Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C[Si]([N:26]=[N+:27]=[N-:28])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:26]1[C:20]([CH2:19][CH2:18][C:16]2[N:17]=[C:12]([C:4]3[S:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:2](=[O:1])[N:3]=3)[CH:13]=[CH:14][CH:15]=2)=[N:21][N:28]=[N:27]1
Reactant: N#CCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(CCc3nnn[nH]3)n2)sc2ccccc12
Yield: 70 %

Procedure:
3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionitrile (0.25 g, 0.85 mmol) and trimethylsilylazide (0.20 g, 1.7 mol) were dissolved in toluene (5 ml), and dibutyltin (IV) oxide (0.02 g, 0.08 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs and kept at room temperature. The precipitated crystals were collected by filtration, washed with toluene and recrystallized from ethanol to give the titled compound (0.20 g, 68%) as white crystals.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](C1C=CC(B(O)O)=CC=1)([OH:23])=[O:22]>>[O:20]=[C:19]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([C:21]([OH:23])=[O:22])=[CH:5][CH:6]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17][NH:18]1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (530 mg, 2.00 mmol) and 4-carboxyphenylboronic acid (365 mg, 2.20 mmol) were coupled to yield 4-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzoic acid, 340 mg (56%) as a pale yellow solid: m.p. 345.5-346.5° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ3.10 (m, 2H), 3.40 (m, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.59 (dd, J=8.1, 0.9 Hz, 1H), 7.70 (dd, J=7.5, 0.6 Hz, 1H), 7.78 (m, 2H), 8.10 (m, 3H), 11.73 (br s, 1H), 13.00 (br s, 1H). MS (electrospray, MH+) 307. Anal. (C18H14N2O3.0.9 H2O) C, H, N.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@H:6]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[O:3]1.[I:21][CH3:22]>ClCCl>[I-:21].[CH3:1][C@H:2]1[CH2:7][C@H:6]([NH+:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]([CH3:22])[CH2:9]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[O:3]1
Reactant: CI
Reactant: COC(=O)c1cncn1[C@H]1C[C@H](C)Oc2ccccc21
Solvent: ClCCl
Product: COC(=O)C1=CN(C)C[NH+]1[C@H]1C[C@H](C)Oc2ccccc21
Product: [I-]

Procedure:
A solution of 4.2 parts of methyl trans-1-(2,3-dihydro-2-methyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate and 12 parts of iodomethane in 65 parts of dichloromethane is stirred for 20 hours at room temperature. The reaction mixture is evaporated and the residue is crystallized twice from 2,2'-oxybispropane. The product is filtered off and dried, yielding trans-1-(2,3-dihydro-2-methyl-4H-1-benzopyran-4-yl)-5-(methoxycarbonyl)-3-methyl-1H-imidazolium iodide (compound 7.04).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[N:5](C(=O)C(F)(F)F)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1([CH3:37])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCN(C(=O)C(F)(F)F)c2cc(NC(=O)N3CCN(c4ncccc4C(F)(F)F)CC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)CCNc2cc(NC(=O)N3CCN(c4ncccc4C(F)(F)F)CC3)ccc21
Temperature: 60 °C

Procedure:
A suspension of N-(4,4-dimethyl-1-trifluoroacetyl-1,2,3,4-tetrahydroquinol -7-yl)-4-(3-trifluoromethyl-2-pyridyl)-piperazine-1-carboxamide (50 mg, 0.0955 mmol) and potassium carbonate (40 mg, 0.287 mmol) in methanol (5 ml) and water (5 ml) was heated at 60° C. for 4 h. After this period, the solvents were evaporated in vacuo and the residue partitioned between DCM (50 ml) and water (30 ml). The aqueous layer was re-extracted with DCM (3×50 ml) and then the combined organic layers dried (Na2SO4) and the solvents evaporated in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.45 (dd, 1H), 7.90 (dd, 1H), 7.00-7.05 (m, 2H), 6.70 (d, 1H), 6.70 (d, 1H), 6.43 (dd, 1H), 6.32 (br-s, 1H), 3.60-3.65 (br, 4H), 3.20-3.30 (m, 6H), 1.65-1.70 (m, 2H), 1.26 (s, 6H). MS (ES): MH+ 434.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][C:27]#[N:28])=[CH:21][CH:20]=1.C([O-])(=O)C.[NH4+:34]>C(O)C.C(O)(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:34][C:15]([CH3:16])=[C:12]([C:13]#[N:14])[CH:11]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[NH:4][N:3]=[C:2]4[CH3:1])[C:26]=2[C:27]#[N:28])=[CH:21][CH:20]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: [NH4+]
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(c2ccc(F)cc2)N1

