Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[Br:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[C:12](=[O:16])[C:13]([O-:15])=O.[C:17]([N:25]1[CH2:30][CH2:29][NH:28][C@H:27]([CH3:31])[CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[C:12]([C:8]2[C:7]3[C:11](=[C:3]([Br:2])[N:4]=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[O:16])[C@H:27]([CH3:31])[CH2:26]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Br)nccc12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Agent: [K+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2c(Br)nccc12

Procedure:
Precursor 5f, 1-benzoyl-3-(R)-methyl-4-[(7-bromo-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a, starting from (7-bromo-6-azaindol-3-yl)-oxoacetic acid potassium salt, Precursor 4g, and 1-benzoyl-3-(R)-methylpiperazine. MS m/z: (M+H)+ calcd for C21H20BrN4O3: 455.07; found 455.14. HPLC retention time: 1.45 minutes (column B).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[OH:13])([O-:3])=[O:2].[F:14][C:15]1[C:16]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[N:17][CH:18]=[N:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:14][C:15]1[C:16]([O:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=3[OH:13])=[CH:31][CH:30]=2)=[N:17][CH:18]=[N:19][C:20]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: Nc1ccc(Oc2ncnc(Oc3ccccc3)c2F)cc1
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Oc2ncnc(Oc3ccccc3)c2F)cc1)c1cccc([N+](=O)[O-])c1O
Temperature: 50 °C
Yield: 40.9 %

Procedure:
A mixture of 1.7 g (9 mmol) of 3-nitrosalicylic acid and 2.7 g (9 mmol) of 4-(5-fluoro-6-phenoxy-pyrimidin-4-yloxy)-phenylamine in 20 ml of toluene is heated with stirring to 50° C. 0.5 g of phosphorus trichloride is added, and the mixture is heated at the boil under reflux for a further 4 hours. After cooling, the mixture is concentrated and the residue is extracted with dichloromethane. The organic phase is washed repeatedly with water and dried over sodium sulphate. The solvent is distilled off, giving 1.7 g (41% of theory) of N-[4-(5-fluoro-6-phenoxy-pyrimidin-4-yloxy)-phenyl]-2-hydroxy-3-nitrobenzamide.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].Cl[C:15]([O:17][CH3:18])=[O:16].Cl>O.CCOCC>[CH3:18][O:17][C:15]([NH:1][C@@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4])=[O:16]
Reactant: C=CC[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: C=CC[C@H](NC(=O)OC)C(=O)O
Temperature: 0 °C
Reaction time: 20 h
Yield: 83.1 %

