Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[F:12][C:13](I)([F:15])[F:14].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([C:13]([F:15])([F:14])[F:12])=[N:8]2)=[C:4]([NH2:11])[N:3]=1
Reactant: FC(F)(F)I
Reactant: Nc1nc(N)c2[nH]cnc2n1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CS(C)=O
Product: Nc1nc(N)c2[nH]c(C(F)(F)F)nc2n1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
0.15 g (1.0 mmol) of 2,6-diaminopurine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 4.0 ml of dimethyl sulfoxide, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 2,6-diamino-8-trifluoromethylpurine (19F-NMR yield: 45%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 2,6-Diamino-8-trifluoromethylpurine was obtained as a white solid (0.050 g, yield: 23%) by column chromatography.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([N:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:13][CH2:14][N:28]([CH:25]2[CH2:26][CH2:27][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(Cc3ccccc3)CC2)C1

Procedure:
6.23 g (26.8 mmol) of benzylbis(2-chloroethyl)amine hydrochloride were dissolved in ethanol (100 ml) and, while stirring, 5.00 g (26.8 mmol) of N-Boc-3-aminopyrrolidine and 9.02 g (107 mmol) of sodium bicarbonate were added. The resulting reaction solution was heated under reflux for 4 h. The cooled reaction mixture was concentrated in vacuo, 100 ml of water were added, and the aqueous phase was extracted with ethyl acetate (4×60 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% methanol in dichloromethane). Yield: 6.15 g (66%) of yellow solid
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]=[C:17]2[C:20]2([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1)=[O:5].[BH4-].[Na+].CO>O>[Cl:1][C:2]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH:17]2[C:20]2([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1)=[O:5]
Reactant: O=C(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2)c1ccc(Cl)cc1Cl
Yield: 73.3 %

Procedure:
2,4-dichloro-N-(2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-ethyl)-benzamide (80.0 mg, 0.15 mmol) and sodium borohydride (12.0 mg, 0.32 mmol) were dissolved in H2O (10 ml) and MeOH (0.5 ml) and stirred for 14 h at RT. Water was added and the mixture was extracted with ethyl acetate. The organic layers were washed with water and saturated NaCl solution, dried with MgSO4, and the solvent was removed. The residue was transferred into the hydrochloride salt using HCl dissolved in isopropanole (6 molar solution). Crystallization gave 2,4-Dichloro-N-(2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-1,2,3,4-tetrahydro-isoquinolin-7-yloxy}-ethyl)-benzamide (60.0 mg, 0.11 mmol, 70%) as white solid.
Reaction SMILES: [BrH]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>>[CH2:12]([O:11][C:9](=[O:10])[CH:2]([S:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:13]
Reactant: COc1ccc(S)cc1
Product: CCCCCCC(Sc1ccc(OC)cc1)C(=O)OCC

Procedure:
2-(4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromocanate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g, 43 mmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].[CH2:10]([N:12]([CH2:34][CH3:35])[CH:13]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[C:24]([CH3:25])=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[CH:33])[CH:27]=3)[NH:22][N:21]=2)=[O:19])[CH2:14]1)[CH3:11]>>[Cl:9][C:3]1[CH:4]=[C:5]([C:33]#[C:32][C:28]2[CH:27]=[C:26]([C:23]3[NH:22][N:21]=[C:20]([C:18]([N:15]4[CH2:16][CH2:17][CH:13]([N:12]([CH2:34][CH3:35])[CH2:10][CH3:11])[CH2:14]4)=[O:19])[C:24]=3[CH3:25])[CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#Cc4ccc(Cl)c(Cl)c4)c3)c2C)C1

