Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][S:8][C:4]=2[CH:3]=1.[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([NH:9][C:10](=[O:11])[O:12][CH2:13][CH3:14])=[CH:7][S:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)CCCBr
Reactant: CCOC(=O)Nc1csc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Nc1csc2cc(OCCCC(F)(F)F)ccc12
Yield: 90.8 %

Procedure:
A mixture of 2.0 g (8.4 mmol) of ethyl 6-hydroxybenzothiophene-3-carbamate (obtained in Stage 13.5. of Example 13), 2.4 g (12.6 mmol) of 4,4,4-trifluoro-1-bromobutane and 2.3 g (16.8 mmol) of potassium carbonate in 30 ml of acetonitrile is heated at reflux for 90 min. The mixture is evaporated under reduced pressure and the residue is triturated in petroleum ether. 2.65 g of product are obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([C:17]2[CH:52]=[CH:51][C:20]([C:21]([O:23][C@@H:24]3[CH2:32][C@@H:27]4[O:28][C:29](=[O:31])[CH2:30][C@@H:26]4[C@H:25]3[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:22])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)=O.C(=O)=O.CO>C1(C)C=CC=CC=1>[C:11]1([C:17]2[CH:52]=[CH:51][C:20]([C:21]([O:23][C@@H:24]3[CH2:32][C@@H:27]4[O:28][CH:29]([OH:31])[CH2:30][C@@H:26]4[C@H:25]3[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:22])=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: O=C(O[C@@H]1C[C@@H]2OC(O)C[C@@H]2[C@H]1CC[C@H](CCc1ccccc1)OC1CCCCO1)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A 1.5 M solution of diisobutylaluminum hydride in toluene (6.0 mL, 9.0 mmol) was added dropwise to a stirred solution of compound [9a] (4.1 g, 7.2 mmol) in toluene (60 mL) at −70-−80° C. (acetone/dry ice bath) and the resulting mixture was stirred during 1 h at the same temperature. Methanol (10 mL) was added dropwise to the stirred mixture at −70-−80° C. The mixture was stirred for 1 hour at room temperature, filtered and evaporated under reduced pressure. Dichloromethane (30 mL) was added to the residue. The resulting solution was washed with brine (2×10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 2:1 v/v) to obtain 2.0 g (49% yield) of the compound [10a]. 1H NMR (CDCl3) δ: 6.4-6.5 (m, 1H); 5.0-5.2 (m, 1H); 4.7-4.9 (m, 1H); 4.5-4.7 (m, 1H); 3.8-4.0 (m, 1H); 3.6-3.8 (m, 1H); 3.4-3.6 (m, 1H). 13C NMR (CDCl3) δ: 20.1; 25.5; 28.6; 31.3; 31.6; 36.7; 37.7; 40.3; 41.1; 46.2; 51.6; 63.0; 81.3; 82.0; 97.8; 100.2; 125.6; 127.1; 127.2; 128.1; 128.3; 128.4; 128.9; 129.2; 130.0; 130.1; 140.0; 145.7; 166.0. IR (KBr): 3500, 2945, 1712, 1605, 1278, 1117, 1026, 752 cm−1.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1>CCO>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccnc1)(NC(C)=O)C(=O)OCC
Yield: 30.2 %

Procedure:
Sodium metal (1.40 g, 61 mmol) was dissolved in EtOH (100 mL) and diethyl acetamidomalonate (6.62 g, 30.5 mmol) and 3-picolylchloride hydrochloride (5.00 g, 30.5 mmol) were added. The mixture was heated to reflux for 6 hours, and then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture was taken up into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL). The solvent was removed and the residue purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to give diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate (2.84 g, 30%).
Reaction SMILES: [C:1]1([CH:11](O)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>>[ClH:21].[C:1]1([CH:11]([Cl:21])[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OC(Cn1ccnc1)c1cccc2ccccc12
Product: Cl
Product: ClC(Cn1ccnc1)c1cccc2ccccc12

