Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[CH:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:15][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1
Reactant: C=Cc1cc(C)nc(-n2nc(C)nc2C)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(C)nc(-n2nc(C)nc2C)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methyl-4-vinylpyridine (25-1) (200 mg, 0.933 mmol) in toluene (8 mL) was added at reflux ethyl diazoacetate (852 mg, 7.47 mmol) in three portions over 4 hours. The mixture was refluxed for another 2 hours, cooled to room temperature, and concentrated. The residue was purified by silica gel column chromatography (0-70% ethyl acetate in hexanes) to give ethyl trans-2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridin-4-yl)cyclopropanecarboxylate (25-2) as a yellow oil. 1H NMR (300 MHz, CDCl3) 57.32 (br s, 1H), 6.83 (br s, 1H), 4.18 (q, 2H, J=7.2 Hz), 2.80 (s, 3H), 2.55-2.46 (m, 1H), 2.51 (s, 3H), 2.41 (s, 3H), 2.09-1.99 (m, 1H), 1.73-1.63 (m, 1H), 1.46-1.36 (m, 1H), 1.28 (t, 1H, J=7.2 Hz). LRMS m/z (M+H) 301 found, 301 required.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([Cl:10])[CH:4]=1.Br.[CH3:12][N:13]1[C:18]2[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.[OH:24]O>O.N.CC(C)=O>[Cl:10][C:5]1[CH:4]=[C:3]([NH:2][C:21]2[C:20](=[O:23])[CH:19]=[C:18]([N:13]([CH2:14][CH2:15][OH:24])[CH3:12])[C:17](=[O:16])[CH:22]=2)[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CN1CCOc2ccc(O)cc21
Reactant: OO
Agent: Br
Agent: Cl
Agent: N
Solvent: CC(C)=O
Solvent: O
Product: CN(CCO)C1=CC(=O)C(Nc2ccc(O)c(Cl)c2)=CC1=O
Reaction time: 3 h

Procedure:
To a solution of 0.90 g (0.005 mol) of 4-amino-2-chlorophenol hydrochloride in 5 ml of water and 2 ml of 20% aqueous ammonia is added a solution of 1.23 g (0.005 mol) of 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-ol hydrobromide in 3 ml of water, 1 ml of 20% aqueous ammonia and 10 ml of acetone. The pH is adjusted to 9.5 with 20% aqueous ammonia. 17 ml of 6% aqueous hydrogen peroxide solution are added. After 3 hours, the precipitate is filtered off. 0.99 g of 2-(3-chloro-4-hydroxyphenylamino)-5-[(2-hydroxyethyl)methylamino][1,4]benzoquinone (compound 7) is obtained in the form of a brown powder.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:11](N)([NH2:14])(=[O:13])=[O:12]>O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: C1CC2(CCN1)OCCO2
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC2(CC1)OCCO2

Procedure:
A solution of 1,4-dioxa-8-aza-spiro[4.5]decane (2 mL) and sulfamide (1.65 g) in 1,4-dioxane (28 mL) was heated at reflux for 48 h, then the volatiles were evaporated to afford the title compound as a pale yellow solid. Yield: 3.4 g
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1.CN(C)C=O.[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].C(=O)(O)[O-].[Na+]>O.ClCCl>[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH:17][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: Nc1ccc(F)cc1F
Reactant: ClCc1cncnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc(NCc2cncnc2)c(F)c1

Procedure:
A 26.7 g. portion of 5-chloromethylpyrimidine was dissolved in 25 ml. of dimethylformamide, and 9.4 g. of 2,4-difluoroaniline was added, followed by 6.1 g. of sodium bicarbonate. The mixture was stirred for several days with gentle heating. It was then diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and evaporated under vacuum to obtain 13.75 g. of oil. The oil was dissolved in dichloromethane and purified over silica gel, eluting with dichloromethane, to obtain 4.9 g. of the desired intermediate product.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([CH2:15][CH2:16][CH3:17])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=1)#[CH:19]>CN(C)C=O.C(N(CC)CC)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>[CH2:15]([C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([C:19]#[C:18][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=4)=[CH:14][CH:13]=3)[CH2:5][C:6]=2[CH:7]=1)[CH2:16][CH3:17]
Reactant: C#Cc1ccc(F)c(F)c1
Reactant: CCCc1ccc2c(c1)Cc1cc(I)ccc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1ccc2c(c1)Cc1cc(C#Cc3ccc(F)c(F)c3)ccc1-2