Procedure:
A mixture of (S)-2-aminopent-4-enoic acid (1.0 g, 8.69 mmol) and NaHCO3 (2.26 mg, 26.9 mmol) in H2O (40 mL) was cooled to 0° C. A mixture of methyl chloroformate (740 μL, 9.55 mmol) dissolved in Et2O (4 mL) was slowly added to the aqueous mixture and stirred for 20 hours coming to ambient temperature. Mixture was adjusted to pH 3.0 with HCl (conc). The mixture was extracted with EtOAc and then dried (MgSO4), filtered and concentrated to afford 1.25 g (83%) of the title compound. MS (ESI) m/z 174 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:32])[NH:12][C:13]1[S:14][CH2:15][C@@H:16]2[CH2:22][C@H:21]([CH2:23][OH:24])[O:20][CH2:19][C@:17]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[N:18]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][S:2]([O:24][CH2:23][C@@H:21]1[O:20][CH2:19][C@:17]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:18]=[C:13]([NH:12][C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:32])[S:14][CH2:15][C@@H:16]2[CH2:22]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](CO)C[C@H]2CS1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CO[C@@H](COS(C)(=O)=O)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (36.2 μL, 0.474 mmol) was added drop-wise to a 0° C. solution of tert-butyl[(4aR,6R,8aS)-8a-(2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]carbamate (C18) (94 mg, 0.24 mmol) and triethylamine (0.198 mL, 1.42 mmol) in dichloromethane (1 mL). The reaction was allowed to warm to room temperature and stir for 18 hours. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane) provided the product as a white solid. Yield: 86 mg, 0.18 mmol, 75%. LCMS m/z 475.4 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.53 (s, 9H), 1.60-1.68 (br m, 1H), 1.92-2.07 (br m, 1H), 2.56 (dd, J=12.9, 2.9 Hz, 1H), 2.93 (dd, J=12.7, 3.9 Hz, 1H), 3.07-3.19 (br m, 1H), 3.09 (s, 3H), 3.79 (d, J=12.1 Hz, 1H), 3.96-4.04 (m, 1H), 4.21 (dd, J=12.0, 1.5 Hz, 1H), 4.27 (dd, half of ABX pattern, J=11.3, 6.2 Hz, 1H), 4.32-4.38 (br m, 1H), 7.06-7.13 (m, 1H), 7.18-7.24 (m, 1H), 7.30-7.39 (br m, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=O)=[CH:14][CH:13]=1.ClC(OCC)=O.Cl[CH:35](F)[F:36]>C(O)(=O)C.O1CCCC1>[F:36]/[CH:35]=[C:20](\[CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)/[CH2:21][OH:23]
Reactant: CC(C)(C)OC(=O)CCCc1ccc(F)cc1
Reactant: FC(F)Cl
Agent: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC/C(=C/F)CCc1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
Cool a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (545 kg, 2M, 877 mol) to -10° C. Slowly add, t-butyl 4-(p-fluorophenyl)butyrate (84.1 kg, 80% by weight in toluene, 353 mol). After 15 minutes, slowly add ethyl chloroformate (38.6 kg, 356 mol) at such a rate that the reaction temperature is maintained at or below -5° C. After 20 minutes, warm the reaction mixture to 40° C.-45° C. Seal the reaction vessel and add chlorodifluoromethane (38.15 kg, 445 mol) to the head space. After 1 hour, cool to 15° C.-20° C. and vent the reaction vessel. Add a solution of acetic acid (421 kg, 20% in water) and stir. After 30 minutes, separate the aqueous layer and evaporate the organic layer in vacuo to obtain a residue. Add toluene (45 kg) and evaporate in vacuo until the internal temperature of the reaction vessel is 55° C. to obtain the title compound as a toluene solution.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:6][C:5]=2[NH:4][N:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl.O>C(O)C>[ClH:18].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH2:6][C:5]2[NH:4][N:3]=[C:2]([CH3:1])[C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 174.5 %

Procedure:
A mixture of 3-methyl-6-(2-chlorophenyl)-4,5,6,7-tetrahydroindazol-4-one (0.22 g), aminoguanidine hydrochloride (0.098 g), concentrated hydrochloric acid (0.084 ml), water (0.084 ml) and ethanol (40 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was washed with diethylether and concentrated under reduced pressure, and the resulting crystals were recrystallized from water-ethanol to give 4-guanidinoimino-6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 21) (0.26 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:8]([F:14])([F:13])[CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CCOCC>[F:14][C:8]1([F:13])[C:9]2[C:4](=[C:3]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:28]=3)[C:2]([F:1])=[C:11]([F:12])[CH:10]=2)[CH2:5][CH2:6][CH:7]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCC1CCc2c(cc(F)c(F)c2-c2ccc(O)cc2)C1(F)F
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2c(F)c(F)cc3c2CCC(CCCCCCCC)C3(F)F)cc1

Procedure:
From 4-(2,3,5,5-tetrafluoro-6-octyl-5,6,7,8-tetrahydronaphthalen-1-yl)phenol and 1-octyl bromide by the Williamson ether synthesis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[C:7]([O:22][CH3:23])=[CH:8][C:9]([O:20][CH3:21])=[C:10]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=1.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[C:7]([O:22][CH3:23])=[CH:8][C:9]([O:20][CH3:21])=[C:10]([CH:11]=1)[C:12]([C:13](=[CH:30][N:31]([CH3:33])[CH3:32])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: CCOC(=O)CC(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1OC
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1OC
Temperature: 95 °C
Reaction time: 10 h