Procedure:
1-[2-(1-naphthyl)-2-hydroxyethyl]imidazole (2.0 g.) and 5 ml. of thionyl chloride are stirred at room temperature for 30 minutes. Thereafter, the reaction mixture is evaporated to dryness and the residue treated with ethyl acetate and filtered to yield 1-[2-(1-naphthyl)-2-chloroethyl]imidazole hydrochloride as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[N:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[NH2:27][CH2:28][CH:29]([CH:31]1[CH2:33][CH2:32]1)[OH:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH:31]1([CH:29]([OH:30])[CH2:28][NH:27][C:18]([C:15]2[N:16]=[N:17][C:12]([N:9]3[CH2:10][CH2:11][CH:6]([O:5][C:4]4[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=4[C:2]([F:26])([F:1])[F:25])[CH2:7][CH2:8]3)=[CH:13][CH:14]=2)=[O:19])[CH2:33][CH2:32]1
Reactant: NCC(O)C1CC1
Reactant: O=C(O)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(O)C1CC1)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine-3-carboxylic acid (120 mg, 0.3 mmol), 2-amino-1-cyclopropylethanol (57 mg, 0.56 mmol) and HATU (249 mg, 0.65 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (285 μL, 3.4 mmol) at room temperature. The mixture was stirred at room temperature for 4 h, diluted with water and extracted with EtOAc. The EtOAc extract was washed with water, diluted twice with brine, dried (Na2SO4) and concentrated. CombiFlash chromatography (10 g, 90-100% EtOAc in hexanes in 20 min, 20 mL/min, 18 mL/fraction) gave the title compound as a light brown foam. 1H NMR (400 MHz, acetone-d6): δ 0.30-0.52 (m, 4H), 0.93-1.01 (m, 1H), 1.92-2.00 (m, 2H), 2.14-2.24 (m, 2H), 3.22-3.28 (m, 1H), 3.43-3.49 (m, 1H), 3.71-3.77 (m, 1H), 3.94-4.08 (m, 4H), 4.24 (d, 1H), 5.04 (m, 1H), 7.13 (t, 1H), 7.38 (m, 2H), 7.62-7.68 (m, 2H), 7.94 (d, 1H), 8.35 (s, 1H). MS (+ESI) m/z 451 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21](O)=[O:22])[CH:14]=[N:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:50])[C:30]=1[CH:31]([O:42][Si:43]([CH2:48][CH3:49])([CH2:46][CH3:47])[CH2:44][CH3:45])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=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>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:50])[C:30]=1[CH:31]([O:42][Si:43]([CH2:48][CH3:49])([CH2:46][CH3:47])[CH2:44][CH3:45])[CH2:32][N:33]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:21]([C:15]1[CH:14]=[N:13][N:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)[C:16]=1[C:17]([F:18])([F:20])[F:19])=[O:22]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)CC1
Reactant: CC[Si](CC)(CC)OC(CNCc1ccc(F)cc1)c1c(Cl)cncc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(Cc3ccc(F)cc3)CC(O[Si](CC)(CC)CC)c3c(Cl)cncc3Cl)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of acid D1 (6.22 g, 18.6 mmol) and amine A1 (8.67 g, 20.4 mmol) in DMF (100 mL) were added HATU (8.48 g, 22.3 mmol) and DIPEA (4.74 mL, 27.9 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to afford compound 1-1 (15 g, crude) as a brown gum.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.O>O1CCCC1>[CH:15]1([CH2:21][NH:22][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NS(=O)(=O)c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 2C (7.70 g) in tetrahydrofuran (35 mL) was added dropwise a solution of cyclohexylmethylamine (6.0 mL, 5.22 g) and diisopropylethylamine (8.0 mL, 5.92 g) in tetrahydrofuran (15 mL). After the addition, tetrahydrofuran (20 mL) was added, and the reaction was stirred at room temperature for 16 hours. The solution was added to water and extracted with a solution of ethyl acetate and dichloromethane (1:1 by volume). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate volume was reduced to isolate the title compound by crystallization.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][SH:7])[CH3:3].[H-].[Na+].[C:12]1([C:18]2[C:22]([N+]([O-])=O)=[N:21][O:20][N+:19]=2[O-:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[ClH:1].[C:12]1([C:18]2[C:22]([S:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:2][CH3:3])=[N:21][O:20][N+:19]=2[O-:26])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCN(CC)CCS
Reactant: O=[N+]([O-])c1no[n+]([O-])c1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1no[n+]([O-])c1-c1ccccc1
Reaction time: 1 h