Procedure:
2-iodo-7-propyl-fluorene in dimethylformamide and triethylamine was reacted with 4-ethynyl-1,2-difluorobenzene in the presence of tetrakis(triphenylphosphine)palladium (0), and the product was purified by silica gel column chromatography (hexane) and then recrystallized from ethanol to yield 2-propyl-7-(3,4-difluorophenylethynyl)fluorene.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:20][C@H:19]4[C:21]([OH:23])=O)[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:24]=1.C(OC(C(=NOC(N(C)C)=[N+](C)C)C#N)=O)C.F[B-](F)(F)F.CN1CCOCC1.[CH3:56][C@H:57]1[CH2:62][CH2:61][C@H:60]([NH2:63])[CH2:59][CH2:58]1>CN(C=O)C>[CH3:56][C@H:57]1[CH2:62][CH2:61][C@H:60]([NH:63][C:21]([C@@H:19]2[CH2:20][C@H:18]2[CH2:17][N:14]2[CH2:15][CH2:16][N:11]([C:10]3[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:25])[F:26])=[CH:24][C:7]=4[S:8][CH:9]=3)[CH2:12][CH2:13]2)=[O:23])[CH2:59][CH2:58]1
Reactant: O=C(O)[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Reactant: C[C@H]1CC[C@H](N)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1

Procedure:
Stir a solution of trans-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid (Example 7a) (1.99 g, 5.0 mmol), and O-[(ethoxycarbonyl)-cyanomethylenamino]-N,N, N′,N′-tetramethyluronium-tetrafluoroborate (TOTU, 2.05 g, 6.3 mmol) in DMF (50 mL) at 20° C. for 0.5 h. Add N-methylmorpholine (0.58 mL, 5.3 mmol), after which add trans-4-methylcyclohexylamine (1.13 g, 10 mmol), and stir the reaction for 5 h. Concentrate the reaction under reduced pressure to obtain an oil. Purify by column chromatography over silica gel (EtOAc/heptane/methanol/triethylamine, 20:20:1:1) to obtain 1.86, (76%) of colorless crystals LC/MS, m/z=480 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:28][CH2:29]OS(C)(=O)=O)[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[C:21]([NH:23][CH2:24]CCO)=[O:22])(=[O:4])=[O:3].[Li+].[Br-:36].CCO[C:40]([CH3:42])=[O:41]>>[CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:28][CH2:29][Br:36])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[C:21]([NH:23][CH2:24][CH:40]([OH:41])[CH3:42])=[O:22])(=[O:4])=[O:3]
Reactant: [Br-]
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1c(C(=O)NCCCO)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Li+]
Product: CC(O)CNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N(CCBr)CCOS(C)(=O)=O

Procedure:
Treatment of 24 (0.25 g, 0.45 mmol) with LiBr (53 mg, 0.61 mmol) in EtOAc (50 mL) at 60° C. for 3 h, and chromatography of the product on silica gel, eluting with EtOAc/petroleum ether (from 2:1 to 1:0) gave IIb-13 (0.16 g, 66%): as yellow foam; 1H NMR [(CD3)2SO] δ 8.74 (d, J=2.8 Hz, 1 H), 8.73 (m, 1 H), 8.31 (d, J=2.8 Hz, 1 H), 4.28 (m, 2 H), 3.65-3.44 (m, 10 H), 3.13 (s, 3 H), 1.70 (m, 2 H); 13C NMR δ 165.1, 145.7, 145.4, 141.0, 136.2, 127.3, 122.1, 67.5, 58.4, 51.1, 36.7, 36.5, 31.7, 29.6. HRMS (FAB) Calcd. For C15H2279BrN4O9S [M+H+] m/z 513.0291. Found; 513.0281.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N+:3]=1[O-].O=P(Cl)(Cl)[Cl:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cc(C(F)(F)F)ccc1Cl
Product: FC(F)(F)c1ccc(Cl)nc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
2-Chloro-5-trifluoromethyl-pyridine-N-oxide (17, 4 mmol) was dissolved in freshly distilled POCl3 (4.5 mL). The reaction mixture was heated to 80° C. for 17 h. After cooling to room temperature, the solvent was removed under reduced pressure. Ice was added, and the mixture was allowed to stand for 4 h. The mixture was partition between CH2Cl2 (50 mL) and saturated aqueous NaHCO3. Column chromatography afforded compound 18 as yellow oil (yield: 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:13]#[N:14])=[CH:10][NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:15]N1C(=O)CCC1=O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Cl:15][C:12]1[NH:11][CH:10]=[C:9]([C:13]#[N:14])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1c[nH]cc1-c1cccc(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c[nH]c(Cl)c1-c1cccc(F)c1
Reaction time: 24 h
Yield: 93.7 %