Procedure:
Under a nitrogen atmosphere, ethyl 3-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxyphenyl)-3-oxopropionate (2.76 g) and N,N-dimethylformamide dimethyl acetal (1.36 g) were dissolved in toluene. This solution was stirred at 95° C. for 10 hr, and the completion of the reaction was confirmed by HPLC. The reaction mixture was cooled to room temperature to give a solution of ethyl 2-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylate in toluene. The reaction mixture was directly used in the next step.
Reaction SMILES: [Si]([O:8][C:9]1[CH:23]=[C:22]([CH3:24])[C:12]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]2)=[C:11]([CH3:25])[CH:10]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[CH:23]=[C:22]([CH3:24])[C:12]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]2)=[C:11]([CH3:25])[CH:10]=1
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1OCC1CCCN(C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1OCC1CCCN(C)C1
Reaction time: 8 h

Procedure:
To a solution of 3-[4-(tert-butyidimethylsilyloxy)-2,6dimethylphenoxymethyl]-1-methylpiperidine (3.2 g, 8.8 mmol) in tetrahydrofuran (50 mL) containing 20% acetic acid (5.5 mL, 19 mmol) at 0° C. was added 1M tetrabutylammonium fluoride in tetrahydrofuran (17.5 mL). The mixture was stirred from 0° C. to room temperature overnight and concentrated in vacua. The residue was partitioned between water and dichloromethane. The organic layer was dried and concentrated and the residue purified on silica gel, eluting with 5% methanol in dichloromethane containing 0.25% ammonium hydroxide, to give 3-(4-hydroxy-2,6-dimethylphenoxymethyl)-1 -methylpiperidine.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[NH4+].[Cl-]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]([S:20]([CH3:19])(=[O:22])=[O:21])[S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1I)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
To a solution containing 2-iodo-4-nitroaniline (25 g; 95 mmol) and triethylamine (43 ml; 312 mmol) in CH2Cl2 (250 ml), a solution containing methanesulphonyl chloride (36 g; 312 mmol) was added dropwise. The reaction mixture was left under stirring at room temperature for 18 hours, then NH4Cl (saturated solution) was added (250 ml). The biphasic solution was transferred into a separating funnel, the organic phase was separated, dried over Na2SO4 and the solvent was removed by evaporation under reduced pressure. The residue was suspended in EtOH (200 ml) and heated under stirring until a yellow solid precipitated. The crude product was filtered, washed with EtOH (750 ml), and dried under vacuum to give N-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide (32 g) which was used in the following reaction without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH3:24]>CN(C=O)C>[CH2:23]([O:14][C:13]([C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1)=[O:15])[CH3:24]
Reactant: CCI
Reactant: COc1ccc2nccc(C(=O)O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccnc2ccc(OC)cc12
Temperature: 55 °C

Procedure:
To a suspension of 6-methoxy-quinoline-4-carboxylic acid (prepared according to U.S. Pat. No. 5,338,851; 43.8 g, 215.6 mmol) in DMF (215 mL) were added K2CO3 (99%; 60.2 g, 431.2 mmol) and iodoethane (19.4 mL, 237.2 mmol). The mixture was heated at 55° C. overnight. The solvent was evaporated to dryness, and the residue was partitioned between EA (1.5 L) and water (600 mL). The org. layer was washed twice with brine (2×300 mL), dried over Na2SO4, filtered and concentrated to dryness to yield a purple solid (37.5 g).
Reaction SMILES: [S:1](N)(N)(=[O:3])=[O:2].[CH2:6]([NH:13][CH2:14][CH2:15][NH2:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH2:6]([N:13]1[CH2:14][CH2:15][NH:16][S:1]1(=[O:3])=[O:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NS(N)(=O)=O
Reactant: NCCNCc1ccccc1
Solvent: c1ccncc1
Product: O=S1(=O)NCCN1Cc1ccccc1
Yield: 79 %