Procedure:
4.75 g of 2-diethylaminoethyl mercaptan hydrochloride are slowly treated with 3.3 g of a 50% strength sodium hydride in oil suspension in 100 ml of THF under a nitrogen atmosphere. After 1 hour, 5 g of 3-phenyl-4-nitrofuroxan are introduced and the mixture is stirred for 20 hours. The inorganic salts are filtered off with suction and the filtrate is concentrated. The residue is taken up in water and extracted with methylene chloride. After drying and concentrating, the residue is dissolved in ethyl acetate and the product is precipitated by introducing hydrogen chloride and filtered off with suction.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[I:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(n2cc(I)ccc2=O)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(I)ccc3=O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-iodo-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([NH:12][CH3:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Nc1cc2ccccc2cc1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1cc2ccccc2cc1N
Temperature: 2.5 °C
Reaction time: 0.12 h
Yield: 30.9 %

Procedure:
A solution of 2,3-diaminonaphthalene (500 mg, 3.16 mmol) in anhydrous dimethylformamide (3 mL) was cooled in an ice bath and treated with sodium hydride (130 mg of a 61% dispersion in mineral oil, 3.31 mmol). The mixture was stirred at 0-5° C. for 7 minutes, then treated with methyl iodide (0.206 mL, 3.31 mmol) and stirred in the cold for an additional 15 minutes. After warming to room temperature, the mixture was diluted with ethyl acetate (30 mL), washed with water (5×30 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and evaporated under vacuum to a dark solid (0.5 g). The crude product was purified by silica gel chromatography (2.75×24 cm column) using 5% ethyl acetate in dichloromethane as eluting solvent. The product fractions were combined and evaporated to afford 2-amino-3-methylamino-naphthalene (168 mg) as a solid.
Reaction SMILES: C([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)C.[CH:37]1(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)[CH2:39][CH2:38]1.ClC1N=C(N2CCOC[C@@H]2C)C2CCN(C(OC(C)(C)C)=O)CC=2N=1>>[CH:37]1([NH:3][C:4]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]4[CH3:35])[C:15]4[CH2:21][CH2:20][NH:19][CH2:18][C:16]=4[N:17]=3)=[CH:10][CH:11]=2)=[O:36])[CH2:39][CH2:38]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C(=O)OC(C)(C)C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCNC2

Procedure:
Method as described for intermediate 5 using 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea and intermediate 4 as starting materials. Followed by method as described for example 3 step 2.
Reaction SMILES: O[C:2]1[C:11]2C(=C(C(F)(F)F)C=CC=2)N=C(C(O)CC)[C:3]=1C(NC1SC=CN=1)=O.[C:28]([OH:33])(=[O:32])[CH2:29][CH2:30][CH3:31]>>[C:28]([O:33][CH2:3][CH2:2][CH3:11])(=[O:32])[CH2:29][CH2:30][CH3:31]
Reactant: CCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reactant: CCCC(=O)O
Product: CCCOC(=O)CCC