Procedure:
To a solution of 41.0 g (220 mmol) of 4-(3-fluorophenyl)-1H-pyrrole-3-carbonitrile in 400 ml of tetrahydrofuran are added portionwise 33.0 g (242 mmol) of N-chlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 24 hours at reflux. After cooling, 200 ml of water containing 5 g of sodium thiosulfate are added and, after stirring for 5 minutes, the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 45.5 g of 5-chloro-4-(3-fluorophenyl)-1H-pyrrole-3-carbonitrile in the form of a whitish powder after triturating in 200 ml of dichloromethane, filtering off and drying.
Reaction SMILES: [CH2:1]([C:7]1[N:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I:18][CH3:19]>>[I-:18].[CH2:1]([C:7]1[N+:8]([CH3:19])=[N:9][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCCCc1cn(-c2ccccc2)nn1
Product: CCCCCCc1cn(-c2ccccc2)n[n+]1C
Product: [I-]
Temperature: 40 °C

Procedure:
4-hexyl-1-phenyl-1H-1,2,3-triazole and excess iodomethane were added to a 20 mL vial. The reaction was heated at 40° C. for 3 days. The iodomethane was allowed to evaporate in the hood. The following structure of 4-hexyl-3-methyl-1-phenyl-1H-1,2,3-triazol-3-ium iodide was confirmed:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])[C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(O)c2ccc(F)c(Cl)c2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(c2ccc(F)c(Cl)c2)N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a solution of 69a/69b (364.3 mg, 1.105 mmol) in THF (5.5 mL, 0.2 M) under nitrogen was added phthalimide (178.8 mg, 1.215 mmol) and PPh3 (376.7 mg, 1.436 mmol). The reaction was cooled to 0° C. and diethyl azodicarboxylate (654.0 μL, 1.436 mmol) was added dropwise via syringe. The reaction was allowed to warm to RT and stirred for 16 h. The reaction was concentrated to dryness by rotovap, diluted to 30 mL with EtOAc and washed with water (2×30 mL) and brine (1×30 mL). The organics were isolated, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with a hexanes/acetone gradient (5 to 70% acetone) to afford 212 mg (42%) of 71a/71b as a clear oil containing approximately a 1:1 mixture of diastereomers.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[Br:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>>[Br:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21]
Reactant: BrCc1ccccc1Br
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Product: O=c1c2sc3ccccc3c2n(Cc2ccccc2Br)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-bromobenzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.58 (s, 2H); 7.16-7.19 (m, 1H); 7.25-7.31 (m, 2H); 7.34-7.43 (m, 1H); 7.48-7.57 (m, 2H); 7.78-7.81 (m, 1H); 8.43 (d, J=8 Hz, 1H); 11.10 (br s, 1H); Ret. time=2.87 min., m/z=403.0.
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][O:23][C:17]=3[CH2:16]2)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O-])(=O)C.[CH3:30][NH2+:31][CH2:32][CH2:33][O:34][CH3:35].C=O>C(O)(=O)C>[CH3:35][O:34][CH2:33][CH2:32][N:31]([CH2:26][C:22]1[O:23][C:17]2[CH2:16][N:15]([C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:25][CH:24]=3)[CH2:20][CH2:19][C:18]=2[CH:21]=1)[CH3:30]
Reactant: CC(=O)[O-]
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Reactant: C[NH2+]CCOC
Agent: C=O
Solvent: CC(=O)O
Product: COCCN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.341 g (1.029 mmol) of 6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.18 g (1.2 mmol) of N-methyl-2-methoxyethylammonium acetate and 0.10 g (1.2 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[N:7][N:6]=1)[CH3:4].[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:3]([C:5]1[S:9][C:8](=[N:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[N:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([I:17])=[CH:19][CH:20]=2)[N:6]=1)[CH3:4]
Reactant: CCc1nnc(NC(=O)C(F)(F)F)s1
Reactant: BrCc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C(F)(F)F)s1
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a suspension of sodium hydride (0.44 g) in N,N-dimethylformamide (10 ml) was added 5-ethyl-2-trifluoroacetylamino-1,3,4-thiadiazole (2.25 g) in three portions on ice. After the resulting mixture was stirred at the same temperature for 30 minutes, to the mixture was added 4-iodobenzyl bromide (2.97 g), and the mixture was stirred at room temperature for two hours. To the reaction mixture, ethyl acetate (50 ml) was added. The resulting mixture was washed successively with 10% aqueous citric acid solution and water and dried over anhydrous magnesium sulfate, followed by the removal through distillation. The residue so obtained was crystallized from n-hexane, collected by filtration and then dried, whereby 2.2 g of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:18]([N:20]([CH2:21][CH3:22])[C:2]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])[CH3:19]
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Cl
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Temperature: 110 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a suspension of 2-chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (400 mg, 1.489 mmol) and diethylamine (0.773 ml, 7.44 mmol) in DMF (4 ml) was added K2CO3 (1.02 g, 7.44 mmol). The mixture was stirred for 4 hours at 110° C. The reaction mixture was diluted with EtOAc (30 ml) and then washed two times with 1N-HCl (30 ml) and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographed to yield the 2-diethylamino-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (400 mg, 88%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:14][C:15]1[N:19]2[N:20]=[C:21](F)[CH:22]=[CH:23][C:18]2=[N:17][CH:16]=1.[CH2:25](N(CC)CC)C>C(O)(C)C>[C:1]([O:5][C:6](=[O:13])[N:7]([C@H:8]1[CH2:12][CH2:11][N:10]([C:21]2[CH:22]=[CH:23][C:18]3[N:19]([C:15]([Br:14])=[CH:16][N:17]=3)[N:20]=2)[CH2:9]1)[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CC(C)O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Temperature: 140 °C
Yield: 95.9 %