Procedure:
In analogy to the procedure described in Example 31F], 1,2-dichloro-4-iodobenzene and (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone (Example 31E]) gave the title compound in 71% yield yellow foam. MS: 495.2 (MH+, 2 Cl).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=S)[CH2:18][C:19](=O)[CH3:20])=[O:4].[CH:23]1([NH:27][NH2:28])[CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:27]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[N:28]=[C:19]([CH3:20])[CH:18]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O
Reactant: NNC1CCC1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 445c) was reacted with cyclobutylhydrazine (CAS Reg. No. 742673-64-9) to give the title compound as brown solid. MS (ESI): m/z=382.2 [M+H]+.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:3][CH:2]=1.C[O:19][C:20](=[O:33])[CH:21]([O:30][CH2:31][CH3:32])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](O)[CH:24]=1.C1(C2C=CC=CC=2)C=CC(OCCOC2C=CC(C[C@H](OC)C(O)=O)=CC=2)=CC=1>>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:27]2[CH:28]=[C:23]([CH2:22][CH:21]([O:30][CH2:31][CH3:32])[C:20]([OH:33])=[O:19])[CH:24]=[CH:25][CH:26]=2)=[CH:3][CH:2]=1
Reactant: CCOC(Cc1cccc(O)c1)C(=O)OC
Reactant: OCCCOc1ccc(-c2ccccc2)cc1
Agent: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Product: CCOC(Cc1cccc(OCCCOc2ccc(-c3ccccc3)cc2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-(biphenyl-4-yloxy)-propan-1-ol (Example 291, Step 6) and 2-ethoxy-3-(3-hydroxy-phenyl)-propionic acid methyl ester (Example 378, Step 4) via the same procedure used for the preparation of (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3) to produce a white solid. The crude material was submitted to chiral HPLC separation to afford the single enantiomer isomer 2. MS (ES) for C26H28O5 [M+NH4]+: 438.0, [M+Na]+: 443.0.
Reaction SMILES: FC1C(=O)NC(=O)NC=1.C(I)C.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([N:21]1[CH:28]=[C:27]([F:29])[C:25](=[O:26])[N:24](CC)[C:22]1=[O:23])[CH3:20]>CC(C)=O>[CH2:19]([N:21]1[CH:28]=[C:27]([F:29])[C:25](=[O:26])[NH:24][C:22]1=[O:23])[CH3:20]
Reactant: CCn1cc(F)c(=O)n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [K+]
Solvent: CCI
Solvent: CC(C)=O
Product: CCn1cc(F)c(=O)[nH]c1=O

Procedure:
5-fluorouracil, namely Compound (5), (1.30 g; 10 mmol), ethyl iodide (2.34 g; 15 mmol) and potassium carbonate (0.69 g; 5 mmol) were added to acetone (20 ml). The resulting mixture was processed in the same manner as in Example 4 (a) to isolate 1-ethyl-5-fluorouracil, namely Compound (7) (316 mg), and 1,3-diethyl-5-fluorouracil, namely Compound (8) (232 mg), respectively, as white-colored needles.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]2(OCC[O:14]2)[CH2:12][CH3:13])=[N:5][N:4]=[N:3]1.O.Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH3:13])=[N:5][N:4]=[N:3]1
Reactant: CCC1(CCCSc2nnnn2C)OCCO1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)CCCSc1nnnn1C
Yield: 80.4 %

Procedure:
1-Methyl-5-(4,4-ethylenedioxyhexyl)thio-1,2,3,4-tetrazole (0.6 g) is dissolved in acetic acid (5 ml). Water (2.5 ml) and conc. hydrochloric acid (0.5 ml) are added to the solution and the mixture is heated on a water bath for 1 hour. Water is added to the reaction mixture and the mixture is extracted with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography (Kieselgel 60). The column is eluted with benzene-ether (10:1) to obtain 1-methyl-5-(3-propionylpropyl)thio-1,2,3,4-tetrazole (0.4 g) as colorless liquid, nD25 =1.5042.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].[C:22]([NH:26][C:27](=[O:30])[CH2:28]Cl)([CH3:25])([CH3:24])[CH3:23]>CC#N>[C:22]([NH:26][C:27](=[O:30])[CH2:28][N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH3:1])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[S:4][C:5]=2[N:6]=[CH:7]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1sc2nc[nH]c(=O)c2c1C
Reactant: CC(C)(C)NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1sc2ncn(CC(=O)NC(C)(C)C)c(=O)c2c1C

Procedure:
To a suspension of methyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (2.69 g, 12 mmol) in CH3CN (30 mL) was added K2CO3 (2.01 g, 14.5 mmol), KI (2.0 g, 12 mmol), and N-tert-butyl-2-chloroacetamide (1.8 g, 12 mmol). The reaction mixture was refluxed overnight and quenched with H2O (150 mL). The resulting precipitate was filtered and dried to afford methyl 3-(2-(tert-butylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, as a solid (yield: quantitative).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[Sn](C)C.C[Sn](C)C.I[C:19]1[CH:27]=[C:26]2[C:22]([C:23](/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:19]2[CH:27]=[C:26]3[C:22]([C:23](/[CH:36]=[CH:37]/[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:24][N:25]3[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccc(I)cc21
Reactant: COc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(/C=C/c4ccccc4)nn(COCC[Si](C)(C)C)c3c2)cn1
Yield: 40.1 %