Procedure:
To a refluxing solution of sulfamide (27.12 g, 282 mmol) in anhydrous pyridine (250 ml) was added dropwise N-benzylethylenediamine (42.4 ml, 282 mmol) over 3 hours. The resulting solution was refluxed under nitrogen for a further 16 hours before the solvent was removed under vacuum. The residue was dissolved in dichloromethane (100 ml) and washed with 2N hydrochloric acid (1×100 ml). The aqueous layer was extracted with dichloromethane (2×100 ml) and the combined organic solutions were washed with brine (50 ml), dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane-methanol 95:5) gave 47.3 g (79%) of the title compound as a white solid; δH (360 MHz, CDCl3) 7.32 (5H, m, Ph), 4.34 (1H, br s, --NH--), 4.18 (2H, s, Ar--CH2N--), 3.47 (2H, q, J= 6.4 Hz,--CH2NH--),3.27(2H, t, J=6.4 Hz,--CH2 --); m/z (CI) 213 (M+ +1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[CH2:19]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(Cl)Cl>CC#N>[C:4]([C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCCCCCNCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1C#N
Temperature: 80 °C
Reaction time: 40 h
Yield: 87.4 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzonitrile (1.83 g, 10.0 mmol) in CH3CN (20 mL) were added K2CO3 (2.76 g, 20.0 mmol) and dihexylamine (1.85 g, 9.98 mmol) and the mixture was stirred at 80° C. for 40 h. The mixture was cooled to rt, poured into 100 mL of DCM and washed with water (100 mL×3), brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=125:2) to give the title compound as yellow oil (2.89 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[C:19](OC(=O)C)(=[O:21])C>C(O)=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([CH:19]=[O:21])[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)CNC1CCCc2ccc(OC)cc21
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)CN(C=O)C1CCCc2ccc(OC)cc21
Reaction time: 70 h
Yield: 101.1 %

Procedure:
2.40 g of N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)glycine methyl ester are added dropwise with cooling to 5° C. to 5.52 g of formic acid. Additionally 1.79 g of acetic anhydride are added, and the mixture is kept at room temperature for 70 hours. Destillation under vacuum affords 2.7 g (97% of theory) of N-formyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)glycine methyl ester as a colourless resin.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH:25]([CH3:28])[CH2:26][NH2:27])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:29]=O>Cl>[CH3:28][CH:25]1[CH2:26][NH:27][CH2:29][CH:24]2[N:20]=[CH:21][NH:22][CH:23]12
Reactant: CC(CN)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C=O
Agent: Cl
Product: CC1CNCC2N=CNC12
Temperature: 95 °C