Procedure:
A mixture of (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.8 g, 15 mmol), 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (2.16 g, 10 mmol), and triethylamine (5.58 ml, 40 mmol) in isopropyl alcohol (10 ml) was heated in a microwave at 140° C. for 30 min. The reaction mixture was concentrated and the residue was passed through a short column to afford the desired product (3.8 g). To a solution of above product (3.8 g) in DMF (40 ml) at 0° C. was added MeI (1.13 ml). The mixture was stirred at 0° C. for 5 min., NaH (800 mg, 60% oil dispersion, 20 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 5 min. and at rt for 30 min., then it was treated with water and diluted with EtOAc (250 ml). The mixture was washed with water (100 ml) and brine (100 ml). The aqueous layer was back extracted with EtOAc (2×50 ml). The combined EtOAc was dried (Na2SO4) and concentrated. The residue was subjected to ISCO (120 g column) to afford the titled compound (3.1 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9H) 2.04-2.22 (m, 2H) 2.78 (s, 3H) 3.37 (dd, J=10.80, 7.28 Hz, 1H) 3.46 (dt, J=10.36, 8.05 Hz, 1H) 3.65-3.72 (m, 2H) 4.87 (br. s., 1H) 6.53 (d, J=9.70 Hz, 1H) 7.44 (s, 1H) 7.64 (d, J=9.70 Hz 1H). LRMS (ESI) m/z 396 and 398.1 [(M+H)]+, calc'd for C16H22BrN6O2: 396.29.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:32]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:42]=[CH:43][C:34]([CH2:32][NH:17][CH2:16][C:13]2[N:12]=[C:11]([C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])([CH:19]3[CH2:31][C:22]4[NH:23][C:24]5[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=5[C:21]=4[CH2:20]3)[F:18])[O:15][N:14]=2)=[CH:35][CH:36]=1
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CNCc2noc(C(F)(C3Cc4[nH]c5ccc(Cl)cc5c4C3)S(=O)(=O)c3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a stirred solution of 50 mg (0.1 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 5 mL MeOH at 0° C. was added 19 mg (0.1 mmol, 1 eq) of methyl 4-formylbenzoate, 7 mg (0.1 mmol, leg) sodium cyanoborohydride and one drop of acetic acid. The reaction mixture was stirred at 0° C. for 20 minutes and then the temperature was raised to RT and the reaction quenched with saturated aqueous solution of NaHCO3. The reaction mixture was poured on water and extracted with EtOAc. The organic phase were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (heptane/EtOAc 1:1) yielded 30 mg (45%) of (RS,SR)-4-[({5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-amino)-methyl]-benzoic acid methyl ester as a light yellow powder, MS: 609 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:38][CH:37]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
To a solution of compound 1D (26 mg, 0.10 mmol) in DMF (2 mL) were added K2CO3 (138 mg, 1.00 mmol) and p-phenoxyaniline (20 mg, 0.11 mmol) at 25° C. The reaction mixture was stirred for 12 h and then diluted with dichloromethane (15 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4 and concentrated and the resulting residue was triturated with methanol to afford 31 mg (76% yield) of the desired compound as a yellow solid. HPLC: 100% at 4.62 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 413.12 [M+H]+.