Procedure:
Using the procedure of Example5, 8 g of 4-hydroxy-2(1-hydroxypropyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide and 2 ml of butyric acid were reacted to obtain 7.8 g of 1-[4-hydroxy 3-[(2-thiazolylamino)-carboxyl]-8-trifluoromethyl)-2quinolinyl]-propyl butanoate melting at 203° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14](C4C=C(C=CC=4)C#N)=[C:6]2[C:5](=[O:24])[N:4]([CH3:25])[C:3]1=[O:26])[CH2:12][CH2:11][CH2:10][C:9]3=[O:23].Br[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1.Br[CH2:36]CCC(OC)=O.BrCC(C)CC(OC)=O>>[F:34][C:30]1[CH:29]=[C:28]([C:14]2[N:13]3[C:8]([C:9](=[O:23])[CH2:10][CH:11]([CH3:36])[CH2:12]3)=[C:7]3[N:2]([CH3:1])[C:3](=[O:26])[N:4]([CH3:25])[C:5](=[O:24])[C:6]=23)[CH:33]=[CH:32][CH:31]=1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(=O)CCC3
Reactant: Fc1cccc(Br)c1
Reactant: COC(=O)CCCBr
Agent: COC(=O)CC(C)CBr
Product: CC1CC(=O)c2c3c(c(-c4cccc(F)c4)n2C1)c(=O)n(C)c(=O)n3C

Procedure:
The title compound was prepared analogously to 3-(1,3-dimethyl-2,4,10-trioxo-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile (Example 9 steps 1-7) by replacing 3-bromobenzonitrile (step 3) with 1-bromo-3-fluorobenzene (commercially available) and methyl 4-bromobutanoate (Step 5) with methyl 4-bromo-3-methylbutanoate (Intermediate T).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1([F:13])[CH2:9][CH:8]1[CH2:10][CH2:11][OH:12].C(N(CC)CC)C.O>C1COCC1>[CH3:1][S:2]([O:12][CH2:11][CH2:10][CH:8]1[CH2:9][C:7]1([F:13])[F:6])(=[O:4])=[O:3]
Reactant: OCCC1CC1(F)F
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCC1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (1.35 mL) was added to a solution of 2-(2,2-difluorocyclopropyl)ethanol (1.42 g) and triethylamine (3.24 mL) in THF (20 mL) dropwise at 0° C. The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.31 g) as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH2:12][NH:13][C:14](=[O:16])[CH3:15].C(OCCCC)(=O)C>S(=O)(=O)(O)O>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[CH2:12][NH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)NCO
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Solvent: CCCCOC(C)=O
Product: CC(=O)NCc1cc([N+](=O)[O-])ccc1C
Yield: 38 %

Procedure:
A solution of p-nitrotoluene (6.85 g; 0.05 mol) in concentrated sulfuric acid (60 ml) is cooled in an ice bath and N-(hydroxymethyl)acetamide (4.45 g; 0.05 mol) is added. The reaction mixture is stirred until a solution is obtained and then continuously stirred for 16 hours at 55° C. The mixture is then poured onto ice and the resulting precipitate is isolated. This solid material is extracted with 85 ml of butyl acetate on a steambath. Concentration of the butyl acetate solution with subsequent cooling gives 3.9 g (i.e., 38% yield) of product. The butyl acetate insoluble material (2.5 g) is methylene bis(4-nitro-o-toluene).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].[CH3:7][Si:8]([CH3:15])([CH3:14])[O:9][CH2:10][CH2:11][CH2:12]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:7][Si:8]([CH3:15])([CH3:14])[O:9][CH2:10][CH2:11][CH2:12][C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)OCCCBr
Reactant: c1cc[cH-]c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OCCCC1=CC=CC1
Reaction time: 12 h
Yield: 43 %

