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].CCCC[Sn]([C:59]1[CH:64]=[CH:63][CH:62]=[N:61][CH:60]=1)(CCCC)CCCC>>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([N:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:59]2[CH:60]=[N:61][CH:62]=[CH:63][CH:64]=2)=[CH:19][CH:18]=1)[NH:13][CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:11])[C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: COC(=O)N[C@H](C(=O)N(Cc1ccc(-c2cccnc2)cc1)NC[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method A, using compound 19 (90.0 mg, 0.132 mmol), 3-(1,1,1-tributylstannyl)pyridine (194 mg, 0.527 mmol), Pd(PPh)3Cl2 (4.63 mg, 0.0065 mmol) and CuO (10.5 mg, 0.132 mmol). The product (24.0 mg, 27%) was afforded as a white solid after purification by RP-LC-MS (40 min gradient of 10-100% CH3CN in 0.05% aqueous formic acid).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3OC(=O)[S:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:23](#[N:27])[C:24]([CH3:26])=[O:25]>C1(C)C(C)=CC=CC=1>[CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:27]=[C:23]([C:24](=[O:25])[CH3:26])[S:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3nsc(=O)o3)s2)cc1
Reactant: CC(=O)C#N
Solvent: Cc1ccccc1C
Product: CC(=O)c1nc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)ns1
Yield: 84 %

Procedure:
A mixture of Example 100B (2.0 g, 0.0057 mol) and excess pyruvonitrile (2 mL) in xylene was heated at reflux in a pressure tube overnight. The solvent was removed and the residue was purified on silica gel (5˜30% ethyl acetate in hexane) to give 1.74 g of product as a light yellow solid (84% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J=6.25 Hz, 6H) 2.77 (s, 3H) 4.46-4.61 (m, 1H) 6.89-6.99 (m, 2H) 7.18-7.25 (m, 2H) 8.03 (s, 1H). MS (ESI), M/Z: 394.0 (M+33)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([NH2:18])=[C:10]([NH2:19])[CH:9]=2)[CH:4]=[CH:3]1.[C:20](O)(=[O:24])[C:21](O)=[O:22].Cl>>[O:1]=[C:2]1[CH:3]=[CH:4][N:5]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:12][C:13]=2[C:14]([F:16])([F:17])[F:15])[NH:18][C:21](=[O:22])[C:20](=[O:24])[NH:19]3)[CH:6]=[CH:7]1
Reactant: Nc1cc(-n2ccc(=O)cc2)c(C(F)(F)F)cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2C(F)(F)F)cc1
Yield: 60 %

Procedure:
First, a mixture containing 300 mg of 4-(4-oxo-4H-pyridin-1-yl)-5-trifluoromethyl-1,2-phenylenediamine, 301 mg of oxalic acid, and 6 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 7 hours. The mixture was cooled and precipitated crystals were filtered. Then, 333 mg of the crude crystals thus obtained were recrystallized with a mixture of dimethylformamide and water to give 216 mg of 6-(4-oxo-4H-pyridin-1-yl)-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH:9]=2)[CH:4]=[C:3]1[C:18]([O:20]CC)=[O:19].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH:9]=2)[CH:4]=[C:3]1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3cc(C(=O)O)n(C)c3c2)cc1
Reaction time: 24 h
Yield: 94.8 %

Procedure:
Into a mixed solution of ethyl 1-methyl-6-(4-methylphenyl)-1H-indole-2-carboxylate (0.7 g) in ethanol/THF (20/10 ml) was added at room temperature a 2 N aqueous solution of sodium hydroxide (1.5 ml), and the resulting mixture was stirred for 24 hours. After addition of 1 N hydrochloric acid (5 ml), the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to obtain 1-methyl-6-(4-methylphenyl)-1H-indole-2-carboxylic acid (600 mg) as colorless crystals.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7](O)([CH3:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17](#[N:19])[CH3:18]>C1C=CC=CC=1>[CH3:18][C:17]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]([CH3:15])([CH3:6])[N:19]=1
Reactant: CC#N
Reactant: CC(C)(O)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC1=NC(C)(C)Cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a concentrated sulfuric acid (10 ml) was added a solution of 2-methyl-1-phenylpropan-2-ol (7.0 g) and acetonitrile (1.62 ml) in benzene (7.0 ml) dropwise at 0° C. and the mixture was stirred for 24 hours at room temperature. The reaction mixture was neutralized by adding dropwise to a mixture of ice and a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ether and thereto was added a 5N aqueous solution of sodium hydroxide and was extracted with 1N hydrochloric acid and a 2N hydrochloric acid. The extract was washed with ether and thereto was added a 5N aqueous solution of sodium hydroxide and was extracted with ether twice. The extract was washed with water and brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (2.53 g) having the following physical data.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[CH:12](O)=O.C=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([CH3:12])[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: O=CO
Reactant: CCOC(=O)C1CCNCC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C)CC1
Reaction time: 1 h
Yield: 61 %

Procedure:
Ethyl isonipecotate (3.0 g, 19.1 mmol) was added to a mixture of 90% formic acid (10 mL) and 30% aqueous formaldehyde (10 mL, 100 mmol) then the mixture was heated at reflux for 24 h. After cooling, the mixture was concentrated in vacuo to give an oil which was dissolved in dichloromethane. Solid sodium bicarbonate (1 g) was added and the mixture stirred for 1 h then filtered. The filtrate was concentrated in vacuo to afford 1-methyl-piperidine-4-carboxylic acid ethyl ester (2.0 g, 61%) as a liquid, which was used as such for the next step.