Procedure:
A mixture of 200 mg (0.89 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A), 159 mg (0.98 mmol) 3-(4-fluorophenyl)-3-oxopropanenitrile and 205 mg (2.66 mmol) ammonium acetate in ethanol/acetic acid (4:1 v/v, 11 ml) was heated to reflux overnight. After cooling, the reaction mixture was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to afford 136 mg (41% of th.) of the racemic title compound.
Reaction SMILES: [C:1]([NH:8][C:9](=[NH:12])SC)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:35][CH2:36][C:37]1[CH:42]=[C:41]([Cl:43])[C:40]([NH:44][C:45](=[O:47])[CH3:46])=[C:39]([Cl:48])[CH:38]=1>C(Cl)Cl>[C:45]([NH:44][C:40]1[C:39]([Cl:48])=[CH:38][C:37]([CH2:36][NH:35]/[C:9](/[NH2:12])=[N:8]\[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:42][C:41]=1[Cl:43])(=[O:47])[CH3:46]
Reactant: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Reactant: CSC(=N)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)Nc1c(Cl)cc(CN/C(N)=N\C(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of mono-N-Boc-S-methylisothiourea (Preparation C, 764 mg, 4.0 mmol) and DIPEA (3.0 mL) in CH2Cl2 (8.0 mL) was added trifluoroacetic anhydride (924 mg, 4.4 mmol). The mixture was stirred at rt for 30 min, and then N-(4-(aminomethyl)-2,6-dichlorophenyl)acetamide (930 mg, 4.0 mmol) was added. The resulting mixture was stirred at rt overnight. The solvent was removed. Then 15 mL of MeOH and K2CO3 (1.2 g) were added. After stirring at rt for 30 min, the MeOH was removed. 50 mL of HCl (1 N) was added, and the mixture was washed with Et2O (50 mL) and then neutralized with 50% NaOH to pH=12. The aqueous layer was then extracted with EtOAc (2×100 mL). The organic layer was dried and concentrated to give 1.1 g (yield 73%) of the title compound. MS (ESI) (M+H)+=375.06. 1H NMR (500 MHz, CD3OD) δ 7.39 (s, 2 H), 4.41 (s, 2 H), 2.19 (s, 3 H), 1.45 (s, 9 H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.[Na+].[I-:30]>CC(C)=O.O>[CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][I:30]
Reactant: [I-]
Reactant: COC(CCCCC=O)OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COC(CCCCCI)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
81 g (0.5 Mole) of 6,6-dimethoxy-1-hexanal was added to an ice-cooled mixture of 99.3 g (0.52 Mole) of p-toluene-sulfonyl chloride and 72 ml (0.9 Mole) of pyridine at such a rate that the temperature remained below 15°. Stirring was continued for 2 h at 5°-10°, then cold water was added and the mixture was extracted with ether. The organic layer was washed with 5% aq. AcOH, cold 2% NaOH, dried (Na2SO4), and evaporated at 20°. The residue (190 g) was dissolved in 500 ml of acetone, then a solution of 97.5 g (0.65 Mole) of NaI in 500 ml of acetone was added, and the mixture was stirred for 24 h at room temperature. Most of the solvent was removed in vacuo, then ether was added. The mixture was washed with water, dried (Na2SO4), evaporated and distilled to give 124.9 g (92%) of 1,1-dimethoxy-6-iodohexane, b.p. 76°-78°/0.05 Torr.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17].[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)(=O)C.N1CCCCC1.C(COC)OC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[S:13][C:12]1=[S:17]
Reactant: CCCCCCCC=O
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: C1CCNCC1
Product: CCCCCCCC=C1SC(=S)N(N=c2sc3ccccc3s2)C1=O