Procedure:
3.2 g 2-(1-trityl-1H-imidazol-4-yl)-propylamine is suspended in aqueous HCl (1 N). After the addition of 2.9 mL formaldehyde the mixture is heated to 95° C. with stirring. After 5 h it is cooled to RT, suction filtered to remove the precipitate formed and the solvent is eliminated in vacuo. This crude product is used in the following reaction step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[NH:10][C:7]2=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc2cc(N)cnc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
An autoclave is charged with 2.9 g (13.12 mmol) of methyl 5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Azasynth), 290 mg of palladium on charcoal 10% and 200 mL of methanol. The reaction mixture is placed under 20 bar of hydrogen, and stirred for 18 h at room temperature. The solution is then filtered on Celite, and the Celite is rinsed with 3×100 mL of hot methanol. The filtrate is evaporated under reduced pressure. 2.38 g of a yellow solid is obtained at a yield of 95%.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH:19]2[CH:11]([C:12](=[O:29])[C:13]3[C:18]2=[CH:17][C:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[CH:15][CH:14]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:29])[C@H:11]1[C@@H:19]2[CH2:20][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2C(=O)c3ccc(-c4ccc(Cl)cc4Cl)cc3C2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccc(-c3ccc(Cl)cc3Cl)cc2[C@H]2CNCC[C@@H]12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(2,4-dichloro-phenyl)-9-oxo-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid tert-butyl ester in CH2Cl2 (3.2 mL) was added trifluoroacetic acid (0.8 mL). The reaction mixture was stirred for 2 h at 20° C. then concentrated in vacuo. The residue was basified with NH4OH then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (42 mg, 0.13 mmol): MS (ES) 332.1 (M+H).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:18]=[CH:19][CH:20]=1)/[CH:12]=[CH:13]/[C:14](=[N:16]O)[NH2:15].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:18]=[CH:19][CH:20]=1)/[CH:12]=[CH:13]/[C:14]1[N:16]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[O:4][N:15]=1
Reactant: NC(/C=C/c1cccc(Cl)c1F)=NO
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Fc1c(Cl)cccc1/C=C/c1noc(C(Cl)(Cl)Cl)n1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
12.7 g (0.07 mol) of trichloroacetyl chloride are added dropwise to a suspension consisting of 6.4 g (0.03 mol) of (E)-3-chloro-2-fluoro-cinnamamide oxime in 90 ml of chloroform and 6 ml (0.07 mol) of dry pyridine. During this process, there is a slight evolution of heat. Subsequently, the mixture is stirred for 1 hour and the pyridine hydrochloride which separates out is filtered off and washed with chloroform. The filtrate is concentrated in vacuo and the remaining solid material is recrystallized. 5.0 g (48.7% of theory) of (E)-3-(3-chloro-2-fluoro-styryl)-5-trichloromethyl-1,2,4-oxadiazole are obtained.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:22]4=[CH:23][C:24]5[O:28][CH2:27][O:26][C:25]=5[CH:29]=[C:21]4[O:20][CH2:19]3)[C:11]2=[O:30])=[CH:5][CH:4]=1.[I-].[Na+].Cl[Si](C)(C)C>O.C(#N)C>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:22]4=[CH:23][C:24]5[O:28][CH2:27][O:26][C:25]=5[CH:29]=[C:21]4[O:20][CH2:19]3)[C:11]2=[O:30])[CH:5]=[CH:4]1
Reactant: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1N(Cc2ccc(=O)[nH]c2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a mixture of 1′-[(6-methoxypyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.23 g, 0.57 mmol), sodium iodide (0.28 g, 1.87 mmol), water (2 drops) in anhydrous acetonitrile (5.00 mL) was added chlorotrimethylsilane (0.19 g, 1.78 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h and quenched with sodium bisulfite (0.20 g). The reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine (2×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with ether (2×10.0 mL) to give the title compound (0.16 g, 72%) as la ight yellow solid: mp 247-250° C.; 1H NMR (300 MHz, DMSO-d6,) δ 11.50 (br, 1H), 7.50 (bd, 1H), 7.36-7.24 (m, 2H), 7.17-7.12 (m, 2H), 7.01 (dt, 1H), 6.67 (s, 1H), 6.28 (d, 1H), 6.09 (s, 1H), 5.91-5.88 (m, 2H), 4.78 (d, 1H), 4.67-4.62 (m, 3H); MS (ES+) m/z 389.15 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[OH:12])=[C:4]([O:15][CH3:16])[CH:3]=1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][N:10]([CH3:19])[CH2:9][C@H:8]2[OH:12])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Br)ccc1OC1CNCC1O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(Br)ccc1O[C@@H]1CN(C)C[C@H]1O
Reaction time: 8 h
Yield: 95.6 %

Procedure:
Dissolve 4-(4-bromo-2-methoxy-phenoxy)-pyrrolidin-3-ol (409 mg, 1.42 mmol) in dichloroethane (15 mL) and add formaldehyde (0.117 mL, 1.56 mmol, 37% aqueous solution), sodium triacetoxyborohydride (451 mg, 2.13 mmol), and acetic acid (0.325 mL, 5.68 mmol). Stir the mixture overnight. Dilute with saturated sodium bicarbonate and extract three times with dichloromethane. Combine all the organics and dry over sodium sulfate, filter, and evaporate the filtrate. Purify by silica gel chromatography, eluting with 0-6% MeOH in dichloromethane with 2 N ammonia to give 410 mg (95%) of the title compound as a clear oil. LC-MS/ES m/z (81Br) 304.0 [M+H]−.