Procedure:
To 50 ml of a 2.3 M solution of sodium cyclopentadienylide (115 mmol), a solution of 24.3 g (115 mmol) of 3-trimethylsiloxy-1-bromo-propane in tetrahydrofurane is added. The quick formation of a pinkish solid is observed. The reaction is maintained under stirring for 12 hours and then it is neutralized with an ammonium chloride solution; the organic phase is extracted and concentrated to dryness in order to give an orange oil. (9.8 g, 50 mmol. Yield: 43%). 1H-NMR (CDCl3): 6.47-6.00 (m,3H), 3.62 (m,2H), 2.95 (m,1H), 2.87 (m,1H), 2.43 (m,2H), 1.80 (m,2H), 0.17 (s,9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH:8]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].O[N:23]=[C:24]([NH2:36])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(C1NC=CN=1)(C1NC=CN=1)=O>CN(C=O)C.C(=O)(O)[O-].[Na+]>[C:15]1([S:14][CH2:13][CH:8]([CH2:9][C:10]2[O:12][N:23]=[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:36]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(CCCCNc1ccccn1)=NO
Reactant: CC(C)(C)OC(=O)CC(CSc1ccccc1)CC(=O)O
Agent: O=C([O-])O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(CSc1ccccc1)Cc1nc(CCCCNc2ccccn2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
The product from step 2 (54 mg, 0.175 mmoles), N′-hydroxy-5-(pyridin-2-ylamino)pentanimidamide (40 mg, 0.192 mmoles) and carbonyl diimidazole (45 mg, 0.28 mmoles) were combined in DMF 1.5 mL and stirred at RT for 4 h then heated at 65° C. overnight. N′-hydroxy-5-(pyridin-2-ylamino)pentanimidamide (36 mg 0.175 mmoles) and carbonyl diimidazole (50 mg, 0.31 mmoles) were added in and reaction was stirred at RT for 2 h followed by heating to 80° C. for 24 h. Reaction was cooled, diluted with a sodium bicarbonate solution (6 ml, 1:1 saturated bicarbonate solution and water) and extracted with ethyl acetate 3×3 mL. The combined organics were washed with water 2×3 mL, brine 3 mL, dried and passed through a pad of silica eluting with a further 10 mL of ethyl acetate. The solvent was removed under reduced pressure to give the product 50.4 mg (60%). MS (ESI+) for C26H34N4O3S m/z 483 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=[C:9]([O:19][CH2:20][O:21][CH3:22])[C:8]=1[O:23][CH3:24].CN(C)CCN(C)C.C([Li])CCC.I[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]1[C:49]([O:50][CH2:51][O:52][CH3:53])=[C:48]([O:54][CH3:55])[CH:47]=[C:46]([O:56][CH2:57][O:58][CH3:59])[C:45]=1[O:60][CH3:61]>C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C>[CH3:61][O:60][C:45]1[C:46]([O:56][CH2:57][O:58][CH3:59])=[CH:47][C:48]([O:54][CH3:55])=[C:49]([O:50][CH2:51][O:52][CH3:53])[C:44]=1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:10]1[C:9]([O:19][CH2:20][O:21][CH3:22])=[C:8]([O:23][CH3:24])[C:7]([CH2:6][CH2:5][O:4][CH2:3][O:2][CH3:1])=[C:12]([O:13][CH2:14][O:15][CH3:16])[C:11]=1[O:17][CH3:18]
Reactant: COCOCCc1c(OC)c(OCOC)cc(OC)c1OCOC
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCI)c1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c(OC)c1OCOC
Temperature: -78 °C
Reaction time: 4 h

Procedure:
1.0 Gram of 1-methoxymethoxy-2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]ethane was dissolved in a mixed solvent of 20 ml of toluene with 5 ml of hexamethylphosphoric triamide, to this solution was added 0.52 ml of N,N,N',N'-tetramethylethylenediamine and the whole mixture was cooled to -78° C. in a dry ice-acetone bath, then 2.7 ml of n-butyllithium (1.6 mole solution) was added dropwise to the reaction mixture. 15 Minutes later, a solution prepared by dissolving 1.56 g of 1-(5-iodopent-1-yl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene in 12 ml of toluene was added to the reaction mixture, and the temperature of the reaction mixture was gradually elevated to room temperature and the reaction mixture was stirred further for 4 hours. 50 Milliliters of diethyl ether was added to the reaction mixture, and the organic layer was washed with water, and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate. After concentration, the residue thus obtained was purified by means of a silica gel column chromatography (diameter 3 cm×length 10 cm, Merck, eluent: 30% ethyl acetate-n-hexane) to obtain 2.1 g of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(2-methoxymethyloxyethyl)phenyl]pentane. Amorphous powdery substance.