Procedure:
A slurry of 2.0g of 3-[(1,3-benzodithiol-2-ylidene)amino]- 2-thioxo-4-thiazolidinone (see example 37), octanal (15 ml, excess) and acetic acid/piperidine (10 drops) in anhydrous glyme (400 ml) is heated at reflux for 18 hours. The reaction mixture is chilled in an ice bath and the resultant precipitate collected by filtration. The precipitate is recrystallized twice from dimethylformamide to yield 1.02g of the title compound, melting point 185° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[C:7]([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:6]1.[C:25]1([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH:31]([N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=3)[C:7]([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)=[CH:6]2)[CH2:34][CH2:33]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc2c(Cn3ccnc3)cn(CCCCl)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(Cn3ccnc3)cn(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)c2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
1-(3-Chloropropyl)-6-ethoxycarbonyl-3-(1H-imidazol-1-ylmethyl)-1H-indole (1.5 g) was dissolved in DMF (15 ml), and thereto were added 1-diphenylmethylpiperazine (1.59 g), potassium carbonate (1.28 g), and potassium iodide (145 mg), followed b stirring at 80° C. for 16 hours. Water and ethyl acetate we added to the reaction mixture for extraction, followed by washing with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (Daisogel 60 g, elution; CHCl3 /MeOH=10/1) to give 2.4 g of the title compound as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[NH3:11].[C-:12]#[N:13].CCCCCC.CCOC(C)=O>CO>[NH2:11][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=1)[C:12]#[N:13]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: [C-]#N
Reactant: N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: N#CC(N)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Through a solution of 3,4-difluorobenzaldehyde (25.0 g, 0.18 mol) in MeOH (500 mL) in a round bottom flask was bubbled ammonia gas for two hours at room temperature The flask was then cooled to 0° C. and trimethylsily]L cyanide (1.3 eq., 0.23 mmol) was then added slowly. The reaction mixture was stirred for 2 hours when TLC analysis indicted that the reaction was complete (Rf=0.35, 3:2 hexane/EtOAc). Solvent was removed in vacuo and the residue was subjected to flash column chromatography on silica gel to obtain 25.0 g (81%) of amino-(3,4-difluorophenyl)-acetonitrile as a yellow syrup.
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23](=[O:26])([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([NH:11][C:12](=[O:14])[CH2:13][C:2]2[CH:1]=[CH:10][CH:9]=[C:23]([O:26][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:3]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1cccc2ccccc12
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1cccc2ccccc12
Yield: 95.9 %

Procedure:
A mixture of 2-3-hydroxyphenyl)-N-naphthylacetamide (5.00 g, 18.03 mmol), benzyl bromide (3.76 g, 22.0 mmol), and potassium carbonate (4.14 g, 30.0 mmol) in acetone (50 mL) was heated to reflux overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound (3.176 g, 48% yield): 1H NMR (DMSO-d6) 10.13 (br, 1H), 8.06 (m, 1H), 7.94 (m, 1H), 7.77 (d, 1H), 7.67 (d, 1H), 7.26 -7.56 (m, 9H), 6.92-7.11 (m, 3H), 5.11 (s, 2H), 3.79 (s, 2H); ES-MS (m/z) 368 [M+H]+.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:42]=[N:41][CH:40]=[C:39]([Cl:43])[C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:21][C:22]2[C:25]3([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:24](=[O:31])[C:23]=2[C:32]2[CH2:33][N:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)=[O:6].[H][H]>CCO.[Pt](=O)=O>[Cl:43][C:39]1[CH:40]=[N:41][CH:42]=[C:3]([Cl:2])[C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:21][C:22]2[C:25]3([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[C:24](=[O:31])[C:23]=2[CH:32]2[CH2:37][CH2:36][CH2:35][N:34]([CH3:38])[CH2:33]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1)=[O:6]
Reactant: [H][H]
Reactant: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC1=C(C2=CC=CN(C)C2)C(=O)C12CCCCC2
Agent: O=[Pt]=O
Agent: [I-]
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC1=C(C2CCCN(C)C2)C(=O)C12CCCCC2
Yield: 100.1 %