Procedure:
A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol), hexamethylditin (1.15 g, 6.10 mmol), and Pd(PPh3)4 (0.28 g, 0.24 mmol) in degassed dioxane (10 ml ) was refluxed under for 16 h. 6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (2.90 g, 6.10 mmol) was added to above mixture, followed by Pd(PPh3)4 (0.35 g, 0.31 mmol). The reaction mixture was refluxed for 16 h. The mixture was then diluted with ethyl acetate (150 ml), and washed with brine (30 ml). The organics were dried over MgSO4, then concentrated under reduced pressure. Purification by silica gel chromatography gave 6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a yellow solid (1.12 g, 40%). 1H NMR (300 MHz, CDCl3) δ 8.51 (d, 1H, J=2.5 Hz), 8.50 (d, 1H, J=9.1 Hz), 7.93 (dd, 1H, J=2.5, 8.6 Hz), 7.69 (s, 1H), 7.69-7.28 (m, 8H), 6.89 (d, 1H, J=8.6 Hz), 5.83 (s, 2H), 4.03 (s, 3H), 3.64 (t, 2H, J=8.3 Hz), 0.93 (t, 2H, J=8.3 Hz), −0.03 (s, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc2c(c1)NCCC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.3 %

Procedure:
To 7-bromo-1,2,3,4-tetrahydroquinoline (1E) (1.0 g, 4.7 mmol) in DCM (30 mL) was added TEA (1.6 mL, 12 mmol), acetic anhydride (1.1 mL, 12 mmol), and pyridine (1.0 mL, 10.0 mmol). The reaction was allowed to stir at rt for 24 hours while monitoring by LCMS. To the reaction mixture was added TEA (1.6 mL, 12 mmol), acetic anhydride (1.1 mL, 12.0 mmol), and pyridine (1.0 mL, 10 mmol). The reaction was allowed to stir at rt for 24 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 100% EtOAc in hexanes to provide 1.09 g (91%) of the desired product 1-(7-bromo-3,4-dihydroquinolin-1(2H)-yl)ethanone (1F): LC/MS (APCI): m/z 255.7 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[C:7]([NH:17]C(=O)OCC3C=CC=CC=3)[C:6]2=[O:28])[CH2:3][CH2:2]1>[Pd].C(O)C>[NH2:17][CH:7]1[CH2:8][CH:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:10][N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]1=[O:28]
Reactant: O=C(Nc1cc(-c2ccccc2)cn(CC2CC2)c1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC1CC(c2ccccc2)CN(CC2CC2)C1=O
Yield: 0.1 %

Procedure:
Benzyl 1-(cyclopropylmethyl)-2-oxo-5-phenyl-1,2-dihydropyridin-3-ylcarbamate (0.061 g, 0.163 mmol) and 10% palladium on carbon (0.060 g) were stirred in ethanol (15 ml) for 6 h under hydrogen atmosphere (50 psi). Catalyst was filtered from the solution and solvent removed in vacuo to produce the title compound (0.031 mg). MS 245 (M+1)
Reaction SMILES: O.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][CH2:11][CH:12]([F:14])[F:13])=[CH:5][CH:4]=1.[CH2:15]1[C:20](=[O:21])[O:19][CH2:18][C:16]1=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]([CH2:11][CH:12]([F:14])[F:13])[C:16]2[CH2:18][O:19][C:20](=[O:21])[CH:15]=2)=[CH:5][CH:4]=1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Reactant: O=C1COC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Yield: 52 %

Procedure:
On a water separator, 21.90 g (106.0 mmol) of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethane-1-amine (III-1), 14.85 g (148.4 mmol) of tetronic acid and 183 mg (1.1 mmol) of 4-toluenesulphonic acid in 250 ml of toluene are heated under reflux for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is then taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate gives 15.9 g (52% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=2)=[CH:8][C:7]=1[CH:22]1[C:35]2[C:34](=[O:36])[CH2:33][C:32]([CH3:38])([CH3:37])[CH2:31][C:30]=2[O:29][C:28]2[CH2:27][C:26]([CH3:40])([CH3:39])[CH2:25][C:24](=[O:41])[C:23]1=2>O.C1COCC1>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)=[CH:8][C:7]=1[CH:22]1[C:35]2[C:34](=[O:36])[CH2:33][C:32]([CH3:37])([CH3:38])[CH2:31][C:30]=2[O:29][C:28]2[CH2:27][C:26]([CH3:40])([CH3:39])[CH2:25][C:24](=[O:41])[C:23]1=2
Reactant: COC(=O)c1cc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2)ccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnc(C(=O)O)c2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 1 h
Yield: 73.2 %