Procedure:
The compound of Example 86 (127 mg, 0.21 mmol) was dissolved in EtOH (10 ml) and hydrogenated over platinum dioxide (50 mg) at room temperature and 1 atmosphere hydrogen for 5 days. The catalyst was removed by evaporation in vacuo to afford the title compound as a yellow oil (129 mg, 100%). δH (DMSO d6) 10.48 (1H, br s), 8.70 (2H, s), 7.59 (2H, d, J 8.1 Hz), 7.30 (2H, d, J 8.1 Hz), 4.25 (1H, m), 4.22 (2H, q, J 4.0 Hz), 3.23 (1H, m), 3.08 (1H, m), 1.70-1.50 (22H, m), 1.26 (3H, m); m/z (ES+, 70V) 613.2 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:23]=[CH:22][C:8]2[CH:9]=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]([C:13]([F:16])([F:15])[F:14])[O:12][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].C(O)(=O)C.O.[Cl:29]Cl>C(OCC)(=O)C.[Zn]>[Cl:29][C:23]1[C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])=[CH:6][C:7]2[O:12][CH:11]([C:13]([F:15])([F:16])[F:14])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][C:8]=2[CH:22]=1
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C)cc2OC1C(F)(F)F
Reactant: ClCl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)C)cc2OC1C(F)(F)F
Temperature: 15 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
A one liter three-neck flask equipped with mechanical stirrer and gas inlet tube was charged with the ester (Step 2) (100 g, 0.3 mole) and acetic acid (300 mL). While cooling (water bath) the reaction mixture, chlorine gas (37.6 g, 0.53 mole) was added which caused the temperature to rise to 48° C. After stirring for two hours, the reaction was cooled in an ice-water bath to 15° C. Zinc powder (19.5 g, 0.3 mole) was added in one portion which caused the temperature to rise to 72° C. After cooling to room temperature additional zinc powder (5.0 g, 0.08 mole) was added and the mixture was stirred for 0.5 hour longer. The crude mixture was filtered through diatomaceous earth and was concentrated in vacuo yielding an oil. The oil was dissolved in ethyl acetate (700 mL) washed with brine-water (1:1, 1 L) and brine (0.5 L). The resulting aqueous phase was extracted with ethyl acetate (700 mL). This ethyl acetate phase was washed with brine-water (1:1, 1 L) and brine (0.5 L). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo yielding the title compound as a yellow oil (116 g, 106%). This material, which contained some entrained ethyl acetate, was of suitable purity to be used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][Sn:2](Cl)([CH3:4])[CH3:3].Cl[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[CH:8]=1>COCCOC>[CH:13]([C:9]1[CH:8]=[C:7]([Sn:2]([CH3:4])([CH3:3])[CH3:1])[CH:12]=[CH:11][N:10]=1)([CH3:15])[CH3:14]
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)c1cc(Cl)ccn1
Solvent: COCCOC
Product: CC(C)c1cc([Sn](C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold suspension (0° C.) of Na (25% in toluene, 10 g, 104 mmol) in DME (100 mL) add a solution of trimethyltin chloride (9.4 g, 47.4 mmol) in DME (20 mL) dropwise. Stir the mixture at 0° C. for 3 h followed by addition of the solution of cold (0° C.) 4-chloro-2-isopropyl-pyridine (Comins & Mantlo (1985) J. Org. Chem. 50:4410-4411) (4.9 g, 31.6 mmol) in DME (20 mL). Stir the mixture at 0° C. for 2 h and warm to room temperature. Filter, concentrate the filtrate, and dilute the residue with ether. Filter and concentrate the filtrate. Distil the residue (bp 75-80° C. at 1 mm Hg) to afford the title compound as a light oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=[O:14].[Li].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.CCCCCC.O>[C:7]1([C:4]2[C:3]([C:13]([OH:15])=[O:14])=[C:2]([CH2:1][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: Cl
Agent: [Li]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccccc2)noc1CCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 1.5 g of 5-methyl-3-phenyl-4-isoxazolecarboxylic acid in 50 mL of anhydrous tetrahydrofuran stirred at −78° C. under N2 atmosphere, 5.9 mL of a 2.5M solution of n-buthyl lithium in n-hexane was added and the solution was stirred at −78° C. for 2 hours. Afterwards, 0.89 mL of benzyl bromide was added at −78° C. and the solution stirred at room temperature for 2 hours. After overnight resting, the solution was poured into water (300 mL), acidified with hydrochloric acid and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water, dried (sodium sulphate) and the solvents were evaporated to dryness. The solid residue was washed with petroleum ether to give 1.82 g (84%) of the title compound as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=2)Cl)=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:45]([C:42]1[CH:43]=[CH:44][C:39]([CH:37]([C:34]2[CH:35]=[CH:36][C:31]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=2)[O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:9]=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)=[O:7])=[CH:25][CH:26]=2)=[CH:40][CH:41]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)c2ccccn12
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)cc2)c2ccccn12
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.9 %

Procedure:
A mixture of ethyl 4-[1-(4-hydroxybenzoyl)indolizin-3-yl]butyrate (334 mg), bis(4-isobutylphenyl)chloromethane (599 mg) and potassium carbonate (394 mg) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with n-hexane and ethyl acetate (3:1) to give ethyl 4-[1-[4-[bis(4-isobutylphenyl)methoxy]benzoyl]indolizin-3-yl]butyrate (95 mg) as an oil.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[N:16]=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].C1C(=O)N([Br:26])C(=O)C1>C1COCC1>[Br:26][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[N:16]=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2nnnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2nnnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
The mixture of 4-pentyl-4,7-dihydro-8H-tetrazolo[1,5-a]purin-8-one (94.6 mg, 0.38 mmol) and NBS (75 mg, 0.42 mmol) in THF (20 ml) was stirred at 70° C. for 1 hour. After evaporation of solvent, the residue was purified by preparative LC-MS to yield the desired product (17.1 mg, 13.7%). LCMS calculated for C10H13BrN7O(M+H): 326.0; found: 326.0.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9]N[CH2:7][CH2:6]2)OCC1.Cl.Cl[C:13]1[CH:18]=[CH:17]N=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC(C)C>[CH3:15][CH2:14][CH2:13][CH2:18][CH2:17][CH2:9][CH2:10][CH2:5][CH2:6][CH3:7]
Reactant: Clc1ccncc1
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Product: CCCCCCCCCC

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4,5]decane (51.2 ml), 4-chloropyridine hydrochloride (20 g) and potassium carbonate (18.4 g) in isoamyl alcohol (400 ml) was gently refluxed for 18 hr. The reation mixture was cooled and filtered. The filtrate was evaporated to give a waxy solid which was triturated with hexane to give 8-(4-pyridyl)-1,4-dioxa-8-azaspiro]4,5]decane (24.16 g) as a colourless solid; NMR (d6DMSO) δ 1.65-1.70(4H,m), 3.45-3.55(4H,m), 3.9(4H,s), 6.90(2H,m), 8.15(2H,m); m/Z 221 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:8]([CH3:19])=[CH:7]2.[Br:20]N1C(=O)CCC1=O.C(OCC)C.C(OCC)(=O)C>CN(C)C=O>[Br:20][C:8]1([CH3:19])[CH2:7][C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[C:10](=[O:12])[N:9]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cccc(F)c2c(=O)n1-c1cccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(Br)Cc2cccc(F)c2C(=O)N1c1cccnc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
8-Fluoro-3-methyl-2-pyridin-3-yl-2H-isoquinolin-1-one (550 mg, 2.2 mmol) and N-bromosuccinimide (396 mg, 2.23 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 50° C. for 60 minutes and poured into diethyl ether (50 mL) and ethyl acetate (20 mL). A white solid precipitated, which was removed by filtration. The filtrate was washed with diluted brine (water/sat. NaCl (aq.)=1:1; 4×20 mL), dried over MgSO4 and rotavaped. 1H NMR (500 MHz, CDCl3): 2.27 (s, 3H, Me), 7.2 (dd, J=8.4 Hz, J=10.7 Hz, 1H), 7.52 (dd, J=4.9 Hz, J=7.9 Hz, 1H), 7.64 (d (d of unresolved m), J=8 Hz, 1H), 7.72 (td, J(d)=5 Hz, J(t)=8.1 Hz, 1H), 7.84 (d, J=8.2 Hz), 8.53 (d, J=1.8 Hz, 1H), 8.74 (d, J=4.3 Hz, 1H).