Procedure:
A solution of lithium hydroxide monohydrate (21.7 mg, 0.52 mmol) in water (2.4 ml) was added to a solution of the methyl 4-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylate produced in Example 2-1 (121 mg, 0.23 mmol) in THF (4.8 ml) at room temperature, and the mixed solution was then stirred at the same temperature as above for 1 hour. Thereafter, water was added to the reaction solution, and the mixed solution was then washed with diethyl ether. A 1 N aqueous solution of hydrochloric acid (0.52 ml) was added to the water layer, and the mixed solution was then extracted with dichloromethane four times. The organic layer thus obtained was dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, and the residue thus obtained was then washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (84.5 mg, yield: 72%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13](CS([O-])(=O)=O)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[N:21]([C@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12]2)[CH2:15][CH2:14]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)([O-])C[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 90 °C

Procedure:
(3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl methanesulfonate (1.686 g, 5.71 mmol) from Step C and sodium azide (0.557 g, 8.56 mmol) were combined in N,N-dimethylacetamide (10 mL). The reaction was heated at 90° C. for 15 hours. The reaction was cooled and diluted with 200 mL of ethyl acetate and then quenched with 30 mL water. The organic layer was removed and washed with 2×20 mL of water, then 20 mL of brine. The solvent was removed in vacuo to give (3aS,4R,6aR)-4-azido-2-benzyloctahydrocyclopenta[c]pyrrole: 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.27 (m, 4H), 7.22 (dd, J=2.9, 5.8, 1H), 3.72-3.61 (m, 1H), 3.54 (s, 2H), 2.76-2.60 (m, 1H), 2.55-2.40 (m, 4H), 2.35 (dd, J=3.5, 9.1, 1H), 2.07-1.86 (m, 2H), 1.72-1.60 (m, 1H), 1.49-1.38 (m, 1H).
Reaction SMILES: [H-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:22][CH2:21]3)[CH2:14][CH2:13]2)=[CH:4]1.[CH3:32]I>O1CCCC1>[CH3:32][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:22][CH2:21]3)[CH2:14][CH2:13]2)=[CH:4]1
Reactant: c1ccc(N2CCN(CC[C@H]3CC[C@H](c4c[nH]c5ccccc54)CC3)CC2)nc1
Reactant: CI
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc([C@H]2CC[C@H](CCN3CCN(c4ccccn4)CC3)CC2)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of potassium hydride (0.24 g, 6 mmol) in tetrahydrofuran is cooled to 0° C. and a solution of trans 1-(2-{4-[1H-3-indolyl]cyclohexyl}ethyl)-4-(2-pyridinyl)piperazine (Example 1) (2.0 g, 5.14 mmol) in 20 mL of tetrahydrofuran is added. After 20 minutes 3 mL of methyl iodide is added and the reaction is warmed to room temperature overnight. The reaction is quenched with ammonium chloride and the tetrahydrofuran is removed under reduced pressure. The residue is partitioned between chloroform and ammonium chloride and the organics are dried with sodium sulfate and solvents are evaporated. The residue is chromatographed on silica gel (2% methanol in chloroform) to give the desired product.
Reaction SMILES: Br[C:2]1[C:3]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:4][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([C:18](=[O:37])/[N:19]=[C:20]4\[S:21][C:22]5[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=5[N:24]\4[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[CH:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[Br-].[O:75]1[CH2:79][CH2:78][O:77][CH:76]1[CH2:80][CH2:81][Zn+].P>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:75]1[CH2:79][CH2:78][O:77][CH:76]1[CH2:80][CH2:81][C:2]1[C:3]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])=[N:4][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([C:18](=[O:37])/[N:19]=[C:20]4\[S:21][C:22]5[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=5[N:24]\4[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4\sc5ccccc5n4COCC[Si](C)(C)C)c3C2)ccc1Br
Reactant: [Zn+]CCC1OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4\sc5ccccc5n4COCC[Si](C)(C)C)c3C2)ccc1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
A mixture of compound 94C (2.97 g, 4.27 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.35 g, 0.854 mmol) and palladium acetate (0.096 g, 0.427 mmol) in THF (20 mL) was stirred at room temperature for 5 min. To this solution was added 0.5 M (2-(1,3-dioxolan-2-yl)ethyl)zinc(II) bromide (17.08 mL, 8.54 mmol) dropwise at room temperature. The reaction was stirred overnight. To the solution were added 2′,6′-dimethoxybiphenyl-2-yl)phosphine (170 mg), palladium acetate (42 mg) and (2-(1,3-dioxolan-2-yl)ethyl)zinc(II) bromide (15 mL). The resulting mixture was stirred for another 6 hours and concentrated. The residue was loaded on a silica gel column and eluted with 7:3/hexanes:EtOAc to afford 2.75 g of desired product 94D which is a mixture of two isomers. APCI (+) LC/MS: 717 (M+H)+.